Showing papers by "Michael S. Gordon published in 2015"

Phase I study combining anti-PD-L1 (MEDI4736) with BRAF (dabrafenib) and/or MEK (trametinib) inhibitors in advanced melanoma.

Abstract: 3003 Background: Inhibition of the MAPK pathway with dabrafenib (D) and trametinib (T) is efficacious in BRAF-mutant melanoma. MEK inhibitors have also shown activity in BRAF WT melanoma, particula...

Avelumab (MSB0010718C), an anti-PD-L1 antibody, in patients with previously treated, recurrent or refractory ovarian cancer: A phase Ib, open-label expansion trial.

Abstract: 5509 Background: The programmed death-1 receptor (PD-1) and its ligand (PD-L1) are key therapeutic targets in the reactivation of the immune response against multiple cancers. Avelumab (proposed IN...

Clinical activity, safety and predictive biomarkers of the engineered antibody MPDL3280A (anti-PDL1) in non-small cell lung cancer (NSCLC): update from a phase Ia study.

Abstract: 8029 Background: NSCLC exhibits mutational complexity, which is associated with increased tumor immunogenicity PD-L1 expression in the tumor microenvironment can inhibit antitumor immunity MPDL32

Updated efficacy of the MEK inhibitor trametinib (T), BRAF inhibitor dabrafenib (D), and anti-EGFR antibody panitumumab (P) in patients (pts) with BRAF V600E mutated (BRAFm) metastatic colorectal cancer (mCRC).

Abstract: 103 Background: BRAF V600E mutations occur in 5–10% of mCRC and confer a poor prognosis. Unlike BRAFm melanoma, BRAF and MEK inhibitors have minimal activity in BRAFm mCRC. Preclinical data suggest...

Assessment of the drug interaction potential and single- and repeat-dose pharmacokinetics of the BRAF inhibitor dabrafenib

Abstract: The induction of CYP2C9 by dabrafenib using S-warfarin as a probe and the effects of a CYP3A inhibitor (ketoconazole) and a CYP2C8 inhibitor (gemfibrozil) on dabrafenib pharmacokinetics were evaluated in patients with BRAF V600 mutation-positive tumors. Dabrafenib single- and repeat-dose pharmacokinetics were also evaluated. S-warfarin AUC(0- ∞) decreased 37% and Cmax increased 18% with dabrafenib. Dabrafenib AUC(0- τ) and C(max) increased 71% and 33%, respectively, with ketoconazole. Hydroxy- and desmethyl-dabrafenib AUC(0-τ) increased 82% and 68%, respectively, and AUC for carboxy-dabrafenib decreased 16%. Dabrafenib AUC(0-τ) increased 47%, with no change in C(max), after gemfibrozil co-administration. Gemfibrozil did not affect systemic exposure to dabrafenib metabolites. Single- and repeat-dose dabrafenib pharmacokinetics were consistent with previous reports. All cohorts used the commercial capsules. More-frequent monitoring of international normalized ratios is recommended in patients receiving warfarin during initiation or discontinuation of dabrafenib. Substitution of strong inhibitors or strong inducers of CYP3A or CYP2C8 is recommended during treatment with dabrafenib.

Phase I study of XL281 (BMS-908662), a potent oral RAF kinase inhibitor, in patients with advanced solid tumors

Abstract: Background XL281 is a potent and selective inhibitor of wild-type and mutant RAF kinases with anti-tumor activity in multiple xenograft models. Mutations in KRAS or BRAF can activate the RAF/MEK/ERK pathway in human tumors and may confer sensitivity to RAF kinase inhibitors. Methods We performed a phase I study of XL281 in patients with advanced solid tumors. Patients were enrolled in successive cohorts of XL281 orally once daily in 28-day cycles. Twice daily dosing, different formulations, and the effect of food and famotidine were also studied. At the MTD expanded cohorts with defined mutations were treated. Results In total, 160 patients were treated. The MTD on the QD schedule was 150 mg. The most common toxicities were diarrhea, nausea, and fatigue. Plasma Cmax and AUC increased with dose. Famotidine resulted in lower AUC while food had no effect. Two patients had partial responses by RECIST: One with papillary thyroid cancer with NRAS mutation and one with uveal melanoma. Another nine patients had tumor decrease of >10 % but did not meet RECIST criteria for PR. Matched tumors pairs from 33 patients showed evidence of RAF inhibition with significant decreases in pERK, pMEK and pAKT. Conclusions XL281 was generally well tolerated and the MTD was established at 150 mg/day. Partial responses and clinical benefit were observed in several patients. Tumor biopsies demonstrated effective target inhibition.

Safety, tolerability, and pharmacokinetics of single and multiple doses of intravenous cixutumumab (IMC-A12), an inhibitor of the insulin-like growth factor-I receptor, administered weekly or every 2 weeks in patients with advanced solid tumors

Abstract: Background: Type 1 insulin-like growth factor receptor (IGF-IR) signaling is often dysregulated in cancer. Cixutumumab, a fully human IgG1 monoclonal antibody, blocks IGF-IR and inhibits downstream signaling. The current study determined the recommended dose, safety, and pharmacokinetic (PK) profile of weekly or every-2-week dosing of cixutumumab. Patients and Methods: Two open-label, multicenter phase I studies evaluated weekly (3–15 mg/kg) or every-2-weeks (6–15 mg/kg) dosing of cixutumumab in patients with advanced solid tumors. Serial blood samples for PK were collected up to 168–336 h (day 8–15) following the first administration of cixutumumab. Efficacy was evaluated as best overall tumor response. Results: A total of 24 and 16 patients were enrolled in the weekly and every-2-week dosing studies, respectively. Treatment-emergent adverse events (≥10 %) included hyperglycemia, fatigue, anemia, nausea, and vomiting. Severe adverse events (AE) were infrequent; one serious AE (grade 3 electrocardiogram QT prolongation) was deemed possibly cixutumumab-related (10 mg/kg every-2-weeks). One death occurred due to disease progression (6 mg/kg weekly cohort). Maximum serum concentrations increased with dose. A maximum tolerated dose was not identified; pre-determined target serum minimum concentrations (60 μg/mL) were achieved with ≥6 mg/kg weekly and ≥10 mg/kg every-2-week dosing. Cixutumumab terminal elimination half-life is approximately a week (individual range, t1/2 = 4.58–9.33 days based upon 10 mg/kg every 2 weeks). Overall, stable disease was achieved in 25 % of all patients. Conclusions: Cixutumumab was associated with favorable safety and PK profiles. A dosing regimen of 10 mg/kg every 2 weeks was recommended for subsequent disease-focused clinical trials.

Relative bioavailability of pediatric oral solution and tablet formulations of trametinib in adult patients with solid tumors

Abstract: Trametinib (Mekinist®) is a selective inhibitor of mitogen-activated protein kinase kinase (MEK) approved in the United States as a single agent and in combination with dabrafenib (Tafinlar®) for treatment of patients with unresectable or metastatic melanoma with a positive BRAF V600E/V600K mutation for which a pediatric oral solution formulation is being developed. This open-label, two-period, two-treatment, randomized, crossover study assessed the relative bioavailability of the trametinib pediatric oral solution compared to the tablet formulation after a single-dose administration to adult patients with solid tumors. Primary pharmacokinetic endpoints derived from standard non-compartmental methods were AUC0-inf , AUC0-t , and Cmax . As expected, Cmax was higher and Tmax earlier for the pediatric oral solution compared to the tablet formulation. Administration of the trametinib pediatric oral solution resulted in a 12%, 10%, 18%, and 71% higher AUC0-inf , AUC0-last , AUC0-24 , and Cmax , respectively, as compared to the tablet formulation. Safety results were aligned with the known safety profile of trametinib. No serious or non-serious adverse events resulted in study drug withdrawal. Palatability of the pediatric oral solution was evaluated and found to be acceptable to most adult patients, but may differ in the pediatric population.

A Phase I dose-escalation study of afatinib combined with nintedanib in patients with advanced solid tumors

Abstract: Aims: To evaluate the safety and maximum tolerated dose (MTD) of afatinib combined with nintedanib. Materials & methods: Patients received afatinib 10–20 mg daily plus nintedanib 150–200 mg twice daily (28-day cycle). Dose escalation followed a 3+3 design. Results: Patients received afatinib/nintedanib: 10/150 mg (n = 11); 10/200 mg (n = 13; MTD); 20/200 mg (n = 4). Four patients had dose-limiting toxicities (all grade 3): increased alanine aminotransferase (afatinib/nintedanib: 10/150 mg), diarrhea (10/200 mg), dehydration (20/200 mg), diarrhea with elevated liver enzymes (20/200 mg). Frequent treatment-related adverse events were diarrhea, nausea, anorexia, fatigue and vomiting. In total, 14 patients (46.2%) had objective responses at the MTD. Conclusion: The MTD, afatinib 10 mg daily plus nintedanib 200 mg twice daily, had a manageable safety profile, but was considered subtherapeutic for Phase II evaluation.

Phase 1 study of the PSMA-targeted tubulysin small-molecule drug conjugate EC1169 in patients with metastatic castrate-resistant prostate cancer (mCRPC).

Abstract: 2586Background: EC1169 is a small molecule drug conjugate designed to bind to prostate cancer (PCa) cells via prostate specific membrane antigen (PSMA) and, following endocytosis, to then release t...

ABT-414 in patients with advanced solid tumors likely to overexpress the epidermal growth factor receptor (EGFR).

Abstract: 2510 Background: Aberrant EGFR expression and signaling has been identified as a hallmark of cancer growth and survival. ABT-414 is an antibody-drug conjugate composed of the antibody ABT-806, targ...

A phase Ib dose-escalation study of binimetinib (MEK162) in combination with weekly paclitaxel in patients with platinum-resistant epithelial ovarian, fallopian tube or primary peritoneal cancer.

Abstract: 5516 Background: Ovarian cancer is associated with key genetic alterations, including those that lead to activation of the RAS/RAF/MEK/ERK pathway. Binimetinib (BINI) is a potent, selective, allost...