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Recombinant interleukin (IL)-18 (SB-485232) is an immunostimulatory cytokine, with shown antitumor activity in combination with pegylated liposomal doxorubicin (PLD) in preclinical models. This phase I study evaluated the safety, tolerability, and biologic activity of SB-485232 administered in combination with PLD in subjects with recurrent ovarian cancer. The protocol comprised four cycles of PLD (40 mg/m2) on day 1 every 28 days, in combination with SB-485232 at increasing doses (1, 3, 10, 30, and 100 μg/kg) on days 2 and 9 of each cycle, to be administered over five subject cohorts, followed by discretionary PLD monotherapy. Sixteen subjects were enrolled. One subject withdrew due to PLD hypersensitivity. Most subjects (82%) were platinum-resistant or refractory, and had received a median of three or more prior chemotherapy regimens. SB-485232 up to 100 μg/kg with PLD had an acceptable safety profile. Common drug-related adverse events were grade 1 or 2 (no grade 4 or 5 adverse events). Concomitant PLD administration did not attenuate the biologic activity of IL-18, with maximal SB-485232 biologic activity already observed at 3 μg/kg. Ten of 16 enrolled subjects (63%) completed treatment, whereas five (31%) subjects progressed on treatment. A 6% partial objective response rate and a 38% stable disease rate were observed. We provide pilot data suggesting that SB-485232 at the 3 μg/kg dose level in combination with PLD is safe and biologically active. This combination warrants further study in a phase II trial. Cancer Immunol Res; 1(3); 168–78. ©2013 AACR.

5039 Background: Standard-of-care (SOC) chemotherapy may contribute to immunosuppression by elevating intratumoral levels of adenosine, activating the A2a and A2b receptors on immune cells. Extracellular adenosine is primarily produced by the enzyme CD73; in prostate cancer, additional adenosine is also produced by the highly expressed protein, prostatic acid phosphatase (PAP). Etrumadenant (etruma) is an orally bioavailable, small-molecule, selective dual adenosine receptor antagonist and has been well tolerated in dose escalation studies as monotherapy or combined with chemo/immunotherapy. Adenosine axis inhibition combined with SOC regimens and/or immunotherapy may have a synergistic effect on the induction of sustained antitumor immunity against mCRPC. Initial results from the etruma + zimberelimab (zim; anti–PD-1 mAb) + docetaxel (doc) arm are presented herein. Methods: ARC-6 (NCT04381832) is an ongoing, phase 1b/2, open-label, multicohort platform study to evaluate efficacy and safety of etruma combination therapy. All eligible patients (pts) have mCRPC that has progressed on androgen deprivation therapy and are checkpoint inhibitor-naive; additionally, for this arm, pts must be androgen signaling inhibitor (ASI)-experienced and taxane-naive. Study pts receive 150 mg etruma orally once daily + 360 mg zim IV every 3 weeks + SOC doc (EZD). The primary objectives are to evaluate safety and antitumor activity (prostate-specific antigen [PSA], radiographic, and composite response rates) of EZD. PSA levels are assessed every 3 weeks, and radiographic scans are performed every 12 weeks. PSA response-evaluable pts have baseline (BL) + ≥2 consecutive post-BL PSA assessments; radiographic response-evaluable pts have RECIST measurable or non-measurable disease per BL imaging + ≥1 post-BL radiographic assessment. Results: As of 22Jan2021, 17 pts have received EZD in phase 1b; 14 are PSA response-evaluable and 8 are radiographic response-evaluable. 15 (88%) pts reported treatment emergent adverse events (TEAEs); the most common ( > 30%) were lymphocyte count decreased and neutrophil count decreased (7 pts each; 41%), and hyponatremia and alopecia (6 pts each; 35%). Grade ≥3 treatment-related TEAEs were reported by 9 pts (53%). As of 22Jan2021, 16 pts were continuing treatment; median time on EZD for all pts was 9.9 weeks (0.1–27.4+ weeks). In response-evaluable pts, PSA response rate was 36% (5/14), radiographic response rate was 38% (3/8; 1 CR), and the composite response rate was 43% (6/14). Conclusions: Phase 1b results indicate that EZD treatment in pts with mCRPC had a manageable safety profile and was associated with clinical benefit. Having met phase 2 advancement criteria, randomized pt enrollment to EZD vs. doc is ongoing. Clinical trial information: NCT04381832.

Background: The release of ATP from dying cancer cells in response to platinum-based chemotherapy increases extracellular immunosuppressive adenosine (A), which binds to and activates the A2a and A2b receptors on immune cells resulting in an ineffective anti-tumor immune response. Concomitant adenosine receptor blockade may therefore enhance the therapeutic efficacy of some chemotherapeutic agents. AB928, the first clinical-stage small molecule dual adenosine receptor antagonist, is highly potent, pharmacodynamically active, and has been well tolerated in dose escalation studies as a single agent or in combination with chemo/immunotherapy. Methods: ARC-3 (NCT03720678) is a Phase 1/1b, open-label study in participants (pts) with advanced CRC. Phase 1 escalation identified AB928 150 mg orally once daily as the recommended dose in combination with standard mFOLFOX-6. Phase 1b expansion is ongoing and includes at least 15 and up to 40 pts. Eligible pts must have unresectable or mCRC, ECOG performance status 0-1, and at least one RECIST measurable lesion. Phase 1 eligibility included up to 5 lines of prior therapy; Phase 1b is similarly scoped. Exploratory biomarker analyses include immunohistochemistry of the adenosine axis, tumoral next gene sequencing, and tumor/blood immune correlates. Results: As of 27Dec19, 21 pts received AB928 150 mg + mFOLFOX-6: 7 in Phase 1 and 14 in Phase 1b. All previously treated pts (n=12) were FOLFOX- and/or FOLFIRI-experienced. Prior metastatic therapies range from 3 to 5 in Phase 1 escalation and 0 to 3 in Phase 1b expansion. Adverse events (AEs) reported in >30% of pts included fatigue, diarrhea, and thrombocytopenia. AEs related to AB928 occurred in 13 pts and were mostly mild to moderate. AB928-related Grade 3 AEs reported by 3 pts were diarrhea, AST increase, and neutropenia; there were no Grade 4-5 AB928-related AEs. Out of 15 evaluable pts, by investigator assessment, the disease control rate was 100% with 2 partial responses (13%; 1 confirmed, 1 pending confirmation) and 13 stable disease (87%). Of pts with stable disease, 6/13 (46%) had tumor shrinkage >15%. Median time on treatment was 15.4 (range: 1.7 - 40.6+) and 11.9 (range: 2.7 - 15.7+) weeks for Phase 1 and Phase 1b, respectively, with initiation of Phase 1b dosing on 09Sep19. Enrollment up to 40 pts is proceeding based on early efficacy gates; 15 pts are currently receiving study treatment. Conclusions: AB928 with mFOLFOX-6 has been well tolerated without significant evidence of additive toxicity in pts with mCRC. Combination treatment was associated with disease control in all evaluable pts, including those with microsatellite stable and RAS/BRAF mutated mCRC. Additional updates on the safety, clinical activity, and correlative biomarker results for all escalation/expansion pts will be presented. Citation Format: Michael Cecchini, Manuel Modiano, Fadi Braiteh, Olivia S. Gardner, Houston N. Gilbert, Daniel DiRenzo, Lisa Seitz, Matt J. Walters, Fangfang Yin, Rachel Woloski, Melissa C. Paoloni, Ki Y. Chung. Efficacy and safety of AB928 plus modified FOLFOX-6 (mFOLFOX-6) in participants with metastatic colorectal cancer (mCRC): Initial results at the recommended dose for expansion (ARC-3) [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 LB-387.

e21659 Background: Adenosine, derived from ATP released by dying cancer cells in response to chemotherapy, binds to and activates the A2a and A2b receptors on immune cells, resulting in an ineffective anti-tumor immune response. Adenosine receptor blockade may therefore enhance the efficacy of chemotherapy when co-administered with a checkpoint inhibitor. AB928, the first clinical-stage small molecule dual A2aR/ A2bR antagonist, is highly potent and was well tolerated in dose escalation studies as a single agent or in combination with chemo/immunotherapy. Methods: ARC-4 (NCT03846310) is a Phase 1/1b, open-label study in participants (pts) with metastatic, locally advanced, or recurrent non-squamous NSCLC with no alternative or curative therapy option. Pts whose tumor has a genetic alteration for which targeted therapy exists must be chemo/immunotherapy naïve. Pts must have ECOG PS 0-1 and at least one measurable lesion. Two escalating doses of AB928 (75 or 150 mg) administered orally daily were given with standard doses of carboplatin, pemetrexed and pembrolizumab. Results: As of 27Dec19, 7 pts have received AB928 in Ph 1: 75 mg (n = 3), 150 mg (n = 4). Number of prior therapies range from 0 to 6 (median = 3). Most treatment emergent AEs (TEAEs) were Grade 1 or 2, with no Grade 5 events. The most common AEs were anemia, nausea and AST elevation. One pt experienced an SAE (Gr4 thrombocytopenia) that was at least possibly related to AB928. One pt discontinued before assessment due to adverse event (muscle weakness). Of the 6 patients with post-baseline disease assessments, all demonstrated decrease size of target lesion. Three patients (43%) achieved a confirmed partial response: one treatment naïve patient, one patient with EGFRmut disease that had previously progressed on treatment with erlotinib and osimertinib, and one patient who had progressed on therapy with ipilimumab and nivolumab. One additional pt had a > 30% decrease in target lesions and findings consistent with new lesions but opted to continue study treatment. Conclusions: Addition of AB928 to carboplatin, pemetrexed and pembrolizumab did not significantly add to the established safety profile of the standard agents. Combination treatment was associated with disease control in all evaluable pts, including responses in those with PD after TKI and immunotherapy. Expansion is on-going in pts with EGFRmut NSCLC that has failed treatment with TKI. Additional updates on the safety, clinical activity, and correlative biomarker results will be presented. Clinical trial information: 03846310.

TPS272 Background: The tumor microenvironment contains high levels of immunosuppressive adenosine, which binds to and activates the A2a and A2b receptors (R) on immune cells, resulting in an ineffective anti-tumor immune response. Extracellular adenosine is primarily produced by the enzyme CD73. In prostate cancer (PC), the activity of prostatic acid phosphatase produces additional adenosine. AB928 is the first clinical-stage small molecule dual antagonist of both A2aR and A2bR, which is highly potent, pharmacodynamically active, and has been well tolerated in dose escalation studies as a single agent or in combination with chemo/immunotherapy. Targeting the adenosine pathway in combination with standard of care regimens may have a more profound effect on activating and inducing sustained anti-tumor immunity. Methods: This Phase 1b/2, open-label, multi-cohort platform study will evaluate the efficacy and safety of AB928 combination therapy in participants with metastatic castrate resistant PC (mCRPC). Each cohort will independently assess AB928 plus AB122 (anti-PD-1 antibody) in combination with standard of care (SOC; enzalutamide, docetaxel) or AB928 plus AB680 (CD73 inhibitor) with or without AB122. Cohort eligibility is informed by prior treatment history. In Ph1b, up to 15 participants will receive investigational products at the single-agent recommended dose with SOC per label guidance. Provided safety and activity stopping criteria are not met, further accrual will proceed in Ph2 and, depending on treatment cohort, may involve randomization to enzalutamide or docetaxel; crossover to experimental therapy will be allowed following progression on control treatment. Investigator-assessed antitumor response (radiologic, prostate specific antigen) will follow PCWG3 criteria. Conclusions: This Ph1b/2 study is the first to target the adenosine axis using a dual A2aR/A2bR antagonist (AB928) together with a small molecule CD73 inhibitor (AB680), anti-PD-1 antibody (AB122), and SOC for mCRPC. Study enrollment is proceeding in the United States; results will be shared in upcoming scientific conferences.

2536 Background: Cell-surface protein PSCA is upregulated in many solid tumors and correlates with disease stage. BPX-601, an autologous T-cell product expressing a PSCA-CD3ζ CAR and a rimiducid (Rim)-inducible MyD88/CD40 co-activation switch to augment T-cell proliferation and persistence, is designed to have enhanced efficacy in solid tumors vs traditional CARs. This ongoing first-in-human study assesses safety, biologic, and clinical activity of BPX-601+Rim in PSCA+ cancers. Updated results, including those from patients (pts) who underwent LD with Flu/Cy, are presented. Methods: BP-012 is a 2-part, open-label trial. Part 1 is a 3+3 dose escalation of BPX-601 (1.25–5.0x106 cells/kg; Day [D] 0) given prior to a single, fixed Rim dose (0.4 mg/kg; D7) in pts with previously treated PSCA+ metastatic pancreatic, gastric, or prostate cancers with measurable disease. Results: As of Jan-22-2019, 15 pts have received BPX-601±Rim. Two pts at the highest cell dose received Flu/Cy for LD on D−5 to D−3 before BPX-601; LD after Flu/Cy was 96.6% and 84.3%. Thirteen pts received Cy alone on D−3; in these pts, LD ranged from 0–68.6%. Rapid cell expansion by D4 was observed in all pts with peak vector copy number 8.3-fold higher with Flu/Cy (n = 2) vs Cy LD (n = 13). Serum IP-10, IL-6 and TNFα increased > 2-fold from baseline in ≥1 pt in all Rim cohorts, with 3- to 20-fold Rim-dependent cell expansion in 6 pts. No CRS or DLTs were reported. After Rim, one Flu/Cy pt experienced a serious Grade 2 AE (encephalopathy) related to BPX-601+Rim that resolved with IV steroids; despite time-matched nonserious Grade 1 pyrexia, the pt had no other CRS symptoms. After BPX-601+Rim and ≥1 scan, best responses were 8 SD and 3 PD (1 non-evaluable). With a median follow-up of 9.8 wks, time to next treatment (tx) after BPX-601 ranged from 2.7–22.1 wks (n = 8) and ongoing tx-free intervals range from 9.1–30.1 wks (n = 4). Conclusions: BPX-601+Rim was well-tolerated with manageable safety and early evidence of enhanced CAR T-cell expansion and prolonged persistence after Flu/Cy vs Cy. Additional pts will undergo Flu/Cy LD prior to BPX-601 with single- and repeat-dose Rim. Clinical trial information: NCT02744287.

283 Background: PSCA, a cell surface protein, is upregulated in many solid tumors and correlates with disease stage. BPX601 is an autologous, T-cell product engineered to contain a PSCA-CD3ζ CAR plus the small molecule rimiducid (Rim)-inducible MyD88/CD40 costimulatory domain. BPX601 is optimized for antigen-directed and independent T cell activation, proliferation and persistence, potentially enhancing efficacy in solid tumors versus traditional CARs. This first-in-human study assesses the safety, biological and clinical activity of BPX601 plus Rim in select PSCA-positive cancers. Methods: NCT02744287 is a two-part, open-label trial. Part 1 is an ongoing 3+3 cell dose escalation to identify the recommended BPX601 cell dose (Day 0) given in combination with a fixed, single Rim dose (0.4 mg/kg; Day 7). Eligibility criteria include previously treated metastatic pancreatic cancer (mPDAC) with measurable disease & positive PSCA expression. Results: Patients received only cyclophosphamide (CTX) for lymphodepletion (LD) within three days before BPX601 infusion. Nine adults have been treated across three cell dose levels (cells/kg): 1.25x106 (cells only), 1.25x106+Rim, 2.5x106+Rim. All had mPDAC with ≥ two prior therapies. Common AEs were fatigue and nausea. No DLTs, related SAEs, neurotoxicity or CRS events were reported. Rapid cell engraftment by Day 4 was observed in all patients. No evidence of LD with CTX was seen. Of six patients that received Rim: two had cell expansion 10- to 20-fold within seven days; two had cell persistence > three weeks; all had elevated serum cytokines (IP-10, TNFα) correlated with cell expansion. Best response after ≥ one scan was 4 SD ≥ eight weeks with two minor responses (not confirmed; one patient had matched CA19-9 decrease) and 2 PD. Disease control without new therapy was 16 and > 11 weeks (ongoing) in one and two patients, respectively. Conclusions: BPX601 with single-dose Rim was well-tolerated and resulted in enhanced T cell expansion and prolonged persistence in some patients despite lack of LD. Evidence of clinical benefit in this heavily pretreated mPDAC population was seen. Part 2 is planned to open soon and will include CTX/fludarabine LD to maximize engraftment as well as gastric and prostate cancers. Clinical trial information: NCT02744287.

Interleukin-18 (IL-18) is an immunostimulatory cytokine with antitumor activity in preclinical models. Rituximab is a CD20 monoclonal antibody with activity against human B cell lymphomas. A phase I study of recombinant human (rh) IL-18 given with rituximab was performed in patients with CD20+ lymphoma. Cohorts of 3–4 patients were given infusions of rituximab 375 mg/m2 weekly for 4 weeks with escalating doses of rhIL-18 as a 2-hour intravenous infusion weekly for 12 consecutive weeks. Toxicities were graded using standard criteria. Blood samples were obtained for safety, pharmacokinetic, and pharmacodynamic studies. Nineteen patients with CD20+ B cell non-Hodgkin's lymphoma were given rituximab in combination with rhIL-18 at doses of 1, 3, 10, 20, 30, and 100 μg/kg. Common side effects included chills, fever, headache, and nausea. Common laboratory abnormalities included transient, asymptomatic lymphopenia, hyperglycemia, anemia, hypoalbuminemia, and bilirubin and liver enzyme elevations. No dose-limiting toxicities were observed. Biologic effects of rhIL-18 included transient lymphopenia and increased expression of activation antigens on lymphocytes. Increases in serum concentrations of IFN-γ, GM-CSF, and chemokines were observed following dosing. Objective tumor responses were seen in 5 patients, including 2 complete and 3 partial responses. rhIL-18 can be given in biologically active doses by weekly infusions in combination with rituximab to patients with lymphoma. A maximum tolerated dose of rhIL-18 plus rituximab was not determined. Further studies of rhIL-18 and CD20 monoclonal antibodies in B cell malignancies are warranted.

© 2016 International Association for the Study of Lung Cancer Objectives This two-part study evaluated trametinib, a MEK1/2 inhibitor, in combination with anticancer agents. Inhibition of MEK, a downstream effector of KRAS, demonstrated preclinical synergy with chemotherapy in KRAS-mutant NSCLC cell lines. Part 1 of this study identified recommended phase 2 doses of trametinib combinations. Part 2, reported herein, evaluated the safety, tolerability, pharmacokinetics, and efficacy of trametinib combinations in patients with NSCLC with and without KRAS mutations. Methods Phase 1b evaluated trametinib plus docetaxel with growth factor support (trametinib, 2.0 mg once daily, and docetaxel, 75 mg/m2 every 3 weeks) or pemetrexed (trametinib, 1.5 mg once daily, and pemetrexed, 500 mg/m2 every 3 weeks). Eligibility criteria for the expansion cohorts included metastatic NSCLC with measurable disease, known KRAS mutation status, Eastern Cooperative Oncology Group performance status of 1 or lower, and no more than two prior regimens. Results The primary end point of overall response rate (ORR) was met for both combinations. A confirmed partial response (PR) was observed in 10 of the 47 patients with NSCLC who received trametinib plus docetaxel (21%). The ORR was 18% (four PRs in 22 patients) in those with KRAS wild-type NSCLC versus 24% (six PRs in 25 patients) in those with KRAS-mutant NSCLC. Of the 42 patients with NSCLC treated with trametinib plus pemetrexed, six (14%) had a PR; the ORR was 17% (four of 23) in patients with KRAS-mutated NSCLC versus 11% (two of 19) in KRAS wild-type NSCLC. Adverse events—most commonly diarrhea, nausea, and fatigue—were manageable. Conclusions Trametinib-plus-chemotherapy combinations were tolerable. Clinical activity exceeding the ORRs previously reported with docetaxel or pemetrexed alone in KRAS-mutated NSCLC and meeting prespecified criteria was observed.

The immune checkpoint CTLA-4 can be targeted with antibodies that are applied as single agent therapy or in combination with other therapies including surgery, radiation and chemotherapy. Anti-CTLA-4 antibodies may also augment other immunotherapies. Indeed, in syngeneic mouse tumor models anti-CTLA-4 strongly enhanced anti-tumor efficacy of live, attenuated double-deleted Listeria monocytogenes (LADD) and of the STING pathway activator ADU-S100. Anti-CTLA-4 therapy has shown clinical activity and durable responses in advanced cancers, but is also associated with severe immune-related adverse events (irAEs), although manageable and reversible. Local anti-CTLA4 application could limit the induction of irAEs while retaining its capacity to induce and enhance tumor-specific T cell responses. Here we present the results from the preclinical development of ADU-1604, a novel hIgG1 anti-CTLA-4 antibody. ADU-1604 binds a unique epitope on human CTLA-4 and was extensively characterized in vitro demonstrating potent CTLA-4 binding and blockade of CD80 and CD86 and its capability to enhance human T cell responses. As the antibody cross-recognizes CTLA-4 of cynomolgus monkeys this species was selected for the preclinical studies. Male animals received a single intravenous dose of the antibody to assess its pharmacokinetics and pharmacodynamics. ADU-1604 was well tolerated and showed an acceptable half-life. The antibody also enhanced the T cell-dependent antibody response in hepatitis B surface antigen immunized animals. After the single dose PK study a GLP 4-week repeat-dose toxicity study was conducted in cynomolgus monkeys administered 5 doses of ADU-1604 intravenously once a week followed by an 8-week recovery period. In general, ADU-1604 was well tolerated at up to 30 mg/kg/dose. Histopathology data is being processed and recovery data is pending. Proof of concept for the local administration of anti-CTLA-4 antibodies was conducted in syngeneic mouse models with the mouse CTLA-4 antibody 9D9 and in NSCLC humanized PDX models using ADU-1604 in the context of CD45+ human immune cells. These models demonstrated anti-tumor activity of systemically applied ADU-1604, comparable to a reference anti-CTLA-4 antibody. Intratumoral application of ADU-1604 in these models also induced tumor growth inhibition In conclusion, the preclinical development package warrants clinical investigation of ADU-1604 as monotherapy and for future combinations with other Aduro proprietary platforms including STING agonists and (p)LADD. Currently ADU-1604 is progressing through regulatory filing in preparation of clinical development. Citation Format: Maaike Hendriks, Joost Kreijtz, Paul Vink, David Lutje Hulsik, Imke Lodewijks, Astrid Bertens, Jos van de Crommert, Maurice Habraken, Wout Janssen, Judith Stammen-Vogelzang, Olivia Gardner, Weiwen Deng, Meredith Leong, Sarah McWhirter, Hans van Eenennaam, Andrea van Elsas. Assessment of pharmacology and toxicology of anti-CTLA-4 antibody (ADU-1604) in non-human primates and evaluation of local anti-CTLA-4 application [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1702.

To characterize the pharmacokinetics of oral trametinib, a first in class MEK inhibitor, identify covariates, and describe the relationship between exposure and clinical effects in patients with BRAF V600 metastatic melanoma. Trametinib concentrations obtained in three clinical studies were included in the population pharmacokinetic analysis. Trametinib 2 mg once daily was administered in the Phase 2 and 3 studies. The impact of exposure [trough (C min) or average concentration] on response rates and progression-free survival (PFS) was examined. Plasma concentrations (n = 3120) obtained in 493 patients were described using a two-compartment model. Trametinib oral clearance was lower in women relative to men (1.26-fold) and increased with body weight. There was no significant effect of age, mild or moderate renal impairment, or mild hepatic impairment on oral clearance. Between-subject variability was low (24 %). The number of responders was consistent across median exposure range, although tended to be lower at trough concentration

Duvortuxizumab (also known as JNJ-64052781 and MGD011) is a bispecific CD19 x CD3 DART® molecule designed to simultaneously target CD19-positive cells for recognition and elimination by CD3-expressing T-lymphocytes as effector cells. Duvortuxizumab is currently in clinical development for the potential treatment of B-cell malignancies. Here we report the results from a translational PK model that utilized duvortuxizumab pharmacokinetic (PK) data from cynomolgus monkeys to predict duvortuxizumab PK in humans. The PK of duvortuxizumab administered by intravenous infusion was evaluated in cynomolgus monkeys in two separate studies. Study 1 evaluated intra-animal escalating doses from 0.5 to 100 µg/kg or repeated doses from 0.005 to 0.5 µg/kg administered over a period of up to 4 weeks. Serum concentrations of duvortuxizumab above the lower limit of quantification were obtained at dose levels >0.5 µg/kg. Study 2 evaluated duvortuxizumab doses of 0.2, 2, 5, or 10 µg/kg administered once weekly for 4 weeks. Dose-proportional increases in maximum concentration (Cmax) were observed across the dose ranges evaluated, and no significant differences between male and female animals were observed. PK modeling analysis, which integrated data from both study 1 and study 2 at 0.2 to 100 µg/kg dose levels, was performed to further understand the PK behavior of duvortuxizumab in cynomolgus monkeys. Duvortuxizumab PK was reasonably characterized using a two compartment model with linear clearance (CL) from the central compartment. Model estimated parameters were CL = 0.797 mL/h/kg; volume of distribution for the central compartment (V1) = 51.7 mL/kg; intercompartmental clearance (Q) = 2.29 mL/h/kg; and volume of distribution for the peripheral compartment (V2) = 88.8 mL/kg. Assuming a body weight of 3 kg and 70 kg for a cynomolgus monkey and a human, respectively, human PK parameters were estimated using an allometric scaling factor of 0.75 for CL and 1.0 for volume in the translational PK model. Observed duvortuxizumab PK values obtained from an ongoing, first-in-human (FIH), phase 1 dose-escalation trial in patients with relapsed or refractory B-cell malignancies (NCT02454270) were used to validate the translational PK model. Comparison of the predicted and observed duvortuxizumab PK profiles suggested that the translational PK model using the allometric scaling method reasonably predicted duvortuxizumab PK profiles in humans at multiple dose levels (15 to 100 ng/kg). In conclusion, the developed translational PK model successfully predicted duvortuxizumab PK in humans and has been used to aid dose escalation of duvortuxizumab in the ongoing FIH study. This work showcases the potential of translational PK modeling in supporting the selection of a FIH dose escalation strategy utilizing preclinical PK information. Citation Format: Xiling Jiang, Hua Li, Jeff Nordstrom, Jennifer Brown, Liqin Liu, Syd Johnson, Ralph Alderson, Pamela L. Clemens, Jacintha Shenton, Imran Khan, Olivia Gardner, Yu-Nien Sun, Weirong Wang. Quantitative prediction of human pharmacokinetics for duvortuxizumab from cynomolgus monkey data: a translational pharmacokinetic modeling approach [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4089. doi:10.1158/1538-7445.AM2017-4089

Recombinant interleukin (IL)-18 (SB-485232) is an immunostimulatory cytokine, with shown antitumor activity in combination with pegylated liposomal doxorubicin (PLD) in preclinical models. This phase I study evaluated the safety, tolerability, and biologic activity of SB-485232 administered in combination with PLD in subjects with recurrent ovarian cancer. The protocol comprised four cycles of PLD (40 mg/m2) on day 1 every 28 days, in combination with SB-485232 at increasing doses (1, 3, 10, 30, and 100 μg/kg) on days 2 and 9 of each cycle, to be administered over five subject cohorts, followed by discretionary PLD monotherapy. Sixteen subjects were enrolled. One subject withdrew due to PLD hypersensitivity. Most subjects (82%) were platinum-resistant or refractory, and had received a median of three or more prior chemotherapy regimens. SB-485232 up to 100 μg/kg with PLD had an acceptable safety profile. Common drug-related adverse events were grade 1 or 2 (no grade 4 or 5 adverse events). Concomitant PLD administration did not attenuate the biologic activity of IL-18, with maximal SB-485232 biologic activity already observed at 3 μg/kg. Ten of 16 enrolled subjects (63%) completed treatment, whereas five (31%) subjects progressed on treatment. A 6% partial objective response rate and a 38% stable disease rate were observed. We provide pilot data suggesting that SB-485232 at the 3 μg/kg dose level in combination with PLD is safe and biologically active. This combination warrants further study in a phase II trial. Cancer Immunol Res; 1(3); 168–78. ©2013 AACR.

Purpose BRAF mutations promote melanoma cell proliferation and survival primarily through activation of MEK. The purpose of this study was to determine the response rate (RR) for the selective, allosteric MEK1/MEK2 inhibitor trametinib (GSK1120212), in patients with metastatic BRAF-mutant melanoma. Patients and Methods This was an open-label, two-stage, phase II study with two cohorts. Patients with metastatic BRAF-mutant melanoma previously treated with a BRAF inhibitor (cohort A) or treated with chemotherapy and/or immunotherapy (BRAF-inhibitor naive; cohort B) were enrolled. Patients received 2 mg of trametinib orally once daily. Results In cohort A (n = 40), there were no confirmed objective responses and 11 patients (28%) with stable disease (SD); the median progression-free survival (PFS) was 1.8 months. In cohort B (n = 57), there was one (2%) complete response, 13 (23%) partial responses (PRs), and 29 patients (51%) with SD (confirmed RR, 25%); the median PFS was 4.0 months. One patient each with BRAF K601E and BRAF V600R had prolonged PR. The most frequent treatment-related adverse events for all patients were skin-related toxicity, nausea, peripheral edema, diarrhea, pruritis, and fatigue. No cutaneous squamous cell carcinoma was observed. Conclusion Trametinib was well tolerated. Significant clinical activity was observed in BRAF-inhibitor–naive patients previously treated with chemotherapy and/or immunotherapy. Minimal clinical activity was observed as sequential therapy in patients previously treated with a BRAF inhibitor. Together, these data suggest that BRAF-inhibitor resistance mechanisms likely confer resistance to MEK-inhibitor monotherapy. These data support further evaluation of trametinib in BRAF-inhibitor–naive BRAF-mutant melanoma, including rarer forms of BRAF-mutant melanoma.

5065 Background: SB-485232, a recombinant human form of interleukin-18 (IL-18), is being studied as a novel cytokine for tumor immunotherapy. IL-18 has been shown to increase the anti-tumor activity of doxorubicin in other cancer mouse models. Methods: This multi-center study enrolled 16 patients (pts), and evaluated four cycles (28 days each) of standard pegylated liposomal doxorubicin (PLD) (40 mg/m2 day 1) in combination with increasing doses of IL-18 (1, 3, 10, 30, and 100 mg/kg) on days 2 and 9 of each cycle with a 1 yr follow-up to further evaluate safety and efficacy. Results: Of the 16 pts, 10 (63%) completed study treatment and 6 (37%) did not because of disease progression (5 pts) and PLD hypersensitivity (1 pt). Thirteen (82%) were platinum resistant/refractory having received a median of > 3 prior lines of therapy. SB-485232 up to 100 mg/kg in combination with PLD had an acceptable safety profile. All 16 pts experienced at least 1 AE including chills (81%), nausea (75%), anemia (63%), fatigue (56%), hyperglycemia, and pyrexia (50% each). Eight of 16 pts had Grade 3 AEs including anemia (19%), and 6% each for abdominal pain, asthenia, dehydration, PLD hypersensitivity, edema, fatigue, hyperglycemia, hyperkalemia, jaundice, pain, nausea, vomiting, and pyelonephritis. There were no grade 4/5 AEs. Four subjects experienced 10 non-fatal SAEs with 3 related to study drug: anemia, PLD hypersensitivity, and cytokine release syndrome. Maximal SB-485232 biological activity, assessed by peripheral blood NK and T cell markers, was observed at 10mg/kg-100mg/kg. This drug combination resulted in a 6% partial response rate (RR) and a 38% stable disease rate using RECIST 1.0. Median (95% CI) time of progression-free survival (PFS) was 4.50 (3.52,--) months. Conclusions: The SB-485232/PLD combination was tolerable with minimal toxicity. These preliminary efficacy data are comparable to the historical RR and PFS observed with PLD monotherapy in platinum-resistant ovarian cancer. However, given the small sample size, this combination warrants further investigation.

3023 Background: Trametinib, an oral MEK1/MEK2 inhibitor, has demonstrated single-agent clinical activity. In vitro studies of trametinib plus docetaxel (doc), pemetrexed (pem) and erlotinib (erl) showed enhanced growth inhibition of lung cancer cell lines with and without RAS/RAF mutations. Trametinib+doc significantly increased apoptosis compared with either agent alone. Methods: This is a two-part, five-arm, phase I/Ib, open-label study to evaluate the safety and tolerability of trametinib plus doc, erl, pem, pem+carboplatin (pem+carbo), or nab-paclitaxel (nab-pac) (NCT01192165). Part I is dose escalation in patients (pts) with advanced solid tumors; part II is dose expansion in pts with lung and pancreatic cancers. A 3+3 dose-escalation design was used to determine the maximum tolerated dose (MTD) and the recommended phase II regimen (RP2R) for each combination. Dose-limiting toxicities (DLTs) were determined during the first treatment cycle (21 days). Trametinib was started at 0.5 mg/day; chemotherapy was given at full recommended doses. Erl was escalated from 50 mg/day. Pharmacokinetic (PK) samples were collected pre-, and 1, 2, 3 and 6 hours post-dose. Results: As of January 2012, 80 pts have been enrolled across all arms except trametinib+nab-pac. Preliminary exposure results of trametinib+doc, erl, or pem suggest no PK drug-drug interaction. The predominant DLT for trametinib+doc without growth factors (MTD = 0.5 mg+60 mg/m2) was neutropenia. When administered with growth factors, trametinib+doc has been given up to 1.5 mg+75 mg/m2 with no DLTs. The predominant DLTs for trametinib+erl (MTD = 1 mg+100 mg) were diarrhea and mucositis and for trametinib+pem (MTD = 1.5 mg+500 mg/m2) were mucositis and febrile neutropenia. The MTD for trametinib+pem+carbo has not yet been determined. To date there are 5 PRs in the trametinib+doc group and 2 PRs in the trametinib+pem group. An NSCLC expansion cohort for trametinib+pem is enrolling. Conclusions: Trametinib+doc and trametinib+pem have shown acceptable tolerability and initial evidence of clinical activity.

Abstract 3697 Background: Iboctadekin (recombinant human interleukin-18; rhIL-18) is an immunostimulatory cytokine with anti-tumor activity in preclinical animal models. Phase I clinical trials have demonstrated that rhIL-18 is well-tolerated as monotherapy for patients with advanced solid tumors. Preclinical and clinical data indicate that rhIL-18 acts a costimulatory cytokine that may be optimally used in combination with other agents such as monoclonal antibodies. Methods: Patients with CD20+ B-cell non-Hodgkin's lymphoma (NHL) were given rituximab 375 mg/m2 IV weekly for 4 consecutive weeks in combination with rhIL-18 (in six dose cohorts of 1, 3, 10, 20, 30, and 100 mcg/kg) IV weekly for 12 weeks. Eligible patients had disease which progressed after standard therapy or for which there was no effective standard treatment. Assessments included safety/tolerability, pharmacokinetics, pharmacodynamics (serum cytokines, peripheral blood phenotypic markers and tumor biomarkers), immunogenicity, and anti-tumor activity. Results: Nineteen patients were enrolled on study (10 follicular NHL, 5 mantle cell lymphoma, 2 diffuse large B-NHL, 2 other subtypes). The combination was well-tolerated with a safety profile similar to that observed with rituximab or rhIL-18 given as monotherapy. The pharmacodynamic response is as expected based on results of prior clinical trials of rhIL-18 as monotherapy for cancer. Using the IWC response criteria, two (11%) of 18 evaluable patients had complete responses (CR) and 3 (16%) had partial responses (PR). Six (33%) patients had stable disease. Overall response rate for follicular lymphoma was 33% (1 CR, 2 PR). Conclusions: The combination of rhIL-18 and rituximab is safe, well-tolerated, and induces potent biological activity. A maximum tolerated dose of rhIL-18 was not identified. Further study of rhIL-18 plus rituximab in patients with CD20+ B cell malignancies is warranted. Disclosures: Bauman: GlaxoSmithKline: Employment, Equity Ownership. Gardner:GlaxoSmithKline: Employment, Equity Ownership. Jonak:GlaxoSmithKline: Employment, Equity Ownership. Struemper:GlaxoSmithKline: Employment, Equity Ownership. Germaschewski:GlaxoSmithKline: Employment, Equity Ownership. Koch:GlaxoSmithKline: Employment, Equity Ownership. Murray:GlaxoSmithKline: Employment, Equity Ownership. Toso:GlaxoSmithKline: Employment, Equity Ownership.

8566 Background: Iboctadekin (rhIL-18) is an immunostimulatory cytokine that has demonstrated anti-tumor activity in several preclinical models. When administered as monotherapy in phase I clinical studies, rhIL-18 was safe, well tolerated and induced potent biological responses (e.g. Th1 cytokine production and expression of activation markers on NK, CD8+ and CD4+ cells). These data affirm the endogenous role of IL-18 as a co-stimulatory cytokine and suggest that its optimal use would be in a combination with other immune modulators such as rituximab. Methods: Patients with CD20+ B cell non-Hodgkin's lymphoma are being given rituximab (375 mg/m2) IV weekly for 4 consecutive weeks in combination with ascending doses of intravenous rhIL-18 (1 to 100 mcg/kg in 6 cohorts of 3 patients each) IV weekly for 12 weeks to identify a dose that is safe and tolerable and gives a maximum biological effect. Eligible patients must have disease which progressed after standard therapy or for which there is no effective standard treatment. Assessments include safety/tolerability, pharmacokinetics, pharmacodynamics (serum cytokines, peripheral blood phenotypic markers and tumor biomarkers), immunogenicity and anti-tumor activity. Results: To date, thirteen subjects have been enrolled in the first four cohorts (1, 3, 10 and 20 mcg /kg of rhIL-18). The combination is well tolerated with a safety profile similar to that observed with rituximab or rhIL-18 monotherapy. The pharmacodynamic response is as expected with a dose-dependent decrease in circulating activated (CD69+) NK cells within 4 hours after completing the rhIL-18 infusion which rebound to pre-dose levels within 2–4 days. Using the International Working Group response criteria for lymphoma, two subjects had complete responses at 10 and 20 mcg/kg, one subject had a partial response at 10 mcg/kg and three subjects had stable disease at 1, 3 and 3 mcg/kg. Conclusions: These data show that the combination of rhIL-18 and rituximab is safe, well tolerated and induces potent biological activity. This study will define the dose level to be used in a future phase II trial evaluating this combination in patients with relapsed or refractory follicular lymphoma. [Table: see text]