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Venetoclax is an approved BCL-2 inhibitor, currently under evaluation in different hematological malignancies in adult and pediatric populations. Venetoclax is available as 10, 50, and 100 mg tablets. To provide an alternative to patients who find taking the commonly prescribed 100 mg tablet a challenge, the interchangeability of lower-strength tablets with the 100 mg tablet was investigated. Additionally, newly developed oral suspension powder formulations to facilitate dosing in pediatrics were evaluated.Pharmacokinetic data from 80 healthy female participants from three phase I studies were utilized to evaluate the bioavailability of (1) 10 and 50 mg tablets relative to a 100 mg tablet; (2) 0.72 and 7.2% (drug to total weight) oral powder formulations relative to the 100 mg tablet; and (3) oral powder formulations administered using different vehicles (apple juice, apple sauce, and yogurt) relative to water under fed conditions.Bioavailability assessments at a 100 mg dose of venetoclax demonstrated bioequivalence across the 10, 50, and 100 mg tablet strengths. Oral powder formulations met the bioequivalence criteria (0.80-1.25) with respect to area under the concentration-time curve to time of the last measurable concentration (AUCThe smaller-sized tablets (10 and 50 mg) and the newly developed oral powder formulations of venetoclax can be used interchangeably with the 100 mg tablets to improve the patients' experience, while maintaining adequate exposure. CLINICAL TRIALS IDENTIFIERS: NCT01682616, 11 September 2012; NCT02005471, 9 December 2013; NCT02242942, 17 September 2014; NCT02203773, 30 July 2014; NCT02287233, 10 November 2014; NCT02993523, 15 December 2016; NCT03069352, 3 March 2017.

This study aims to investigate pharmacokinetics (PK) and exposure-response parameters of the 400 mg once-daily venetoclax dose regimen in combination with obinutuzumab, which was approved for the first-line (1L) treatment of chronic lymphocytic leukemia (CLL) based on data from the phase 3 CLL14 study and the phase 1b dose-finding GP28331 study.Parameter estimates and uncertainty, which were estimated by a previously developed population PK (popPK) model, were used as informative priors for this analysis. They were re-estimated, and then used to evaluate additional covariate effects, describe venetoclax PK when administered with obinutuzumab, and provide empirical Bayes estimates of PK parameters and exposure. Exposure-progression-free survival (PFS) and exposure-safety relationships were assessed using data from CLL14, with steady-state nominal venetoclax exposure (CPK data from 274 patients (CLL14, n = 194; GP28331, n = 80) were included. The final model provided good fit of the observed data. Obinutuzumab co-administration, history of prior treatments, and disease severity at baseline had no appreciable influence on venetoclax steady-state exposure. No significant correlations were observed between venetoclax exposure and PFS, or between venetoclax exposure and the probability of treatment-emergent grade ≥ 3 neutropenia, grade ≥ 3 thrombocytopenia, grade ≥ 3 infections, and SAEs. Median dose intensities for venetoclax and obinutuzumab remained similar across venetoclax exposure tertiles.PopPK and exposure-efficacy, exposure-safety, and exposure-tolerability analyses support the 400 mg once-daily venetoclax dose plus obinutuzumab for 1L treatment in patients with CLL.ClinicalTrials.gov Identifiers NCT02242942 and NCT02339181.

Supplementary Figure S1. CA125 response to lifastuzumab vedotin in ovarian cancer patients. All patients with radiographic responses also had {greater than or equal to}50 decrease in CA125 from baseline levels.

Purpose:This phase I trial assessed the safety, tolerability, and preliminary antitumor activity of lifastuzumab vedotin (LIFA), an antibody–drug conjugate of anti-NaPi2b mAb (MNIB2126A) and a potent antimitotic agent (monomethyl auristatin E).Patients and Methods:LIFA was administered to patients with non–small cell lung cancer (NSCLC) and platinum-resistant ovarian cancer (PROC), once every 3 weeks, by intravenous infusion. The starting dose was 0.2 mg/kg in this 3+3 dose-escalation design, followed by cohort expansion at the recommended phase II dose (RP2D).Results:Overall, 87 patients were treated at doses between 0.2 and 2.8 mg/kg. The MTD was not reached; 2.4 mg/kg once every 3 weeks was selected as the RP2D based on overall tolerability profile. The most common adverse events of any grade and regardless of relationship to study drug were fatigue (59%), nausea (49%), decreased appetite (37%), vomiting (32%), and peripheral sensory neuropathy (29%). Most common treatment-related grade ≥3 toxicities among patients treated at the RP2D (n = 63) were neutropenia (10%), anemia (3%), and pneumonia (3%). The pharmacokinetic profile was dose proportional. At active doses ≥1.8 mg/kg, partial responses were observed in four of 51 (8%) patients with NSCLC and 11 of 24 (46%) patients with PROC per RECIST. All RECIST responses occurred in patients with NaPi2b-high by IHC. The CA-125 biomarker assessed for patients with PROC dosed at ≥1.8 mg/kg showed 13 of 24 (54%) had responses (≥50% decline from baseline).Conclusions:LIFA exhibited dose-proportional pharmacokinetics and an acceptable safety profile, with encouraging activity in patients with PROC at the single-agent RP2D of 2.4 mg/kg.

Purpose:Targeting CD79B using antibody–drug conjugates (ADC) is an effective therapeutic strategy in B-cell non-Hodgkin lymphoma (B-NHL). We investigated DCDS0780A, an anti-CD79B ADC with THIOMAB technology (TDC) that consistently conjugates two anti-neoplastic molecules per antibody, in contrast with ADCs with heterogeneous loads.Patients and Methods:This phase 1 study enrolled 60 patients with histologically confirmed B-NHL that had relapsed/failed to respond following ≥1 prior treatment regimens; 41 (68%) had diffuse large B-cell lymphoma (DLBCL). Fifty-one patients received DCDS0780A monotherapy once every 3 weeks (0.3–4.8 mg/kg); 9 received combination therapy (3.6–4.8 mg/kg) with rituximab.Results:Fifty-four (90%) patients experienced adverse events related to study drug, the most common of which were blurred vision, fatigue, corneal deposits, neutropenia, nausea, and peripheral neuropathy. 4.8 mg/kg was the highest dose tested and the recommended phase II dose. The pharmacokinetic profile was linear at doses ≥1.2 mg/kg. Response rate in all-treated patients (N = 60) was 47% (n = 28), including 17 complete responses (28%) and 11 partial responses (18%). The median duration of response (15.2 months) was the same for all responders (n = 28) and patients with DLBCL (n = 20).Conclusions:DCDS0780A as the TDC format for CD79B was tested at higher doses than its ADC counterpart investigated earlier, leading to deep responses. However, dose intensity was limited by ocular toxicities seen at the higher doses indicating that the TDC format was unable, in the current study, to expand the therapeutic index for the CD79B target. The encouraging antitumor activity advocates continuation of investigations into novel ADC technologies.

Supplementary Figure S2. Representative NaPi2b ICH images for PROC and NSCLC patients.

Supplementary Table S1. Adverse events regardless of relationship to study drug occurring in 10 or more patients Supplementary Table S2. Adverse events grades 3-5 regardless of relationship to study drug occurring in 2 or more patients Supplementary Table S3. Pulmonary adverse events by frequency of occurrence in all patients regardless of relationship to study drug Supplementary Table S4. Pulmonary adverse events of NCI-CTCAE grade 3 or higher by frequency of occurrence in all patients regardless of relationship to study drug Supplementary Table S5. Mean (standard deviation) of the pharmacokinetic parameters for antibody-conjugated MMAE in plasma Supplementary Table S6. Mean (standard deviation) of the pharmacokinetic parameters for total antibody in plasma Supplementary Table S7. Mean (standard deviation) of the pharmacokinetic parameters for unconjugated MMAE in plasma Supplementary Table S8. Response outcomes and duration

Supplementary Figure from Anti-CD79B Antibody–Drug Conjugate DCDS0780A in Patients with B-Cell Non-Hodgkin Lymphoma: Phase 1 Dose-Escalation Study

Supplementary Data from Anti-CD79B Antibody–Drug Conjugate DCDS0780A in Patients with B-Cell Non-Hodgkin Lymphoma: Phase 1 Dose-Escalation Study

Antibody-drug conjugates (ADCs) combine the specificity of an antibody with the cytotoxicity of a chemical agent. They represent a rapidly evolving area of oncology drug development and hold significant promise. There are currently nine ADCs on the market, more than half of which gained US Food and Drug Administration approval more recently, since 2019. Despite their enormous promise, the therapeutic window for these ADCs remains relatively narrow, especially when compared with other oncology drugs, such as targeted therapies or checkpoint inhibitors. In this review, we provide a detailed overview of the five dosing regimen optimization strategies that have been leveraged to broaden the therapeutic window by mitigating the safety risks while maintaining efficacy. These include body weight cap dosing; treatment duration capping; dose schedule (e.g., dosing frequency and dose fractionation); response-guided dosing recommendations; and randomized dose-finding. We then discuss how the lessons learned from these studies can inform ADC development going forward. Informed application of these dosing strategies should allow researchers to maximize the safety and efficacy for next-generation ADCs.

The phase 2 CAVALLI (NCT02055820) study assessed efficacy and safety of venetoclax, a selective B-cell lymphoma-2 (Bcl-2) inhibitor, with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in first-line (1L) diffuse large B-cell lymphoma (DLBCL), including patients demonstrating Bcl-2 protein overexpression by immunohistochemistry (Bcl-2 IHC+). Eligible patients were ≥18 years of age and had previously untreated DLBCL, Eastern Cooperative Oncology Group performance status ≤2, and International Prognostic Index 2 to 5. Venetoclax 800 mg (days 4-10, cycle 1; days 1-10, cycles 2-8) was administered with rituximab (8 cycles) and cyclophosphamide, doxorubicin, vincristine, and prednisone (6-8 cycles) in 21-day cycles. Primary end points were safety, tolerability, and research_plete response (CR) at end of treatment (EOT). Secondary end points were progression-free survival (PFS) and overall survival. Comparative analyses used covariate-adjusted R-CHOP controls from the GOYA/BO21005 study, an appropriate contemporary benchmark for safety and efficacy. Safety and efficacy analyses included 206 patients. CR rate at EOT was 69% in the overall population and was maintained across Bcl-2 IHC+ subgroups. With a median follow-up of 32.2 months, trends were observed for improved investigator-assessed PFS for venetoclax plus R-CHOP in the overall population (hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.43-0.87) and Bcl-2 IHC+ subgroups (HR, 0.55; 95% CI, 0.34-0.89) vs R-CHOP. Despite a higher incidence of grade 3/4 hematologic adverse events (86%), related mortality was not increased (2%). Chemotherapy dose intensity was similar in CAVALLI vs GOYA. The addition of venetoclax to R-CHOP in 1L DLBCL demonstrates increased, but manageable, myelosuppression and the potential of improved efficacy, particularly in high-risk Bcl-2 IHC+ patient subgroups. Key Points: • The phase 2 CAVALLI study assessed efficacy and safety of venetoclax + R-CHOP in patients with DLBCL, including Bcl-2+ subpopulations. • Venetoclax + R-CHOP showed potential for improved efficacy vs R-CHOP alone, supporting further investigation of venetoclax in Bcl-2+ DLBCL.

Purpose: This phase I trial assessed the safety, tolerability, and preliminary antitumor activity of lifastuzumab vedotin (LIFA), an antibody–drug conjugate of anti-NaPi2b mAb (MNIB2126A) and a potent antimitotic agent (monomethyl auristatin E). Patients and Methods: LIFA was administered to patients with non–small cell lung cancer (NSCLC) and platinum-resistant ovarian cancer (PROC), once every 3 weeks, by intravenous infusion. The starting dose was 0.2 mg/kg in this 3+3 dose-escalation design, followed by cohort expansion at the recommended phase II dose (RP2D). Results: Overall, 87 patients were treated at doses between 0.2 and 2.8 mg/kg. The MTD was not reached; 2.4 mg/kg once every 3 weeks was selected as the RP2D based on overall tolerability profile. The most common adverse events of any grade and regardless of relationship to study drug were fatigue (59%), nausea (49%), decreased appetite (37%), vomiting (32%), and peripheral sensory neuropathy (29%). Most common treatment-related grade ≥3 toxicities among patients treated at the RP2D (n = 63) were neutropenia (10%), anemia (3%), and pneumonia (3%). The pharmacokinetic profile was dose proportional. At active doses ≥1.8 mg/kg, partial responses were observed in four of 51 (8%) patients with NSCLC and 11 of 24 (46%) patients with PROC per RECIST. All RECIST responses occurred in patients with NaPi2b-high by IHC. The CA-125 biomarker assessed for patients with PROC dosed at ≥1.8 mg/kg showed 13 of 24 (54%) had responses (≥50% decline from baseline). Conclusions: LIFA exhibited dose-proportional pharmacokinetics and an acceptable safety profile, with encouraging activity in patients with PROC at the single-agent RP2D of 2.4 mg/kg.

Aims: To investigate pharmacokinetics (PK) and exposure-response of the 400 mg once daily venetoclax dose regimen in combination with obinutuzumab in the phase 3 CLL14 study approved for the treatment of first-line (1L) chronic lymphocytic leukaemia (CLL). Methods: Parameter estimates and uncertainty estimated by a previously developed population PK (popPK) model were used as informative priors for this analysis. They were re-estimated, then used to evaluate additional covariate effects, describe venetoclax PK when administered with obinutuzumab, and provide empirical Bayes estimates of PK parameters and exposure. Exposure-progression-free survival (PFS) and exposure-safety relationships were assessed using CLL14 data, with steady-state exposure at the nominal target dose (C) as the predictor variable. Exposure-safety analyses were conducted using logistic regression for selected treatment-emergent grade ≥3 adverse events (AEs) and serious AEs (SAEs). Dose intensities were summarized by tertiles of C. Results: PK data from 274 patients (CLL14, n=194; phase 1b dose-finding study GP28331, n=80) were included. The final model provided good fit of observed data. Obinutuzumab co administration, history of prior treatments, and disease severity at baseline had no appreciable influence on venetoclax steady-state exposure. No significant correlations were observed between venetoclax exposure and PFS, or between venetoclax exposure and the probability of treatment-emergent grade ≥3 neutropenia, grade ≥3 thrombocytopenia, grade ≥3 infections and SAEs. Median dose intensities for venetoclax and obinutuzumab remained similar across venetoclax exposure tertiles. Conclusion: PopPK and exposure efficacy, -safety and -tolerability analyses support the 400 mg once-daily venetoclax dose plus obinutuzumab in patients with 1L CLL.

Introduction Outcomes remain poor in patients with diffuse large B cell lymphoma (DLBCL) who overexpress BCL-2 protein. We present population pharmacokinetics (PopPK) and exposure–response (ER) analyses for venetoclax (a selective BCL-2 inhibitor) administered with rituximab-cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with relapsed/refractory (R/R) and previously untreated (1L) non-Hodgkin lymphoma (NHL) from the phase 1b/2 CAVALLI study, to confirm dose selection for future studies. Methods Analyses included 216 patients with R/R or 1L NHL treated for eight 21-day cycles with 400–800 mg venetoclax (cycle 1: days 4–10; cycles 2–8: days 1–10) in combination with R for eight cycles and CHOP for 6–8 cycles. A legacy PopPK model for venetoclax was used to describe the observed data and provide post hoc PK parameters. Venetoclax steady-state exposure (AUCss) was used to predict clinical efficacy, safety, or tolerability. To isolate the effect of venetoclax, ER analyses referenced data from the R-CHOP arm of a historical control study, GOYA, in 1L DLBCL. Results There was no significant association between venetoclax AUCss and progression-free survival or complete response either for all-comers or the BCL-2-immunohistochemistry-positive subpopulation. No statistically significant trends were observed with venetoclax AUCss and the key grade ≥ 3 adverse events and serious adverse events. Similar dose intensities were observed for venetoclax and R-CHOP components across venetoclax exposures, suggesting venetoclax did not impact delivery of the R-CHOP backbone. Conclusions The PopPK and ER analyses, in addition to the positive benefit–risk observed in the clinical data, support the selection of 800 mg venetoclax given with R-CHOP for future studies in BCL-2-immunohistochemistry-positive patients with 1L DLBCL. Trial Registration ClinicalTrials.gov Identifier NCT02055820. Supplementary Information The online version contains supplementary material available at 10.1007/s12325-021-01919-z.

Peripheral neuropathy (PN) is a common long‐term debilitating toxicity of antimicrotubule agents. PN was the most frequent adverse event resulting in dose modifications and/or discontinuation of treatment for valine‐citrulline‐monomethylauristatin E antibody–drug conjugates (ADCs) developed at Genentech. A pooled time‐to‐event analysis across eight ADCs (~700 patients) was performed to evaluate the relationship between the ADC exposure and the risk for developing a clinically significant (grade ≥ 2) PN. In addition, the impact of demographic and pathophysiological risk factors on the risk for PN was explored. The time‐to‐event analysis suggested that the development of PN risk increased with ADC exposure, treatment duration, body weight, and previously reported PN. This model can be used to inform clinical strategies such as adaptations to dosing regimen and/or treatment duration as well as inform clinical eligibility to reduce the incidence of grade ≥ 2 PN.

Prediction of human pharmacokinetics (PK) based on preclinical information for antibody–drug conjugates (ADCs) provide important insight into first‐in‐human (FIH) study design. This retrospective analysis was conducted to identify an appropriate scaling method to predict human PK for ADCs from animal PK data in the linear range. Different methods for projecting human clearance (CL) from animal PK data for 11 ADCs exhibiting linear PK over the tested dose ranges were examined: multiple species allometric scaling (CL vs. body weight), allometric scaling with correction factors, allometric scaling based on rule of exponent, and scaling from only cynomolgus monkey PK data. Two analytes of interest for ADCs, namely total antibody and conjugate (measured as conjugated drug or conjugated antibody), were assessed. Percentage prediction errors (PEs) and residual sum of squares (RSS) were compared across methods. Human CL was best estimated using cynomolgus monkey PK data alone and an allometric scaling exponent of 1.0 for CL. This was consistently observed for both conjugate and total antibody analytes. Other scaling methods either underestimated or overestimated human CL, or produced larger average absolute PEs and RSS. Human concentration‐time profiles were also reasonably predicted from the cynomolgus monkey data using species‐invariant time method with a fixed exponent of 1.0 for CL and 1.0 for volume of distribution. In conclusion, results from this retrospective analysis of 11 ADCs indicate that allometric scaling of CL with an exponent of 1.0 using cynomolgus monkey PK data alone can successfully project human PK profiles of an ADC within linear range.

Novel strategies, such as chemosensitization with targeted agents, that build on the success of standard immunochemotherapy show promise for the treatment of non-Hodgkin lymphoma (NHL). Here, we report a phase 1b study investigating dose escalation of the BCL2 inhibitor, venetoclax, in combination with rituximab or obinutuzumab and cyclophosphamide, doxorubicin, vincristine, and prednisone (R-/G-CHOP) chemotherapy in B-cell NHL. Objectives included safety assessment and determination of a recommended phase 2 dose (RP2D). Fifty-six patients were enrolled, most with follicular lymphoma (43%) or diffuse large B-cell lymphoma (DLBCL; 32%). Dose-limiting toxicities were reported in 3/14 patients at the first venetoclax dose (200 mg/d), after which dosing was changed from daily to 10 days per cycle and escalated to 800 mg. A further reduction to 5 days per cycle occurred at the 800-mg dose level in the G-CHOP arm. Cytopenias were predominant among grade 3/4 events and reported at a higher rate than expected, particularly in the G-CHOP arm; however, safety was manageable. Overall response rates were 87.5% (R-CHOP and G-CHOP combinations); complete response (CR) rates were 79.2% and 78.1%, respectively. Most double-expressor (BCL2+ and MYC+) DLBCL patients (87.5%; n = 7/8) achieved CR. Although the maximum tolerated dose was not reached, the RP2D for venetoclax with R-CHOP was established at 800 mg days 4 to 10 of cycle 1 and days 1 to 10 of cycles 2 to 8; higher doses were not explored, and this dosing schedule demonstrated an acceptable safety profile. This regimen is subsequently being evaluated in first-line DLBCL in the phase 2 portion of the study. This trial was registered at www.clinicaltrials.gov as #NCT02055820.

TPS8069 Background: Treatment of relapsed/refractory (R/R) multiple myeloma (MM) is challenging, especially in later lines where drug resistance reduces therapeutic options and remission duration. Prognosis is poor (estimated survival: < 1 year) for patients with MM who have received > 3 prior lines of therapy and are triple refractory to immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs) and anti-CD38 agents (Gandhi et al. 2019). Thus R/R MM constitutes a significant unmet medical need. Fragment crystallizable receptor-like 5 (FcRH5) is expressed on myeloma cells with near 100% prevalence (Li et al. 2017), constituting a novel therapeutic target. Cevostamab is an IgG1-based T-cell-engaging bispecific antibody engineered to target the most membrane-proximal domain of FcRH5 on myeloma cells and cluster of differentiation 3 (CD3) on T-cells, resulting in T-cell killing of myeloma cells. Clinical data from the first-in-human Phase I study (GO39775) suggest that cevostamab monotherapy is highly active in heavily pretreated patients with R/R MM, with an overall response rate of 56.7% at the 132–198mg dose level (Trudel et al. ASH 2021 Oral presentation). Thus, cevostamab’s activity and safety profile support further development. Due to their stimulatory effects on T-cell activity, combination of cevostamab with anti-myeloma agents (pomalidomide [P] or daratumumab [D]) may be synergistic, offering the potential to further improve efficacy. CAMMA 1 (NCT04910568) is an open-label, multicenter Phase Ib trial evaluating the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics of cevostamab-containing combination regimens (Arm B: cevostamab plus P and dexamethasone [d] [Pd]; Arm C: cevostamab plus Dd) in patients with R/R MM. A modified weekly schedule for cevostamab is also under investigation (Arm A: cevostamab monotherapy). Methods: Patients must be aged ≥18 years, have an ECOG performance status of 0 or 1 and a life expectancy of > 12 weeks. Patients in all arms have R/R MM; Arms B and C include patients with prior IMiD and PI exposure. Patients with prior CAR-T therapy may enroll with a washout period of 12 weeks post-CAR-T infusion. Cevostamab is administered by intravenous infusion q1w (C1–2)/q2w (C3–6)/q4w (C7–13) in Arm A, q2w (C1–6)/q4w (C7+) in Arm B, and q3w (C1–8)/q4w (C9+) in Arm C. Each arm consists of a safety run-in and an expansion cohort. Enrolment for Arm A is ongoing, with patients receiving up to 13 treatment cycles. Arms B and C are planned; patients will receive treatment until disease progression or unacceptable toxicity. The primary objective is to evaluate the safety and tolerability of cevostamab plus Pd, cevostamab plus Dd and cevostamab monotherapy. Secondary objectives include assessment of activity, PK, immunogenicity, and pharmacodynamic biomarkers. Clinical trial information: NCT04910568.

Model-informed drug development (MIDD) has become an important approach to improving clinical trial efficiency, optimizing drug dosing, and proposing drug labeling in the absence of dedicated clinical trials. For the first time, we developed a physiologically based pharmacokinetic (PBPK) model-based approach to assess CYP3A-mediated drug-drug interaction (DDI) risk for polatuzumab vedotin (Polivy), an anti-CD79b-vc-monomethyl auristatin E (MMAE) antibody-drug conjugate (ADC). The model was developed and verified using data from the existing clinical DDI study for brentuximab vedotin, a similar vc-MMAE ADC. Analogous to the brentuximab vedotin clinical study, polatuzumab vedotin at the proposed labeled dose was predicted to have a limited drug interaction potential with strong CYP3A inhibitor and inducer. Polatuzumab vedotin was also predicted to neither inhibit nor induce CYP3A. The present work demonstrated a high-impact application using a PBPK MIDD approach to predict the CYP3A-mediated DDI to enable drug labeling in the absence of any dedicated clinical DDI study. The key considerations for the PBPK report included in the Biologics License Application/Marketing Authorization Application submission, as well as the strategy and responses to address some of the critical and challenging questions from the health authorities following the submission are also discussed. Our experience and associated perspective using a PBPK approach to ultimately enable a drug interaction label claim for polatuzumab vedotin in lieu of a dedicated clinical DDI study, as well as the interactions with the regulatory agencies, further provides confidence in applying MIDD to accelerate the registration and approval of new drug therapies.

Antibody‐drug conjugates are important molecular entities in the treatment of cancer, with 8 antibody‐drug conjugates approved by the US Food and Drug Administration since 2000 and many more in early‐ and late‐stage clinical development. These conjugates combine the target specificity of monoclonal antibodies with the potent anticancer activity of small‐molecule therapeutics. The complex structure of antibody‐drug conjugates poses unique challenges to pharmacokinetic (PK) and pharmacodynamic (PD) characterization because it requires a quantitative understanding of the PK and PD properties of multiple different molecular species (eg, conjugate, total antibody, and unconjugated payload) in different tissues. Quantitative clinical pharmacology using mathematical modeling and simulation provides an excellent approach to overcome these challenges, as it can simultaneously integrate the disposition, PK, and PD of antibody‐drug conjugates and their components in a quantitative manner. In this review, we highlight diverse quantitative clinical pharmacology approaches, ranging from system models (eg, physiologically based pharmacokinetic [PBPK] modeling) to mechanistic and empirical models (eg, population PK/PD modeling for single or multiple analytes, exposure‐response modeling, platform modeling by pooling data across multiple antibody‐drug conjugates). The impact of these PBPK and PK/PD models to provide insights into clinical dosing justification and inform drug development decisions is also highlighted.

vc-MMAE antibody–drug conjugates (ADCs) consist of a monoclonal antibody (mAb) covalently bound with a potent anti-mitotic toxin (MMAE) through a protease-labile valine-citrulline (vc) linker. The objective of this study was to characterize the pharmacokinetics (PK) and explore exposure–response relationships of eight vc-MMAE ADCs, against different targets and for diverse tumor indications, using data from eight first-in-human Phase 1 studies. PK parameters of the three analytes, namely antibody-conjugated MMAE (acMMAE), total antibody, and unconjugated MMAE, were estimated using non-compartmental approaches and compared across the eight vc-MMAE ADCs. Relationships between analytes were assessed by linear regression. Exposure–response relationships were explored with key efficacy (objective response rate) and safety (Grade 2+ peripheral neuropathy) endpoints. PK profiles of acMMAE, total antibody and unconjugated MMAE following the first dose of 2.4 mg/kg were comparable across the eight ADCs; the exposure differences between molecules were small relative to the inter-subject variability. acMMAE exposure was strongly correlated with total antibody exposure for all the eight ADCs, but such correlation was less evident between acMMAE and unconjugated MMAE exposure. For multiple ADCs evaluated, efficacy and safety endpoints appeared to correlate well with acMMAE exposure, but not with unconjugated MMAE over the doses tested. PK of vc-MMAE ADCs was well characterized and demonstrated remarkable similarity at 2.4 mg/kg across the eight ADCs. Results from analyte correlation and exposure–response relationship analyses suggest that measurement of acMMAE analyte alone might be adequate for vc-MMAE ADCs to support the clinical pharmacology strategy used during late-stage clinical development.

Background: Fc receptor-homolog 5 (FcRH5) is a type I membrane protein that is expressed exclusively in the B-cell lineage, and at a higher level on myeloma cells than on normal B cells. Cevostamab is a FcRH5xCD3 bispecific antibody (BsAb) that facilitates T cell-directed killing of myeloma cells. Initial data from the dose-escalation phase of the ongoing Phase I study (NCT03275103) of cevostamab monotherapy in patients (pts) with heavily pre-treated RRMM demonstrated promising activity and manageable safety, along with near ubiquitous FcRH5 expression on myeloma cells (Cohen et al. ASH 2020; Sumiyoshi et al. EHA 2021). We present updated safety and efficacy data from a larger cohort of pts, including results comparing Cycle (C) 1 single step-up (SS) and double step-up (DS) dosing for the mitigation of cytokine release syndrome (CRS). Methods: Participants have RRMM for which no established therapy is available or appropriate. Cevostamab (intravenous infusion) is administered in 21-day cycles. In the SS cohorts, the step dose (0.05-3.6mg) is given on C1 Day (D) 1 and the target dose (0.15-198mg) on C1D8. In the DS cohorts, the step doses are given on C1D1 (0.3-1.2mg) and C1D8 (3.6mg), and the target dose (60-160mg) on C1D15. In both regimens, the target dose is given on D1 of subsequent cycles. Cevostamab is continued for a total of 17 cycles, unless progressive disease or unacceptable toxicity occurs. CRS is reported using ASTCT criteria (Lee et al. Biol Blood Marrow Transplant 2019). Results: At data cut-off (18 May 2021), 160 pts had been enrolled (median age: 64 years, range: 33-82 years; male: 58.1%); 21.3% of pts had extramedullary disease. Median number of prior lines of therapy was 6 (range: 2-18). Most pts (85.0%) were triple-class refractory (PI, IMiD, anti-CD38 antibody). 28 pts (17.5%) had received ≥1 prior CAR-T, 13 pts (8.1%) ≥1 prior BsAb, 27 pts (16.9%) ≥1 prior antibody-drug conjugate (ADC), and 54 pts (33.8%) ≥1 prior anti-BCMA targeting agent. Median follow-up in exposed pts was 6.1 months. Almost all had ≥1 adverse event (Table). The most common was CRS (128/160 pts [80.0%]; Grade [Gr] 1: 42.5%; Gr 2: 36.3%; Gr 3: 1.3%). Immune effector cell-associated neurotoxicity syndrome (ICANS) associated with CRS was observed in 21 pts (13.1%) and in 34/211 (16.1%) CRS events (Gr 1: 8.5%; Gr 2: 6.2%; Gr 3: 1.4%). Most CRS events occurred in C1 (87.2%), arose within 24 hours of cevostamab administration (70.5%), and resolved within 48 hours of onset (83.4%). In the pts with CRS, tocilizumab was used for CRS management in 43.8% and steroids in 25.8% (both agents: 18.0%). In SS dose-escalation (68 pts), 3.6mg was chosen as the most effective C1D1 SS dose for limiting CRS in C1, with no target dose-dependent increase in the rate or severity of CRS observed after the C1D8 administration. Likewise, in DS dose-escalation (30 pts), 0.3/3.6mg was identified as the preferred C1D1/C1D8 DS dose for limiting CRS in C1. Notably, the overall rate of CRS was lower in the pts who received the 0.3/3.6mg/target DS regimen than in those who received the 3.6mg/target SS regimen (77.3% [34/44] vs 88.2% [75/85], respectively). The rate of ICANS associated with CRS was also lower in the 0.3/3.6mg/target DS cohort than in the 3.6mg/target SS cohort (4.5% [2/44] vs 21.2% [18/85], respectively). At data cut-off, 158/160 pts were efficacy evaluable. In dose-escalation, responses were observed at the 20-198mg target dose levels, and data suggested a target dose-dependent increase in clinical efficacy. Median time to response was 29 days (range: 20-179 days). Two dose-expansion cohorts were opened: ORR was higher at the 160mg dose level (54.5%, 24/44 pts) than at the 90mg dose level (36.7%, 22/60). At target dose levels >90mg, ORRs in pts with prior exposure to CAR-Ts, BsAbs, ADCs, and anti-BCMA targeting agents were 44.4% (4/9 pts), 33.3% (3/9), 50.0% (7/14), and 36.4% (8/22) respectively. Median follow-up among all responders (n=61) was 8.1 months; estimated median duration of response was 15.6 months (95% CI: 6.4, 21.6). Conclusions: Cevostamab monotherapy continues to show clinically meaningful activity in a large cohort of pts with heavily pre-treated RRMM, with a target dose-dependent increase in ORR, but no increase in CRS rate. Responses appear durable, and are observed in pts with prior exposure to CAR-Ts, BsAbs, and ADCs. Compared with SS dosing, DS dosing at the 0.3/3.6mg level appears to be associated with a trend for an improved C1 safety profile. Figure 1 Figure 1. Disclosures Trudel: Amgen: Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Roche: Consultancy; Genentech: Research Funding; Pfizer: Honoraria, Research Funding; BMS/Celgene: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Sanofi: Honoraria. Cohen: BMS/Celgene: Consultancy; GlaxoSmithKline: Consultancy, Research Funding; Oncopeptides: Consultancy; Novartis: Research Funding; Genentech/Roche: Consultancy; AstraZeneca: Consultancy; Janssen: Consultancy; Takeda: Consultancy. Krishnan: MAGENTA: Consultancy; BMS: Consultancy, Current equity holder in publicly-traded company, Speakers Bureau; JANSSEN: Consultancy, Research Funding; City of Hope Cancer Center: Current Employment; REGENERON: Consultancy; SANOFI: Consultancy; GSK: Consultancy; Amgen: Speakers Bureau. Fonseca: Kite: Consultancy; Juno: Consultancy; Merck: Consultancy; Sanofi: Consultancy; Pharmacyclics: Consultancy; Novartis: Consultancy; OncoTracker: Consultancy, Membership on an entity's Board of Directors or advisory committees; Aduro: Consultancy; Caris Life Sciences: Membership on an entity's Board of Directors or advisory committees; Patent: Prognosticaton of myeloma via FISH: Patents & Royalties; AbbVie: Consultancy; GSK: Consultancy; Scientific Advisory Board: Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy; Amgen: Consultancy; Mayo Clinic in Arizona: Current Employment; Celgene: Consultancy; BMS: Consultancy; Takeda: Consultancy; Janssen: Consultancy. Spencer: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Berdeja: Bluebird bio, BMS, Celgene, CRISPR Therapeutics, Janssen, Kite Pharma, Legend Biotech, SecuraBio, Takeda: Consultancy; Abbvie, Acetylon, Amgen: Research Funding; EMD Sorono, Genentech: Research Funding; Celularity, CRISPR Therapeutics: Research Funding; GSK, Ichnos Sciences, Incyte: Research Funding; Lilly, Novartis: Research Funding; Poseida, Sanofi, Teva: Research Funding. Lesokhin: Serametrix, Inc: Patents & Royalties; Behringer Ingelheim: Honoraria; Genetech: Research Funding; Iteos: Consultancy; Janssen: Honoraria, Research Funding; pfizer: Consultancy, Research Funding; bristol myers squibb: Research Funding; Trillium Therapeutics: Consultancy. Forsberg: University of Colorado: Current Employment; Karyopharm, Sanofi, Genentech: Research Funding. Costa: Karyopharm: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Rodriguez-Otero: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene-BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Regeneron: Honoraria; Clínica Universidad de Navarra: Current Employment. Kaedbey: Takeda, Sanofi: Honoraria; Celgene/BMS, Janssen: Honoraria; Royal Victoria Hospital Lakeshore Hospital: Ended employment in the past 24 months; Jewish General Hospital - McGill University: Current Employment. Richter: Janssen, Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Adaptive biotechnologies: Speakers Bureau; BMS, Karyopharm, Antengene: Membership on an entity's Board of Directors or advisory committees; Tisch Cancer Institute: Icahn School of Medicine at Mount Sinai: Current Employment. Mateos: Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene - Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sea-Gen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria; Bluebird bio: Honoraria; GSK: Honoraria; Oncopeptides: Honoraria. Thomas: Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Acerta Pharma: Research Funding; X4 Pharma: Research Funding; Ascentage Pharma: Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding. Wong: Genentech: Current Employment; CTMX, UBX, BMRN: Current equity holder in publicly-traded company. Li: Genentech/Roche: Current Employment, Current equity holder in publicly-traded company. Choeurng: Genentech: Current Employment, Current equity holder in publicly-traded company. Vaze: Roche/Genentech: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Samineni: Genentech: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Sumiyoshi: Genentech: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Cooper: Genentech: Current Employment; Roche: Current holder of individual stocks in a privately-held company. Harrison: Haemalogix: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche/Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene/ Juno/ BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Eusa: Consultancy, Honoraria, Speakers Bureau; Terumo BCT: Consultancy, Honoraria. OffLabel Disclosure: Cevostamab is a FcRH5xCD3 bispecific antibody that facilitates T cell-directed killing of myeloma cells. Cevostamab is an investigational agent.

Venetoclax is a first in class BCL-2 inhibitor that is approved for treatment of CLL and AML. It is currently under evaluation in other indications in adult and pediatric populations. Venetoclax is available as 10 mg, 50 mg, and 100 mg film-coated tablets. While the 100 mg tablet is most commonly used, the smaller size of the lower strength tablets is preferred by patients experiencing difficulty swallowing large tablets. Moreover, two powder formulations for suspension (0.72% and 7.2%) to be mixed with delivery vehicles were developed. In this abstract we present data from clinical studies that evaluated the bioavailability of the different venetoclax formulations relative to the commercially available 100 mg tablet. Three open-label, single-dose, crossover bioavailability studies in healthy female subjects were conducted. The first study evaluated the bioavailability of the commercially available 10 and 50 mg tablets relative to the 100 mg tablet. Forty subjects received a 100 mg dose of venetoclax (1x100 mg tablet, 2x50 mg tablets or 10x10 mg tablets) at the start of each period after a low-fat breakfast. The second study evaluated the bioavailability of the two powder formulations relative to the 100 mg tablet. Sixteen subjects received a 100 mg dose of venetoclax (1x100 mg film-coated tablet; 100 mg 0.72% powder formulation; 100 mg 7.2% powder formulation; and 4x25 mg dispersible tablets for oral suspension used in the Phase 1 study) in each of the 4 periods after a high fat breakfast. The third study evaluated the bioavailability of the two powder formulations when administered with different dosing vehicles relative to water. Twenty-four subjects (12 per cohort) received 100 mg of venetoclax (0.72% powder formulation or the 7.2% powder formulation) with either water, apple juice, apple sauce or yogurt in each of the 4 periods after a moderate fat breakfast. Bioavailability assessment of the commercial tablets demonstrated that ten 10 mg tablets were bioequivalent to one 100 mg tablet, two 50 mg tablets were bioequivalent to one 100 mg tablet, and two 50 mg tablets were bioequivalent to ten 10 mg tablets. The two powder formulations for oral suspension (0.72% and 7.2%) met the bioequivalence criteria (0.80-1.25) to the commercial 100 mg tablet with respect to AUCt and AUC∞, but the lower bound of the 90% CI of the Cmax extended slightly below 0.80. The delivery vehicles (water, apple juice, apple sauce and yogurt) did not affect the bioavailability of venetoclax 0.72% or 7.2% oral suspensions Citation Format: Mohamed Badawi, Bo Tong, Xin Chen, Tammy Palenski, Su Young Kim, Divya Samineni, David Hoffman, Rajeev Menon, Ahmed Hamed Salem. Clinical assessment of the bioavailability of venetoclax tablet and powder formulations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 641.

Antibody-drug conjugates (ADCs) developed using the valine-citrulline-MMAE (vc-MMAE) platform, consist of a monoclonal antibody (mAb) covalently bound with a potent anti-mitotic toxin (MMAE) through a protease-labile vc linker. Recently, clinical data for a variety of vc-MMAE ADCs has become available. The goal of this analysis was to develop a platform model that simultaneously described antibody-conjugated MMAE (acMMAE) pharmacokinetic (PK) data from eight vc-MMAE ADCs, against different targets and tumor indications; and to assess differences and similarities of model parameters and model predictions, between different compounds. Clinical PK data of eight vc-MMAE ADCs from eight Phase I studies were pooled. A population PK platform model for the eight ADCs was developed, where the inter-compound variability (ICV) was described explicitly, using the third random effect level (ICV), and implemented using LEVEL option of NONMEM 7.3. The PK was described by a two-compartment model with time dependent clearance. Clearance and volume of distribution increased with body weight; volume was higher for males, and clearance mildly decreased with the nominal dose. Michaelis-Menten elimination had only minor effect on PK and was not included in the model. Time-dependence of clearance had no effect beyond the first dosing cycle. Clearance and central volume were similar among ADCs, with ICV of 15 and 5%, respectively. Thus, PK of acMMAE was largely comparable across different vc-MMAE ADCs. The model may be applied to predict PK-profiles of vc-MMAE ADCs under development, estimate individual exposure for the subsequent PK-pharmacodynamics (PD) analysis, and project optimal dose regimens and PK sampling times.

Introduction: New targets and treatment modalities are needed for multiple myeloma (MM). Fc receptor-homolog 5 (FcRH5) is a type I membrane protein that is expressed on B cells and plasma cells, and is found on myeloma cells with near 100% prevalence. BFCR4350A, a humanized immunoglobulin G-based T-cell-engaging bispecific antibody (bsAb), targets the most membrane-proximal domain of FcRH5 on myeloma cells and CD3 on T cells. Dual binding facilitates efficient immunological synapse formation, resulting in T-cell activation and potent killing of myeloma cells (Li et al. Cancer Cell 2017). GO39775 (NCT03275103) is an ongoing, multicenter Phase I trial evaluating the safety, activity, pharmacodynamics, and pharmacokinetics of BFCR4350A monotherapy in pts with relapsed/refractory (R/R) MM. We present dose-escalation data from the single step-up dosing cohort (Arm A). Methods: All pts have R/R MM for which no established therapy is available, appropriate, or tolerated. Prior exposure to CAR-T cells, T-cell engaging bsAbs, and antibody-drug conjugates (ADCs), including those targeting BCMA, is allowed. In dose-escalation, pts receive BFCR4350A by IV infusion in 21-day cycles (Q3W). In Arm A, a single step-up dose is used in Cycle (C) 1 to mitigate the risk for cytokine release syndrome (CRS), with the step dose (0.05-3.6mg) given on C1 Day (D) 1 and the target dose (0.15-132mg) given on C1D8, and on D1 of each subsequent cycle. Results: At cut-off (April 13, 2020), 51 pts (median age: 62.0 years [range: 33-80]; high-risk [HR] cytogenetics [1q21, t(4;14), t(14;16), or del(17p)]: 28 pts) had been enrolled into Arm A. Median number of prior lines of therapy was 6 (range: 2-15). Prior treatments included: proteasome inhibitors (PIs), 100% (94.1% refractory); immunomodulatory drugs (IMiDs), 100% (98.0% refractory); anti-CD38 mAbs, 78.4% (92.5% refractory); autologous stem cell transplant, 86.3%. Overall, 66.7% of pts were triple-class refractory (≥1 PI, ≥1 IMiD, and ≥1 anti-CD38 mAb), and 94.1% of pts were refractory to their last therapy. At cut-off, 46/51 pts were evaluable for efficacy. Responses were observed at the 3.6/20mg dose level and above, in 15/29 pts (51.7%) (Table). Responses included 3 stringent CRs, 3 CRs, 4 VGPRs, and 5 PRs (Table). At the 3.6/20mg dose level and above, responses were observed in pts with HR cytogenetics (9/17), triple-class refractory disease (10/20), and prior exposure to anti-CD38 mAbs (11/22), CAR-Ts (2/3), or ADCs (2/2). Duration of response data are evolving, with 6/15 pts in response for >6 months at cut-off. Median follow-up for safety was 6.2 months (range: 0.2-26.3 months). Almost all pts (49/51) had ≥1 treatment-related AE. The most common treatment-related AE was CRS (Lee et al. 2014 criteria; 38/51 pts, 74.5%). CRS was Grade (Gr) 1 in 20 pts (39.2%), Gr 2 in 17 pts (33.3%), and Gr 3 in 1 pt (2%) (due to Gr 4 transaminase elevation). CRS was most common in C1 (38 pts) and was uncommon or absent in subsequent cycles (4 pts). Most CRS events (49/58, 84.5%) resolved within 2 days. 18/38 (47.3%) pts with CRS received tocilizumab and/or steroids. Other treatment-related AEs in ≥5 pts were neutropenia and lymphocyte count decreased (6 pts each, 11.8%), aspartate aminotransferase increased and platelet count decreased (5 pts each, 9.8%). Treatment-related Gr 3-4 AEs (20 pts, 39.2%) in ≥3 pts were lymphocyte count decreased (6 pts, 11.8%), neutropenia (5 pts, 9.8%), anemia and platelet count decreased (3 pts each, 5.9%). No treatment-related Gr 5 (fatal) AEs were observed. Treatment-related AEs leading to withdrawal of treatment were uncommon (1 pt, 2.0%). One DLT (Gr 3 pneumonia) was observed in the 3.6/90mg cohort, but the MTD was not reached. BFCR4350A PK was linear across the active dose levels tested and the estimated half-life was supportive of the Q3W dosing regimen. Conclusions: BFCR4350A monotherapy demonstrates promising activity in heavily pre-treated R/R MM, with deep and durable responses observed in pts with HR cytogenetics, triple-class refractory disease, and/or prior exposure to anti-CD38 mAbs, CAR-Ts, or ADCs. Toxicity was manageable, with C1 single step-up dosing effectively mitigating the risk for severe CRS and allowing escalation to clinically active doses. Updated data will be presented. Disclosures Cohen: Novartis: Other: Patents/Intellectual property licensed, Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda,: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Membership on an entity's Board of Directors or advisory committees. Harrison:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Patents & Royalties: wrt panobinostat; BMS: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Haemalogix: Consultancy; Janssen: Honoraria; CRISPR Therapeutics: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Krishnan:Sutro: Membership on an entity's Board of Directors or advisory committees; Z Predicta: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Regeneron: Consultancy; Takeda: Speakers Bureau; Amgen: Speakers Bureau; BMS/Celgene: Consultancy, Other: Stock BMS, Speakers Bureau; Sanofi: Consultancy. Fonseca:Amgen: Consultancy; BMS: Consultancy; Celgene: Consultancy; Takeda: Consultancy; Bayer: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Pharmacyclics: Consultancy; Sanofi: Consultancy; Merck: Consultancy; Juno: Consultancy; Kite: Consultancy; Aduro: Consultancy; OncoTracker: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy; GSK: Consultancy; AbbVie: Consultancy; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees. Forsberg:Celgene: Speakers Bureau; Genentech, Inc., Sanofi, Karyopharm, Abbvie: Research Funding. Spencer:AbbVie, Celgene, Haemalogix, Janssen, Sanofi, SecuraBio, Specialised Therapeutics Australia, Servier and Takeda: Consultancy; Amgen, Celgene, Haemalogix, Janssen, Servier and Takeda: Research Funding; AbbVie, Amgen, Celgene, Haemalogix, Janssen, Sanofi, SecuraBio, Specialised Therapeutics Australia, Servier and Takeda: Honoraria; Celgene, Janssen and Takeda: Speakers Bureau. Berdeja:BMS: Consultancy, Research Funding; Glenmark: Research Funding; Genentech, Inc.: Research Funding; Bioclinica: Consultancy; Teva: Research Funding; Vivolux: Research Funding; Abbvie: Research Funding; Cellularity: Research Funding; Acetylon: Research Funding; CURIS: Research Funding; Legend: Consultancy; Lilly: Research Funding; Constellation: Research Funding; EMD Sorono: Research Funding; Celgene: Consultancy, Research Funding; Novartis: Research Funding; Janssen: Consultancy, Research Funding; Prothena: Consultancy; Poseida: Research Funding; Amgen: Consultancy, Research Funding; Servier: Consultancy; Takeda: Consultancy, Research Funding; Bluebird: Research Funding; Karyopharm: Consultancy; Kite Pharma: Consultancy; CRISPR Therapeutics: Consultancy, Research Funding; Kesios: Research Funding. Li:Genentech, Inc./ F. Hoffmann-La Roche: Current Employment. Choeurng:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company. Vaze:Genentech, Inc./ F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company. Samineni:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company. Sumiyoshi:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Cooper:Genentech, Inc./ F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company. Fine:Genentech, Inc.: Current Employment; F. Hoffmann-La Roche: Current equity holder in publicly-traded company. Trudel:Janssen: Honoraria, Research Funding; Sanofi: Honoraria; GSK: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Karyopharm: Honoraria; AstraZeneca: Honoraria; BMS: Consultancy, Honoraria, Research Funding; Genentech, Inc.: Research Funding; Amgen: Consultancy, Research Funding; Takeda: Honoraria. OffLabel Disclosure: BFCR4350A is a humanized IgG-based T-cell-engaging bispecific antibody that targets the most membrane-proximal domain of FcRH5 on myeloma cells and CD3 on T cells. Dual binding facilitates efficient immunological synapse formation, resulting in T-cell activation and killing of myeloma cells. BFCR4350A is an investigational agent.

Suboptimal treatment for monoclonal antibodies (mAbs) directed against endogenous circulating soluble targets and the shed extracellular domains (ECD) of the membrane-bound targets is an important clinical concern due to the potential impact of mAbs on the in vivo efficacy and safety. Consequently, there are considerable challenges in the determination of an optimal dose and/or dosing regimen. Areas covered: This review outlines the impact of shed antigen targets from membrane-bound proteins and soluble targets on the PK and/or PD of therapeutic mAbs that have been approved in the last decade. We discuss various bioanalytical techniques that have facilitated the interpretation of the PK/PD properties of therapeutic mAbs and also considered the factors that may impact such measurements. Quantitative approaches include target-mediated PK models and bi- or tri-molecular interaction PK/PD models that describe the relationships between the antibody PK and the ensuing effects on PD biomarkers, to facilitate the mAb PK/PD characterization. Expert commentary: The proper interpretation of PK/PD relationships through the integrated PK/PD modeling and bioanalytical strategy facilitates a mechanistic understanding of the disease processes and dosing regimen optimization, thereby offering insights into developing effective therapeutic regimens. This review provides an overview of the impact of soluble targets or shed ECD on mAb PK/PD properties. We provide examples of quantitative approaches that facilitate the characterization of mAb PK/PD characteristics and their corresponding bioanalytical strategies.

DMOT4039A, a humanized anti-mesothelin mAb conjugated to the antimitotic agent monomethyl auristatin E (MMAE), was given to patients with pancreatic and ovarian cancer every 3 weeks (0.2–2.8 mg/kg; q3w) or weekly (0.8–1.2 mg/kg). A 3+3 design was used for dose escalation followed by expansion at the recommended phase II dose (RP2D) to evaluate safety and pharmacokinetics. Antitumor response was evaluated per RECIST 1.1 and serum CA19-9 or CA125 declines. Tumor mesothelin expression was determined by IHC. Seventy-one patients (40 pancreatic cancer; 31 ovarian cancer) were treated with DMOT4039A. For the q3w schedule (n = 54), the MTD and RP2D was 2.4 mg/kg, with dose-limiting toxicities of grade 3 hyperglycemia and grade 3 hypophosphatemia at 2.8 mg/kg. For the weekly schedule (n = 17), the maximum assessed dose was 1.2 mg/kg, with further dose escalations deferred because of toxicities limiting scheduled retreatment in later cycles, and therefore the RP2D level for the weekly regimen was determined to be 1 mg/kg. Across both schedules, the most common toxicities were gastrointestinal and constitutional. Treatment-related serious adverse events occurred in 6 patients; 4 patients continued treatment following dose reductions. Drug exposure as measured by antibody-conjugated MMAE and total antibody was generally dose proportional over all dose levels on both schedules. A total of 6 patients had confirmed partial responses (4 ovarian; 2 pancreatic) with DMOT4039A at 2.4 to 2.8 mg/kg i.v. q3w. DMOT4039A administered at doses up to 2.4 mg/kg q3w and 1.0 mg/kg weekly has a tolerable safety profile and antitumor activity in both pancreatic and ovarian cancer. Mol Cancer Ther; 15(3); 439–47. ©2016 AACR.

Minimal residual disease (MRD) is an important clinical endpoint in chronic lymphocytic leukemia (CLL) because it correlates with progression free survival and overall survival. The objective of this work is to investigate the impact of venetoclax (VEN) exposures on undetectable MRD rates in blood and bone marrow (BM) in relapsed/refractory (R/R) CLL patients receiving VEN monotherapy or combination therapy with rituximab (RTX). Data from a total of 708 patients from four VEN monotherapy studies and one combination Phase 1b study (VEN + 6-9 cycles of RTX) in R/R CLL patients were utilized to perform this analysis. The median number of prior therapies in these studies was 3, 42% of the patients had 17p chromosomal deletion and 28% had prior B-Cell Receptor inhibitor (BCRi) therapy. Blood and BM MRD assessments were available for 70% and 38%, respectively, of patients included in the analysis. Absence of an MRD measurement was assumed as detectable MRD for the purposes of this analysis. The average concentration (Cavg) of VEN was computed for each patient by fitting a population pharmacokinetic model to the observed VEN concentration data. The model was used to calculate area under the curve and compute Cavg accounting for VEN dose ramp-ups, reductions and interruptions. The relationships between venetoclax Cavg and undetectable MRD rates were assessed by using quartile plots. Logistic regression analyses were also conducted to quantify the exposure-response relationship. With VEN monotherapy, the undetectable MRD rates in blood and BM increased with the increase in VEN exposures. With VEN + RTX combination treatment, the undetectable MRD rates in blood and BM showed an increase with increasing VEN average concentration, but the benefit saturated with limited increase at exposures beyond 400mg. Logistic regression analyses indicated statistically significant (p These results demonstrate that higher venetoclax concentrations are associated with higher undetectable MRD rates in both blood and BM. When VEN is combined with RTX, an increase in VEN dose beyond 400mg is unlikely to result in higher undetectable MRD rates. Citation Format: Sathej Gopalakrishnan, Rajeev Menon, Brenda Chyla, Divya Samineni, Amanda Jacobson, Su Young Kim, Sven Mensing, Ahmed Hamed Salem. Relationship between venetoclax concentrations and undetectable MRD in patients with chronic lymphocytic leukemia [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3024.

FcRH5 is a cell surface marker enriched on malignant plasma cells when compared to other hematologic malignancies and normal tissues. DFRF4539A is an anti-FcRH5 antibody-drug conjugated to monomethyl auristatin E (MMAE), a potent anti-mitotic agent. This phase I study assessed safety, tolerability, maximum tolerated dose (MTD), anti-tumor activity, and pharmacokinetics of DFRF4539A in patients with relapsed/refractory multiple myeloma. DFRF4539A was administered at 0.3–2.4 mg/kg every 3 weeks or 0.8–1.1 mg/kg weekly as a single-agent by intravenous infusion to 39 patients. Exposure of total antibody and antibody-conjugate-MMAE analytes was linear across the doses tested. There were 37 (95%) adverse events (AEs), 8 (21%) serious AEs, and 15 (39%) AEs ≥ grade 3. Anemia (n = 10, 26%) was the most common AE considered related to DFRF4539A. Two cases of grade 3 acute renal failure were attributed to DFRF4539A. There were no deaths; the MTD was not reached. DFRF4539A demonstrated limited activity in patients at the doses tested with 2 (5%) partial response, 1 (3%) minimal response, 18 (46%) stable disease, and 16 (41%) progressive disease. FcRH5 was confirmed to be expressed and occupied by antibody post-treatment and thus remains a valid myeloma target. Nevertheless, this MMAE-based antibody-drug-conjugate targeting FcRH5 was unsuccessful for myeloma.

Monomethyl auristatin E (MMAE, a cytotoxic agent), upon releasing from valine-citrulline-MMAE (vc-MMAE) antibody-drug conjugates (ADCs), is expected to behave like small molecules. Therefore, evaluating the drug–drug interaction (DDI) potential associated with MMAE is important in the clinical development of ADCs. The objective of this work was to build a physiologically based pharmacokinetic (PBPK) model to assess MMAE–drug interactions for vc-MMAE ADCs. A PBPK model linking antibody-conjugated MMAE (acMMAE) to its catabolite unconjugated MMAE associated with vc-MMAE ADCs was developed using a mixed ‘bottom-up’ and ‘top-down’ approach. The model was developed using in silico and in vitro data and in vivo pharmacokinetic data from anti-CD22-vc-MMAE ADC. Subsequently, the model was validated using clinical pharmacokinetic data from another vc-MMAE ADC, brentuximab vedotin. Finally, the verified model was used to simulate the results of clinical DDI studies between brentuximab vedotin and midazolam, ketoconazole, and rifampicin. The pharmacokinetic profile of acMMAE and unconjugated MMAE following administration of anti-CD22-vc-MMAE was well described by simulations using the developed PBPK model. The model’s performance in predicting unconjugated MMAE pharmacokinetics was verified by successful simulation of the pharmacokinetic profile following brentuximab vedotin administration. The model simulated DDIs, expressed as area under the concentration-time curve (AUC) and maximum concentration (C max) ratios, were well within the two-fold of the observed data from clinical DDI studies. This work is the first demonstration of the use of PBPK modelling to predict MMAE-based DDI potential. The described model can be extended to assess the DDI potential of other vc-MMAE ADCs.

Antibody drug conjugates (ADC), in which small molecule cytotoxic agents are non-specifically linked to antibodies, can enable targeted delivery of chemotherapeutics to tumor cells. ADCs are often produced and administered as a mixture of conjugated antibodies with different drug to antibody ratios (DAR) resulting in complex and heterogeneous disposition kinetics. We developed a mechanism-based platform model that can describe and predict the complex pharmacokinetic (PK) behavior of ADCs with protease-cleavable valine-citrulline (VC) linker linked to Monomethylmonomethyl auristatin F/E by incorporating known mechanisms of ADC disposition. The model includes explicit representation of all DAR species; DAR-dependent sequential deconjugation of the drug, resulting in the conversion of higher DAR to lower DAR species; and DAR-dependent antibody/ADC clearance. PK profiles of multiple analytes (total antibody, drug-conjugated antibody, and/or antibody-conjugated drug) for different ADC molecules and targets in rodents and cynomolgus monkeys were used for model development. The integrated cross-species model was successful in capturing the multi-analyte PK profiles after administration of purified ADCs with defined DAR species and ADCs with mixtures of DAR. Human PK predictions for DSTP3086S (anti-STEAP1-vc-MMAE) with the platform model agreed well with PK (total antibody and antibody-conjugated drug concentrations) measurements in the dose-ranging phase I clinical study. The integrated model is applicable to various other ADCs with different formats, conjugated drugs, and linkers, and provides a valuable tool for the exploration of mechanisms governing disposition of ADCs and enables translational predictions.

Background Quilizumab, a humanized IgG1 monoclonal antibody, targets the M1-prime segment of membrane-expressed IgE, leading to depletion of IgE-switched and memory B cells. In patients with mild asthma, quilizumab reduced serum IgE and attenuated the early and late asthmatic reaction following whole lung allergen challenge. This study evaluated the efficacy and safety of quilizumab in adults with allergic asthma, inadequately controlled despite high-dose inhaled corticosteroids (ICS) and a second controller. Methods Five hundred seventy-eight patients were randomized to monthly or quarterly dosing regimens of subcutaneous quilizumab or placebo for 36 weeks, with a 48-week safety follow-up. Quilizumab was evaluated for effects on the rate of asthma exacerbations, lung function, patient symptoms, serum IgE, and pharmacokinetics. Exploratory analyses were conducted on biomarker subgroups (periostin, blood eosinophils, serum IgE, and exhaled nitric oxide). Results Quilizumab was well tolerated and reduced serum total and allergen-specific IgE by 30–40 %, but had no impact on asthma exacerbations, lung function, or patient-reported symptom measures. At Week 36, the 300 mg monthly quilizumab group showed a 19.6 % reduction (p = 0.38) in the asthma exacerbation rate relative to placebo, but this was neither statistically nor clinically significant. Biomarker subgroups did not reveal meaningful efficacy benefits following quilizumab treatment. Conclusions Quilizumab had an acceptable safety profile and reduced serum IgE. However, targeting the IgE pathway via depletion of IgE-switched and memory B cells was not sufficient for a clinically meaningful benefit for adults with allergic asthma uncontrolled by standard therapy. Trial registration ClinicalTrials.gov NCT01582503 Electronic supplementary material The online version of this article (doi:10.1186/s12931-016-0347-2) contains supplementary material, which is available to authorized users.

HIV-1 protease inhibitors often cause dyslipidemia, necessitating the use of lipid-lowering agents such as rosuvastatin. However, when given concomitantly, these therapeutic agents often exhibit adverse drug interactions. In this study (phase I open-label trial, n = 12 HIV-1 seronegative participants), the authors assessed the drug interactions between darunavir/ritonavir given in combination with rosuvastatin. Participants were randomized to receive rosuvastatin (10 mg/day) or darunavir/ritonavir (600/100 mg twice daily) alone for 7 days in a crossover design followed by combination therapy for 7 days with intervening 7-day washout periods. Intensive blood sampling for pharmacokinetics and fasting lipids was performed on days 7, 21, and 35. The geometric mean AUC(0-24 h) of rosuvastatin increased from 109 to 161 ng·h/mL (P < .005) and C(max) increased 6.7 to 16.3 ng/mL (P < .001) when coadministered with darunavir/ritonavir. In the presence of darunavir/ritonavir and rosuvastatin, total cholesterol and triglyceride levels increased by 10% (P = .007) and 56% (P = .011), whereas the high-density lipoprotein cholesterol levels decreased by 13% (P = .006) relative to rosuvastatin administration alone. There were no significant adverse events attributable to the coadministration of these drugs. Rosuvastatin levels increase in the presence of darunavir/ritonavir coadministration, whereas the lipid-lowering benefits are blunted. The clinical significance of these changes requires further investigation.

Human immunodeficiency virus (HIV) protease inhibitors (PIs) produce profound and unpredictable drug-drug interactions (DDIs) that cannot be explained fully by their inhibition/inactivation of CYP3A enzymes. Delineating and quantifying the CYPs and transporters inducible by PIs are crucial in developing an integrative mechanistic understanding and prediction of PI-based DDIs. To do so, two LC-MS/MS cocktail assays were modified and validated simultaneously to quantify the CYP activity of CYP3A, 2B6, 2C8, 2C9, 2C19, 1A, 2E1, 2A6 and 2D6 enzymes. These new assays were applied to evaluate the induction potential of eight PIs in microsomes isolated from PI-treated human hepatocytes. The mRNA expression of these CYPs and transporters (OATP1B1, OATP1B3, OATP1A2, MDR1, MRP2 and MRP4) was also evaluated using relative RT-PCR. The majority of PIs were net inducers of CYP3As and 2B6 at both the mRNA and activity level (> 2-fold), while ritonavir, saquinavir, nelfinavir or lopinavir did not induce CYP3A activity ( 2-fold) by the PIs. Amprenavir was the most potent net inducer. In conclusion, our validated cocktail assays can be implemented to comprehensively quantify CYP activities in human liver microsomes and hepatocyte studies. The results also provide the much needed data on the net induction potential of the PIs for hepatic CYPs and transporters. A qualitative agreement was observed between our results and published PI-based DDIs, suggesting that human hepatocytes are a useful platform for more extensive and quantitative in vitro-in vivo prediction of PI-based DDIs.

Introduction FL is characterized by the translocation t(14;18), resulting in constitutive overexpression of the key anti-apoptotic protein BCL2. Ven, a selective, potent oral inhibitor of BCL2, has shown profound efficacy combined with anti-CD20 antibodies in chronic lymphocytic leukemia and is in development for treating other hematologic malignancies, including non-Hodgkin lymphoma (NHL). Preclinical and early clinical data in indolent NHL suggest addition of Ven to R or chemo may improve efficacy. The open-label CONTRALTO study (NCT02187861) assessed efficacy and safety of a chemo-free regimen with Ven+R or randomized Ven + standard chemoimmunotherapy regimen BR vs BR for treatment of R/R FL. Methods Pts ≥18 yrs, with confirmed grade (Gr) 1-3a R/R FL, ≥1 line of prior therapy for lymphoma, and adequate hematologic and organ function with no history of B-refractory disease (chemo arms), were assigned at investigators' discretion to receive Ven+R or be randomized to BR +/- Ven, with stratification by 1 vs 0 GELF criteria and ≥ vs Results 163 pts were enrolled; 52 received Ven+R, 9 in the safety run-in, 51 Ven+BR, 51 BR (Table 1). Median lines of prior treatment: 3 (1-6) in both Ven-treated arms and 2 (1-4) in BR arm. Ann Arbor stages III/IV: 88%, 73.5%, and 72.5% of pts in Ven+R, Ven+BR and BR arms, respectively. BCL2 expression by IHC and BCL2 translocations were observed in most pts (88% and 81% respectively); expression of MCL1 (1%) and BCLxL (29%) were low. 44 pts (90%) in Ven+BR arm required dose interruptions/modifications of any therapy compared with 21 (42%) in BR and 30 (58%) in Ven+R; most were of Ven: 20 (38.5%) in Ven+R arm and 43 (88%) in Ven+BR. 17 pts (35%) in Ven+BR arm and 2 (4%) in Ven+R discontinued Ven early. 30 pts (61%) in Ven+BR arm required dose interruption/modification of B versus 20 (40%) in BR; 10 pts (20%) in Ven+BR and 2 (4%) in BR discontinued B. Neutropenia and thrombocytopenia were the most common Gr 3-4 adverse events (AEs) overall (Table 2B), and led to dose interruptions/modifications. They were highest in Ven+BR arm (59% neutropenia, 45% thrombocytopenia). Serious AEs were seen more frequently with Ven+BR (Table 2A) than Ven+R or BR; most were infection/infestation events: 22% Ven+BR, 11.5% Ven+R, 8% BR. In Ven+R arm, 17% of pts reached CMR at 6 mo; 25% achieved CMR as best overall response (BOR), of whom all achieved minimal residual disease (MRD) negativity at mid-induction. A population of pts who were non-refractory to prior therapy had improved response (54% overall response rate, 35% CMR as BOR). Six-mo CMR rates were 74% and 68% with Ven+BR and BR, respectively, and were equal at 1 yr (Table 3). PFS analysis did not show a difference between these arms (adjusted HR, 0.69; p=0.2088). Although only 61.2% of pts in Ven+BR arm had ≥90% B dose intensity vs 95.8% in BR arm, efficacy in the 2 arms was comparable in CMR and PFS. Of note, pts maintaining all cycles of Ven+BR had a 6-mo CMR of 100%. Efficacy was comparable in biomarker subgroups, and did not identify clear predictors of response. Conclusion Ven+R had an acceptable toxicity in the population studied; this arm included a high number of pts with refractory status and shorter DOR to prior treatments, potentially leading to modest overall efficacy. Improved response rates and MRD negativity, and longer PFS were observed in a subgroup of pts with non-refractory FL, showing efficacy of Ven+R in FL. Addition of Ven to BR at the dose and schedule studied resulted in increased toxicity (Gr 3-4 cytopenias and gastrointestinal events), leading to dose interruptions/discontinuations, with consequent limitation of overall tolerability. However, despite lower dose intensity of BR in Ven+BR arm, efficacy remained the same between the 2 chemo-containing arms, mandating optimal dose delivery for improved efficacy in combination with chemo in future studies. Disclosures Zinzani: Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SERVIER: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Honoraria, Speakers Bureau; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astra Zeneca: Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Speakers Bureau. Flinn:Portola: Research Funding; Curis: Research Funding; Incyte: Research Funding; Genentech: Research Funding; Trillium: Research Funding; Takeda: Research Funding; Verastem: Consultancy, Research Funding; Forty Seven: Research Funding; Forma: Research Funding; Novartis: Research Funding; Kite: Research Funding; Celgene: Research Funding; ArQule: Research Funding; BeiGene: Research Funding; Infinity: Research Funding; Pharmacyclics: Research Funding; Verastem: Research Funding; Calithera: Research Funding; Agios: Research Funding; Seattle Genetics: Research Funding; Merck: Research Funding; Constellation: Research Funding; Pfizer: Research Funding; Gilead: Research Funding; TG Therapeutics: Research Funding; Janssen: Research Funding. Yuen:Seattle Genetics: Research Funding. Topp:F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer Ingelheim: Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; Regeneron Pharmaceuticals, Inc.: Honoraria, Research Funding. Rusconi:Celgene: Honoraria, Research Funding; Takeda: Honoraria; Janssen: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria. Fleury:Novartis Pharmaceuticals Corporation: Consultancy; Merck: Consultancy; Janssen: Consultancy; Seattle Genetics: Consultancy; Gilead: Consultancy; Lundbeck: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy; Celgene: Consultancy. Pro:Takeda Pharmaceuticals: Honoraria, Other: Travel expenses; kiowa: Honoraria; Seattle Genetics: Consultancy, Other: Travel expenses, Research Funding; portola: Honoraria. Gritti:Autolus: Consultancy. Crump:F. Hoffmann-La Roche Ltd: Consultancy; Servier Canada: Consultancy; Jansen-Ortho: Consultancy. Samineni:Genentech Inc: Employment, Other: Ownership interests non-PLC. Sinha:F. Hoffmann-La Roche Ltd: Employment. Punnoose:Roche: Equity Ownership; Genentech Inc: Employment. Szafer-Glusman:F. Hoffmann-La Roche Ltd: Employment, Other: Ownership interests PLC. Danesi:F. Hoffmann-La Roche Ltd: Employment. Petrich:Abbvie: Employment, Other: Ownership interests PLC. Kornacker:F. Hoffmann-La Roche Ltd: Employment. Humphrey:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Mobasher:Genentech Inc: Employment; F. Hoffmann-La Roche Ltd: Other: Ownership interests non-PLC. Hiddemann:F. Hoffman-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Introduction: BCL2 overexpression leading to evasion of apoptosis is common in hematologic malignancies. In DLBCL, 50% of patients (pts) overexpress BCL2 protein, 30% overexpress BCL2 and MYC (double-expressor [DE]) and 5-10% have translocations of BCL2 and MYC (double-hit [DH]), all of which are associated with a poor prognosis. We hypothesized that combination of the BCL2 inhibitor venetoclax (Ven) with chemotherapy would improve DLBCL outcomes based on pre-clinical and early clinical data. The Phase Ib part of the CAVALLI (NCT02055820) study assessed the maximum tolerated dose (MTD) of CHOP + rituximab (R) or obinutuzumab (G) with Ven (200-800mg) in non-Hodgkin lymphoma, recommending 800mg of Ven + R-CHOP for Phase II. The single-arm, multicenter Phase II part of CAVALLI investigated the efficacy of Ven + R-CHOP in all first-line (1L) DLBCL pts, by BCL2 immunohistochemistry (IHC) status within cell-of-origin (COO) subtypes, by BCL2 fluorescence in situ hybridization (FISH) and in DE and DH pts, with the intent to compare against a matched pt population in the R-CHOP arm of the GOYA Phase III study. Here we report the first safety, efficacy and biomarker analyses in all pts from this ongoing Phase II study. Methods: Eligible pts (age ≥18 yrs; Eastern Cooperative Oncology Group performance status ≤2; 1L DLBCL; International Prognostic Index score 2-5; ≥1 measurable lesion >1.5cm) were assigned to receive six 3-weekly cycles of R-CHOP + 800mg Ven daily for 10 days (Days 1-10, except Cycle 1: Days 4-10), followed by two 3-weekly cycles of 800mg Ven on Days 1-10 + R on Day 1. The primary endpoint was PET-CT response 6-8 weeks after the last R dose (EoT), according to a modified version of Lugano 2014 criteria. Secondary endpoints were progression-free survival (PFS) and safety. Biomarker analyses in CAVALLI and GOYA were performed in pre-treatment tumor samples including a BCL2 IHC assay (cutoff: 50% medium/high expression), MYC IHC assay (cutoff 40% signal), BCL2 and MYC FISH, and COO assay (Nanostring). Results: 211 pts were enrolled; 208 received any treatment and were included in efficacy and safety analyses. Overall, pt characteristics were similar for CAVALLI and GOYA, except CAVALLI enrolled more Ann Arbor Stage IV (65.4% vs 47.1%) and BCL2 IHC-positive pts (57.7% vs 50.0%). The EoT complete response rate in all pts did not differ significantly between CAVALLI and GOYA (69.2% vs 62.8%, respectively; Table 1), but was improved in BCL2-positive subgroups, specifically in BCL2 FISH-positive (70.0% vs 47.5%) and DH (71.4% vs 25.0%) pts. With 20 months' median follow-up in CAVALLI, disease progression and death had occurred in 29 and 6 pts, respectively. When compared with GOYA and adjusted for baseline covariates by Cox methodology, PFS improvement was observed in BCL2 IHC-positive pts (HR, 0.53; 95% CI: 0.30-0.93), including within both activated B-cell (ABC; HR, 0.43; 95% CI: 0.19-0.94) and germinal center B-cell (GCB; HR, 0.41; 95% CI: 0.17-0.95) COO subgroups. No PFS benefit was observed in BCL2 IHC-negative GCB pts; the BCL2 IHC-negative ABC subgroup was too small for evaluation (Figure 1). Grade 3-4 adverse events (AEs) occurred in 85% (176/208) of pts in CAVALLI versus 66% (373/574) in GOYA; the majority were cytopenias, infections and febrile neutropenia (Table 2). In CAVALLI, 1% (3/208) of AEs were fatal versus 5% (30/564) in GOYA but follow-up was longer in GOYA (57 vs 20 months). The higher rate of AEs in CAVALLI led to dose interruptions/discontinuations of both Ven and R-CHOP; 61% of pts had >90% relative dose intensity (RDI) of Ven; 73.2% of CAVALLI pts had >90% RDI of each of doxorubicin and cyclophosphamide versus 76.4% for doxorubicin and 77.6% for cyclophosphamide in GOYA. There were no major differences in grade 3-4 AEs or the RDI of R-CHOP across intention-to-treat and BCL2-positive subgroups. GCSF prophylaxis was recommended, but not uniformly delivered. Conclusions: The addition of Ven to R-CHOP in 1L DLBCL treatment resulted in improved efficacy in BCL2 IHC-positive pts compared with matched GOYA controls. Higher rates of cytopenia, infection and febrile neutropenia were observed in CAVALLI versus the R-CHOP arm in GOYA. These data further support exploration of Ven + R-CHOP in a high-risk population of BCL2-positive 1L DLBCL, including DH pts. Disclosures Morschhauser: Epizyme: Consultancy; Servier: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Feugier:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Flinn:Agios: Research Funding; Verastem: Research Funding; Celgene: Research Funding; Pharmacyclics: Research Funding; Merck: Research Funding; ArQule: Research Funding; Constellation: Research Funding; Curis: Research Funding; Genentech: Research Funding; Forma: Research Funding; Novartis: Research Funding; BeiGene: Research Funding; Pfizer: Research Funding; Forty Seven: Research Funding; TG Therapeutics: Research Funding; Portola: Research Funding; Calithera: Research Funding; Seattle Genetics: Research Funding; Verastem: Consultancy, Research Funding; Trillium: Research Funding; Gilead: Research Funding; Incyte: Research Funding; Infinity: Research Funding; Janssen: Research Funding; Kite: Research Funding; Takeda: Research Funding. Gasiorowski:Novartis: Honoraria; MSD: Honoraria. Greil:Astra Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; MSD: Honoraria, Research Funding; Sandoz: Honoraria, Research Funding; Amgen: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Illés:Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. Johnson:Merck: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Other: travel, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Seattle Genetics: Honoraria; Lundbeck: Consultancy, Honoraria, Other: travel, Research Funding; AbbVie Inc.: Consultancy, Honoraria, Research Funding. Lugtenburg:Genmab: Consultancy; Squibb: Consultancy; Takeda: Consultancy, Research Funding; Celgene: Consultancy; Sandoz: Consultancy; Bristol-Meyers: Consultancy; Servier: Consultancy, Research Funding; Roche: Consultancy. Salles:BMS: Honoraria, Other: Advisory Board; Servier: Honoraria, Other: Advisory Board; Servier: Honoraria; Celgene: Honoraria, Other: Advisory Board, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Epizyme: Honoraria; Morphosys: Honoraria; Abbvie: Honoraria; Acerta: Honoraria; Amgen: Honoraria; Novartis: Consultancy, Honoraria; Takeda: Honoraria; Merck: Honoraria; Pfizer: Honoraria; Janssen: Honoraria, Other: Advisory Board; Gilead: Honoraria, Other: Advisory Board. Trněný:Morphosys: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; F. Hoffman-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Gilead: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Sandoz: Honoraria; Abbvie: Honoraria, Research Funding. Mir:F. Hoffmann-La Roche: Employment. Kornacker:F. Hoffmann-La Roche Ltd: Employment. Punnoose:Roche: Equity Ownership; Genentech Inc: Employment. Samineni:Genentech Inc: Employment, Other: Ownership interests non-PLC. Szafer-Glusman:F. Hoffmann-La Roche Ltd: Employment, Other: Ownership interests PLC. Petrich:Abbvie: Employment, Other: Ownership interests PLC. Sinha:F. Hoffmann-La Roche Ltd: Employment. Mobasher:Genentech Inc: Employment; F. Hoffmann-La Roche Ltd: Other: Ownership interests non-PLC. Zelenetz:Celgene: Consultancy; Abbvie: Research Funding; Gilead: Consultancy, Research Funding; AstraZeneca: Consultancy; Genentech/Roche: Consultancy, Research Funding; Novartis/Sandoz: Consultancy; Amgen: Consultancy.

2529 Background: MSLN is a tumor antigen over-expressed in PC and OC. The ADC DMOT4039A is a humanized IgG1 anti-MSLN monoclonal antibody and anti-mitotic agent, MMAE, that shows anti-proliferative...

Human immunodeficiency virus (HIV) protease inhibitors (PIs) produce profound and unpredictable drug-drug interactions (DDIs) that cannot be explained fully by their inhibition/inactivation of CYP3A enzymes. Delineating and quantifying the CYPs and transporters inducible by PIs are crucial in developing an integrative mechanistic understanding and prediction of PI-based DDIs. To do so, two LC-MS/MS cocktail assays were modified and validated simultaneously to quantify the CYP activity of CYP3A, 2B6, 2C8, 2C9, 2C19, 1A, 2E1, 2A6 and 2D6 enzymes. These new assays were applied to evaluate the induction potential of eight PIs in microsomes isolated from PI-treated human hepatocytes. The mRNA expression of these CYPs and transporters (OATP1B1, OATP1B3, OATP1A2, MDR1, MRP2 and MRP4) was also evaluated using relative RT-PCR. The majority of PIs were net inducers of CYP3As and 2B6 at both the mRNA and activity level (2-fold), while ritonavir, saquinavir, nelfinavir or lopinavir did not induce CYP3A activity (2-fold), presumably due to CYP3A inactivation. OATP1B1 and MDR1 were the only two hepatic transporters induced (2-fold) by the PIs. Amprenavir was the most potent net inducer. In conclusion, our validated cocktail assays can be implemented to comprehensively quantify CYP activities in human liver microsomes and hepatocyte studies. The results also provide the much needed data on the net induction potential of the PIs for hepatic CYPs and transporters. A qualitative agreement was observed between our results and published PI-based DDIs, suggesting that human hepatocytes are a useful platform for more extensive and quantitative in vitro-in vivo prediction of PI-based DDIs.

To investigate recombinant human TIMP-1 ((125)I-rhTIMP-1) half-life in blood and its distribution in rat brain tissue after cerebral ischemia/reperfusion as part of a therapeutic development paradigm.A suture model of the middle cerebral artery occlusion was used. (125)I-labeled rhTIMP-1 at 60 μg/kg (11.23 μCi/μg) was administered to rats intravenously at the beginning of reperfusion. Blood and brain tissue were collected. The radioactivity was detected with a gamma counter and analyzed by autoradiography.The blood half-life T(1/2) of (125)I-rhTIMP-1 was 42.2 hours. Thirty minutes after (125)I-rhTIMP-1 administration, an increased accumulation of (125)I-rhTIMP-1 in the ischemic hemisphere was observed. The maximum brain tissue concentration C(max) was 26.1 ng/g at 1.5 hours in the striatum and 13.9 ng/g at 5 hours in the cortex when the uptake percentage of brain tissue to blood was 6.1±0.4 and 6.7±2.1%, respectively. The cortex and striatum elimination half-lives T(1/2) were 45.3 and 39.2 hours, respectively. Electrophoretic analysis of ischemic samples for (125)I-rhTIMP-1 showed a clear 28 kDa band 1.5 hours after (125)I-rhTIMP-1 administration in the cortex and striatum. The intensity of the 28 kDa band decreased after 3.0 hours of the administration. Some (125)I-rhTIMP-1 maintained its molecular integrity for 8.5 hours in ischemic striatum after reperfusion.(125)I-labeled rhTIMP-1 was distributed quickly into ischemic brain tissue and had a slow elimination in both blood and brain tissue. These results, along with other studies suggesting therapeutic benefits, will aid in the development of TIMP-1 for protecting ischemic stroke.

Dyslipidemia is common among HIV-infected patients receiving antiretroviral therapy. A higher risk of coronary heart disease (CHD) is associated with specific antiretroviral medications. The aging of HIV infected people and the intersection of other CHD risk factors have led to the need for developing effective interventions to lower the risk of CHD events.The authors review current literature on the use of fenofibrate and related derivatives in HIV-infected people with dyslipidemia using antiretroviral therapy.Fibrates have been demonstrated to reduce the risk of CHD events in HIV seronegative individuals with mixed results on survival benefits. There are no published studies of CHD outcomes using fibrates in people with HIV infection. Several studies conducted in HIV infected people demonstrate the ability of fenofibrate to lower triglycerides and increase high-density lipoprotein cholesterol levels with few adverse events. The authors review the pharmacology and clinical efficacy/safety of the use of fenofibrate in people with HIV infection.Fenofibrate is a generally safe and useful agent for the treatment of mixed dyslipidemia and hypertriglyceridemia in people with HIV infection though limited data are available particularly on clinical outcomes.