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
Overview
- Phase
- Phase 1
- Intervention
- PF-07284892
- Conditions
- Solid Tumor
- Sponsor
- Pfizer
- Enrollment
- 53
- Locations
- 16
- Primary Endpoint
- Part 1 and Part 2- Number of participants with treatment-emergent adverse events (AEs)
- Status
- Terminated
- Last Updated
- last year
Overview
Brief Summary
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •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).
Exclusion Criteria
- •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)
Arms & Interventions
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
Intervention: PF-07284892
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
Intervention: PF-07284892
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
Intervention: lorlatinib
Expansion Phase (Cohort 1)
PF-07284892 + lorlatinib in participants with ALK+ NSCLC with prior lorlatinib
Intervention: PF-07284892
Expansion Phase (Cohort 1)
PF-07284892 + lorlatinib in participants with ALK+ NSCLC with prior lorlatinib
Intervention: lorlatinib
Expansion Phase (Cohort 2)
PF-07284892 + lorlatinib in participants with ALK+ NSCLC with no prior lorlatinib
Intervention: PF-07284892
Expansion Phase (Cohort 2)
PF-07284892 + lorlatinib in participants with ALK+ NSCLC with no prior lorlatinib
Intervention: lorlatinib
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)
Intervention: PF-07284892
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)
Intervention: cetuximab
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)
Intervention: encorafenib
Expansion Phase (Cohort 4)
PF-07284892 + encorafenib + cetuximab in participants with BRAF V600E mutant CRC with no prior BRAFi plus EGFRi
Intervention: PF-07284892
Expansion Phase (Cohort 4)
PF-07284892 + encorafenib + cetuximab in participants with BRAF V600E mutant CRC with no prior BRAFi plus EGFRi
Intervention: cetuximab
Expansion Phase (Cohort 4)
PF-07284892 + encorafenib + cetuximab in participants with BRAF V600E mutant CRC with no prior BRAFi plus EGFRi
Intervention: encorafenib
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)
Intervention: PF-07284892
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)
Intervention: binimetinib
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
Intervention: PF-07284892
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
Intervention: cetuximab
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
Intervention: encorafenib
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
Intervention: PF-07284892
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
Intervention: binimetinib
Outcomes
Primary Outcomes
Part 1 and Part 2- Number of participants with treatment-emergent adverse events (AEs)
Time Frame: 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)
Time Frame: 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
Time Frame: 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
Time Frame: 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
Time Frame: 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)
Secondary Outcomes
- 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)