A Phase I Study of PD 0332991: Complete CDK4/6 Inhibition and Tumor Response In Sequential Combination with Bortezomib and Dexamethasone for Relapsed and Refractory Multiple Myeloma

PD 0332991, the only known selective inhibitor of cyclin-dependent kinase (CDK) 4/6, is reversible and orally bioavailable. Inhibition of CDK4/6 phosphorylation of retinoblastoma (Rb) induces prolonged early G1 cell cycle arrest and synchronous progression to S phase upon withdrawal, which sensitizes human multiple myeloma (MM) cells to killing by bortezomib (B) or dexamethasone (D) in vitro and in animal models. This multicenter phase I trial is investigating the combination of PD 0332991 with these agents in MM during prolonged G1 arrest alone (Schedule A) or together with synchronization into S phase (Schedule B). The primary objective was to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of PD 0332991 and the schedule for combination.

Adults with Rb protein-positive, symptomatic, relapsed and/or refractory MM (International Myeloma Working Group [IMWG] definition) after ≥1 prior treatment were eligible. Patients (pts) received oral PD 0332991 once daily on Days 1–21 of a 28-day cycle (Schedule A) or Days 1–12 of a 21-day cycle (Schedule B) for a maximum of 10 cycles. The starting dose of PD 0332991 was 100 mg, with planned escalation to 125 mg or de-escalation to 75 mg. Intravenous B 1.0 mg/m² (with planned escalation to 1.3 mg/m²) and oral D 20 mg were administered on Days 8, 11, 15, and 18 on both schedules. A 3+3 dose-escalation scheme was used. The MTD was defined as the dose level at which ≤1/6 pts experienced dose-limiting toxicity (DLT), with the next higher dose level having ≥2/3 or ≥2/6 pts with DLTs. The RP2D was determined based on the MTD and overall safety and tolerability. The primary endpoint was first-cycle DLTs; tumor response (per IMWGURC) and PD 0332991-mediated inhibition of CDK4/6 activity and cell proliferation by immunohistochemistry (IHC) of CDK4/6-specific phosphorylation of Rb (pSRb) and Ki67, respectively, in bone marrow MM cells were secondary endpoints. The effects of B and D on PD 0332991 pharmacokinetics were also evaluated.

Twenty-one pts were enrolled: 9 on Schedule A (3 on PD 0332991 100 mg and 6 on 75 mg); 12 on Schedule B (7 on 100 mg and 5 on 125 mg). Sixty-seven percent of pts had an Eastern Cooperative Oncology Group performance status of 1. At baseline, median β₂ microglobulin was 3.9 (range 1.6–14.8), median hemoglobin was 10.9 (7.3–13.4), and median calcium was 9.1 (6.6–11.5). The median number of prior therapies was 4 (range 1–9); 86% had received prior B. Eighteen pts have discontinued (14 due to progressive disease; 4 due to an adverse event [AE]). On Schedule A, 2/3 pts on PD 0332991 100 mg and 2/6 pts on 75 mg experienced DLTs (inability to receive ≥80% of PD 0332991 or B doses due to treatment-related toxicity), thus the MTD was not determined. On Schedule B, 1/6 DLT-evaluable pts on 100 mg and 2/4 on 125 mg experienced DLTs, and the MTD was determined to be PD 0332991 100 mg plus B 1.0 mg/m² and D 20 mg. The most common treatment-related AEs were grade ≥3 thrombocytopenia (n=13) and neutropenia (n=7). There were no pts with QTc intervals >500 msec observed on study. The mean plasma AUC_(0–12) of PD 0332991 was 539 ng · h/mL in the absence and 555 ng · h/mL in the presence of B and D (n=6). IHC showed preferential and complete (13/16 pts) or >80% (3/16 pts) inhibition of both pSRb and Ki67 in bone marrow MM cells before initiation of B and D treatment on Day 8, and cell cycle progression following PD 0332991 withdrawal on Day 18 of Schedule B (7/7 pts). One pt achieved a very good partial response (VGPR), 1 achieved a PR, and 3 had stable disease ≥3 months.

In this first phase I trial of PD 0332991 in combination therapy, the MTD and RP2D have been determined to be PD 0332991 100 mg plus B 1.0 mg/m² and D 20 mg on Schedule B in MM. The most commonly reported AEs were cytopenias, consistent with the known safety profiles of PD 0332991 and B. B and D had no apparent impact on the plasma AUC_(0–12) of PD 0332991. Regardless of treatment history, PD 0332991 preferentially and completely inhibited CDK4/6 and cell cycle progression in MM cells, and this was reversible. Encouraging antitumor activity was observed in this heavily pretreated MM population, including VGPR in a pt with t(4:14) who had relapsed on lenalidomide, bortezomib, and carfilzomib therapies and a stem cell transplant. The phase II portion of the trial to evaluate the antitumor activity of targeting CDK4/6 with PD 0332991 using the Schedule B combination is underway.

Niesvizky:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millenium: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Consultancy, Research Funding. Lentzsch:Celgene Corp: Research Funding. Singhal:Takeda/Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx: Research Funding; Celgene: Speakers Bureau. Zonder:Millennium: 10/16/2010 Myeloma and Amyloidosis Patient Day Symposium – Corporate support from multiple sponsors for a one-day educational event, Consultancy, Research Funding; Celgene: 10/16/2010 Myeloma and Amyloidosis Patient Day Symposium – Corporate support from multiple sponsors for a one-day educational event; Novartis: 10/16/2010 Myeloma and Amyloidosis Patient Day Symposium – Corporate support from multiple sponsors for a one-day educational event; Proteolix: 10/16/2010 Myeloma and Amyloidosis Patient Day Symposium – Corporate support from multiple sponsors for a one-day educational event. Courtney:Pfizer: Employment, Equity Ownership. Shaik:Pfizer Inc: Employment, Equity Ownership. Kim:Pfizer Inc.: Employment, Equity Ownership. Randolph:Pfizer: Employment, Equity Ownership.