PHASE 1/2A DOSE ESCALATION AND EXPANSION STUDY EVALUATING SAFETY, TOLERABILITY, PHARMACOKINETIC, PHARMACODYNAMICS AND ANTI-TUMOR ACTIVITY OF PF-06873600 AS A SINGLE AGENT AND IN COMBINATION WITH ENDOCRINE THERAPY
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 发起方
- Pfizer
- 入组人数
- 155
- 试验地点
- 45
- 主要终点
- Number of Participants With Worst Post-Baseline Hematology Results Based on Common Terminology Criteria for Adverse Events (CTCAE) Grade: Part 1 + Part 2
研究概览
简要总结
The purpose of this clinical trial is to learn about the safety and effects of study medicine (PF-06873600) when taken alone or with hormone therapy by people with cancer.
People may be able to participate in this study if they have the following types of cancer: Hormone Receptor positive (HR+) breast cancer; Human Epidermal Growth Factor Receptor 2 (HER2)-negative breast cancer that is advanced or metastatic (spread to other parts of the body); triple negative breast cancer; epithelial ovarian cancer; fallopian tube cancer; or primary peritoneal cancer.
All participants in this study will receive the study medicine by mouth, 1 to 2 times a day at home. The dose of the study medicine may be changed during the study.
Some participants will also receive hormone therapy. The hormone therapy will be either letrozole by mouth once a day at home, or fulvestrant as a shot into the muscle. Fulvestrant will be given every two weeks at the study clinic for the first month, and then once a month after that.
Participants will take part in this study for at least 7 to 8 months, depending on how they respond to the therapy. During this time participants will visit the study clinic once a week for the first 2 cycles and every cycle thereafter.
详细描述
This is a Phase 1/2a, open-label, multi-center, non-randomized, multiple dose, safety, tolerability, pharmacokinetic, and pharmacodynamic study of PF-06873600 administered as a single agent in sequential dose levels and then in combination with endocrine therapy. In Part 1A and Part 1C, successive cohorts of patients will receive escalating doses of PF-06873600 and then in dose finding (Part 1B) with PF-06873600 in combination with endocrine therapy (ET). This study contains 2 parts, dose escalation with single agent (Part 1A and 1C) and then dose finding with PF-06873600 in combination with endocrine therapy (Part 1B) followed by dose expansion arms of PF-06873600 in combination with endocrine therapy (Part 2).
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Have a diagnosis of Hormone Receptor Positive (HR+), Human Epidermal Growth Factor Receptor 2 Negative (HER2-) breast cancer
- •Prior combined CDK 4/6 inhibitor and endocrine therapy and 1 or 2 prior lines of chemotherapy
- •Have a diagnosis of metastatic triple negative breast cancer (TNBC)
- •Up to 1-2 prior lines of chemotherapy
- •Have a diagnosis of advanced platinum resistant epithelial ovarian cancer (EOC)/fallopian tube cancer/primary peritoneal cancer (PPC)
- •Up to 2-3 prior lines of therapy
- •Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1
- •Measurable disease or non-measurable disease and refractory to or intolerant of existing therapies (Part 1)
- •Measurable disease as defined by RECIST 1.1 is required (Part 1B and Part 2 only)
排除标准
- •Known active uncontrolled or symptomatic Central Nervous System (CNS) metastases
- •Other active malignancy within 3 years prior to randomization, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ
- •Major surgery or radiation within 4 weeks prior to study entry
- •Last anti-cancer treatment within 2 weeks prior to study entry
- •Participation in other studies involving investigational drug(s) within 4 weeks prior to study entry
- •Pregnant or breastfeeding female patients
- •Active inflammatory gastrointestinal (GI) disease, known diverticular disease or previous gastric resection or lap band surgery including impairment of gastro intestinal function or GI disease
研究组 & 干预措施
Dose Expansion Arm C
PF-06873600 in Combination with Endocrine Therapy 1
干预措施: Endocrine Therapy 1 (Drug)
Dose Expansion Arm C
PF-06873600 in Combination with Endocrine Therapy 1
干预措施: PF-06873600 (Drug)
Dose Escalation
Single Agent Dose Escalation
干预措施: PF-06873600 (Drug)
Dose Finding Endocrine Therapy 1 Combination
Part 1B PF-06873600 plus Endocrine Therapy 1
干预措施: PF-06873600 (Drug)
Dose Finding Endocrine Therapy 1 Combination
Part 1B PF-06873600 plus Endocrine Therapy 1
干预措施: Endocrine Therapy 1 (Drug)
Dose Finding Endocrine Therapy 2 Combination
Part 1B PF-06873600 plus Endocrine Therapy 2
干预措施: PF-06873600 (Drug)
Dose Finding Endocrine Therapy 2 Combination
Part 1B PF-06873600 plus Endocrine Therapy 2
干预措施: Endocrine Therapy 2 (Drug)
Dose Expansion Arm A
PF-06873600 as a Single Agent
干预措施: PF-06873600 (Drug)
Dose Expansion Arm B
PF-06873600 as a Single Agent in Various Tumor Types
干预措施: PF-06873600 (Drug)
Dose Expansion Arm D
PF-06873600 in Combination with Endocrine Therapy 1
干预措施: PF-06873600 (Drug)
Dose Expansion Arm D
PF-06873600 in Combination with Endocrine Therapy 1
干预措施: Endocrine Therapy 1 (Drug)
Dose Expansion Arm E
PF-06873600 in Combination with Endocrine Therapy 2
干预措施: PF-06873600 (Drug)
Dose Expansion Arm E
PF-06873600 in Combination with Endocrine Therapy 2
干预措施: Endocrine Therapy 2 (Drug)
结局指标
主要结局
Number of Participants With Worst Post-Baseline Hematology Results Based on Common Terminology Criteria for Adverse Events (CTCAE) Grade: Part 1 + Part 2
时间窗: Day 1 up to 28 days after the last dose of study intervention, up to approximately 24 months
Severity was graded as NCI CTCAE version 4.03:Grade 1: asymptomatic or mild symptoms, clinical or diagnostic observations only, intervention not indicated; Grade 2: moderate, minimal, local or noninvasive intervention indicated, limiting age-appropriate instrumental activities of daily life (ADL); Grade 3: severe or medically significant but not immediately life-threatening, hospitalization or prolongation of existing hospitalization indicated, disabling, limiting self-care ADL; Grade 4: life-threatening consequence, urgent intervention indicated; Grade 5: death related to AE.
Number of Participants With Post-Baseline Vital Sign Abnormalities Meeting Pre-Defined Categorization - Part 1 + Part 2
时间窗: Day 1 up to 28 days after the last dose of study intervention, up to approximately 24 months
Pre-defined criteria included: 1) systolic blood pressure (SBP) (mm Hg) minimum (min) value \<90; 2) SBP change from baseline (CFB) (mm Hg) maximum (max) decrease \>=30 or max increase \>=30; 3) diastolic blood pressure (DBP) (mm Hg) min \<50; 4) DBP CFB (mm Hg) max decrease \>=20 or max increase \>=20; 5) supine heart rate (HR) beats per minute (bpm) min \<40 or max \>120.
Number of Participants With Post-Baseline Electrocardiogram (ECG) Changes Meeting Pre-Defined Categorization - Part 1 + Part 2
时间窗: Day 1 up to 28 days after the last dose of study intervention, up to approximately 24 months
ECG pre-defined categories for QTc interval adjusted according to Fridericia formula (QTcF) (msec) included: 450 \<= max. \<=480, 481 \<= max. \<=500, max \>=501; QTcF CFB: 30 \< max \<=60, max \>60; for PR and QRS: PR (msec): max \>=300; PR increase from baseline: Baseline \>200 and max. \>=25% increase, Baseline \<=200 and max. \>=50% increase; QRS (msec): max \>=200; QRS (msec) increase from baseline: Baseline \>100 and max. \>=25% increase, Baseline \<=100 and max. \>=50% increase. Categories, with at least 1 participant having ECG abnormality in any of the reporting arms, were reported in this outcome measure.
Overall Response Rate (ORR): Part 2
时间窗: From the start of the treatment until disease/clinical progression or death or early study discontinuation, whichever happened earlier (approximately up to 24 months)
ORR: percentage of participants with confirmed complete response (CR) or partial response (PR). Response evaluation criteria in solid tumors (RECIST) v1.1: a) CR = disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions that had a reduction in short axis to less than (\<) 10 millimeter (mm). Disappearance of all non-target lesions. In addition, all lymph nodes assigned a non-target lesion must be non-pathological in size (\<10 mm short axis) and b) PR = at least a 30 percent (%) decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. Any radiological assessments taken more than 30 days after the last dose of study therapy or after antineoplastic agents other than study treatments taken by the participants was excluded from the best overall response derivation. Confirmation of CR or PR was to be at least 4 weeks apart from the previous radiological assessment.
Number of Participants With Dose Limiting Toxicities (DLTs) - Part 1
时间窗: Cycle 1 (within 28 days after the first dose of study intervention)
DLT was defined as any of the following adverse events (AEs) occurring in the first cycle of treatment (28 days) which were attributable to one, the other, or both agents in the combination: Hematologic - grade(G) 4 neutropenia lasting \>7 days; Febrile neutropenia defined as an absolute neutrophil count (ANC) \<1.0 \* 10\^9/L with a single temperature of \>38.3°C, or a sustained temperature of ≥38°C, for more than 1 hour; G≥3 neutropenia with associated infection; G3 thrombocytopenia with clinically significant bleeding as indicated by ≥ G2 bleeding; G4 thrombocytopenia. Nonhematologic: Confirmed case of Drug Induced Liver Injury (DILI) (Hy's Law); G≥3 AEs that were clinically significant.
Number of Participants With Adverse Events (AEs) and Serious AEs (SAEs) - Part 1 + Part 2
时间窗: Day 1 up to 28 days after the last dose of study intervention, up to approximately 24 months
An AE was defined as the appearance of (or worsening of any pre-existing) undesirable sign(s), symptom(s), or medical condition(s) that occurred after participants' signed informed consent has been obtained. An SAE was an AE resulting in any of the following outcomes: was fatal or life-threatening; resulted in persistent or significant disability/incapacity; constituted a congenital anomaly/birth defect; was medically significant; required inpatient hospitalization or prolongation of existing hospitalization. Treatment Related AEs were treatment emergent AEs with cause categorized by the investigator as related to study treatment.
Number of Participants With Worst Post-Baseline Chemistry Results Based on Common Terminology Criteria for Adverse Events (CTCAE) Grade: Part 1 + Part 2
时间窗: Day 1 up to 28 days after the last dose of study intervention, up to approximately 24 months
Severity was graded as NCI CTCAE version 4.03:Grade 1: asymptomatic or mild symptoms, clinical or diagnostic observations only, intervention not indicated; Grade 2: moderate, minimal, local or noninvasive intervention indicated, limiting age-appropriate instrumental activities of daily life (ADL); Grade 3: severe or medically significant but not immediately life-threatening, hospitalization or prolongation of existing hospitalization indicated, disabling, limiting self-care ADL; Grade 4: life-threatening consequence, urgent intervention indicated; Grade 5: death related to AE.
次要结局
- Accumulation Ratio Based on AUC (Rac) of PF-06873600 Following Multiple Doses of Study Intervention on Cycle 1 Day 15 - Part 1(Pre-dose, 0.25, 0.5, 1, 2, 3, 4, 6, 12 hours post-dose on C1D15)
- Accumulation Ratio Based on Cmax (Observed) (Rac,Cmax) of PF-06873600 Following Multiple Doses of Study Intervention on Cycle 1 Day 15 - Part 2(Pre-dose, 1, 2, 4, 6 hours post-dose on C1D15)
- Pharmacodynamic (PD) Biomarker Phospho-retinoblastoma Protein (pRb) in Tumor Tissue in Participants - Part 1 + Part 2(Screening and Cycle 2 Day 1)
- PD Biomarker Ki67 in Tumor Tissue in Participants - Part 1 + Part 2(Screening and Cycle 2 Day 1)
- Maximum Observed Plasma Concentration (Cmax) of PF-06873600 Following a Single Oral Dose of Study Intervention on Cycle 1 Day 1 - Part 1 + Part 2(Part 1: pre-dose, 0.25, 0.5, 1, 2, 3, 4, 6, 12 hours post-dose on Cycle 1 Day 1 (C1D1); Part 2: pre-dose, 1, 2, 4, 6 hours post-dose on C1D1)
- Time to Reach Cmax at Steady State (Tmax) of PF-06873600 Following a Single Oral Dose of Study Intervention on Cycle 1 Day 1 - Part 1 + Part 2(Part 1: pre-dose, 0.25, 0.5, 1, 2, 3, 4, 6, 12 hours post-dose on C1D1; Part 2: pre-dose, 1, 2, 4, 6 hours post-dose on C1D1)
- Apparent Clearance (CL/F) of PF-06873600 Following a Single Oral Dose of Study Intervention on Cycle 1 Day 1 - Part 1(Pre-dose, 0.25, 0.5, 1, 2, 3, 4, 6, 12 hours post-dose on C1D1)
- Apparent Volume of Distribution (Vz/F) of PF-06873600 Following a Single Oral Dose of Study Intervention on Cycle 1 Day 1 - Part 1(Pre-dose, 0.25, 0.5, 1, 2, 3, 4, 6, 12 hours post-dose on C1D1)
- Terminal Half-life (t1/2) of PF-06873600 Following a Single Oral Dose of Study Intervention on Cycle 1 Day 1 - Part 1(Pre-dose, 0.25, 0.5, 1, 2, 3, 4, 6, 12 hours post-dose on C1D1)
- Steady State Maximum Concentration (Css,Max) of PF-06873600 Following Multiple Doses of Study Intervention on Cycle 1 Day 15 - Part 1 + Part 2(Part 1: pre-dose, 0.25, 0.5, 1, 2, 3, 4, 6, 12 hours post-dose on C1D15; Part 2: pre-dose, 1, 2, 4, 6 hours post-dose on C1D15)
- Area Under the Concentration-Time Profile From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) of PF-06873600 Following a Single Oral Dose of Study Intervention on Cycle 1 Day 1 - Part 1(Pre-dose, 0.25, 0.5, 1, 2, 3, 4, 6, 12 hours post-dose on C1D1)
- Area Under the Concentration-Time Profile From Time 0 Extrapolated to Infinite Time (AUCinf) of PF-06873600 Following a Single Oral Dose of Study Intervention on Cycle 1 Day 1 - Part 1(Pre-dose, 0.25, 0.5, 1, 2, 3, 4, 6, 12 hours post-dose on C1D1)
- Time to Maximum Plasma Concentration at Steady State (Tss,Max) of PF-06873600 Following Multiple Doses of Study Intervention on Cycle 1 Day 15 - Part 1 + Part 2(Part 1: pre-dose, 0.25, 0.5, 1, 2, 3, 4, 6, 12 hours post-dose on C1D15; Part 2: pre-dose, 1, 2, 4, 6 hours post-dose on C1D15)
- Steady State Minimum Plasma Concentration (Css,Min) of PF-06873600 Following Multiple Doses of Study Intervention on Cycle 1 Day 15 - Part 1 + Part 2(Part 1: pre-dose, 0.25, 0.5, 1, 2, 3, 4, 6, 12 hours post-dose on C1D15; Part 2: pre-dose, 1, 2, 4, 6 hours post-dose on C1D15)
- Steady-State Area Under the Plasma Concentration Versus Time Curve Within One Dose Interval (AUCss,Tau) of PF-06873600 Following Multiple Doses of Study Intervention on Cycle 1 Day 15 - Part 1(Pre-dose, 0.25, 0.5, 1, 2, 3, 4, 6, 12 hours post-dose on C1D15)
- Steady-State Apparent Oral Plasma Clearance (CLss/F) of PF-06873600 Following Multiple Doses of Study Intervention on Cycle 1 Day 15 - Part 1(Pre-dose, 0.25, 0.5, 1, 2, 3, 4, 6, 12 hours post-dose on C1D15)
- Apparent Volume of Distribution at Steady State (Vss/F) of PF-06873600 Following Multiple Doses of Study Intervention on Cycle 1 Day 15 - Part 1(Pre-dose, 0.25, 0.5, 1, 2, 3, 4, 6, 12 hours post-dose on C1D15)