A PHASE 1/2A DOSE ESCALATION AND EXPANSION STUDY TO EVALUATE SAFETY, TOLERABILITY, PHARMACOKINETIC, PHARMACODYNAMIC, AND ANTI-TUMOR ACTIVITY OF PF-07248144 IN PARTICIPANTS WITH ADVANCED OR METASTATIC SOLID TUMORS
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- Pfizer
- 入组人数
- 320
- 试验地点
- 68
- 主要终点
- Safety and Tolerability as assessed by adverse event monitoring for participants enrolled in the Dose Expansion Arms
研究概览
简要总结
This is an open-label, multi center study to evaluate safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of PF-07248144 and early signs of clinical efficacy of PF-07248144 as a single agent and in combination with other agents
详细描述
Study has two parts, Part 1 (dose escalation) and Part 2 (dose expansion). Part 1 is divided into Parts 1A, 1B, 1C, 1D and 1E and Part 2 is divided into Parts 2A, 2B, 2D and 2E. In Part 1A, single escalating doses of PF-07248144 alone will be administered to determine the maximum tolerable dose (MTD) and select the recommended dose for expansion (RDE). In Part 1B, 1C, 1D and 1E PF-07248144 will be administered in combination with either fulvestrant (Part 1B); palbociclib + letrozole (Part 1C) or PF-07220060+fulvestrant (Part 1D) or vepdegestrant (Part 1E). After the determination of the monotherapy RDE in Part 1A, PF-07248144 will be evaluated in a dose expansion cohort as a monotherapy in Part 2A.
After determination of the combination RDE from Part 1B, PF-07248144 in combination with fulvestrant, PF-07248144 will be evaluated in a combination dose expansion with fulvestrant in Part 2B. In Part 1C, PF-07248144 in combination with letrozole + palbociclib will be evaluated for dose finding to determine the MTD and RDE for this combination. After determination of the triple combination RDE from Part 1D, PF-07248144 in combination with PF-07220060 + fulvestrant will be evaluated in a combination dose-expansion cohort, Part 2D. After determination of the combination RDE from Part 1E, PF-07248144 in combination with vepdegestrant will be evaluated in a combination dose-expansion cohort, Part 2E.
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
- •Disease Characteristics - Breast, Prostate, and Lung Cancer
- •Part 1A (Monotherapy Dose Escalation) Histological or cytological diagnosis of locally advanced or metastatic ER+HER2- breast cancer, CRPC, or NSCLC that is intolerant or resistant to standard therapy or for which no standard therapy is available.
- •Part 1B, Part 1C, Part 1D and Part 1E (Combination Dose Escalation) Histological or cytological diagnosis of locally advanced or metastatic ER+HER2- breast cancer. Participants must have progressed after at least 1 prior line of treatment with an endocrine therapy and CDK4/6 inhibitor in the advanced or metastatic setting.
- •Part 2A (ER+HER2- breast cancer 2L+, monotherapy) Histological or cytological diagnosis of locally advanced or metastatic ER+HER2- breast cancer. Participants must have progressed after at least 1 prior line of CDK4/6 inhibitor and 1 line of endocrine therapy.
- •Part 2B (ER+HER2- breast cancer 2-4L, combination with fulvestrant) Histological or cytological diagnosis of advanced or metastatic ER+HER2- breast cancer. Participants must have progressive disease after at least 1 prior line of a CDK4/6 inhibitor and at least 1 prior line of endocrine therapy.. Participants must not have received more than 3 prior lines of systemic therapies including up to 1 line of cytotoxic chemotherapy for visceral disease in advanced or metastatic setting; Participants may have but are not required to have prior treatment with fulvestrant.
- •Part 2D (ER+HER2- breast cancer 2-4L, combination with PF-07220060 (CDK4i) and fulvestrant):
- •Histological or cytological diagnosis of advanced or metastatic ER+HER2- breast cancer. Participants must have progressive disease after at least 1 prior line of a CDK4/6 inhibitor and at least 1 prior line of endocrine therapy.
- •Participants must have not received more than 3 lines of systemic therapies including up to 1 line of cytotoxic chemotherapy for visceral disease in advanced or metastatic setting; Participants may have but are not required to have prior treatment with fulvestrant.
- •Part 2E (ER+HER2- breast cancer 2-4L, combination with vepdegestrant): Histological or cytological diagnosis of advanced or metastatic ER+HER2- breast cancer. Participants must have progressive disease after at least 1 prior line of a CDK4/6 inhibitor and at least 1 prior line of endocrine therapy; Participants must have not received more than 3 lines of systemic therapies including up to 1 line of cytotoxic chemotherapy for visceral disease in advanced or metastatic setting; Participants may have received fulvestrant
- •Participants with ER+HER2- advanced or metastatic breast cancer must have documentation of ER-positive tumor (≥1% positive stained cells) based on most recent tumor biopsy utilizing an assay consistent with local standards.
- •Participants with ER+HER2- advanced or metastatic breast cancer must have documentation of HER2-negative tumor: HER2-negative tumor is determined as immunohistochemistry score 0/1+ or negative by in situ hybridization (FISH/CISH/SISH/DISH) defined as a HER2/CEP17 ratio <2 or for single probe assessment a HER2 copy number <
- •Female participants with ER+HER2- advanced or metastatic breast cancer considered to be of childbearing potential (or have tubal ligations only) must be willing to undergo medically induced menopause by treatment with the approved LHRH agonist such as goserelin, leuprolide or equivalent agents to induce chemical menopause.
- •Female participants with ER+HER2- advanced or metastatic breast cancer of nonchildbearing potential must meet at least 1 criteria of achieving postmenopausal status.
- •Participants must have at least 1 measurable lesion as defined by RECIST version 1.1 that has not been previously irradiated.
- •Eastern Cooperative Oncology Group (ECOG) Performance Status PS 0 or 1
- •Female or male patients aged ≥ 18 years (Japan ≥ 20 years) (South Korea ≥ 19 years).
- •Adequate renal, liver, and bone marrow function.
- •Resolved acute effects of any prior therapy to baseline severity or CTCAE Grade 1 except for adverse events (AEs) not constituting a safety risk by investigator judgment.
排除标准
- •Unmanageable ascites (limited medical treatment to control ascites is permitted, but all participants with ascites require review by sponsor's medical monitor).
- •Participants with any other active malignancy within 3 years prior to enrollment, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ.
- •Major surgery, radiation therapy, or systemic anti-cancer therapy within 3 weeks prior to study entry.
- •Prior irradiation to >25% of the bone marrow.
- •ECG clinically relevant abnormalities (eg, QTc >470 msec, complete LBBB, second/third degree AV block, ST elevation or EKG changes suggesting myocardial infarction or active myocardia ischemia).
- •Therapeutic anticoagulation. However, low molecular weight heparin is allowed. Vitamin K antagonists or factor Xa inhibitors may be allowed following discussion with the Sponsor.
- •Known or suspected hypersensitivity or severe allergy to active ingredient/excipients of PF-
- •Active inflammatory GI disease, refractory and unresolved chronic diarrhea or previous gastric resection, lap band surgery or other GI conditions and surgeries that may significantly alter the absorption of PF-07248144 tablets. Gastroesophageal reflux disease under treatment is allowed.
- •Pregnant or breastfeeding female participants.
研究组 & 干预措施
2B Combination Dose Expansion Arm
PF-07248144 with Fulvestrant Dose Expansion
干预措施: PF-07248144 (Drug)
1A Monotherapy Dose Escalation
PF-07248144 Monotherapy Escalation
干预措施: PF-07248144 (Drug)
1E Combination Dose Escalation
PF-07248144 with Vepdegestrant Combination Dose Escalation
干预措施: PF-07850327, ARV-471, vepdegestrant (Drug)
2E Combination Dose Expansion Arm
PF-07248144 with Vepdegestrant Combination Dose Expansion
干预措施: PF-07850327, ARV-471, vepdegestrant (Drug)
2D Combination Dose Expansion Arm
PF-07248144 with PF-07220060 +Fulvestrant Dose Expansion
干预措施: Fulvestrant (Drug)
1C Combination Dose Escalation
PF-07248144 with Letrozole + Palbociclib Combination Dose Escalation
干预措施: PF-07248144 (Drug)
1B Combination Dose Escalation
PF-07248144 with Fulvestrant Combination Dose Escalation
干预措施: PF-07248144 (Drug)
1C Combination Dose Escalation
PF-07248144 with Letrozole + Palbociclib Combination Dose Escalation
干预措施: Palbociclib (Drug)
1D Combination Dose Escalation
PF-07248144 with PF-07220060 +Fulvestrant
干预措施: PF-07248144 (Drug)
1B Combination Dose Escalation
PF-07248144 with Fulvestrant Combination Dose Escalation
干预措施: Fulvestrant (Drug)
2A Monotherapy Dose Expansion Arm
PF-07248144 Monotherapy Dose Expansion
干预措施: PF-07248144 (Drug)
2B Combination Dose Expansion Arm
PF-07248144 with Fulvestrant Dose Expansion
干预措施: Fulvestrant (Drug)
1D Combination Dose Escalation
PF-07248144 with PF-07220060 +Fulvestrant
干预措施: Fulvestrant (Drug)
1C Combination Dose Escalation
PF-07248144 with Letrozole + Palbociclib Combination Dose Escalation
干预措施: Letrozole (Drug)
2E Combination Dose Expansion Arm
PF-07248144 with Vepdegestrant Combination Dose Expansion
干预措施: PF-07248144 (Drug)
1D Combination Dose Escalation
PF-07248144 with PF-07220060 +Fulvestrant
干预措施: PF-07220060 (Drug)
2D Combination Dose Expansion Arm
PF-07248144 with PF-07220060 +Fulvestrant Dose Expansion
干预措施: PF-07220060 (Drug)
China Monotherapy Dose Expansion
PF-07248144 Monotherapy Dose Expansion
干预措施: PF-07248144 (Drug)
1E Combination Dose Escalation
PF-07248144 with Vepdegestrant Combination Dose Escalation
干预措施: PF-07248144 (Drug)
2D Combination Dose Expansion Arm
PF-07248144 with PF-07220060 +Fulvestrant Dose Expansion
干预措施: PF-07248144 (Drug)
结局指标
主要结局
Safety and Tolerability as assessed by adverse event monitoring for participants enrolled in the Dose Expansion Arms
时间窗: Up to 24 months
Adverse Events as characterized by type, frequency, severity (as graded by NCI CTCAE version 5.0), timing, seriousness, and relationship to study therapy.
Safety and Tolerability as assessed by adverse event monitoring for participants enrolled in the Dose Escalation Arms.
时间窗: Up to 24 months
Adverse Events as characterized by type, frequency, severity (as graded by NCI CTCAE version 5.0), timing, seriousness, and relationship to study therapy.
Safety and Tolerability through monitoring of laboratory assessments for participants enrolled in the Dose Escalation Arms.
时间窗: Up to 24 months
Laboratory abnormalities as characterized by type, frequency, severity (as graded by NCI CTCAE version 5.0), and timing.
Number of participants with dose-limiting toxicities in the Dose Escalation Arms.
时间窗: Up to 29 days
Dose-limiting toxicities (DLTs)
Safety and Tolerability through monitoring of laboratory assessments for participants enroled in the Dose Expansion Arms
时间窗: Up to 24 months
Laboratory abnormalities as characterized by type, frequency, severity (as graded by NCI CTCAE version 5.0), and timing.
次要结局
- Overall survival (OS) observed in participants enrolled in Dose Expansion Arms(Up to 24 months)
- Duration of Response (DOR) observed in participants in the dose expansion arms(up to 24 months)
- Best Overall Response (BOR) observed in participants in the dose expansion arms(Up to 24 months)
- Clinical Benefit Rate (CBR) observed in participants in the Dose Expansion Arms(up to 24 months)
- Single Dose: Maximum Observed Concentration (Cmax) in the Dose Escalation and Dose Finding Arms(Up to 24 months)
- Single Dose: Time to Maximum concentration (Tmax) in the Dose Escalation and Dose Finding Arms(Up to 24 months)
- Single Dose: AUC from time zero to time of last measurable concentration (AUClast) in the Dose Escalation and Dose Finding Arms(Up to 24 months)
- Single and Multiple Dose: Terminal Elimination half-life (t1/2) in the Dose Escalation and Dose Finding Arms(Up to 24 months)
- Multiple Dose: Steady-State Cmax (Cmax,ss) in the Dose Escalation and Dose Finding Arms(Up to 24 months)
- Multiple Dose: Steady-state Tmax (Tmax,ss) in the Dose Escalation and Dose Finding Arms(Up to 24 months)
- Multiple Dose: Steady state AUC during a dosage interval (τ) (AUCτ,ss) in the Dose Escalation and Dose Finding Arms(Up to 24 months)
- Multiple Dose: Steady-state Cmin (Cmin,ss) in the Dose Escalation and Dose Finding Arms.(Up to 24 months)
- Multiple Dose: Steady-state apparent total clearance (CLss/F) in the Dose Escalation and Dose Finding Arms.(Up to 24 months)
- Palbociclib trough concentrations at steady instate (Cmin,ss) in the 1C combination dose finding arm.(Up to 24 months)
- Peak concentrations of PF-07248144, PF-07220060 (Part 2D) and vepdegestrant and ARV-473 (Part 2E) for selected cycles in the Dose Expansion Arms(Up to 24 months)
- Trough concentrations of PF-07248144 for selected cycles in the Dose Expansion Arms(Up to 24 months)
- Maximum Observed Concentration (Cmax) in the participants in the food effect subset in monotherapy dose expansion arm(Cycle 1 Day -7 and Cycle 1 Day 1 (each cycle is 28 days))
- Time to Maximum concentration (Tmax) in the participants in the food effect subset in monotherapy dose expansion arm(Cycle 1 Day -7 and Cycle 1 Day 1 (each cycle is 28 days))
- AUC from time zero to time of last measurable concentration (AUClast) in the participants in the food effect subset in monotherapy dose expansion arm(Cycle 1 Day -7 and Cycle 1 Day 1 (each cycle is 28 days))
- Amount of PF-07248144 excreted in urine relative to dose administered (%) in a sub-set of participants in monotherapy dose expansion arm.(Up to 24 months)
- Renal clearance (CLr) in a sub-set of participants in monotherapy dose expansion arm(Up to 24 months)
- Progression Free Survival (PFS) observed in participants in the Dose Expansion Arms(Up to 24 months)
- Time to Progression (TTP) observed in participants enrolled in the Dose Expansion Arms(Up to 24 months)