A PHASE 1/2 STUDY OF THE EFFICACY, SAFETY, AND PHARMACOKINETICS OF ORAL PD-0332991, A CYCLIN-DEPENDENT KINASE 4 AND 6 (CDK4/6) INHIBITOR, AS SINGLE AGENT IN JAPANESE PATIENTS WITH ADVANCED SOLID TUMORS OR IN COMBINATION WITH LETROZOLE FOR THE FIRST-LINE TREATMENT OF POSTMENOPAUSAL JAPANESE PATIENTS WITH ER (+) HER2 (-) ADVANCED BREAST CANCER
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- Pfizer
- 入组人数
- 61
- 试验地点
- 16
- 主要终点
- Number of Participants With Dose Limiting Toxicities (DLT): Part 1 Phase 1
研究概览
简要总结
This study is comprised of two portions: a Phase 1 portion and a Phase 2 portion. The Phase 1 portion is a single-country, non-randomized, open label, clinical trial which will evaluate the safety, tolerability, preliminary efficacy, and PK profile of PD-0332991 as a single agent in Japanese patients with advanced solid tumors, and PD-0332991 in combination with letrozole in the first-line treatment of Japanese patients with ER(+) HER2(-) ABC. The Phase 2 portion is a single-country, non-randomized, open-label, single-cohort, multi-center clinical trial to evaluate the efficacy and safety of PD-0332991 in combination with letrozole for the first-line treatment of postmenopausal Japanese patients with ER(+) HER2(-) ABC.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 20 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •In Part 1, advanced solid tumor (except SCLC or retinoblastoma) proven histologically or cytologically at original diagnosis, that is refractory to standard therapy or for whom no standard of care therapy is available.
- •In Part 2 and Phase 2, post menopausal women with proven diagnosis of ER-positive, HER2-negative adenocarcinoma of the breast with evidence of locoregionally recurrent or metastatic disease (including bone only disease) not amenable to resection or radiation therapy with curative intent and for whom chemotherapy is not clinically indicated.
- •Adequate blood cell counts, kidney function and liver function and and Eastern Cooperative Oncology Group [ECOG] score of 0 or
- •Resolved acute effects of any prior therapy to baseline severity or Grade ≤1
- •Adult women (≥ 20 years of age) with proven diagnosis of adenocarcinoma of the breast with evidence of locoregionally recurrent or metastatic disease not amenable to resection or radiation therapy with curative intent and for whom chemotherapy is not clinically indicated.
- •Documentation of histologically or cytologically confirmed diagnosis of ER(+) breast cancer based on local laboratory results.
- •Adequate blood cell counts, kidney function and liver function and and Eastern Cooperative Oncology Group [ECOG] score of 0 to 2.
排除标准
- •Active uncontrolled or symptomatic CNS metastases.
- •Uncontrolled infection, unstable or sever intercurrent medical condition, or current drug or alcohol abuse
- •Active or unstable cardiac disease or history of heart attack within 6 months
- •HER2 positive tumor based on local laboratory results utilizing one of the sponsor approved assays.
- •Known active uncontrolled or symptomatic CNS metastases, carcinomatous meningitis, or leptomeningeal disease.
- •Prior neoadjuvant or adjuvant treatment with a non steroidal aromatase inhibitor (ie, anastrozole or letrozole) with disease recurrence while on or within 12 months of completing treatment.
研究组 & 干预措施
Single-agent PD-0332991
Phase 1 Part 1
干预措施: PD-0332991 (Drug)
PD-0332991 in combination with letrozole
Phase 1 Part 2
干预措施: PD-0332991 (Drug)
PD-0332991 in combination with letrozole
Phase 1 Part 2
干预措施: letrozole (Drug)
PD-0332991 with letrozole
Phase 2
干预措施: PD-0332991 (Drug)
PD-0332991 with letrozole
Phase 2
干预措施: letrozole (Drug)
结局指标
主要结局
Number of Participants With Dose Limiting Toxicities (DLT): Part 1 Phase 1
时间窗: Lead-in period (Day -7) up to Day 28 (Cycle 1)
DLT was classified as per common terminology criteria for adverse events (CTCAE) version 4.0 as any of the events occurring during 28 days of Cycle 1,attributed to study drug:grade 4 neutropenia(for a duration of greater than \[\>\]7 days); febrile neutropenia (grade greater than or equal to \[\>=\]3 neutropenia,body temperature \>=38.5 degree Celsius);grade \>=3 thrombocytopenia with bleeding episode;grade 4 thrombocytopenia;grade \>=3 non-hematologic toxicity except grade 3 or more nausea, vomiting,electrolyte abnormality(if controllable by therapy);grade 3 QTc prolongation(\>500 millisecond \[msec\])persist after correction of reversible cause such as electrolyte abnormalities or hypoxia. Lack of hematologic recovery (platelets less than \[\<\]50,000/microliter \[mcL\],absolute neutrophil count \<1,000/mcL,hemoglobin \<8.0 gram/deciliter \[g/dL\]) or prolonged non hematologic toxicities that delays initiation of next dose by \>7 days;receipt of \<75 percent of planned dose in first cycle due to toxicity.
Percentage of Participants With 1 Year Progression Free Survival (PFS): Phase 2
时间窗: From initiation of treatment up to 12 months
PFS was defined as the time from first dose of study treatment to the date of the first documentation of objective progression of disease (PD) or death due to any cause in the absence of documented PD, whichever occurred first. PD was defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.1-year PFS was defined as the percentage of participants without PFS events (PD or death due to any cause) at 12 months based on the Kaplan-Meier estimate. Percentage of participants with 1-year PFS with 90% confidence interval (CI) were reported.
Number of Participants With Treatment-Related Adverse Events (AEs) and Serious Adverse Events (SAEs): Part 2 Phase 1
时间窗: Baseline (Day 1) up to 28 days after last dose of study drug (up to 1673 days)
A treatment related AE is any untoward medical occurrence in a clinical investigation participant administered a product or medical device; the event had a causal relationship with the treatment or usage. A 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. Relatedness was judged by investigator. AEs included both serious and non-serious adverse events.
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) By Severity: Part 2 Phase 1
时间窗: Baseline (Day 1) up to 28 days after last dose of study drug (up to 1673 days)
AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An AE was considered treatment emergent if occurred for the first time after the start of study treatment or occurred prior to the start of treatment but increased in National Cancer Institute (NCI) CTCAE grade during study treatment period. AE severity was defined to be the maximum toxicity grade of the TEAEs experienced by the participants during the study. AE was assessed according to severity as: Grade 1 (mild AE), Grade 2 (moderate AE), Grade 3 (severe AE), Grade 4 (life-threatening consequences) and Grade 5 (death related to AE).
次要结局
- Area Under the Plasma Concentration-Time Curve From 0 to Time 24 Hours (AUC24) of PD-0332991 Following Single Dose: Part 1 Phase 1(Single dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12 and 24 hours post-dose in Lead-in period (Day -7))
- Number of Participants With Clinically Significant Laboratory Abnormalities(Part 1 Phase 1: Lead-in period (Day -7) up to 308 days; Part 2 Phase 1: Baseline (Day 1) up to 1673 days; Phase 2: Baseline (Day 1) up to 1526 days)
- AUC24 Dose Normalized to 125 mg of PD-0332991 Following Single Dose: Part 1 Phase 1(Single dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12 and 24 hours post-dose in Lead-in period (Day -7))
- Cmax Dose Normalized to 125 mg of PD-0332991: Part 1 Phase 1(Single dose: 0 hour (pre-dose),1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose in Lead-in period (Day -7), Multiple dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24 hours post-dose on Cycle 1 Day 8)
- Number of Participants With Treatment-Emergent Adverse Events (AEs) By Severity: Phase 1 (Part 1) and Phase 2(Part 1 Phase 1: Lead-in period (Day -7) up to 28 days after last dose of study drug (up to 308 days), Phase 2: Baseline (Day 1) up to 28 days after last dose of study drug (up to 1526 days))
- Area Under the Plasma Concentration Time Curve Over Dosing Interval (AUCtau) of PD-0332991 Following Multiple Dose: Part 1 Phase 1(Multiple dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24 hours post-dose on Cycle 1 Day 8)
- AUCtau Dose Normalized to 125 Milligram (mg) of PD-0332991 Following Multiple Dose: Part 1 Phase 1(Multiple dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24 hours post-dose on Cycle 1 Day 8)
- Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUCinf) of PD-0332991 Following Single Dose: Part 1 Phase 1(Single dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose in Lead-in period (Day -7))
- AUCinf Dose Normalized to 125 mg of PD-0332991 Following Single Dose: Part 1 Phase 1(Single dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose in Lead-in period (Day -7))
- Apparent Oral Clearance of PD-0332991: Part 1 Phase 1(Single dose: 0 hour (pre-dose),1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose in Lead-in period (Day -7), Multiple dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24 hours post-dose on Cycle 1 Day 8)
- Pre-dose Plasma Concentration (Ctrough) of PD-0332991 Following Multiple Dose: Part 1 Phase 1(Multiple dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24 hours post-dose on Cycle 1 Day 8)
- AUClast Dose Normalized to 125 mg of PD-0332991 Following Single Dose: Part 1 Phase 1(Single dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose in Lead-in period (Day -7))
- Area Under the Plasma Concentration Time Curve Over Dosing Interval (AUCtau) of PD-0332991: Phase 2(0 (pre-dose), 1, 2, 4, 6, 8, 10, 24 hours post dose on Cycle 1 Day 15)
- Maximum Observed Plasma Concentration (Cmax) Of PD-0332991: Part 1 Phase 1(Single dose: 0 hour (pre-dose),1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose in Lead-in period (Day -7), Multiple dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24 hours post-dose on Cycle 1 Day 8)
- Number of Participants With Treatment-Related Adverse Events (AEs) and Serious Adverse Events (SAEs): Phase 1 (Part 1) and Phase 2(Part 1 Phase 1: Lead-in period (Day -7) up to 28 days after last dose of study drug (up to 308 days), Phase 2: Baseline (Day 1) up to 28 days after last dose of study drug (up to 1526 days))
- Area Under the Plasma Concentration-Time Curve From 0 to Time of Last Measurable Concentration (AUClast) of PD-0332991 Following Single Dose: Part 1 Phase 1(Single dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose in Lead-in period (Day -7))
- Terminal Half-Life (t1/2) of PD-0332991: Part 1 Phase 1(Single dose: 0 hour (pre-dose),1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose in Lead-in period (Day -7), Multiple dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24 hours post-dose on Cycle 1 Day 8)
- Time to Reach Maximum Observed Plasma Concentration (Tmax) of PD-0332991: Phase 2(0 (pre-dose), 1, 2, 4, 6, 8, 10, 24 hours post dose on Cycle 1 Day 15)
- Linearity (Rss) of PD-0332991 Following Multiple Dose: Part 1 Phase 1(Single dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose in Lead-in period (Day -7), Multiple dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24 hours post-dose on Cycle 1 Day 8)
- Volume of Distribution (Vz/F) of PD-0332991 Following Single Dose: Part 1 Phase 1(Single dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose in Lead-in period (Day -7))
- Maximum Observed Plasma Concentration (Cmax) Of PD-0332991: Phase 2(0 (pre-dose), 1, 2, 4, 6, 8, 10, 24 hours post dose on Cycle 1 Day 15)
- Percentage of Participants With Objective Response: Phase 1(From initiation of treatment up to disease progression (up to 30 months))
- Duration of Response (DOR): Phase 2(From initiation of treatment up to disease progression (up to 1526 days))
- Change From Baseline in Functional Assessment of Cancer Therapy-General (FACT-G): Phase 2 at Day 1 of Cycle 2, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49 and End of Treatment(Baseline (Day 1 of Cycle 1), Day 1 of Cycle 2, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, End of treatment (up to 1526 days))
- Accumulation Ratio (Rac) of PD-0332991 Following Multiple Dose: Part 1 Phase 1(Single dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose in Lead-in period (Day -7), Multiple dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24 hours post-dose on Cycle 1 Day 8)
- Percentage of Participants With Objective Response: Phase 2(From initiation of treatment up to disease progression (up to 1526 days))
- Presence of Tumor Tissue Biomarker- Ki67: Phase 2(Baseline (Day 1))
- Time to Reach Maximum Observed Plasma Concentration (Tmax) of PD-0332991: Part 1 Phase 1(Single dose: 0 hour (pre-dose),1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose in Lead-in period (Day -7), Multiple dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24 hours post-dose on Cycle 1 Day 8)
- Apparent Oral Clearance of PD-0332991: Phase 2(0 (pre-dose), 1, 2, 4, 6, 8, 10, 24 hours post dose on Cycle 1 Day 15)
- Pre-dose Plasma Concentration (Ctrough) of PD-0332991: Phase 2(0 (pre-dose), 1, 2, 4, 6, 8, 10, 24 hours post dose on Cycle 1 Day 15)
- Percentage of Participants With Disease Control (DC): Phase 2(From initiation of treatment up to disease progression (up to 1526 days))
- Duration of Response (DOR): Part 2 Phase 1(baseline up to 1673 days)
- Change From Baseline in Functional Assessment of Cancer Therapy-Breast Cancer (FACT-B): Phase 2 at Day 1 of Cycle 2, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49 and End of Treatment(Baseline (Day 1 of Cycle 1), Day 1 of Cycle 2, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, End of treatment (up to 1526 days))
- Progression Free Survival (PFS): Part 2 Phase 1(baseline up to 1673 days)
- Overall Survival (OS): Phase 2(From initiation of treatment up to follow-up period (up to 1526 days))
- Presence of Tumor Tissue Biomarkers- Estrogen Receptor (ER) H-Score, Retinoblastoma (Rb) H-Score, B-cell Lymphoma-1 (BCL-1) H-Score, P16 H-Score: Phase 2(Baseline (Day 1))
- Change From Baseline in Trial Outcome Index (TOI): Phase 2 at Day 1 of Cycle 2, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49 and End of Treatment(Baseline (Day 1 of Cycle 1), Day 1 of Cycle 2, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, End of treatment (up to 1526 days))