PHASE 1/2, OPEN-LABEL, RANDOMIZED STUDY OF THE SAFETY, EFFICACY, AND PHARMACOKINETICS OF LETROZOLE PLUS PD 0332991 (ORAL CDK 4/6 INHIBITOR) AND LETROZOLE SINGLE AGENT FOR THE FIRST-LINE TREATMENT OF ER POSITIVE, HER2 NEGATIVE ADVANCED BREAST CANCER IN POSTMENOPAUSAL WOMEN
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- Pfizer
- 入组人数
- 177
- 试验地点
- 90
- 主要终点
- Number of Participants With Treatment-Related Adverse Events at Phase 1
研究概览
简要总结
The study is aimed to confirm that letrozole + PD 0332991 is safe and tolerable and to assess the effect of the combination on advanced breast cancer
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •Inoperable estrogen receptor positive and HER2 negative breast cancer.
- •Postmenopausal status.
- •Tumor tissue (archived acceptable) available for biomarker studies. For Phase 2 Part 2 - CCND1 amplification and/or loss of p16 as determined by the central laboratory.
- •Acceptable bone marrow, liver and kidney function.
排除标准
- •Prior or concomitant treatment for advanced breast cancer.
- •Other major cancer in the past 3 years.
- •Important cardiovascular events in the past 6 months.
研究组 & 干预措施
Arm A
letrozole + PD 0332991
干预措施: PD 0332991 (Drug)
Arm A
letrozole + PD 0332991
干预措施: letrozole (Drug)
Arm B
letrozole
干预措施: letrozole (Drug)
结局指标
主要结局
Number of Participants With Treatment-Related Adverse Events at Phase 1
时间窗: Maximum treatment duration (approximately 55 months)
An AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly.
Number of Participants With Treatment-Emergent Adverse Events (TEAEs; All Causalities) at Phase 1
时间窗: Maximum treatment duration (approximately 55 months)
An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly.
Progression-Free Survival (PFS) at Phase 2 - Investigator Assessment
时间窗: From randomization date to date of first documentation of progression or death (assessed up to 41 months)
PFS was defined as the time from randomization (or the first dose of study treatment for non-randomized studies) to the first documentation of objective tumor progression or to death due to any cause, whichever occurred first. PFS calculated as (Weeks or Months) = (first event date minus randomization or the first dose date plus 1) divided by 7 (or 30.44 if in months). PFS is usually characterized by the median, 25% percentile,75% percentile and their 95% Confidence Intervals (CIs).
Number of Participants With Dose Limiting Toxicities at Phase 1
时间窗: Cycle 2 (4 weeks)
Dose limiting toxicity was defined as any of the following TEAEs occurring during the second cycle of treatment and possibly attributable to the combination of letrozole plus Palbociclib: 1. Grade 4 hematologic toxicity (including platelets \<25,000/μL, ANC \<500/μL). 2. Grade 3 neutropenia associated with a documented infection or fever ≥38.5°C. 3. Grade ≥3 non-hematologic toxicities, except those that have not been maximally treated (eg, nausea, vomiting, diarrhea, hypertension). 4. Delay by ≥1 week in receiving the next scheduled dose of either study treatment due to persisting treatment-related toxicities (platelet count \<50,000/μL; ANC \<1,000/μL; nonhematologic toxicities of Grade ≥3 severity). 5. Inability to deliver at least 80% of the planned Palbociclib or letrozole doses during Cycle 2 due to toxicity possibly attributable to the study treatment.
次要结局
- Objective Response Rate - Percentage of Participants With Confirmed Objective Tumor Response at Phase 1(From Baseline up to end of study (assessed up to 55 months))
- Summary of Plasma Letrozole Pharmacokinetic Parameter Following Letrozole Alone and in Combination With Palbociclib: AUC24 at Phase 1(Cycle 2 Day 14, Cycle 2 Day 28)
- Overall Survival (OS) at Phase 2(From randomization until death (assessed up to 86 months))
- Percentage of Participants With Clinical Benefit Response (CBR) at Phase 1(From Baseline up to end of study (assessed up to 55 months))
- Summary of Plasma Palbociclib Steady-state Pharmacokinetic Parameter Following Palbociclib Alone and in Combination With Letrozole: Terminal Plasma Half-life (t1/2) at Phase 1(Cycle 1 Day 14, and Cycle 2 Day 14)
- Summary of Plasma Palbociclib Steady-state Pharmacokinetic Parameter Following Palbociclib Alone and in Combination With Letrozole: Apparent Volume of Distribution (Vz/F) at Phase 1(Cycle 1 Day 14, and Cycle 2 Day 14)
- Number of Participants With Increase From Baseline in Corrected QT (QTc) Interval at Phase 1(Cycle 1 Day 1 prior to dosing, Cycle 1 Day 14 (2, 4 [prior to meal], 8, 24, 48, and 96 hours after dosing of Palbociclib), Cycle 2 Day 1 and Day 14 (prior to and 4 hours after dosing of letrozole))
- Summary of Plasma Palbociclib Steady-state Pharmacokinetic Parameter Following Palbociclib Alone and in Combination With Letrozole: Maximum Observed Plasma Concentration (Cmax) at Phase 1(Cycle 1 Day 14, and Cycle 2 Day 14)
- Summary of Plasma Letrozole Pharmacokinetic Parameter Following Letrozole Alone and in Combination With Palbociclib: Cmax at Phase 1(Cycle 2 Day 14, and Cycle 2 Day 28)
- Summary of Plasma Palbociclib Steady-state Pharmacokinetic Parameter Following Palbociclib Alone and in Combination With Letrozole: Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC24) at Phase 1(Cycle 1 Day 14, and Cycle 2 Day 14)
- Summary of Plasma Palbociclib Steady-state Pharmacokinetic Parameter Following Palbociclib Alone and in Combination With Letrozole: Time to Maximum Plasma Concentration (Tmax) at Phase 1(Cycle 1 Day 14, and Cycle 2 Day 14)
- Summary of Plasma Palbociclib Steady-state Pharmacokinetic Parameter Following Palbociclib Alone and in Combination With Letrozole: Apparent Clearance (CL/F) at Phase 1(Cycle 1 Day 14, and Cycle 2 Day 14)
- Summary of Plasma Letrozole Pharmacokinetic Parameter Following Letrozole Alone and in Combination With Palbociclib: Tmax at Phase 1(Cycle 2 Day 14, and Cycle 2 Day 28)
- Objective Response Rate - Percentage of Participants With Confirmed Objective Response in Participants With Measurable Disease at Phase 2- Investigator Assessment(From randomization up to the end of treatment (approximately 41 months))
- Duration of Response at Phase 2 - Investigator Assessment(From randomization up to the end of treatment (approximately 41 months))
- Summary of Copy Number for CCND1 (CCND1/CEP11) and p16/INK4A (p16/CEP9) at Phase 2(Screening visit (≤ 28 Days prior to dosing))
- Objective Response Rate - Percentage of Participants With Confirmed Objective Response at Phase 2- Investigator Assessment(From randomization up to the end of treatment (approximately 41 months))
- Presence or Absence of Tumor Tissue Biomarkers at Phase 2 - p16/INK4A, CCND1(Screening visit (≤ 28 Days prior to dosing))
- Presence or Absence of Tumor Tissue Biomarkers at Phase 2 - Tumor Retinoblastoma (RB) and CyclinD1(Screening visit (≤ 28 Days prior to dosing))
- Number of Participants With TEAEs (All Causalities) at Phase 2(Baseline up to 28 days after last dose of study drug (for a maximum of 86 months))
- Number of Participants With CBR at Phase 2 - Investigator Assessment(From randomization up to the end of treatment (approximately 41 months))
- Time to Tumor Progression (TTP) at Phase 2-Investigator Assessment(From randomization up to the end of treatment (approximately 41 months))
- Percentage of Participants With Tumor Expression of CYP19A1 and CCND1 Genotypes at Phase 2(Screening visit (≤ 28 Days prior to dosing))
- Change From Baseline in Modified Brief Pain Inventory in Pain Severity Scale (mBPI-sf) Questionnaire at Phase 2(Baseline, End of treatment (approximately 41 months))
- Change From Baseline in Modified Brief Pain Inventory in Pain Interference Scale (mBPI-sf) Questionnaire at Phase 2(Baseline, End of treatment (approximately 41 months))
- Presence or Absence of Tumor Tissue Biomarkers at Phase 2 - Ki67(Screening visit (≤ 28 Days prior to dosing))
- Number of Participants With Treatment-Related Adverse Events at Phase 2(Baseline up to 28 days after last dose of study drug (for a maximum of 86 months))