Phase II study of MEDI-575, an anti-platelet-derived growth factor-α antibody, in patients with recurrent glioblastoma.

MEDI-575, an immunoglobulin G2κ monoclonal antibody, selectively binds to platelet-derived growth factor-α receptor (PDGFR-α) with high specificity. This multicenter, single-arm, open-label, phase II study evaluated the efficacy and safety of MEDI-575 in patients with recurrent glioblastoma. Adults with first recurrence of glioblastoma following surgery, temozolomide, and radiation received MEDI-575 25 mg/kg intravenously over 60 min every 21 days until disease progression or unacceptable toxicity. Six-month progression-free survival rate (PFS-6) was the primary end point; secondary measures included response rate, overall survival (OS), and safety/tolerability. PDGFR-α expression was evaluated by immunohistochemistry. Fifty-six patients were enrolled; median age was 56.5 years (range 23-79), 66 % were male, and 66 % were aged ≥65 years. PFS-6 was 15.4 % [90 % confidence interval (CI) 8.1-24.9]. No complete or partial responses were observed; 23 (41.1 %) patients had stable disease as best response. Median PFS was 1.4 months (90 % CI 1.4, 1.8); median OS was 9.7 months (90 % CI 6.5, 11.8). The most common treatment-related adverse events (AEs) were diarrhea (16 %), nausea (13 %), and fatigue (13 %). Twelve (21 %) patients reported grade ≥3 AEs, with hydrocephalus (n = 3), dysphagia (n = 2), and convulsion (n = 2) reported in more than 1 patient. Two patients had treatment-related Grade ≥3 AEs of decreased lymphocyte count and asthenia (n = 1 each). Seven patients (13 %) discontinued MEDI-575 owing to AEs. Labeling of PDGFRα in glioblastoma cells and tumor-associated stromal cells was highly variable, with no correlation with PFS. MEDI-575, although well tolerated, had limited clinical activity in recurrent glioblastoma.

An open-label, single-arm, phase 1 study to assess biomarker effects, efficacy and safety of ofatumumab in patients with refractory chronic lymphocytic leukemia.

This open-label, phase 1 study evaluated the effects of ofatumumab on QTc intervals, safety, efficacy, B-cell and neutrophil counts, complement levels, and cytokine and chemokine concentrations. Fourteen patients with fludarabine-refractory chronic lymphocytic leukemia received 12 ofatumumab infusions. A higher maximum infusion rate of 400 mL/h was tested at the first two doses and was well tolerated. The 43% overall response rate was similar to previous data (42-51%). B-cell depletion was observed along with complement consumption; median C2 and CH50 levels appeared lower during monthly dosing in patients who responded. Responding patients appeared to have higher median levels of certain pro-inflammatory cytokines and lower median levels of certain immunotolerant cytokines than patients who did not respond. Ofatumumab-induced complement-dependent cytotoxicity activity can be detected clinically by measuring complement and may be associated with clinical activity. The potential relationship between changes in complement or cytokines and clinical response to ofatumumab warrants further study.

Assessment of the effect of ofatumumab on cardiac repolarization.

Ofatumumab is a human monoclonal antibody that binds to a unique CD20 epitope on the surface of B lymphocytes, resulting in efficient lysis of CD20-expressing cells via complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity. The potential effect of ofatumumab on cardiac repolarization and the relationship between ofatumumab concentration and change in corrected QT interval (ΔQTcF) were evaluated in data from three clinical trials in 82 patients with chronic lymphocytic leukemia receiving ofatumumab alone (n = 14), ofatumumab with chemotherapy (n = 33), and chemotherapy alone (n = 35). Because of ofatumumab accumulation, baseline QTcF interval was recorded prior to the first infusion for each patient. No patient had a post-baseline QTcF interval >480 milliseconds or a ΔQTcF >60 milliseconds; five patients (four on ofatumumab) had a ΔQTcF between 30 and 60 milliseconds. At cycle 6 (week 21; 308 µg/mL), there was an increase in QTcF in patients on ofatumumab treatment, with an estimated between-treatment difference (90% CI) of 12.5 (4.5, 20.5) milliseconds. However, at the visit with the highest median concentration (week 8; 1386 µg/mL), median ΔQTcF was 4.8 milliseconds. There was no significant relationship between ofatumumab plasma concentration and ΔQTcF. Ofatumumab did not have a clinically significant effect on cardiac repolarization.

An open-label study of the safety and tolerability of pazopanib in combination with FOLFOX6 or CapeOx in patients with colorectal cancer.

BACKGROUND: Although combining targeted agents with conventional, first-line cytotoxic therapy has improved survival outcomes in patients with advanced colorectal cancer, further improvements in outcomes and tolerability are needed. METHODS: This phase I study evaluated the feasibility of combining oral pazopanib, an agent that targets multiple proangiogenic factors, with FOLFOX6 (oxaliplatin, leucovorin, and 5-fluorouracil) or CapeOx (oxaliplatin and capecitabine). This phase I study evaluated the optimally tolerated regimen of daily pazopanib (dose-escalated) plus standard FOLFOX6 or CapeOx in patients with advanced colorectal cancer. At the optimally tolerated regimen, each cohort was expanded to further evaluate safety and clinical response. RESULTS: The optimally tolerated regimens were pazopanib 800 mg plus FOLFOX6 and pazopanib 800 mg plus reduced CapeOx (capecitabine 850 mg/m(2)). The most commonly reported adverse events in the FOLFOX6 cohorts included decreased appetite, neutropenia, diarrhea, peripheral neuropathy, and vomiting. Similarly, the most commonly reported adverse events in the CapeOx cohorts included fatigue, vomiting, and decreased appetite. The overall response rate was 40 % (8/20 patients) in the pazopanib plus FOLFOX6 cohorts and 38 % (8/21 patients) in the pazopanib plus CapeOx cohorts. CONCLUSION: Pazopanib combined with FOLFOX6 or reduced CapeOx was adequately tolerated in this patient population.

Phase II and biomarker study of the dual MET/VEGFR2 inhibitor foretinib in patients with papillary renal cell carcinoma.

PURPOSE: Foretinib is an oral multikinase inhibitor targeting MET, VEGF, RON, AXL, and TIE-2 receptors. Activating mutations or amplifications in MET have been described in patients with papillary renal cell carcinoma (PRCC). We aimed to evaluate the efficacy and safety of foretinib in patients with PRCC. PATIENTS AND METHODS: Patients were enrolled onto the study in two cohorts with different dosing schedules of foretinib: cohort A, 240 mg once per day on days 1 through 5 every 14 days (intermittent arm); cohort B, 80 mg daily (daily dosing arm). Patients were stratified on the basis of MET pathway activation (germline or somatic MET mutation, MET [7q31] amplification, or gain of chromosome 7). The primary end point was overall response rate (ORR). RESULTS: Overall, 74 patients were enrolled, with 37 in each dosing cohort. ORR by Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 was 13.5%, median progression-free survival was 9.3 months, and median overall survival was not reached. The presence of a germline MET mutation was highly predictive of a response (five of 10 v five of 57 patients with and without germline MET mutations, respectively). The most frequent adverse events of any grade associated with foretinib were fatigue, hypertension, gastrointestinal toxicities, and nonfatal pulmonary emboli. CONCLUSION: Foretinib demonstrated activity in patients with advanced PRCC with a manageable toxicity profile and a high response rate in patients with germline MET mutations.

A comparison of the pharmacokinetics of the anticancer MET inhibitor foretinib free base tablet formulation to bisphosphate salt capsule formulation in patients with solid tumors.

PURPOSE: This phase I, open-label, randomized, 2-part crossover study assessed the safety, pharmacokinetics and relative bioavailability of single doses of the anticancer MET inhibitor foretinib (formerly known as GSK1363089, EXEL-2880 and XL-880) free base tablet formulation compared to a bisphosphate salt capsule formulation (Part 1), and assessed the safety, efficacy, and pharmacokinetics of the bisphosphate salt capsule administered 3 times a week in cancer patients (Part 2). PATIENTS AND METHODS: In Part 1, patients were randomized in a crossover manner to receive a single oral dose of foretinib formulated as a bisphosphate salt capsule (240 mg; 183 mg free base equivalent) followed one week later by a single dose of a free base tablet (180 mg), or vice versa where the treatment sequence was reversed. In Part 2, patients self-administered oral doses of bisphosphate salt capsules (200 mg) 3 times a week until disease progression. RESULTS: Twelve patients with solid tumors were enrolled and completed Part 1, and 10 patients continued into Part 2. Most AEs were mild or moderate in severity. The most common drug-related AEs were fatigue, diarrhea, and nausea. The least-squares (LS) mean total area under the curve was 3144 and 3514 ng*h/mL for the free base tablet and bisphosphate salt capsule, respectively, with a ratio of 0.89 (90% confidence interval, CI: 0.69, 1.16). The LS mean maximal concentration (Cmax) was 81.6 and 98.5 ng/mL for the free base and bisphosphate salt, respectively, with a ratio of 0.83 (90% confidence interval, CI: 0.67, 1.02). The time to reach Cmax was ∼4 h for both formulations. The pharmacokinetics of foretinib were not clinically different between the 2 formulations. Of the 10 patients assessed for efficacy, 3 patients achieved stable disease. CONCLUSIONS: Foretinib was well tolerated as single doses of both the free base and bisphosphate salt formulations. The pharmacokinetics and relative bioavailability of the 2 formulations were not clinically different. The bisphosphate salt formulation was well tolerated on a 3-times a week dosing schedule, and reached steady-state plasma concentration after 2 weeks.

A phase 2, randomized study of SB-485232, rhIL-18, in patients with previously untreated metastatic melanoma.

BACKGROUND: Phase 1 studies demonstrated evidence of recombinant human IL-18 (rhIL-18)-mediated immunomodulatory and clinical activity, and defined a biologically active dose range. METHODS: A phase 2 study of rhIL-18 was conducted in untreated AJCC stage IV melanoma. Patients were randomized to 1 of 3 dose groups (0.01, 0.1, and 1.0 mg/kg/d) of rhIL-18 administered as 5 daily intravenous infusions repeated every 28 days. A 2-stage design with a stopping rule was used. RESULTS: A total of 64 patients (median age, 57.5 years) with metastatic melanoma (M1a/b (30), M1c (34)) were accrued to stage I, and randomized to 3 groups (21 [0.01 mg/kg/d], 21 [0.1 mg/kg/d], 22 [1.0 mg/kg/d]). Five patients experienced 10 grade 3 drug-related adverse events (AEs): polyarthritis (1 subject: 0.01 mg/kg); deep vein thrombosis, pulmonary embolism (1:0.01 mg/kg); cognitive disorder (1:0.1 mg/kg); fatigue, dyspnea, pleural effusion, lymphopenia (1:1.0 mg/kg); fatigue, lymphopenia (1:1.0 mg/kg). One patient experienced a grade 4 AE of increased lipase (0.1 mg/kg) that led to permanent discontinuation from the study. Among 63 subjects evaluable for response, 1 (M1c; 0.01 mg/kg) achieved a partial response after 4 cycles. Four subjects (3 at 0.01 mg/kg and 1 at 1.0 mg/kg) had stable disease maintained for 6 months or longer. Due to the low apparent level of clinical efficacy using RECIST criteria, the study was terminated at the end of stage 1. The median progression free survival for the 3 groups was 7.5 (0.01), 7.4 (0.1), and 7.3 (1.0) weeks. CONCLUSIONS: rIL-18 as tested in this trial was well tolerated, but had limited activity as a single agent in patients with metastatic melanoma.