Search

Abstract 2940 Background: PD 0332991 is an orally bioavailable selective inhibitor of cyclin-dependent kinase (CDK) 4/6. Inhibition of CDK4/6 phosphorylation of retinoblastoma (Rb) induces prolonged early G1 cell cycle arrest (pG1) and synchronous progression to S phase (pG1-S) upon withdrawal, which sensitizes human multiple myeloma (MM) cells to killing by bortezomib (B) or dexamethasone (D) in vitro and in animal models. Based on these observations, a phase 1/2 study in combination with B plus D in patients (pts) with relapsed and/or refractory MM was initiated. The phase 1 part of the study (completed) determined the recommended phase 2 dose and schedule to be PD 0332991 100 mg QD 12 days on followed by 9 days off treatment in a 21-day cycle with intravenous B 1.0 mg/m2 plus oral D 20 mg administered on Days 8 and 11 in pG1 and 15 and 18 in pG1-S (Niesvizky et al. ASH 2010). We present preliminary data from the phase 2 part of the study. Methods: Pts with Rb protein-positive, measurable (as defined by International Myeloma Working Group [IMWG]) progressive, relapsed or refractory MM after ≥1 prior treatment were eligible. Prior B was allowed only if there was a response and disease progression occurred off therapy. Pts received oral PD 0332991 once daily on Days 1–12 in a 21-day cycle in combination with intravenous B 1.0 mg/m2 plus oral D 20 mg administered on Days 8, 11, 15, and 18. The primary endpoint is overall response rate (ORR); secondary endpoints include time to progression (TTP), progression-free survival (PFS), overall survival, duration of response, and safety. PD 0332991-mediated inhibition of CDK4/6-specific phosphorylation of Rb (pSRb) and Ki67 in bone marrow MM cells were also assessed. The phase 2 part of the study is a Simon Two-Stage Minimax design; 25 response evaluable patients were to be enrolled into the first stage. Results: 39 pts have been tested for Rb and 36 pts (92%) were positive. Of the 36 pts, 30 pts have been enrolled to date including 2 pts who did not receive the study treatment, and 23 pts are considered response evaluable as of the data cut-off. 56% of pts had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 1 and 8% had ECOG PS of 2. At baseline, median β2 microglobulin was 3.1 (range 1.6–26.2), median hemoglobin was 11.2 (7.2–13.6), median calcium was 9.4 (8.7–11.9). The median number of prior therapies was 2 (range 1–8); 55% had received prior B. Sixteen pts have discontinued (9 due to progressive disease, 3 due to AE, 2 consent withdrawal, and 2 not treated). The most common treatment-related AEs were thrombocytopenia (44%), nausea (20%), anemia, constipation, fatigue, and neutropenia (all 16%); 32% of pts reported grade ≥3 thrombocytopenia. IHC data showed on-treatment reduction in pSRb and Ki67 in MM cells from bone marrow of 3/3 patients with available samples. To date, 1 pt achieved a complete response (CR), 1 achieved a very good partial response (VGPR), 1 partial response (PR), 1 minor response (MR), and 5 stable disease (SD); 6 pts are too early for assessment. Conclusions: To date, the combination of PD 0332991 and B plus D has shown response in 4 pts with relapsed/refractory MM. The most commonly reported AEs were cytopenias, consistent with the known safety profiles of PD 0332991 and B. PD 0332991 inhibited phosphorylation of Rb and cell cycle progression in MM cells. The accrual to stage 1 is ongoing. Updated efficacy and safety data will be presented. Disclosures: Niesvizky: Millennium Pharmaceuticals: Consultancy; Millennium Pharmaceuticals: Research Funding; Millennium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Hess:Pfizer Oncology: Consultancy; Pfizer Oncology: Research Funding; Pfizer Oncology: Membership on an entity's Board of Directors or advisory committees. Spicka:Janssen-Cilag: Consultancy; Celgene: Consultancy; Celgene: Research Funding; Janssen-Cilag: Honoraria; Celgene: Honoraria; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Jakubczak:Pfizer Oncology: Employment; Pfizer Oncology: Equity Ownership. Kim:Pfizer Oncology: Equity Ownership; Pfizer Oncology: Employment. Randolph:Pfizer Oncology: Employment; Pfizer Oncology: Equity Ownership. Chen-Kiang:Pfizer Oncology: Research Funding.

Abstract 860 Background: 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. Methods: 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. Results: 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. Conclusions: 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. Disclosures: 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.