A PHASE 1, OPEN-LABEL, MULTI-CENTER, DOSE ESCALATION AND DOSE EXPANSION STUDY TO EVALUATE THE SAFETY, TOLERABILITY, PHARMACOKINETICS, AND PRELIMINARY EVIDENCE OF ANTI-TUMOR ACTIVITY OF PF-07284892 (ARRY-558) AS A SINGLE AGENT AND IN COMBINATION THERAPY IN PARTICIPANTS WITH ADVANCED SOLID TUMORS
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 发起方
- Pfizer
- 入组人数
- 53
- 试验地点
- 27
- 主要终点
- Part 1 and Part 2- Number of participants with treatment-emergent adverse events (AEs)
研究概览
简要总结
The purpose of this first-in-patient, open label study is to determine the maximum tolerated dose and/or recommended dose for further study of PF-07284892 as a single agent and in combination with lorlatinib, encorafenib and cetuximab, or binimetinib and evaluate the pharmacokinetics, safety, and preliminary clinical activity of single agent and each combination therapy.
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
- •Age ≥18 years at the time of informed consent
- •Histological or cytological diagnosis of ALK-positive advanced NSCLC, CRC with BRAF V600E mutation, or RAS- mutant, NF1-mutant or BRAF class 3 mutant solid tumor. Participants with ROS-positive NSCLC are also eligible for Part 1 and 2 (Other ROS1-positive solid tumors may be considered after discussion with the sponsor).
- •Documentation evidence of biomarker mutation status
- •ALK-positive NSCLC with prior lorlatinib and no prior platinum-based chemotherapy (Cohort 1); with prior lorlatinib and prior platinum-based chemotherapy (Cohort 2); or with no prior lorlatinib (Cohort 3).
- •BRAF V600E mutant CRC participants resistant to BRAFi plus EGFRi (Cohort 4 ); refractory to BRAFi plus EGFRi (Cohort 5); or BRAFi plus EGFRi naïve (Cohort 6).
- •RAS- mutant, NF1-mutant or BRAF class 3 mutant solid tumors who have received prior SOC (Cohort 7).
排除标准
- •Brain metastasis larger than 4 cm
- •Active malignancy within 3 years
- •Systemic anti-cancer therapy or small molecule therapeutics within 2 weeks prior to start of study treatment. Antibody based agents within 4 weeks prior to start of study treatment. Mitomycin C or nitrosoureas within 6 weeks prior to start of study treatment.
- •For participants who may get lorlatinib or encorafenib on study, history of interstitial lung disease
- •For participants who may get binimetinib on study, history or current evidence of retinal vein occlusion (RVO) or concurrent neuromuscular disorder associated with elevated creatine kinase (CK)
研究组 & 干预措施
Expansion Phase (Cohort 2)
PF-07284892 + lorlatinib in participants with ALK+ NSCLC with no prior lorlatinib
干预措施: lorlatinib (Drug)
Expansion Phase (Cohort 1)
PF-07284892 + lorlatinib in participants with ALK+ NSCLC with prior lorlatinib
干预措施: lorlatinib (Drug)
PF-07284892 in combination with encorafenib and cetuximab (Part 2)
Combination dose escalation of PF-07284892 in combination with encorafenib and cetuximab in participants with BRAF V600E mutant CRC
干预措施: PF-07284892 (Drug)
PF-07284892 in combination with binimetinib (Part 2)
Combination dose escalation of PF-07284892 in combination with binimetinib in participants with Ras-mutant, NF-1 mutant or BRAF class 3 -mutant solid tumors
干预措施: PF-07284892 (Drug)
Expansion Phase (Cohort 1)
PF-07284892 + lorlatinib in participants with ALK+ NSCLC with prior lorlatinib
干预措施: PF-07284892 (Drug)
Expansion Phase (Cohort 4)
PF-07284892 + encorafenib + cetuximab in participants with BRAF V600E mutant CRC with no prior BRAFi plus EGFRi
干预措施: cetuximab (Biological)
PF-07284892 in combination with binimetinib (Part 2)
Combination dose escalation of PF-07284892 in combination with binimetinib in participants with Ras-mutant, NF-1 mutant or BRAF class 3 -mutant solid tumors
干预措施: binimetinib (Drug)
Expansion Phase (Cohort 4)
PF-07284892 + encorafenib + cetuximab in participants with BRAF V600E mutant CRC with no prior BRAFi plus EGFRi
干预措施: encorafenib (Drug)
PF-07284892 in combination with encorafenib and cetuximab (Part 2)
Combination dose escalation of PF-07284892 in combination with encorafenib and cetuximab in participants with BRAF V600E mutant CRC
干预措施: cetuximab (Biological)
Expansion Phase (Cohort 3)
PF-07284892 + encorafenib + cetuximab in participants with BRAF V600E mutant CRC with prior BRAF inhibitor (BRAFi) plus epidermal growth factor receptor inhibitor (EGFRi)
干预措施: encorafenib (Drug)
Expansion Phase (Cohort 5)
PF-07284892 + binimetinib in participants with RAS- mutant, NF1-mutant or BRAF class 3 mutant solid tumors who have received prior standard of care (SOC)
干预措施: binimetinib (Drug)
PF-07284892 monotherapy
Monotherapy dose escalation of PF-07284892 in participants with ALK- or ROS1-positive non-small cell lung cancer (NSCLC), B-type Raf proto-oncogene V600E mutation colorectal cancer (CRC), or RAS- mutant, NF1-mutant or BRAF class 3-mutant solid tumors
干预措施: PF-07284892 (Drug)
Expansion Phase (Cohort 2)
PF-07284892 + lorlatinib in participants with ALK+ NSCLC with no prior lorlatinib
干预措施: PF-07284892 (Drug)
Expansion Phase (Cohort 3)
PF-07284892 + encorafenib + cetuximab in participants with BRAF V600E mutant CRC with prior BRAF inhibitor (BRAFi) plus epidermal growth factor receptor inhibitor (EGFRi)
干预措施: PF-07284892 (Drug)
PF-07284892 in combination with lorlatinib (Part 2)
Combination dose escalation of PF-07284892 in combination with lorlatinib in participants with ALK- or ROS1-positive NSCLC
干预措施: PF-07284892 (Drug)
PF-07284892 in combination with lorlatinib (Part 2)
Combination dose escalation of PF-07284892 in combination with lorlatinib in participants with ALK- or ROS1-positive NSCLC
干预措施: lorlatinib (Drug)
Expansion Phase (Cohort 3)
PF-07284892 + encorafenib + cetuximab in participants with BRAF V600E mutant CRC with prior BRAF inhibitor (BRAFi) plus epidermal growth factor receptor inhibitor (EGFRi)
干预措施: cetuximab (Biological)
Expansion Phase (Cohort 4)
PF-07284892 + encorafenib + cetuximab in participants with BRAF V600E mutant CRC with no prior BRAFi plus EGFRi
干预措施: PF-07284892 (Drug)
Expansion Phase (Cohort 5)
PF-07284892 + binimetinib in participants with RAS- mutant, NF1-mutant or BRAF class 3 mutant solid tumors who have received prior standard of care (SOC)
干预措施: PF-07284892 (Drug)
PF-07284892 in combination with encorafenib and cetuximab (Part 2)
Combination dose escalation of PF-07284892 in combination with encorafenib and cetuximab in participants with BRAF V600E mutant CRC
干预措施: encorafenib (Drug)
结局指标
主要结局
Part 1 and Part 2- Number of participants with treatment-emergent adverse events (AEs)
时间窗: Baseline up to 30 days after last dose of study medication
AEs as characterized by type, frequency, severity, timing, seriousness, and relationship to study therapy
Part 1 and Part 2- Number of participants with dose limiting toxicities (DLTs)
时间窗: Cycle 1 (21 days)
DLTs will be evaluated during the first cycle (21 days) as both a single agent or in combination with lorlatinib, encorafenib + cetuximab, or binimetinib. The number of DLTs will be used to determine the maximum tolerated dose (MTD)/recommended dose for further study
Part 1 and Part 2 - Number of participants with clinically significant change from baseline in laboratory abnormalities
时间窗: Baseline up to 30 days after last dose of study treatment
Laboratory abnormalities as characterized by type, frequency, severity, and timing
Part 1 and Part 2 - Number of dose interruptions, dose modifications, and discontinuations due to AEs
时间窗: Baseline up to 30 days after the last dose of study medication
Incidence of dose interruptions, dose modifications, and discontinuations due to AEs
Part 3- Overall response
时间窗: Baseline to up to 2 years
Response will be evaluated via radiographical tumor assessments by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1)
次要结局
- Part 1 and Part 2- Maximum plasma concentration (Cmax) of PF-07284892 and metabolite(Cycle 1 Day 1 (predose, 1, 2, 4, 6, 8 hours postdose); Cycle 1 Day 18 (predose, 1, 2, 4, 6, 8, 24, and 48 hours postdose); Cycle 2-6 Day 1 (predose and 2 hours postdose); Cycle 7-12 Day 1 predose; end of treatment (EOT))
- Part 1 and Part 2- Area under the plasma concentration-time curve from time 0 to extrapolated to infinity (AUCinf) of PF-07284892 and metabolite(Cycle 1 Day 1 (predose, 1, 2, 4, 6, 8 hours postdose); Cycle 1 Day 18 (predose, 1, 2, 4, 6, 8, 24, and 48 hours postdose); Cycle 2-6 Day 1 (predose and 2 hours postdose); Cycle 7-12 Day 1 predose; EOT)
- Part 1 and Part 2- Metabolite ratio of PF-07284892 and metabolite(Cycle 1 Day 1 (predose, 1, 2, 4, 6, 8 hours postdose); Cycle 1 Day 18 (predose, 1, 2, 4, 6, 8, 24, and 48 hours postdose); Cycle 2-6 Day 1 (predose and 2 hours postdose); Cycle 7-12 Day 1 predose; EOT)
- Part 1 and Part 2- Time to reach maximum plasma concentration (Tmax) of PF-07284892 and metabolite(Cycle 1 Day 1 (predose, 1, 2, 4, 6, 8 hours postdose); Cycle 1 Day 18 (predose, 1, 2, 4, 6, 8, 24, and 48 hours postdose); Cycle 2-6 Day 1 (predose and 2 hours postdose); Cycle 7-12 Day 1 predose; EOT)
- Part 1 and Part 2- Area under the plasma concentration-time curve from time 0 to the last time point of quantifiable concentration (AUClast) of PF-07284892 and metabolite(Cycle 1 Day 1 (predose, 1, 2, 4, 6, 8 hours postdose); Cycle 1 Day 18 (predose, 1, 2, 4, 6, 8, 24, and 48 hours postdose); Cycle 2-6 Day 1 (predose and 2 hours postdose); Cycle 7-12 Day 1 predose; EOT)
- Part 1 and Part 2- Area under the plasma concentration-time curve from 0 to 24 (AUC24) or 48 hours (AUC48) of PF-07284892 and metabolite(Cycle 1 Day 1 (predose, 1, 2, 4, 6, 8 hours postdose); Cycle 1 Day 18 (predose, 1, 2, 4, 6, 8, 24, and 48 hours postdose); Cycle 2-6 Day 1 (predose and 2 hours postdose); Cycle 7-12 Day 1 predose; EOT)
- Part 1 and Part 2- Overall response(Baseline to up to 2 years)
- Part 2- Duration of Response (DOR)(Baseline to up to 2 years)