Pimasertib plus gemcitabine in metastatic pancreatic adenocarcinoma: Results of a safety run-in part of a phase II trial.

Background: Activating MAPK pathway mutations (predominantly RAS) occur with a high incidence in metastatic pancreatic adenocarcinoma (mPaCa). Pimasertib is a MEK1/2 inhibitor with potent activity in cell lines and xenografts with an activated MAPK pathway. This two-part trial in patients (pts) with mPaCa comprises a dose-escalation safety run-in and a randomized phase II part (EudraCT 2009-011992-61). We defined the maximum tolerated dose (MTD), safety, pharmacokinetics (PK) and antitumor activity of two pimasertib dosing schedules (S), and the recommended phase II dose (RP2D). Methods: Dose-escalation (3+3 design) in two dosing S of oral pimasertib: once-daily (qd) - 5 days on, 2 days off (S1); and twice-daily (bid) - continuous (S2) combined with the standard dose of gemcitabine (gem). Results: 53 pts (median age 61 years and ECOG performance status 0-1) have been treated at six dose levels in S1 (15 to 120 mg qd) and at 60 and 75 mg bid in S2. MTDs were defined as 120 mg qd and 75 mg bid. Two pts had a dose-limiting toxicity (DLT) in the DLT observation period: a grade (G) 3 confusion with ataxia and disorientation at 60 mg bid and a G4 suicidal ideation at 75 mg bid. G3-4 adverse events (AEs) in >5% of pts were: neutropenia (32%), thrombocytopenia (25%), asthenia (19%), dyspnea (9%), transaminitis (9%), anemia (8%), and diarrhea, pulmonary embolism, pulmonary sepsis (6% each). Most common AEs were asthenia (70%), ocular AEs (68%), skin rash (62%), nausea (58%), diarrhea (58%), peripheral edema (51%), thrombocytopenia (49%), vomiting (45%), mucositis (43%), neutropenia (38%), decreased appetite (36%) and anemia (34%). The main ocular AE was serous retinal detachment (58%); manageable retinal vein occlusion occurred in five pts. PK data were comparable to pimasertib monotherapy and published gem data. Partial responses were noted in 10 pts and stabilisation ≥3 months in 13 pts. Hot spot mutations in genes activating the MAPK and PI3K/AKT pathway and correlation with clinical outcome are being investigated. Conclusions: Pimasertib MTDs were reached. The RP2D was defined as 60 mg bid. PK was dose proportional and associated with target inhibition. Sustained responses were seen in both dosing schedules. Clinical trial information: 2009-011992-6

Health-related quality of life in patients with a germline BRCA mutation and metastatic pancreatic cancer receiving maintenance olaparib

BACKGROUND: Patients with metastatic pancreatic cancer often have a detriment in health-related quality of life (HRQoL). In the randomized, double-blind, phase III POLO trial progression-free survival was significantly longer with maintenance olaparib, a poly(ADP-ribose) polymerase inhibitor, than placebo in patients with a germline BRCA1 and/or BRCA2 mutation (gBRCAm) and metastatic pancreatic cancer whose disease had not progressed during first-line platinum-based chemotherapy. The prespecified HRQoL evaluation is reported here. PATIENTS AND METHODS: Patients were randomized to receive maintenance olaparib (300 mg b.i.d.; tablets) or placebo. HRQoL was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item module at baseline, every 4 weeks until disease progression, at discontinuation, and 30 days after last dose. Scores ranged from 0 to 100; a ≥10-point change or difference between arms was considered clinically meaningful. Adjusted mean change from baseline was analysed using a mixed model for repeated measures. Time to sustained clinically meaningful deterioration (TSCMD) was analysed using a log-rank test. RESULTS: Of 154 randomized patients, 89 of 92 olaparib-arm and 58 of 62 placebo-arm patients were included in HRQoL analyses. The adjusted mean change in Global Health Status (GHS) score from baseline was <10 points in both arms and there was no significant between-group difference [-2.47; 95% confidence interval (CI) -7.27, 2.33; P = 0.31]. Analysis of physical functioning scores showed a significant between-group difference (-4.45 points; 95% CI -8.75, -0.16; P = 0.04). There was no difference in TSCMD for olaparib versus placebo for GHS [P = 0.25; hazard ratio (HR) 0.72; 95% CI 0.41, 1.27] or physical functioning (P = 0.32; HR 1.38; 95% CI 0.73, 2.63). CONCLUSIONS: HRQoL was preserved with maintenance olaparib treatment with no clinically meaningful difference compared with placebo. These results support the observed efficacy benefit of maintenance olaparib in patients with a gBRCAm and metastatic pancreatic cancer. CLINCALTRIALS.GOV NUMBER: NCT02184195.status: publishe

Health-related quality of life in patients with a germline BRCA mutation and metastatic pancreatic cancer receiving maintenance olaparib

Background: Patients with metastatic pancreatic cancer often have a detriment in health-related quality of life (HRQoL). In the randomized, double-blind, phase III POLO trial progression-free survival was significantly longer with maintenance olaparib, a poly(ADP-ribose) polymerase inhibitor, than placebo in patients with a germline BRCA1 and/or BRCA2 mutation (gBRCAm) and metastatic pancreatic cancer whose disease had not progressed during first-line platinum-based chemotherapy. The prespecified HRQoL evaluation is reported here. Patients and methods: Patients were randomized to receive maintenance olaparib (300 mg b.i.d.; tablets) or placebo. HRQoL was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item module at baseline, every 4 weeks until disease progression, at discontinuation, and 30 days after last dose. Scores ranged from 0 to 100; a ≥10-point change or difference between arms was considered clinically meaningful. Adjusted mean change from baseline was analysed using a mixed model for repeated measures. Time to sustained clinically meaningful deterioration (TSCMD) was analysed using a log-rank test. Results: Of 154 randomized patients, 89 of 92 olaparib-arm and 58 of 62 placebo-arm patients were included in HRQoL analyses. The adjusted mean change in Global Health Status (GHS) score from baseline was <10 points in both arms and there was no significant between-group difference [-2.47; 95% confidence interval (CI) -7.27, 2.33; P = 0.31]. Analysis of physical functioning scores showed a significant between-group difference (-4.45 points; 95% CI -8.75, -0.16; P = 0.04). There was no difference in TSCMD for olaparib versus placebo for GHS [P = 0.25; hazard ratio (HR) 0.72; 95% CI 0.41, 1.27] or physical functioning (P = 0.32; HR 1.38; 95% CI 0.73, 2.63). Conclusions: HRQoL was preserved with maintenance olaparib treatment with no clinically meaningful difference compared with placebo. These results support the observed efficacy benefit of maintenance olaparib in patients with a gBRCAm and metastatic pancreatic cancer. ClincalTrials.gov number: NCT02184195