Array BioPharma & AstraZeneca

Abstract No. 9004

Title: Phase II double-blind, randomized study of selumetinib (SEL) plus dacarbazine (DTIC) versus placebo (PBO) plus DTIC as first-line treatment for advanced BRAF-mutant cutaneous or unknown primary melanoma.

Background: BRAF mutations play an oncogenic role in melanomas. Selumetinib (AZD6244, ARRY-142886) inhibits MEK1/2 downstream of B-Raf and may have an additive effect to chemotherapy. We prospectively evaluated SEL + DTIC vs PBO + DTIC in patients with stage III-IV BRAF mutation-positive advanced cutaneous or unknown primary melanoma (NCT00936221).

Methods: Eligible patients (pts) received iv DTIC 1000 mg/m2, and po SEL 75 mg or matched PBO bd as first-line treatment. The primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and safety and tolerability.

Results: A total of 385 pts were screened across 44 centers; 91 patients were randomized (SEL + DTIC, 45; PBO + DTIC, 46). One pt from each group did not receive the randomized treatment. Baseline characteristics were balanced between the two groups, with the exception of histology, gender and previous medications. At data cut-off, 66 deaths had occurred (73% maturity) and median follow-up was 12.3 mo. OS was longer for SEL + DTIC vs PBO + DTIC (median 13.9 vs 10.5 mo), but this did not meet statistical significance (HR 0.93; 80% CI 0.67, 1.28; 1-sided p=0.3873). PFS was significantly improved for SEL + DTIC vs PBO + DTIC, median 5.6 vs 3.0 mo (HR 0.63; 80% CI 0.47, 0.84; 1-sided p=0.021). ORR was 40% with SEL + DTIC vs 26% with PBO + DTIC. Most frequent adverse events (AEs) observed with SEL + DTIC were: nausea (64%), dermatitis acneiform (52%), diarrhea (48%), vomiting (48%), and peripheral edema (43%). AEs that led to hospitalization were higher for SEL + DTIC vs PBO + DTIC (36 vs 13%), and were mostly infections and gastrointestinal disorders. The incidence of grade greater than equal to 3 AEs (68 vs 42%), serious AEs (50 vs 18%) and discontinuation of the randomized treatment due to AEs were higher for SEL + DTIC vs PBO + DTIC (16 vs 4%).

Conclusions: Clinical activity was observed in patients with BRAF mutation-positive melanoma treated with SEL + DTIC, reflected by a nonsignificant improvement in OS and a significant benefit in PFS. Tolerability of this combination was generally consistent with the monotherapy safety profiles.

BioMarin Pharmaceuticals

Abstract No. 2580

Title: First-in-human trial of novel oral PARP inhibitor BMN 673 in patients with solid tumors.

Background: BMN 673 is the most potent and specific inhibitor of PARP1/2 in clinical development (IC50less than1nM). In tumors genetically dependent on DNA repair by homologous recombination PARP inhibition induces synthetic lethality.

Methods: Pharmacokinetics (PK), pharmacodynamics (PD), safety and anti-tumor activity of BMN 673 were evaluated in a 2-stage dose-escalation study with 3-6 patients (pts)/dose level. In dose escalation (Stage 1) cycle 1 was 6 wks, with drug taken on days 1 and 8-35, for PK and PD assays, followed by daily continuous dosing in 4-wk cycles. Stage 2 (expansion at MTD) recruits pts with tumors defective in DNA repair: Ewing sarcoma, small cell lung cancer or tumors associated with BRCA mutation (mut).

Results: 39 pts (33F/6M) were enrolled in 9 cohorts from 25 to 1100 ug/d that defined a MTD of 1000 ug/d. Median (range) age was 58 (19-81), PS 0 (0-1) and # of prior therapies 4 (1-13). Tumors (# with deleterious BRCA 1/2 mut) included 23 ovarian/primary peritoneal (17); 8 breast (6); 3 pancreas; 2 colon; 1 prostate (1), and 1 mullerian carcinosarcoma. 17 and 8 pts had BRCA 1 and 2 mut, respectively. Dose-limiting thrombocytopenia occurred in 1/6 and 2/5 pts at 900 and 1100 ug/d, respectively. Potentially-related adverse events in greater than 10% of pts (# grade 1 and 2/grade 3 and 4) included fatigue (10/0); nausea (10/0); flatulence (4/0); anemia (5/2); neutropenia (4/3); thrombocytopenia (1/3); and grade 1 alopecia (10).  Inhibition of PARP activity in PBMCs was observed at doses greater than or equal to 100 µg/d.  BMN 673 plasma concentrations peaked 1-2 hrs post-dose; exposure increased dose proportionally. Steady state plasma concentrations were reached by the end of the 2nd week of daily dosing; mean Cmax: 0.30 - 25.4 ng/mL and AUC0-24: 3.96 - 203 ng-hr/mL across the 25 to 1100 ug/d dose range after 28d of daily dosing. RECIST and/or CA-125 responses occurred at doses greater than or equal to 100 ug/d in 11/17 BRCA carrier ovarian/peritoneal cancer pts. Objective responses occurred in 2/6 BRCA-carrier breast cancer pts.

Conclusions: BMN 673 is well tolerated with impressive anti-tumor activity in pts with BRCA mut with a single agent recommended Phase II trial dose of 1000 ug/d due to dose-limiting thrombocytopenia.

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