Abstract 469P
Background
Alterations in cyclin-dependent kinases (CDK) are validated targets for cancer therapy. Palbociclib (palbo) selectively inhibits the CDK4/6/RB pathway. Platinum-based chemotherapy regimens (P) is the backbone for systemic therapy of many solid tumors. CDK4/6 inhibitors potentiate the efficacy of P in preclinical models. This study used an escalating-deescalating design to establish the safety and recommended phase II doses (RP2D) of the combination of palbo and cisplatin (cis; Arm A) or carboplatin (carbo; Arm B) in patients with advanced solid malignancies.
Methods
Enrollment proceeded using the Bayesian adaptive design Escalation with Overdose Control (EWOC). Starting doses were palbo 100mg once daily, cis 60mg/m2 and carbo AUC 4; in a 28-day cycle. Eligible patients included those with stage IV or locally advanced solid organ malignancy; age ≥18 years, ECOG PS 0-2 and measurable disease per RECIST 1.1. Primary endpoint was safety and RP2D of the combination.
Results
We enrolled 39 patients on study (Arm A = 21; Arm B =18). Median age of 63years (range 22-76); 35.9% Black/African ancestry; 46.2% females. Most common primary disease sites were: prostate (25.6%), pancreas (12.8%), breast (10.3%), lung (7.7%), ovarian (7.7%) and gastric (5.1%). Arm A: 3 DLTs (neutropenic fever, grade [Gr] 4 neutropenia and Gr 3 renal failure) were observed at DL2, defining the RP2D as palbo 100mg on days 2-22 + cis 60mg/m2 IV on day 1. Arm B: 2 DLTs (Gr 3 fatigue and Gr 3 anemia) were observed on DL1, with the RP2D defined as palbo 75mg on days 2-22 + carbo AUC 6 IV on day 1. Most common treatment emergent adverse events: Arm A- fatigue (67%), neutropenia (57%) and anemia (48%); Arm B– anemia (61%), neutropenia (44%), nausea (44%) and fatigue (39%). Objective response rates (ORR) were 12.5% (Arm A) and 25% (Arm B). Disease control rates (DCR) were 38% and 39% respectively.
Conclusions
The combination of palbo with cis or carbo had an acceptable safety profile. Clinical responses were observed in patients with multiple treatment refractory advanced cancers.
Clinical trial identification
NCT02897375.
Editorial acknowledgement
Legal entity responsible for the study
Emory University.
Funding
Pfizer.
Disclosure
O.B. Alese: Financial Interests, Personal and Institutional, Research Grant: Pfizer, Taiho Oncology, Ipsen Pharmaceuticals; Financial Interests, Institutional, Research Grant: GSK, Bristol Myers Squibb, PCI Biotech AS, Calithera Biosciences, Inc, SynCore Biotechnology Co., Ltd, Mabspace Biosciences, Corcept Therapeutics Inc, Hutchison MediPharma. All other authors have declared no conflicts of interest.