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Purpose:Molibresib is a selective, small molecule inhibitor of the bromodomain and extra-terminal (BET) protein family. This was an open-label, two-part, Phase I/II study investigating molibresib monotherapy for the treatment of hematological malignancies (NCT01943851).Patients and Methods:Part 1 (dose escalation) determined the recommended Phase 2 dose (RP2D) of molibresib in patients with acute myeloid leukemia (AML), Non–Hodgkin lymphoma (NHL), or multiple myeloma. Part 2 (dose expansion) investigated the safety and efficacy of molibresib at the RP2D in patients with relapsed/refractory myelodysplastic syndrome (MDS; as well as AML evolved from antecedent MDS) or cutaneous T-cell lymphoma (CTCL). The primary endpoint in Part 1 was safety and the primary endpoint in Part 2 was objective response rate (ORR).Results:There were 111 patients enrolled (87 in Part 1, 24 in Part 2). Molibresib RP2Ds of 75 mg daily (for MDS) and 60 mg daily (for CTCL) were selected. Most common Grade 3+ adverse events included thrombocytopenia (37%), anemia (15%), and febrile neutropenia (15%). Six patients achieved complete responses [3 in Part 1 (2 AML, 1 NHL), 3 in Part 2 (MDS)], and 7 patients achieved partial responses [6 in Part 1 (4 AML, 2 NHL), 1 in Part 2 (MDS)]. The ORRs for Part 1, Part 2, and the total study population were 10% [95% confidence interval (CI), 4.8–18.7], 25% (95% CI, 7.3–52.4), and 13% (95% CI, 6.9–20.6), respectively.Conclusions:While antitumor activity was observed with molibresib, use was limited by gastrointestinal and thrombocytopenia toxicities. Investigations of molibresib as part of combination regimens may be warranted.

Molibresib is an orally bioavailable, selective, small molecule BET protein inhibitor. Results from a first time in human study in solid tumors resulted in the selection of a 75 mg once daily dose of the besylate formulation of molibresib as the recommended Phase 2 dose (RP2D). Here we present the results of Part 2 of this study, investigating safety, pharmacokinetics, pharmacodynamics, and clinical activity of molibresib at the RP2D for nuclear protein in testis carcinoma (NC), small cell lung cancer, castration-resistant prostate cancer (CRPC), triple-negative breast cancer, estrogen receptor-positive breast cancer, and gastrointestinal stromal tumor. The primary safety endpoints were incidence of adverse events (AEs) and serious AEs; the primary efficacy endpoint was overall response rate. Secondary endpoints included plasma concentrations and gene set enrichment analysis (GSEA). Molibresib 75 mg once daily demonstrated no unexpected toxicities. The most common treatment-related AEs (any grade) were thrombocytopenia (64%), nausea (43%), and decreased appetite (37%); 83% of patients required dose interruptions and 29% required dose reductions due to AEs. Anti-tumor activity was observed in NC and CRPC (one confirmed partial response each, with observed reductions in tumor size), although predefined clinically meaningful response rates were not met for any tumor type. Total active moiety median plasma concentrations after single and repeated administration were similar across tumor cohorts. GSEA revealed that gene expression changes with molibresib varied by patient, response status, and tumor type. Investigations into combinatorial approaches that use BET inhibition to eliminate resistance to other targeted therapies are warranted. This article is protected by copyright. All rights reserved.

Purpose:Molibresib is a selective, small molecule inhibitor of the bromodomain and extra-terminal (BET) protein family. This was an open-label, two-part, Phase I/II study investigating molibresib monotherapy for the treatment of hematological malignancies (NCT01943851).Patients and Methods:Part 1 (dose escalation) determined the recommended Phase 2 dose (RP2D) of molibresib in patients with acute myeloid leukemia (AML), Non–Hodgkin lymphoma (NHL), or multiple myeloma. Part 2 (dose expansion) investigated the safety and efficacy of molibresib at the RP2D in patients with relapsed/refractory myelodysplastic syndrome (MDS; as well as AML evolved from antecedent MDS) or cutaneous T-cell lymphoma (CTCL). The primary endpoint in Part 1 was safety and the primary endpoint in Part 2 was objective response rate (ORR).Results:There were 111 patients enrolled (87 in Part 1, 24 in Part 2). Molibresib RP2Ds of 75 mg daily (for MDS) and 60 mg daily (for CTCL) were selected. Most common Grade 3+ adverse events included thrombocytopenia (37%), anemia (15%), and febrile neutropenia (15%). Six patients achieved complete responses [3 in Part 1 (2 AML, 1 NHL), 3 in Part 2 (MDS)], and 7 patients achieved partial responses [6 in Part 1 (4 AML, 2 NHL), 1 in Part 2 (MDS)]. The ORRs for Part 1, Part 2, and the total study population were 10% [95% confidence interval (CI), 4.8–18.7], 25% (95% CI, 7.3–52.4), and 13% (95% CI, 6.9–20.6), respectively.Conclusions:While antitumor activity was observed with molibresib, use was limited by gastrointestinal and thrombocytopenia toxicities. Investigations of molibresib as part of combination regimens may be warranted.

Molibresib (GSK525762), an orally bioavailable small molecule with 2 major equipotent active metabolites, is being developed for the treatment of cancers. Molibresib is a substrate of cytochrome P450 (CYP) 3A4 and P‐glycoprotein (P‐gp). To enable administering safe doses of molibresib to healthy volunteers, this 2‐part randomized, open‐label, crossover drug‐drug interaction trial was conducted as an adaptive design study using physiologically based pharmacokinetic (PBPK) modeling and simulation to predict the lowest doses of molibresib that could be safely administered alone (10 mg) or with itraconazole and rifampicin (strong inhibitors and inducers of CYP3A and P‐gp, respectively). PBPK simulation guided the molibresib dose (5 mg) to be administered along with itraconazole in part 1. Itraconazole increased total exposure (AUC) of molibresib by 4.15‐fold with a 66% increase in Cmax, whereas the total AUC and Cmax for the 2 major active metabolites of molibresib decreased by about 70% and 87%, respectively. A second PBPK simulation was conducted with part 1 data to also include the active metabolites to update the recommendation for the molibresib dose (20 mg) with rifampicin. With rifampicin, the AUC and Cmax of molibresib decreased by approximately 91% and 80%, respectively, whereas the AUC of the 2 active metabolites decreased to a lesser extent (8%), with a 2‐fold increase in Cmax. The results of this study confirmed the in vitro data that molibresib is a substrate for CYP3A4. The adaptive design, including Simcyp simulations, allowed evaluation of 2 drug interactions of an oncology drug in a single trial, thus minimizing time and exposures administered to healthy subjects.

Molibresib is an orally bioavailable, selective, small molecule BET protein inhibitor. Results from a first time in human study in solid tumors resulted in the selection of a 75 mg once daily dose of the besylate formulation of molibresib as the recommended Phase 2 dose (RP2D). Here we present the results of Part 2 of our study, investigating safety, pharmacokinetics, pharmacodynamics and clinical activity of molibresib at the RP2D for nuclear protein in testis carcinoma (NC), small cell lung cancer, castration-resistant prostate cancer (CRPC), triple-negative breast cancer, estrogen receptor-positive breast cancer and gastrointestinal stromal tumor. The primary safety endpoints were incidence of adverse events (AEs) and serious AEs; the primary efficacy endpoint was overall response rate. Secondary endpoints included plasma concentrations and gene set enrichment analysis (GSEA). Molibresib 75 mg once daily demonstrated no unexpected toxicities. The most common treatment-related AEs (any grade) were thrombocytopenia (64%), nausea (43%) and decreased appetite (37%); 83% of patients required dose interruptions and 29% required dose reductions due to AEs. Antitumor activity was observed in NC and CRPC (one confirmed partial response each, with observed reductions in tumor size), although predefined clinically meaningful response rates were not met for any tumor type. Total active moiety median plasma concentrations after single and repeated administration were similar across tumor cohorts. GSEA revealed that gene expression changes with molibresib varied by patient, response status and tumor type. Investigations into combinatorial approaches that use BET inhibition to eliminate resistance to other targeted therapies are warranted.

Belantamab mafodotin is an antibody-drug conjugate comprising a humanized anti-B-cell maturation antigen (BCMA) monoclonal antibody conjugated to monomethyl auristatin F (MMAF) via a protease-resistant maleimidocaproyl linker. Single-agent belantamab mafodotin showed clinically meaningful activity and manageable safety in patients with heavily pretreated relapsed/refractory multiple myeloma (RRMM) in the phase I DREAMM-1 and phase II DREAMM-2 studies and is approved by the US Food and Drug Administration and European Medicines Agency for RRMM treatment. To support monotherapy dose selection, the relationship between Cycle 1 exposure (derived using a population pharmacokinetic model) and clinical response (for multiple efficacy and safety end points) was explored. In DREAMM-2, efficacy end points (probability of response (PoR) and progression-free survival (PFS)) were associated with exposure in univariate evaluation; however, once disease burden factors were included in the model (e.g., baseline soluble BCMA, s2 -microglobulin), exposure was no longer significant. Patients with higher disease burden had lower exposure. In DREAMM-1, belantamab mafodotin exposure was the only variable to correlate with PoR and PFS. Probability of corneal events (keratopathy), but not dry eye or blurred vision, was strongly associated with belantamab mafodotin exposure (DREAMM-2). Higher cys-mcMMAF maximum plasma drug concentration (Cmax ) and lower baseline platelet count were associated with increased probability of thrombocytopenia (DREAMM-1 and DREAMM -2). In general, safety end points were more strongly associated with belantamab mafodotin exposure than efficacy end points, particularly after disease factors and patient characteristics were taken into account. Overall, these findings supported the monotherapy dose recommendation of belantamab mafodotin as 2.5 mg/kg every 3 weeks in patients with RRMM who have received four or more prior therapies.

Molibresib (GSK525762) is an investigational, orally bioavailable, small‐molecule bromodomain and extraterminal (BET) protein inhibitor for the treatment of advanced solid tumors. Molibresib was initially evaluated in a first‐time‐in‐human (FTIH) study BET115521 consisting of two parts: Part 1 of the study (dose escalation) was conducted in 94 patients with nuclear protein in testis midline carcinoma and other solid tumors, and Part 2 (expansion cohort) was conducted in 99 patients with different solid tumor types. Molibresib is metabolized by cytochrome P450 3A4 enzymes to produce two major active metabolites that are equipotent to the parent molecule. The metabolites are measured together after full conversion of one to the other and reported as an active metabolite composite (GSK3529246). The molibresib pharmacokinetic (PK) profile has been characterized by a decrease in exposure over time, with the decrease more pronounced at higher doses, and accompanied by a slight increase of the metabolite concentrations. Autoinduction of molibresib metabolism was suspected and confirmed in vitro. Here we report the development of a semimechanistic liver‐compartment population PK model using PK data from the FTIH study, which adequately describes the autoinduction of molibresib clearance and the PK of both molibresib and GSK3529246. Covariate analysis indicated body weight had a significant effect on the volume of distribution of molibresib and GSK3529246, and higher levels of aspartate aminotransferase resulted in the lower clearance of GSK3529246. This model was used to simulate individual patient exposures based on covariate information for use in future alternative dosing strategies and exposure–response analyses.

Belantamab mafodotin (belamaf) is a BCMA-targeted antibody–drug conjugate recently approved as monotherapy for adults with relapsed/refractory multiple myeloma who have received ≥4 prior therapies. Belamaf binds to BCMA and eliminates myeloma cells by multimodal mechanisms of action. The cytotoxic and potential immunomodulatory properties of belamaf have led to novel combination studies with other anticancer therapies. Here, we describe the rationale and design of DREAMM-5, an ongoing Phase I/II platform study evaluating the safety and efficacy of belamaf combined with novel agents, including GSK3174998 (OX40 agonist), feladilimab (an ICOS; GSK3359609), nirogacestat (a gamma-secretase inhibitor; PF-03084014) and dostarlimab (a PD-1 blocker) versus belamaf monotherapy for patients with relapsed/refractory multiple myeloma.Clinical trial registration: NCT04126200 (ClinicalTrials.gov).

Despite advances in HIV‐1 management with antiretroviral therapy, drug resistance and toxicities with multidrug regimens can result in treatment failure. Hence, there is a continuing demand for antiretroviral agents (ARVs) with novel mechanisms of action. Maturation inhibitors inhibit HIV‐1 replication via a unique mechanism of action and can be combined with other ARVs. Two phase I randomized clinical trials were conducted for a maturation inhibitor, GSK3640254, to determine safety, pharmacokinetics (NCT03231943), and relative bioavailability (NCT03575962) in healthy adults. The first trial was conducted in two parts. Part 1 was conducted in a two‐cohort, interlocking, eight‐period fashion in 20 participants with single ascending doses of GSK3640254 (1‐700 mg) or placebo. In Part 2, 58 participants were randomized to receive GSK3640254 (n = 44) or placebo (n = 14). Four participants reported adverse events (AEs) leading to study discontinuation, with one adverse drug reaction (maculopapular rash). There was no relationship between frequency or severity of AEs and dose. Pharmacokinetic assessments showed that GSK3640254 was slowly absorbed, with time to maximum concentration (tmax) occurring between 3.5 and 4 hours and half‐life of ~24 hours. In the relative bioavailability study of GSK3640254 mesylate salt vs bis‐hydrochloride salt capsules in 14 healthy adults, the mesylate salt performed slightly better than the bis‐hydrochloride formulation (12%‐16% increase in area under the concentration‐time curve and maximum concentration); tmax (5 hours) was similar between the formulations. Initial pharmacokinetic and safety data from these healthy‐participant studies informed further development of GSK3640254 for once‐daily dosing for the treatment of HIV‐1 infection., A comparison of GSK3640254 levels in plasma on Day 14 of multiple‐dose administration showed 1.9‐ to 2.6‐fold accumulation compared with Day 1. Statistical assessment of the attainment of steady state was performed on the trough concentrations from all participants. By Day 8, slope of trough concentration vs time data was close to zero with the 90% CI of the slope containing zero.

8017 Background: Belantamab mafodotin (belamaf; BLENREP) is a B-cell maturation antigen-targeting antibody–drug conjugate approved for patients (pts) with RRMM as monotherapy at 2.5 mg/kg Q3W. Preclinical data demonstrate synergy between belamaf and lenalidomide (Len), suggesting added benefit when combined with standard of care such as Len + dexamethasone (Dex). DREAMM-6 (NCT03544281) Arm A is evaluating belamaf in combination with LenDex in pts with RRMM. Methods: This ongoing, two-part, two-arm, open-label study included pts with RMMM previously treated with ≥1 line of therapy (LOT). Pts received 4 belamaf doses/schedules (1.9 mg/kg Q8W or Q4W; 2.5 mg/kg Q4W or Q4W SPLIT dose [50% on Days (D)1, 8] IV) in combination with Len (20 mg PO D1–21) and Dex (20 mg PO/IV D1, 8, 15, 22). Primary objectives were safety (including treatment-related [TR]AEs related to the combination belamaf and LenDex), tolerability, and efficacy (including overall response rate [ORR] defined as ≥partial response). Results: As of this interim analysis (data cut: July 23, 2021), 45 pts received ≥1 dose (12 at 1.9 mg/kg Q8W; 4 at 1.9 mg/kg Q4W; 16 at 2.5 mg/kg Q4W; 13 at 2.5 mg/kg Q4W SPLIT). Across cohorts, the median age was 68 y (range: 36–80). Thirteen pts (29%) had high-risk cytogenetics and 6 (13%) had extramedullary disease. Median prior LOT was 3 (range: 1–11) and 26 (58%) had prior Len treatment. The median duration of follow-up and ORR ranged across cohorts (Table). The median duration of response was only reached in the 1.9 mg/kg Q4W cohort (11.1 mo [95% CI: 3.7–not reached [NR]). At the time of data cut, median progression-free survival was not reached in the 1.9 mg/kg Q8W or 2.5 mg/kg Q4W cohorts. Gr ≥3 TRAEs occurred in 42–85%. Gr ≥3 keratopathy occurred in 0 pts in 1.9 mg/kg Q8W, 1 pt (25%) in 1.9 mg/kg Q4W, 8 pts (50%) in 2.5 mg/kg Q4W, and 6 pts (46%) in 2.5 mg/kg Q4W SPLIT cohorts. Conclusions: Belamaf + LenDex had a tolerable safety profile, with no new safety signals identified in pts with RRMM. AEs, including keratopathy, were common but manageable with dose modifications. Encouraging clinical activity is observed with this combination in pts with RRMM. Follow-up/correlative studies are ongoing. Funding: GSK (Study 207497); drug linker technology licensed from Seagen Inc.; mAb produced using POTELLIGENT Technology licensed from BioWa. Clinical trial information: NCT03544281. [Table: see text]

Introduction: The bortezomib, lenalidomide, and dexamethasone (VRd) regimen is an acceptable standard of care (SoC) for both transplant-eligible and transplant-ineligible newly diagnosed multiple myeloma (TI NDMM). Ongoing development of novel therapies and combinations strive to improve survival outcomes beyond what is expected from SoC. Belantamab mafodotin (belamaf) is a B-cell maturation antigen-binding antibody-drug conjugate that eliminates myeloma cells by a multimodal mechanism and has demonstrated durable responses in patients with relapsed/refractory multiple myeloma (RRMM). Preclinical evidence of belamaf in combination with bortezomib or lenalidomide suggests enhanced anti-myeloma activity, providing rationale for this treatment combination. We report the preliminary findings of belamaf + VRd for TI NDMM patients. Methods: DREAMM-9 (NCT04091126) is an ongoing Phase I, open-label, randomized, dose and schedule evaluation study of belamaf + VRd in patients with TI NDMM. Eligible patients include those ≥18 years old with ECOG status 0-2 and adequate organ system functions. The study evaluates safety and tolerability of belamaf + VRd in up to 8 cohorts, up to 144 patients, to establish the recommended phase 3 dose (RP3D). VRd is administered Q3W until cycle 8, followed by lenalidomide + dexamethasone (Rd) Q4W. Belamaf + VRd is administered until cycle 8, and then in combination with Rd thereafter. The belamaf dose cohorts currently being evaluated are: cohort 1 (1.9 mg/kg Q3/4W), cohort 2 (1.4 mg/kg Q6/8W), cohort 3 (1.9 mg/kg Q6/8W), cohort 4 (1.0 mg/kg Q3/4W), and cohort 5 (1.4 mg/kg Q3/4W). After evaluation of safety data for cohort 1, cohorts 2-5 were opened in parallel and enrolled patients were randomized 1:1:1:1. Safety data, clinical activity, and drug concentrations will be assessed, and used to determine the belamaf RP3D. This analysis reports the preliminary results from cohort 1. Primary endpoints include number of patients with adverse events (AEs). Secondary endpoints include establishing relative dose intensity of lenalidomide and bortezomib in combination with belamaf, cumulative dose of belamaf, pharmacokinetics (PK) profile of belamaf when combined with VRd, overall response rate (ORR), complete response (CR), stringent complete response (sCR), complete response rate ([CRR]; % of patients with a confirmed CR or better), and rate of very good partial response or better (≥VGPR). Exploratory endpoints include assessing minimal residual disease (MRD) in patients who achieve ≥VGPR, and safety and efficacy exposure-response relationships. Results: Twelve patients in cohort 1 were included in this preliminary analysis. Eight patients (67%) were male; median age (range) was 72.5 years (63-77). Ten patients (83%) were white and 2 (17%) were Asian. Nine patients (75%), were ISS stage II or III, and 4 (33%) patients had high-risk cytogenetics (consisting of one or more of the following: t(4;14), t(14;16), del17p, 17p13del). AEs related to study treatment were experienced by all 12 patients. Dose reductions occurred in 12 (100%) patients, all of whom also experienced a dose delay. Most common AEs leading to dose modification were thrombocytopenia, neutropenia, and corneal events. Grade 3 or 4 AEs related to belamaf occurred in 9 (75%) patients. During the trial, one patient experienced a fatal severe AE due to COVID-19 infection (unrelated to study treatment; Table). All patients, 100% (n=12; 95% CI: 73.5-100) achieved ≥VGPR. Early deep responses were observed; 2 (17%) patients achieved VGPR as early as 4 weeks. As of data cut-off, 5 (42%) remain in CR and 3 (25%) in sCR. Based on real-time data captured in the clinical database, 7 out of 9 patients achieved MRD-negative status at the first test after VGPR. Belamaf PK profile was similar to that observed in patients with RRMM taking into consideration baseline patients characteristics. Conclusion: Preliminary data suggest addition of belamaf to VRd did not reveal new safety signals and demonstrates high response rates, albeit with short follow-up. The study is ongoing to confirm safety and evaluate the efficacy of belamaf + VRd. Updated data for cohort 1 will be reported at the congress. Funding: GSK (Study 209664); belamaf drug linker technology licensed from Seagen; belamaf monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa. Figure 1 Figure 1. Disclosures Usmani: Pharmacyclics: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Takeda: Consultancy, Research Funding, Speakers Bureau; Merck: Consultancy, Research Funding; SkylineDX: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Janssen Oncology: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding; EdoPharma: Consultancy; GSK: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding, Speakers Bureau; Array BioPharma: Consultancy, Research Funding; Abbvie: Consultancy; Amgen: Consultancy, Research Funding, Speakers Bureau. Quach: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen/Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Antengene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; CSL: Consultancy, Membership on an entity's Board of Directors or advisory committees. Koh: Pfizer: Consultancy; Jassen: Honoraria; AstraZeneca: Honoraria; Novartis: Honoraria; GSK: Honoraria; Roche: Honoraria; Takeda: Honoraria. Guenther: Novartis: Consultancy; Celgene: Consultancy, Honoraria; Roche: Consultancy; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; AbbVie: Consultancy; Jazz Pharmaceuticals: Honoraria; Janssen Pharmaceuticals: Consultancy, Honoraria. Zhou: GlaxoSmithKline: Current Employment. Kaisermann: GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Mis: GlaxoSmithKline: Current Employment. Williams: GlaxoSmithKline: Current Employment. Yeakey: GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Ferron-Brady: GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Figueroa: GlaxoSmithKline: Current Employment. Kremer: GlaxoSmithKline: Current Employment. Gupta: Novartis: Current equity holder in publicly-traded company; GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Janowski: Celgene: Consultancy; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees.

Introduction: Belamaf (GSK2857916) is a first-in-class BCMA-targeting antibody-drug conjugate (ADC) with a humanized afucosylated anti-BCMA mAb conjugated to a cytotoxic payload mafodotin (MMAF) by a protease-resistant maleimidocaproyl linker (mc). This ADC binds to BCMA and eliminates MM cells by a multimodal mechanism. It delivers MMAF to MM cells, which inhibits microtubule polymerization, resulting in apoptosis; enhances antibody-dependent cellular cytotoxicity and phagocytosis; and induces release of markers characteristic of immunogenic cell death. This analysis assessed the E-R relationships for ocular safety endpoints in the DREAMM-2 study (NCT03525678; Lonial et al. Lancet Oncol 2020). Methods: Heavily pretreated patients with RRMM were administered belamaf 2.5 or 3.4 mg/kg intravenously every 3 weeks in the pivotal Phase II study, DREAMM-2 (N=218; Lonial et al., Lancet Oncol 2020). Population pharmacokinetic (PK) models of belamaf and cys-mcMMAF were developed and used to predict individual Cycle 1 exposure measures (Ferron-Brady et al., AACR 2020; presentation CT196). Exposure-safety analyses evaluated the probability of Grade ≥2 or ≥3 corneal adverse event (CAE; based on ocular examination and graded using a study-specific keratopathy and visual acuity [KVA] scale), or ocular events including Grade ≥1 or ≥2 blurred vision or dry eye (graded with Common Terminology Criteria for Adverse Events [CTCAE] v4.03), definite worsening in best corrected visual acuity (BCVA) in the better-seeing eye, and unilateral or bilateral worsening in BCVA to 20/50 or worse (BCVA measured with Snellen scale). The time to first occurrence of these events was also evaluated. Generalized linear models were used to assess event probabilities, while Cox proportional hazard models were used to assess time to event endpoints. Baseline patient characteristics, including serum levels of free soluble BCMA (sBMCA), a marker of disease burden, and history of eye conditions (Popat et al., ASH 2020; presentation TBD), were also evaluated for association with these endpoints. Results: Higher belamaf Ctau (the predicted concentration on Day 21 at the end of the first cycle) was associated with greater probability of developing Grade ≥2 or ≥3 CAE as well as an earlier onset of these events. History of dry eye was associated with an increased probability of Grade ≥2 CAE; lower baseline sBCMA level was associated with higher probability of Grade ≥2 or ≥3 CAE. Higher belamaf Ctau was not found to be associated with probability of occurrence or timing of first occurrence of blurred vision, dry eye (Ferron-Brady et al. AACR 2020; presentation CT196), definite worsening in BCVA, and unilateral or bilateral worsening in BCVA to 20/50 or worse.Lower baseline sBCMA level was associated with higher probability of occurrence for most of these endpoints, with some showing an earlier occurrence. History of dry eye was associated with higher probability of any grade of blurred vision, while presence of keratopathy at baseline increased the probability of a Grade ≥2 blurred vision with an earlier occurrence of any grade and Grade ≥2 blurred vision. Conclusions: After accounting for patient and disease factors, higher belamaf exposure (Ctau) was associated with an increased probability of corneal AEs (KVA scale) but not with other ocular events (e.g., blurred vision, dry eye, or worsening in visual acuity) in integrated E-R safety analyses of DREAMM-2. Funding: GSK (Study 205678); drug linker technology licensed from Seattle Genetics; mAb produced using POTELLIGENT Technology licensed from BioWa. Disclosures Ferron-Brady: GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Rathi:GSK: Current Employment, Current equity holder in publicly-traded company. Collins:GSK: Current Employment, Current equity holder in publicly-traded company. Struemper:GSK: Current Employment, Current equity holder in publicly-traded company. Opalinska:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Jewell:GSK: Current Employment, Current equity holder in publicly-traded company; Novartis: Current equity holder in publicly-traded company.

Introduction: Single-agent belamaf (GSK2857916), a B-cell maturation antigen-targeting antibody-drug conjugate, demonstrated deep and durable responses with a manageable safety profile in patients with heavily pretreated RRMM (median 7 lines of prior therapy) refractory to an immunomodulatory agent (IMiD), a proteasome inhibitor (PI), and refractory and/or intolerant to an anti-CD38 monoclonal antibody in the pivotal Phase II DREAMM-2 study (NCT03525678). At 13-month follow-up, the overall response rate (ORR) was 32% and the median duration of response (DoR) was 11.0 months in the belamaf 2.5 mg/kg arm (Lonial. ASCO 2020 Poster 436). The multimodal mechanism of action, efficacy and safety profile of belamaf, as well as preclinical data suggest possible synergy with standard of care agents and a potential benefit in combination with IMiDs and PIs. DREAMM-6 (NCT03544281) is an ongoing Phase I/II, two-part study of belamaf in combination with lenalidomide/dexamethasone (Arm A) or BorDex (Arm B) in patients with RRMM who had received ≥1 prior therapy (bortezomib-refractory patients were not excluded); preliminary results from Arm B have been reported (Nooka. ASCO 2020 Oral 8502). Methods: Part 1 (dose escalation) and Part 2 (dose expansion) of Arm B in DREAMM-6 evaluated belamaf (2.5 and 3.4 mg/kg intravenously (IV) every 3 weeks [Q3W]) administered as SINGLE (Day 1) or SPLIT dose (divided equally on Days 1 and 8) plus BorDex (Bor 1.3 mg/m2 [subcutaneously] and Dex 20 mg [IV or orally]). Combination treatment continued for up to 8 cycles, with single-agent belamaf maintenance therapy thereafter. Primary objectives were safety, tolerability, and efficacy (ORR [≥ partial response, PR] per investigator-assessed best confirmed response). We report safety and efficacy results from the 2.5 mg/kg SINGLE dose cohort from Arm B. Results: As of March 30, 2020, 18 patients had received belamaf 2.5 mg/kg SINGLE + BorDex in Parts 1 and 2 of Arm B. The median age was 67 years, 61% were male, and 33% had high-risk cytogenetics; patients had received a median of 3 (range, 1-11) prior lines of therapy. All 18 patients had treatment-related adverse events (AEs), of whom 16 (89%) had Grade 3/4 events (see Table). Treatment-related serious AEs occurred in 5 (28%) patients. There were no Grade 5 AEs of interest. Thirteen (72%) patients had dose reductions (8/13 belamaf) and all patients had dose delays (16/18 belamaf) to manage AEs. Five (28%) patients discontinued a study treatment due to AEs: 4 bortezomib, 2 dexamethasone, no patients discontinued belamaf. Of the AEs of interest, thrombocytopenia occurred in 12 patients (67%; maximum Grade 4 in 8 patients and Grade 3 in 3 patients) and led to dose reduction in 6 (33%) patients, dose delay in 7 (39%) patients, and no discontinuations. Three (17%) patients had Grade 2 infusion-related reactions (with no dose modifications or discontinuations). Changes in the corneal epithelium (keratopathy/microcyst-like epithelial changes [MECs], an eye exam finding with or without symptoms), an anticipated AE associated with monomethyl auristatin F, the payload in belamaf, occurred in all 18 patients (maximum Grade 3 in 10 patients, Grade 2 in 7 patients, and Grade 1 in 1 patient), and led to dose reduction in 7 (39%) patients, dose delay in 15 (83%) patients, with no discontinuations. Response was evaluable in all patients; ORR was 78% (95% CI 52.4-93.6), with very good partial response (VGPR) in 9 (50%) and PR in 5 (28%) patients. One (6%) patient had minimal response, and 3 (17%) patients had stable disease. Clinical benefit rate was 83% (95% CI 58.6-96.4). After a median of 18.2 weeks (range 6.0-46.4 weeks) on treatment, median DoR was not reached. Conclusions: The combination of belamaf 2.5 mg/kg Q3W with standard-of care BorDex demonstrated an acceptable safety profile in patients with RRMM who had received a median of 3 prior lines of therapy, with AEs as expected, and no new safety signals to date. Corneal events were common but manageable with belamaf dose modifications. At interim follow-up, best response data indicate a high ORR of 78%, VGPR of 50%, and clinical benefit rate of 83%. Final data for the 2.5 mg/kg SINGLE + BorDex cohort will be reported at the congress. Funding: GSK (Study 207497); drug linker technology licensed from Seattle Genetics; monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa. Disclosures Popat: AbbVie: Consultancy, Honoraria; GSK: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Takeda: Consultancy, Honoraria, Other: Travel support, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Nooka:Karyopharm Therapeutics, Adaptive technologies: Consultancy, Honoraria, Research Funding; Oncopeptides: Consultancy, Honoraria; Spectrum Pharmaceuticals: Consultancy; Takeda: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Adaptive Technologies: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria, Other: Personal Fees: Travel/accomodations/expenses, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding. Stockerl-Goldstein:Celgene: Consultancy; Abbott Laboratories: Current equity holder in publicly-traded company; Abbvie: Current equity holder in publicly-traded company; GSK: Research Funding; Takeda: Research Funding; BiolineRx: Research Funding; Janssen: Research Funding; Cellerant: Other: Other relationship. Abonour:Takeda: Consultancy; Janssen: Honoraria, Research Funding; Celgene: Consultancy; BMS: Consultancy, Research Funding. Khot:Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Other: Speaker fees; Novartis: Other: Travel grant. Lee:Janssen: Consultancy; Amgen: Consultancy; Celgene/BMS: Consultancy. Augustson:Roche: Other: Support of parent study and funding of editorial support. Spencer:AbbVie, Amgen, Celgene, Haemalogix, Janssen, Sanofi, SecuraBio, Specialised Therapeutics Australia, Servier and Takeda: Honoraria; Amgen, Celgene, Haemalogix, Janssen, Servier and Takeda: Research Funding; AbbVie, Celgene, Haemalogix, Janssen, Sanofi, SecuraBio, Specialised Therapeutics Australia, Servier and Takeda: Consultancy; Celgene, Janssen and Takeda: Speakers Bureau. Mateos:Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Regeneron: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Consultancy, Honoraria; PharmaMar-Zeltia: Consultancy; Abbvie/Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy, 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; Oncopeptides: 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; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: 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. Chopra:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Rogers:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Smith:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Davidge:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Montes de Oca:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Ferron-Brady:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Yeakey:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Talekar:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Kremer:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Gupta:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company; Novartis: Current equity holder in publicly-traded company. Quach:Sanofi: Consultancy, Research Funding; Janssen Cilag: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria, Research Funding; Glaxo Kline Smith: Consultancy, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding.

Introduction: Single-agent belamaf (GSK2857916), a B-cell maturation antigen-targeting antibody-drug conjugate, induced deep and durable responses in patients with RRMM, with a manageable safety profile with 13 months of follow-up (DREAMM-2; NCT03525678; Lonial et al, ASCO 2020, Poster 436). A platform trial design allows efficient evaluation of belamaf in combination with other anti-myeloma agents, such as a humanized wild-type IgG1 anti-OX40 agonist, an IgG4-inducible T-cell co-stimulator (ICOS) agonist, a gamma-secretase inhibitor, and a humanized programmed cell death (PD)-1 antagonist. The unique, multimodal mechanisms of action (MoAs) of belamaf, in combination with MoAs of these agents, has the potential to achieve synergistic effects in RRMM to further enhance anti-myeloma activity without compromising safety. Methods: DREAMM-5 (NCT04126200) is a Phase I/II study that utilizes a master protocol with separate substudies comprised of sequential dose-exploration (DE) and cohort-expansion (CE) phases, to identify promising, effective belamaf combinations when compared with a shared single-agent belamaf control arm (CE phase only). The DE phase consists of multiple dosing cohorts with belamaf combinations in which patients are assigned to treatment slots by a predetermined algorithmic approach (N≤10 per cohort). A recommended Phase II dose (RP2D) for each combination treatment will be identified based on the safety and preliminary efficacy in the DE phase. At the end of the DE phase, an interim analysis of safety, pharmacokinetic, and efficacy data will also be performed for each substudy treatment combination to determine whether the combination should move forward at the RP2D to the CE phase. Patients in the CE phase (N≥35 per cohort) will be randomized to a substudy and within a substudy to either combination treatment or the belamaf monotherapy control arm; patients will also be stratified by number of prior therapies). Eligible patients will have RRMM and will have received ≥3 prior therapy lines, which includes a prior immunomodulatory agent, proteasome inhibitor, and anti-CD38 antibody; all patients will provide informed consent for participation. The primary objectives of the study are to identify the RP2D (DE phase) and the overall response rate (≥partial response, CE phase), along with safety and tolerability, for each combination treatment. Substudies 1 (combination with GSK3174998, OX40 agonist antibody), 2 (combination with GSK3359609, ICOS agonist antibody), and 3 (combination with nirogacestat [PF-03084014; SpringWorks Therapeutics], gamma-secretase inhibitor) are currently open to enrollment. Substudy 4 (combination with dostarlimab; PD-1 antagonist antibody) is under review. Additional substudies will be explored based on scientific rationale and/or preclinical combination study results. Funding: GSK (Study 208887); belamaf drug linker technology licensed from Seattle Genetics; belamaf monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa; nirogacestat gamma-secretase inhibitor produced by and used in collaboration with SpringWorks Therapeutics. Figure: DREAMM-5 study design Figure 1 Disclosures Richardson: Celgene/BMS, Oncopeptides, Takeda, Karyopharm: Research Funding. Nooka:GlaxoSmithKline: Consultancy, Honoraria, Other: Personal Fees: Travel/accomodations/expenses, Research Funding; Karyopharm Therapeutics, Adaptive technologies: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Spectrum Pharmaceuticals: Consultancy; Adaptive Technologies: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Oncopeptides: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding. Quach:Amgen, sanofi, celgene, Karyopharm, GSK: Research Funding; Amgen, Celgene, karyopharm, GSK, Janssen Cilag, Sanofi.: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline, Karyopharm, Amgen, Celgene, Janssen Cilag: Consultancy; GlaxoSmithKline, Karyopharm, Amgen, Celgene, Janssen Cilag: Honoraria. Trudel:Celgene, Janssen, Takeda, Sanofi, Karyopharm, Amgen Canada: Honoraria; Celgene, Amgen, GSK: Consultancy, Research Funding; GSK, Celgene, Janssen, Amgen, Genentech: Research Funding. Routledge:Celgene, Sandoz: Consultancy; Amgen, BMS, Celgene, Sandoz: Honoraria. Song:Otsuka: Honoraria; Janssen: Honoraria, Research Funding; Amgen, Celgene,Takeda: Consultancy, Honoraria; Sanofi: 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; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Paul:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Khan:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Brouch:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Ferron-Brady:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Yeakey:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Shelton:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Montes de Oca:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Smith:SpringWorks: Current Employment, Current equity holder in publicly-traded company. Im:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Ahlers:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Paul:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Holkova:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Gupta:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company; Novartis: Current equity holder in publicly-traded company. Kremer:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Rodriguez-Otero:GlaxoSmithKline: Consultancy, Current Employment, Current equity holder in publicly-traded company, Honoraria; Kite: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Oncopeptides: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Medscape: Membership on an entity's Board of Directors or advisory committees; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Sanofi: Consultancy, Honoraria.

Carcinoma; Concentració de fàrmac en plasma; Farmacocinètica Carcinoma; Concentración de fármaco en plasma; Farmacocinética Carcinoma; Plasma drug concentration; Pharmacokinetics Background Bromodomain and extra-terminal domain proteins are promising epigenetic anticancer drug targets. This first-in-human study evaluated the safety, recommended phase II dose, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of the bromodomain and extra-terminal domain inhibitor molibresib (GSK525762) in patients with nuclear protein in testis (NUT) carcinoma (NC) and other solid tumors. Methods This was a phase I and II, open-label, dose-escalation study. Molibresib was administered orally once daily. Single-patient dose escalation (from 2 mg/d) was conducted until the first instance of grade 2 or higher drug-related toxicity, followed by a 3 + 3 design. Pharmacokinetic parameters were obtained during weeks 1 and 3. Circulating monocyte chemoattractant protein-1 levels were measured as a pharmacodynamic biomarker. Results Sixty-five patients received molibresib. During dose escalation, 11% experienced dose-limiting toxicities, including six instances of grade 4 thrombocytopenia, all with molibresib 60–100 mg. The most frequent treatment-related adverse events of any grade were thrombocytopenia (51%) and gastrointestinal events, including nausea, vomiting, diarrhea, decreased appetite, and dysgeusia (22%–42%), anemia (22%), and fatigue (20%). Molibresib demonstrated an acceptable safety profile up to 100 mg; 80 mg once daily was selected as the recommended phase II dose. Following single and repeat dosing, molibresib showed rapid absorption and elimination (maximum plasma concentration: 2 hours; t1/2: 3–7 hours). Dose-dependent reductions in circulating monocyte chemoattractant protein-1 levels were observed. Among 19 patients with NC, four achieved either confirmed or unconfirmed partial response, eight had stable disease as best response, and four were progression-free for more than 6 months. Conclusions Once-daily molibresib was tolerated at doses demonstrating target engagement. Preliminary data indicate proof-of-concept in NC. This study (BET115521; NCT01587703) was supported by GlaxoSmithKline (GSK). Financial support for this work was also provided by National Institutes of Health (NIH) Cancer Center Support Grants P30 CA016672 and P30 CA006516, as well as NIH grant R01 CA124633 to CAF.

Introduction: Belantamab mafodotin (belamaf; GSK2857916) is a B-cell maturation antigen (BCMA)-targeting antibody-drug conjugate. In the pivotal Phase II DREAMM-2 study, single-agent belamaf demonstrated deep and durable responses with a manageable safety profile in heavily pretreated patients with RRMM (Lonial et al. Lancet Oncol 2020). Responses were sustained at 13 months of follow-up; with belamaf (2.5 mg/kg administered intravenously [IV] every 3 weeks [Q3W]), overall response rate (ORR) was 32% and median duration of response (DoR) was 11.0 months (Lonial et al. ASCO 2020 Poster 436). Preclinical data suggest synergistic antimyeloma activity of belamaf in combination with pomalidomide/dexamethasone (Pd). Preliminary data from an ongoing Phase I/II study (NCT03715478) evaluating belamaf in combination with Pd (B-Pd) suggest an acceptable safety profile and early signs of clinical activity in patients with RRMM. The DREAMM-8 study (NCT04484623) will evaluate the efficacy and safety of B-Pd compared with pomalidomide, bortezomib, and dexamethasone (PVd). Methods: This Phase III, two-arm, randomized, open-label, multicenter study will include patients with measurable RRMM who have received ≥1 prior line of therapy (including lenalidomide), with documented disease progression during or after their most recent line of treatment. Patients aged ≥18 years with Eastern Cooperative Oncology Group Performance Status 0-2, adequate organ system function, and who provide informed consent will be eligible. Patients with prior exposure to BCMA-targeted therapies or pomalidomide and those intolerant/refractory to bortezomib will be excluded. Approximately 450 patients will be randomized (1:1) to Arm A (B-Pd) or Arm B (PVd), stratified by number of prior lines of treatment, prior exposure to bortezomib, and International Staging System status. No more than 50% of participants with two or more prior lines of treatment will be enrolled. In Arm A, patients will receive belamaf 2.5 mg/kg (IV) Q4W on Day 1 in Cycle 1 (28-day cycle) followed by belamaf 1.9 mg/kg (IV) Q4W on Day 1 in Cycle 2 onwards (28-day cycles); pomalidomide 4 mg (orally [PO]) will be administered on Days 1-21 and dexamethasone 40 mg (PO) on Days 1, 8, 15, and 22 in all cycles (28-day cycles). In Arm B, pomalidomide 4 mg (PO) will be administered Q3W on Days 1-14 in all cycles (21-day cycles); bortezomib 1.3 mg/m2 will be administered subcutaneously on Days 1, 4, 8, and 11 in Cycles 1-8, and Days 1 and 8 in Cycle 9+ (21-day cycles). Dexamethasone 20 mg (PO) will be administered on the day of and the day after bortezomib. The dose level of dexamethasone in each arm will be reduced by half in patients >75 years of age. Treatment in both arms will continue until progressive disease, unacceptable toxicity, withdrawal of consent, initiation of another anticancer therapy, or end of study or death. The primary endpoint is progression-free survival (PFS; time from randomization to the earliest date of documented disease progression or death [any cause]). Minimal residual disease negativity rate is a key secondary endpoint. Additional secondary endpoints include ORR, time to response, DoR, time to progression, overall survival, PFS2 (PFS after initiation of new anticancer therapy), safety, health-related quality of life, and pharmacokinetic and pharmacodynamic parameters. The study is planned to start in August 2020. Funding: GSK (Study 207499); drug linker technology licensed from Seattle Genetics; mAb produced using POTELLIGENT Technology licensed from BioWa. Disclosures Trudel: GSK, Celgene, Janssen, Amgen, Genentech: Research Funding; Celgene, Janssen, Takeda, Sanofi, Karyopharm, Amgen Canada: Honoraria; Celgene, Amgen, GSK: Consultancy, Research Funding. Davis:GSK: Current Employment, Current equity holder in publicly-traded company. Lewis:GSK: Current Employment, Current equity holder in publicly-traded company. Bakshi:GSK: Current Employment, Current equity holder in publicly-traded company. Chopra:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Montes de Oca:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Ferron-Brady:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Eliason:GSK: Current Employment, Current equity holder in publicly-traded company. Kremer:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Gupta:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company; Novartis: Current equity holder in publicly-traded company. Wu:GSK: Current Employment, Current equity holder in publicly-traded company.

Background: Belantamab mafodotin (GSK2857916) is a first-in-class B-cell maturation antigen (BCMA)-targeting immunoconjugate with a humanized afucosylated anti-BCMA mAb conjugated to a cytotoxic payload mafodotin (MMAF) by a protease-resistant maleimidocaproyl linker (mc). This antibody-drug conjugate (ADC) binds to BCMA and eliminates MM cells by a multimodal mechanism. It delivers MMAF to MM cells which inhibits microtubule polymerization, resulting in apoptosis, enhances antibody-dependent cellular cytotoxicity and phagocytosis, and induces immunogenic cell death. This analysis assessed PopPK of ADC and cys-mcMMAF and E-R relationships for key endpoints to contribute to monotherapy dose selection. Methods: Heavily pretreated RRMM patients were administered intravenous (IV) doses ranging from 0.03 to 4.6 mg/kg Q3W in DREAMM-1 (n=73) and doses of 2.5 or 3.4 mg/kg Q3W in the pivotal phase 2 study (DREAMM-2; n=218). PopPK models of ADC and cys-mcMMAF were developed and used to predict individual Cycle 1 exposure measures. Exposure-efficacy analyses evaluated the probability of response (PoR), duration of progression-free survival (PFS), and time to response or best response (TTR, TTBR). Exposure-safety analyses evaluated the probability of grade ≥2 or ≥3 ocular exam finding (OEF), grade ≥3 thrombocytopenia (TCP) or neutropenia (NTP), and infusion-related reactions (IRR). Generalized linear models were used to assess event probabilities, while Cox proportional hazard models were used to assess time to event endpoints. Results: The PK data were described well by two-compartment models with linear elimination. The ADC model included time-varying clearance influenced by disease-related factors and body weight. The cys-mcMMAF model included decreasing MMAF:mAb ratio after each dose. In DREAMM-2, PoR and PFS were not related to drug exposure when accounting for the inverse relationship to baseline disease factors. TTR but not TTBR was inversely related to ADC trough concentration (Ctau). Safety endpoints were strongly associated with exposure. Higher ADC Ctau was associated with probability of developing OEF and inversely correlated to time to onset of OEF. Baseline disease factors were inversely associated with probability of OEF. Higher cys-mcMMAF maximum concentration and lower baseline platelet count were associated with increased probability of TCP. No factors were found for probability of NTP or IRR. Conclusion: Integrated E-R analyses suggested that, after accounting for patient and disease factors, increased probability of OEF and TCP with higher exposure or dose was not associated with a commensurate improvement in efficacy in DREAMM-2, supporting a monotherapy dose of 2.5 mg/kg IV Q3W of belantamab mafodotin in RRMM patients. Support: Funded by GSK. Drug linker technology was licensed from Seattle Genetics (Bothell, WA, USA) and the monoclonal antibody was produced with POTELLIGENT Technology licensed from BioWa (Princeton, NJ, USA). Citation Format: Geraldine Ferron-Brady, Chetan Rathi, Jon Collins, Herbert Struemper, Joanna Opalinska, Roxanne C Jewell. Therapeutic dose selection for belantamab mafodotin, a BCMA-targeting agent, in patients with relapsed/refractory multiple myeloma (RRMM): Application of population pharmacokinetics (PopPK) and exposure-response (E-R) analyses [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 CT196.

Introduction This first-time-in-humans study assessed the safety, pharmacokinetics (PK), pharmacodynamics (PD), and clinical activity of GSK2879552 in patients with relapsed or refractory SCLC. Methods This phase I, multicenter, open-label study (NCT02034123) enrolled patients (≥18 years old) with relapsed or refractory SCLC (after ≥1 platinum-containing chemotherapy or refusal of standard therapy). Part 1 was a dose-escalation study; Part 2 was a dose-expansion study. Dose escalations were based on safety, PK, and PD. The primary end point (Part 1) was to determine the safety, tolerability, and recommended dose and regimen of GSK2879552. Secondary end points were to characterize PK and PD parameters and measure disease control rate at week 16. Part 2 was not conducted. Results Between February 4, 2014, and April 18, 2017, a total of 29 patients were allocated to one of nine dose cohorts (0.25 mg–3 mg once daily and 3-mg or 4-mg intermittent dosing). In all, 22 patients completed the study; 7 withdrew, primarily owing to adverse events (AEs). Most patients (24 of 29 [83%]) had at least one treatment-related AE, most commonly thrombocytopenia (12 of 29 [41%]). Twelve serious AEs (SAEs) were reported by nine patients; six were considered treatment related, the most common of which was encephalopathy (four SAEs). Three patients died; one death was related to SAEs. PK was characterized by rapid absorption, slow elimination, and a dose-proportional increase in exposure. Conclusions GSK2879552 is a potent, selective inhibitor of lysine demethylase 1A and has demonstrated favorable PK properties but provided poor disease control and a high AE rate in patients with SCLC. The study was terminated, as the risk-benefit profile did not favor continuation.

TPS8552 Background: Single-agent belantamab mafodotin (GSK2857916), a B-cell maturation antigen targeting immunoconjugate, induced deep and durable responses in patients with RRMM, with a manageable safety profile (DREAMM-2, NCT03525678, Lancet Oncol.2020). A platform trial design allows efficient evaluation of belantamab mafodotin in combination with other anti-myeloma agents, such as a humanized wild-type IgG1 anti-OX40 agonist, an IgG4 inducible T-cell costimulatory (ICOS) agonist, and a gamma-secretase inhibitor. The unique, multimodal mechanisms of action (MoAs) of belantamab mafodotin, in combination with MoAs of these agents, has the potential to achieve synergistic effects in MM, to further enhance anti-myeloma activity without compromising safety. Methods: DREAMM-5 (NCT04162210) utilizes a master protocol with separate sub-studies comprised of sequential dose exploration (DE) and cohort expansion (CE) phases, to identify promising, effective belantamab mafodotin combinations when compared with a shared belantamab mafodotin monotherapy control arm (CE phase only). DE phases consist of multiple dosing cohorts with belantamab mafodotin combinations where patients are assigned to treatment slots by predetermined algorithmic approach (modified toxicity probability interval; N≤10 per cohort). Recommended phase 2 doses (RP2D) will be based on dose-limiting toxicities, safety, and pharmacokinetics. Interim analyses, based on overall response rate (ORR), determine if a RP2D is moved forward to a CE phase (N≥35 per cohort). Patients in the CE (stratified by number of prior therapies) will be randomized equally to open sub-studies. Eligible patients will have received ≥3 prior therapy lines which must include ≥1 immunomodulatory agent, proteasome inhibitor, and anti-CD38 antibody. The primary objectives are to identify RP2D for each combination (DE phase) and ORR (≥partial response, CE phase). Sub-studies 1 (combination with GSK3174998, OX40 agonist antibody) and 2 (combination with GSK3359609, ICOS agonist antibody) are currently enrolling. Sub-study 3 (combination with nirogacestat [PF-03084014; SpringWorks Therapeutics]) is projected to begin enrollment in the first half of 2020. Additional sub-studies will be explored based on scientific rationale and/or preclinical combination study results. Funding: GlaxoSmithKline (207495). Drug linker technology licensed from Seattle Genetics; monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa. Clinical trial information: NCT04162210 .

3618 Background: Molibresib is an orally available, small molecule bromodomain and extra-terminal domain (BET) protein inhibitor under investigation for treatment of advanced solid tumors. Methods: This was an open-label, single- and repeat-dose, 2-part, Phase 1/2 study including patients (aged ≥16 years) with advanced solid tumors. Part 1: patients received different oral doses of molibresib (2–100mg QD; amorphous free-base formulation) to determine recommended Phase 2 dose. Part 2 (expansion cohort): patients with various tumor types received the bioequivalent besylate formulation (75mg) to explore clinical activity at recommended dose. Safety and efficacy (response rate [RR] based on RECIST 1.1 criteria, progression-free survival [PFS], and overall survival [OS]) were evaluated for the total cohort (patients from Part 1 and 2). Safety, pharmacokinetic, pharmacodynamic, and efficacy per tumor type were evaluated in Part 2. Results: Part 1 only data have previously been reported. Overall, 196 patients were included in the total cohort (1 patient in Part 1 was counted twice). In the all treated population, 195 patients (median age 58 years; 46% male) received ≥1 dose of molibresib (Part 1: n = 93; Part 2: n = 102). Adverse events (AEs) were experienced by 193/196 (98%) patients; 180/196 (92%) had a treatment-related AE (TRAE). AEs led to permanent treatment discontinuation in 38/196 (19%) patients. Of different tumor types in Part 2, NUT carcinoma (NC) had the lowest frequency of TRAEs (10/12 [83%]) and AEs leading to permanent treatment discontinuation (1/12 [8%]). In total cohort, 3/31 NC patients and 1/35 with castration-resistant prostate cancer (CRPC) achieved a confirmed partial response. A further 67/196 (34%) achieved stable disease (SD). In Part 2, RR in 12 NC patients was 8% (CI: 0.2–38.5); 50% had SD and median PFS was 4.8 months with median OS of 5.0 months. In CRPC patients, RR was 4% (CI: 0.1–21.9); 22% had SD; median PFS was 8.0 months with median OS of 9.1 months. Plasma concentrations for molibresib and active metabolites were similar between different tumor types. Gene expression analysis from pre- and post-dose biopsy samples collected from 10 mCRPC patients showed transcriptional downregulation of Myc target genes upon treatment with molibresib. Conclusions: Molibresib demonstrated a manageable safety and tolerability profile with single agent activity observed in selected patients with NC and CRPC. Clinical trial information: NCT01587703 .

8502 Background: Belantamab mafodotin, a B-cell maturation antigen targeting immunoconjugate, demonstrated clinically meaningful, single-agent activity in patients with heavily pre-treated RRMM refractory to an immunomodulatory agent, a proteasome inhibitor, and refractory and/or intolerant to an anti-CD38 monoclonal antibody (DREAMM-2, NCT03525678, Lancet Oncol.2020). The multimodal mechanism of action and manageable safety profile make belantamab mafodotin a promising candidate for use in different RRMM combination regimens. Methods: DREAMM-6 (NCT03544281) is an ongoing, two-part, two-arm, study evaluating the safety, tolerability, and clinical activity of belantamab mafodotin in combination with bortezomib/dexamethasone (BorDex) and lenalidomide/dexamethasone in patients previously treated with ≥1 prior therapy line. Here, we present data for belantamab mafodotin in combination with BorDex. Part 1 (dose escalation) and Part 2 (dose expansion) evaluated belantamab mafodotin (2.5 and 3.4 mg/kg) administered as SINGLE (Day 1) or SPLIT dose (divided equally on Days 1 and 8) in combination with BorDex. Results: As of February 6, 2020, 52 patients were enrolled: 6 patients were enrolled at 2.5 mg/kg single dose and 7 at 3.4 mg/kg single dosing in Part 1, and 45 patients in Part 2. No dose-limiting toxicities were observed. Corneal events (including keratopathy, blurred vision, and dry eye) and thrombocytopenia were the most frequently reported AEs and were clinically manageable. Conclusions: In DREAMM-6, preliminary data demonstrate that the combination of belantamab mafodotin and BorDex has an acceptable safety profile, with no new safety signals identified. Funding: GlaxoSmithKline (207497). Drug linker technology licensed from Seattle Genetics; monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa. Clinical trial information: NCT03544281 .

To identify the maximum tolerated dose (MTD) and recommended Phase II dose of MEK/AKT inhibitor combination of trametinib and afuresertib. Eligibility criteria were advanced solid tumors, 18 years or older, Eastern Cooperative Oncology Group performance status 0 or 1, and adequate organ function. Exclusion criteria included Type 1 diabetes, active GI disease, leptomeningeal disease, or current evidence/risk of retinal venous occlusion/central serous retinopathy. Clinical safety parameters and response were evaluated and analyzed. Twenty patients were enrolled. Dose-limiting toxicities (Grade 2 esophagitis; Grade 3 aspartate aminotransferase increased, mucosal inflammation and hypokalemia) were reported at starting dose (1.5 mg trametinib/50 mg afuresertib once daily continuously), exceeding the MTD. Subsequent de-escalation cohorts (1.5 mg/25 mg or 1.0 mg/50 mg trametinib/afuresertib) were defined as MTDs for continuous dosing. Intermittent dosing schedule [1.5 mg trametinib (continuous)/50 mg afuresertib (Days 1–10 every 28 days)] was evaluated and considered tolerable. No patients were enrolled in Phase II. The most common adverse events reported (≥10 % of all patients) included: diarrhea (60 %), dermatitis acneiform (55 %), maculo-papular rash (45 %), fatigue (30 %), dry skin (25 %), nausea (25 %), dyspnea (20 %), and vomiting (20 %). One partial response (BRAF wild-type melanoma) was reported; four patients had stable disease as best response. Continuous daily dosing of trametinib/afuresertib combination was poorly tolerated. Evaluation of intermittent dose schedule showed greater tolerability. Given the interest in combination treatment regimens of MAPK and PI3K/AKT pathway inhibitors, further study of intermittent dose schedule or combination of trametinib with more selective inhibitors may be warranted.

Lapatinib is approved for use in various therapeutic combinations for treating metastatic breast cancers that over-express HER2. To deliver the approved doses, up to six large tablets need to be ingested with the current 250-mg tablets. For ease of ingestion, a powder for oral suspension was developed. This study was an open-label, randomized, adaptive design, two-period crossover bioequivalence study of the powder for suspension relative to the commercial tablet at steady state following once daily dosing for 7 days in patients with advanced cancer. To minimize the number of cancer patients required for a pivotal bioequivalence study (144 in this case), a four-stage adaptive group sequential design with interim analyses after every 36 subjects was implemented to allow for early termination. Bioequivalence for the oral suspension relative to the commercial tablet was demonstrated in both the first (and only) interim analysis and the final analysis, as the 90% confidence intervals for the treatment comparison ratios for both AUC0-24 and Cmax were contained within the acceptance criteria (0.80, 1.25). Additionally, there was no statistical difference in tlag or tmax , suggesting no difference in the absorption rate between treatments. There were no unexpected safety findings during this study.

TPS8053 Background: B-cell maturation antigen (BCMA) is a validated therapeutic target in Multiple Myeloma (MM). GSK2857916 is a humanized (IgG1) anti-BCMA monoclonal antibody conjugated to monomethyl auristatin-F via protease resistant maleimidocaproyl linker and produced in afucosylated form to enhance antibody-dependent cellular cytotoxicity. In FTIH study BMA117159, GSK2857916 was well tolerated and showed unprecedented clinical activity [ORR=60%; mPFS 7.9 months (95% CI, 3.1–not estimable)] as monotherapy in heavily pretreated MM patients. GSK2857916 in combination with SoC regimens, could potentially further improve outcomes for patients with relapsed/refractory (RR) MM. Methods: DREAMM 6 is a 2-part study: Part 1 (dose escalation) is evaluating safety and tolerability of 2 doses (2.5 mg/kg and 3.4 mg/kg) of GSK2857916, in combination with SoC regimens in two independent arms: Arm A with Lenalidomide/Dexamethasone, and Arm B with Bortezomib/Dexamethasone. Modified Toxicity Probability Interval design will guide dose escalation and RP2D of GSK2857916 in each arm for Part 2 (cohort expansion). Part 2 will confirm safety, evaluate clinical activity of GSK2857916 RP2D with either combination and collect pharmacokinetic information on GSK2857916, Lenalidomide and bortezomib. Up to 90 subjects previously treated with at least 1 prior line of therapy who have undergone autologous stem cell transplant or are transplant-ineligible will be enrolled; up to 24 in Part 1 and up to 66 in Part 2. Subjects in Arm A will continue combination treatment until progression, intolerance, consent withdrawal or death. Subjects in Arm B will receive up to 8 cycles of GSK2857916 in combination with Bor/Dex and then continue GSK2857916 monotherapy until progression, intolerance, consent withdrawal, or death. Enrolment on study started in October 2018 and is ongoing. Study funded by GlaxoSmithKline; drug linker technology licensed from Seattle Genetics; monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa. ClinicalTrials.gov Identifier: NCT03544281.

TPS391 Background: Metastatic castrate-resistant prostate cancer (mCRPC) remains an incurable illness as resistance develops after androgen deprivation therapy (ADT) and/or androgen receptor (AR) axis targeted therapies. The bromodomain (BRD) and extraterminal (BET) proteins are critical for transcription. Preclinically, one of these proteins, BRD4, acts in complex with AR to mediate androgen signaling that leads to prostate cell growth and proliferation. GSK525762 is an oral pan-BET inhibitor that suppresses BET dependent activated AR-driven transcription. Combined with androgen production or receptor targeted agents like abiraterone or enzalutamide, GSK525762 may enhance efficacy of or overcome resistance to either agent. Methods: This is a Phase Ib open-label, dose-escalation study to evaluate the safety and efficacy of oral administration of GSK525762 in combination with either abiraterone plus prednisone (Arm A) or enzalutamide (Arm B) in mCRPC patients whose disease has progressed on prior abiraterone or enzalutamide. Patients must have documented prostate cancer progression as assessed by rising PSA or radiographic progression of soft tissue by PCWG3-modified RECIST 1.1 criteria or bone metastasis. Dose escalation is designed to identify safe doses to move into dose expansion. Dose expansion will explore safety and efficacy in patients who failed in first line (L2 population) or after multiple lines of prior therapy (LX population). Primary objectives include defining the safety, tolerability and clinical activity of GSK525762 when combined with products in Arm A or Arm B. Primary clinical activity endpoint is defined as the response rate of subjects achieving a 50% or more reduction from baseline of PSA at 12 weeks or thereafter. Dose escalation will employ a modified Toxicity Probability Interval (mTPI) design. Dose expansion will use a Bayesian adaptive design, which will calculate posterior probability that utility of the dose is clinically significant at interim futility analysis for each dose level. Funding: GSK Clinical trial information: NCT03150056.

Lapatinib is approved for use in various therapeutic combinations for treating metastatic breast cancers that over-express HER2. To deliver the approved doses, up to six large tablets need to be ingested with the current 250-mg tablets. For ease of ingestion, a powder for oral suspension was developed. This study was an open-label, randomized, adaptive design, two-period crossover bioequivalence study of the powder for suspension relative to the commercial tablet at steady state following once daily dosing for 7 days in patients with advanced cancer. To minimize the number of cancer patients required for a pivotal bioequivalence study (144 in this case), a four-stage adaptive group sequential design with interim analyses after every 36 subjects was implemented to allow for early termination. Bioequivalence for the oral suspension relative to the commercial tablet was demonstrated in both the first (and only) interim analysis and the final analysis, as the 90% confidence intervals for the treatment comparison ratios for both AUC0-24 and Cmax were contained within the acceptance criteria (0.80, 1.25). Additionally, there was no statistical difference in tlag or tmax , suggesting no difference in the absorption rate between treatments. There were no unexpected safety findings during this study.

Background Dihydrotestosterone is the main androgen causative of androgenetic alopecia, a psychologically and physically harmful condition warranting medical treatment. Objective We sought to compare the efficacy and safety of dutasteride (type 1 and 2 5-alpha reductase inhibitor) with finasteride (type 2 5-alpha reductase inhibitor) and placebo in men with androgenetic alopecia. Methods Men aged 20 to 50 years with androgenetic alopecia were randomized to receive dutasteride (0.02, 0.1, or 0.5 mg/d), finasteride (1 mg/d), or placebo for 24 weeks. The primary end point was hair count (2.54-cm diameter) at week 24. Other assessments included hair count (1.13-cm diameter) and width, photographic assessments (investigators and panel), change in stage, and health outcomes. Results In total, 917 men were randomized. Hair count and width increased dose dependently with dutasteride. Dutasteride 0.5 mg significantly increased hair count and width in a 2.54-cm diameter and improved hair growth (frontal view; panel photographic assessment) at week 24 compared with finasteride ( P = .003, P = .004, and P = .002, respectively) and placebo (all P Limitations The study was limited to 24 weeks. Conclusions Dutasteride increased hair growth and restoration in men with androgenetic alopecia and was relatively well tolerated.

TPS8556 Background: Bortezomib, lenalidomide, and dexamethasone (VRd) is the standard of care for transplant-eligible and TI NDMM, but relapse is usually inevitable. The median progression-free survival (PFS) is ~3 years for patients with TI NDMM, and with each relapse, the duration of response (DoR) diminishes, highlighting the need for novel, effective, targeted agents. Single-agent belantamab mafodotin is a first-in-class B-cell maturation antigen–binding, humanized, afucosylated, monoclonal immunoconjugate, showing deep and durable responses in heavily pretreated patients with relapsed/refractory multiple myeloma ( Lancet Oncol2020). Preclinical work suggests belantamab mafodotin plus bortezomib or lenalidomide enhances anti-myeloma activity. Therefore, studying clinical activity of belantamab mafodotin in combination with these agents is warranted. Methods: DREAMM-9 (NCT04091126) is a two-part, open-label study to determine efficacy and safety of single-agent belantamab mafodotin with VRd vs. VRd alone in patients with TI NDMM. Patients aged ≥18 years with ECOG status 0–2 and adequate organ system functions will be eligible. Part 1 (dose selection) will evaluate safety/tolerability of belantamab mafodotin with VRd administered by single (Day 1) or split dosing (Days 1 and 8) in ≤5 cohorts (n = 12/cohort): 1.9 mg/kg, 2.5 mg/kg split and single, and 3.4 mg/kg split and single. Six more patients may be added to cohort(s) most likely to be selected as recommended Phase III dose (RP3D). Dose-limiting toxicities and adverse events (AEs) will be assessed, and belantamab mafodotin RP3D determined through modified toxicity probability interval criteria. Part 2 (randomized Phase III) will determine efficacy and safety of belantamab mafodotin at RP3D with VRd vs. VRd alone (n = 750) in two arms randomized 1:1. Dual primary endpoints will be rate of minimal residual disease (MRD) negativity and PFS. Secondary endpoints will be response rates (overall response, complete response, very good partial response or better, sustained MRD negativity), DoR, time to progression, and overall survival. Safety assessment will include AEs, serious AEs and ocular findings. In both parts, belantamab mafodotin will be given with VRd for eight induction cycles and then with Rd for maintenance until disease progression or unacceptable toxicity. Funding: GlaxoSmithKline (209664). Drug linker technology licensed from Seattle Genetics; monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa. Clinical trial information: NCT04091126 .