A Phase I, Open-Label, Dose-Finding Study of GSK2636771, a PI3Kß Inhibitor, Administered with Enzalutamide in Patients with Metastatic Castration-Resistant Prostate Cancer.

PURPOSE: In patients with metastatic castration-resistant prostate cancer (mCRPC), resistance to androgen receptor (AR)-targeted therapies, such as enzalutamide, remains an issue. Inactivation of inhibitory PTEN activates PI3K/AKT signaling and contributes to resistance to androgen deprivation therapy and poor outcomes. Therefore, dual targeting of AR and PI3K/AKT pathways may limit tumor growth and reverse resistance. PATIENTS AND METHODS: In this phase I study (NCT02215096), patients with PTEN-deficient mCRPC who progressed on prior enzalutamide received once-daily enzalutamide 160 mg plus PI3Kß inhibitor GSK2636771 at 300 mg initial dose, with escalation or de-escalation in 100-mg increments, followed by dose expansion. Primary objectives were to evaluate safety/tolerability, determine the recommended phase II dose, and assess the 12-week non-progressive disease (PD) rate. RESULTS: Overall, 37 patients were enrolled; 36 received ≥1 dose of GSK2636771 (200 mg: n = 22; 300 mg: n = 12; 400 mg: n = 2) plus 160 mg enzalutamide. Dose-limiting toxicities occurred in 5 patients (200 mg: n = 1; 300 mg: n = 2, 400 mg: n = 2). No new or unexpected adverse events or evidence of drug-drug interaction were observed. At the recommended dose of GSK2636771 (200 mg) plus enzalutamide, the 12-week non-PD rate was 50% (95% confidence interval: 28.2-71.8, n = 22); 1 (3%) patient achieved a radiographic partial response lasting 36 weeks. Four of 34 (12%) patients had prostate-specific antigen reduction of ≥50%. CONCLUSIONS: Although there was acceptable safety and tolerability with GSK2636771 plus enzalutamide in patients with PTEN-deficient mCRPC after failing enzalutamide, limited antitumor activity was observed.

Targeting B-cell maturation antigen with GSK2857916 antibody-drug conjugate in relapsed or refractory multiple myeloma (BMA117159): a dose escalation and expansion phase 1 trial.

BACKGROUND: B-cell maturation antigen (BCMA) is a cell-surface receptor of the tumour necrosis superfamily required for plasma cell survival. BMCA is universally detected on patient-derived myeloma cells and has emerged as a selective antigen to be targeted by novel treatments in multiple myeloma. We assessed the safety, tolerability, and preliminary clinical activity of GSK2857916, a novel anti-BCMA antibody conjugated to microtubule-disrupting agent monomethyl auristatin F, in patients with relapsed and refractory multiple myeloma. METHODS: We did an international, multicentre, open-label, first-in-human phase 1 study with dose escalation (part 1) and dose expansion (part 2) phases, at nine centres in the USA, Canada, and the UK. Adults with histologically or cytologically confirmed multiple myeloma, Eastern Cooperative Oncology Group performance status 0 or 1, and progressive disease after stem cell transplantation, alkylators, proteasome inhibitors, and immunomodulators were recruited for this study. In part 1, patients received GSK2857916 (0·03-4·60 mg/kg) through 1 h intravenous infusions once every 3 weeks. In part 2, patients received the selected recommended phase 2 dose of GSK2857916 (3·40 mg/kg) once every 3 weeks. Primary endpoints were maximum tolerated dose and recommended phase 2 dose. Secondary endpoints for part 2 included preliminary anti-cancer clinical activity. All patients who received one or more doses were included in this prespecified administrative interim analysis (data cutoff date June 26, 2017), which was done for internal purposes. This study is registered with ClinicalTrials.gov, number NCT02064387, and is ongoing, but closed for recruitment. FINDINGS: Between July 29, 2014, and Feb 21, 2017, we treated 73 patients: 38 patients in the dose-escalation part 1 and 35 patients in the dose-expansion part 2. There were no dose-limiting toxicities and no maximum tolerated dose was identified in part 1. On the basis of safety and clinical activity, we selected 3·40 mg/kg as the recommended phase 2 dose. Corneal events were common (20 [53%] of 38 patients in part 1 and 22 [63%] of 35 in part 2); most (18 [47%] in part 1 and 19 [54%] in part 2) were grade 1 or 2 and resulted in two treatment discontinuations in part 1 and no discontinuations in part 2. The most common grade 3 or 4 events were thrombocytopenia (13 [34%] of 38 patients in part 1 and 12 [34%] of 35 in part 2) and anaemia (6 [16%] in part 1 and 5 [14%] in part 2). There were 12 treatment-related serious adverse events and no treatment-related deaths. In part 2, 21 (60·0%; 95% CI 42·1-76·1) of 35 patients achieved an overall response. INTERPRETATION: At the identified recommended phase 2 dose, GSK2857916 was well tolerated and had good clinical activity in heavily pretreated patients, thereby indicating that this might be a promising candidate for the treatment of relapsed or refractory multiple myeloma. FUNDING: GlaxoSmithKline.

Associations of ofatumumab exposure and treatment outcomes in patients with untreated CLL receiving chemoimmunotherapy.

Relationships between patient characteristics, ofatumumab pharmacokinetics, and treatment outcomes were investigated in this phase 2 trial of ofatumumab plus fludarabine and cyclophosphamide (FC) in untreated chronic lymphocytic leukemia. Patients were randomized 1:1 to receive 500 or 1000 mg ofatumumab (Cycle 1; 300 mg) plus FC every 4 weeks for six cycles. Median Cmax and Ctrough values were similar at Cycle 1 regardless of the ultimate clinical outcome. At later doses, these values were higher for patients with complete response (CR) than for other patients. Higher Cmax and Ctrough values at Cycles 3 and 6 were significantly associated with an increased likelihood of CR, whereas ofatumumab pharmacokinetics were not associated with an objective response (OR) on the basis of univariate analyses. Multivariate analyses indicated that baseline patient/disease factors were predominantly associated with CR (17p status) or OR (bulky lymphadenopathy, gender, and serum thymidine kinase), rather than ofatumumab pharmacokinetics. TRIAL REGISTRATION: www.clinicaltrials.gov (NCT00410163).

Ofatumumab plus fludarabine and cyclophosphamide in relapsed chronic lymphocytic leukemia: results from the COMPLEMENT 2 trial.

In this multicenter, open-label, phase III study, patients with relapsed chronic lymphocytic leukemia (CLL) were randomized (1:1) to receive ofatumumab plus fludarabine and cyclophosphamide (OFA + FC) or FC alone; the primary endpoint being progression-free survival (PFS) assessed by an independent review committee (IRC). Between March 2009 and January 2012, 365 patients were randomized (OFA + FC: n = 183; FC: n = 182). Median IRC-assessed PFS was 28.9 months with OFA + FC versus 18.8 months with FC (hazard ratio = 0.67; 95% confidence interval, 0.51-0.88; p = .0032). Grade ≥3 adverse events (≤60 days after last dose) were reported in 134 (74%) OFA + FC-treated patients compared with 123 (69%) FC-treated patients. Of these, neutropenia was the most common (89 [49%] vs. 64 [36%]). OFA + FC improved PFS with manageable safety for patients with relapsed CLL compared with FC alone, thus providing an alternative treatment option for patients with relapsed CLL. TRIAL REGISTRATION: www.clinicaltrials.gov (NCT00824265).

Phase III, randomized study of ofatumumab versus physicians' choice of therapy and standard versus extended-length ofatumumab in patients with bulky fludarabine-refractory chronic lymphocytic leukemia.

We report results of a randomized, phase III study of ofatumumab versus physicians' choice treatment in patients with bulky fludarabine-refractory chronic lymphocytic leukemia and explore extended versus standard-length ofatumumab treatment. Patients (79 ofatumumab, 43 physicians' choice) completed a median 6 (ofatumumab) or 3 (physicians' choice) months' therapy. Ofatumumab-treated patients with stable disease or better were randomized (2:1) to 6 months' extended ofatumumab treatment or observation. Although the study did not meet the primary endpoint of progression-free survival (PFS) by independent review committee (ofatumumab: 5.4 months, physicians' choice: 3.6 months; p = 0.27), median PFS by investigators was significantly longer for ofatumumab versus physicians' choice (7.0 versus 4.5 months; p = 0.003) as was time to next therapy (median 11.5 versus 6.5 months; p = 0.0004). PFS and time to next therapy were significantly longer with ofatumumab extended treatment than observation (p = 0.026 and p = 0.002, respectively; n = 37). The adverse-event profile of long-term ofatumumab administration showed no unexpected findings (Clinicaltrials.gov identifier: NCT01313689).

Chemoimmunotherapy with O-FC in previously untreated patients with chronic lymphocytic leukemia.

We conducted an international phase 2 trial to evaluate 2 dose levels of ofatumumab, a human CD20 mAb, combined with fludarabine and cyclophosphamide (O-FC) as frontline therapy for chronic lymphocytic leukemia (CLL). Patients with active CLL were randomized to ofatumumab 500 mg (n = 31) or 1000 mg (n = 30) day 1, with fludarabine 25 mg/m(2) and cyclophosphamide 250 mg/m(2) days 2-4, course 1; days 1-3, courses 2-6; every 4 weeks for 6 courses. The first ofatumumab dose was 300 mg for both cohorts. The median age was 56 years; 13% of patients had a 17p deletion; 64% had ß2-microglobulin > 3.5 mg/L. Based on the 1996 National Cancer Institute Working Group (NCI-WG) guidelines, the complete response (CR) rate as assessed by an independent review committee was 32% for the 500-mg and 50% for the 1000-mg cohort; the overall response (OR) rate was 77% and 73%, respectively. Based on univariable regression analyses, ß2-microglobulin and the number of O-FC courses were significantly correlated (P < .05) with CR and OR rates and progression-free survival (PFS). The most frequent Common Terminology Criteria (CTC) grade 3-4 investigator-reported adverse events were neutropenia (48%), thrombocytopenia (15%), anemia (13%), and infection (8%). O-FC is active and safe in treatment-naive patients with CLL, including high-risk patients. This trial was registered at www.clinicaltrials.gov as NCT00410163.