A PHASE 1, OPEN-LABEL, DOSE ESCALATION AND DOSE EXPANSION STUDY TO EVALUATE THE SAFETY, TOLERABILITY, PHARMACOKINETICS, AND ANTI TUMOR ACTIVITY OF PF-07799933 (ARRY-440) AS A SINGLE AGENT AND IN COMBINATION THERAPY IN PARTICIPANTS 16 YEARS AND OLDER WITH ADVANCED SOLID TUMORS WITH BRAF ALTERATIONS
Overview
- Phase
- Phase 1
- Intervention
- PF-07799933
- Conditions
- Non-Small-Cell Lung Cancer
- Sponsor
- Pfizer
- Enrollment
- 267
- Locations
- 83
- Primary Endpoint
- Number of participants with dose limiting toxicities (DLTs) (Part 1 and Part 2)
- Status
- Recruiting
- Last Updated
- 9 days ago
Overview
Brief Summary
The purpose of this clinical trial is to learn about the safety and effects of the study medicine (called PF-07799933) administered as a single agent and in combination with other study medicines in people with solid tumors.
This study is seeking participants who have an advanced solid tumor with a certain type of abnormal gene called "BRAF" and available treatments are no longer effective in controlling their cancer.
All participants in this study will receive PF-07799933. PF-07799933 comes as a tablet to take by mouth, 2 times a day. Depending on the part of the study, participants may also receive another study medicine:
- People with melanoma or other solid tumors may also receive binimetinib. Binimetinib comes as a tablet to take by mouth, 2 times a day.
- People with colorectal cancer may also receive cetuximab or cetuximab and mFOLFOX6 (Chemotherapy regimen). Cetuximab will be given weekly (or every two weeks) in the clinic as a shot given in the vein or port (intravenous, IV).
Participants may receive the study medicines for about 2 years. The study team will monitor how each participant is doing with the study treatment during regular visits at the study clinic.
Investigators
Eligibility Criteria
Inclusion Criteria
- •This study is seeking participants who meet the following key eligibility criteria:
- •Inclusion Criteria:
- •Diagnosis of advanced/metastatic solid tumor including primary brain tumor.
- •Qualifying BRAF alteration (V600 or non-V600 Class II/Class III BRAF alteration), in tumor tissue and/or blood (ie circulating tumor deoxyribonucleic acid \[DNA\], or ctDNA).
- •Disease progressed during/following last prior treatment and no satisfactory alternative treatment options (Part 1, Part 2 (doublet), and Part 3 (cohorts 2, 3, 6, 7)).
- •Tumor specific cohorts (melanoma, colorectal cancer) must have received specific prior approved therapies
- •Part 3 (Cohort 1) (BRAF V600 mutant melanoma): Prior BRAF V600 inhibitor therapy required, prior MEK inhibitor therapy required, and immune checkpoint inhibitor therapy required.
- •Part 3 (Cohort 4) (BRAF V600E CRC): Minimum of 2 cycles of prior 5-FU based chemotherapy required. No prior BRAF inhibitor/EGFR inhibitor allowed. Participants with MSI-H/dMMR mCRC should receive prior immune checkpoint inhibitor therapy.
- •Part 3 (Cohort 5) (BRAF V600E CRC): No more than 2 cycles of prior 5-FU based chemotherapy allowed. No prior BRAF inhibitor/EGFR inhibitors allowed. Participants with MSI-H/dMMR mCRC should receive prior immune checkpoint inhibitor therapy.
Exclusion Criteria
- •Brain metastasis larger than 4 cm
- •Systemic anti-cancer therapy or small molecule therapeutics ongoing at the start of study treatment.
- •History or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO; history of retinal degenerative disease.
- •Concurrent neuromuscular disorder associated with elevated creatine kinase (CK).
Arms & Interventions
Monotherapy dose escalation (Part 1)
Participants will receive PF-07799933
Intervention: PF-07799933
Dose expansion (Part 3) - Tumor and mutation specific Cohort 3
Participants will receive PF-07799933
Intervention: PF-07799933
Dose expansion (Part 3) - Tumor and mutation specific Cohort 3
Participants will receive PF-07799933
Intervention: midazolam
Dose expansion (Part 3) - Tumor and mutation specific Cohort 4
Participants will receive PF-07799933 in combination with cetuximab
Intervention: PF-07799933
Dose expansion (Part 3) - Tumor and mutation specific Cohort 4
Participants will receive PF-07799933 in combination with cetuximab
Intervention: cetuximab
Dose expansion (Part 3) - Tumor and mutation specific Cohort 5
Participants will receive PF-07799933 in combination with cetuximab and mFOLFOX6 regimen
Intervention: PF-07799933
Dose expansion (Part 3) - Tumor and mutation specific Cohort 5
Participants will receive PF-07799933 in combination with cetuximab and mFOLFOX6 regimen
Intervention: cetuximab
Dose expansion (Part 3) - Tumor and mutation specific Cohort 5
Participants will receive PF-07799933 in combination with cetuximab and mFOLFOX6 regimen
Intervention: fluorouracil
Dose expansion (Part 3) - Tumor and mutation specific Cohort 5
Participants will receive PF-07799933 in combination with cetuximab and mFOLFOX6 regimen
Intervention: leucovorin
Combination dose escalation (Part 2)
Participants will receive PF-07799933 in combination with binimetinib or cetuximab
Intervention: PF-07799933
Combination dose escalation (Part 2)
Participants will receive PF-07799933 in combination with binimetinib or cetuximab
Intervention: binimetinib
Combination dose escalation (Part 2)
Participants will receive PF-07799933 in combination with binimetinib or cetuximab
Intervention: cetuximab
Dose expansion (Part 3) - Tumor and mutation specific Cohort 1
Participants will receive PF-07799933
Intervention: PF-07799933
Dose expansion (Part 3) - Tumor and mutation specific Cohort 2
Participants will receive PF-07799933
Intervention: PF-07799933
Dose expansion (Part 3) - Tumor and mutation specific Cohort 2
Participants will receive PF-07799933
Intervention: binimetinib
Dose expansion (Part 3) - Tumor and mutation specific Cohort 5
Participants will receive PF-07799933 in combination with cetuximab and mFOLFOX6 regimen
Intervention: oxaliplatin
Dose expansion (Part 3) - Tumor and mutation specific Cohort 6
Participants will receive PF-07799933
Intervention: PF-07799933
Dose expansion (Part 3) - Tumor and mutation specific Cohort 7
Participants will receive PF-07799933
Intervention: PF-07799933
Outcomes
Primary Outcomes
Number of participants with dose limiting toxicities (DLTs) (Part 1 and Part 2)
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 binimetinib or cetuximab
Number of participants with treatment-emergent adverse events (AEs) (Part 1 and Part 2)
Time Frame: Baseline to 28 days after last dose of study medication
AEs as characterized by type, frequency, severity, timing, seriousness, and relationship to study therapy
Number of participants with clinically significant change from baseline in laboratory abnormalities (Part 1 and Part 2)
Time Frame: Baseline to 28 days after last dose of study treatment
Laboratory abnormalities as characterized by type, frequency, severity, and timing
Number of participants with clinically significant change from baseline in vital sign abnormalities (Part 1 and Part 2)
Time Frame: Baseline to 28 days after last dose of study treatment
Vital sign abnormalities as characterized by type, frequency, severity, and timing
Dose interruptions due to AEs (Part 1 and Part 2)
Time Frame: Baseline to 2 years
Incidence of dose interruptions due to AEs
Dose dose modifications due to AEs (Part 1 and Part 2)
Time Frame: Baseline to 2 years
Incidence of dose modifications due to AEs
Discontinuations due to AEs (Part 1 and Part 2)
Time Frame: Baseline to 2 years
Incidence of discontinuations due to AEs
Overall response rate (ORR) (Part 3)
Time Frame: Baseline to 2 years
Response will be evaluated via radiographical tumor assessments by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1)
Number of participants with clinically significant physical exam abnormalities (Part 1 and Part 2)
Time Frame: Baseline to 28 days after last dose of study treatment
Physical exam abnormalities as as graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0
Number of participants with dose limiting toxicities (DLTs) (Part 1 and Part 2)
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 binimetinib or cetuximab
Number of participants with clinically significant change from baseline in vital sign abnormalities (Part 1 and Part 2)
Time Frame: Baseline to 28 days after last dose of study treatment
Vital sign abnormalities as characterized by type, frequency, severity, and timing
Number of participants with treatment-emergent adverse events (AEs) (Part 1 and Part 2)
Time Frame: Baseline to 28 days after last dose of study medication
AEs as characterized by type, frequency, severity, timing, seriousness, and relationship to study therapy
Number of participants with clinically significant change from baseline in laboratory abnormalities (Part 1 and Part 2)
Time Frame: Baseline to 28 days after last dose of study treatment
Laboratory abnormalities as characterized by type, frequency, severity, and timing
Dose interruptions due to AEs (Part 1 and Part 2)
Time Frame: Baseline to 2 years
Incidence of dose interruptions due to AEs
Dose dose modifications due to AEs (Part 1 and Part 2)
Time Frame: Baseline to 2 years
Incidence of dose modifications due to AEs
Discontinuations due to AEs (Part 1 and Part 2)
Time Frame: Baseline to 2 years
Incidence of discontinuations due to AEs
Overall response rate (ORR) (Part 3)
Time Frame: Baseline to 2 years
Response will be evaluated via radiographical tumor assessments by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1)
Number of participants with clinically significant physical exam abnormalities (Part 1 and Part 2)
Time Frame: Baseline to 28 days after last dose of study treatment
Physical exam abnormalities as as graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0
Secondary Outcomes
- Part 1 and Part 2: ORR(Baseline to 2 years)
- Part 3: Disease Control Rate (DCR)(Baseline to 2 years)
- Part 1/2/3: PK parameters of PF-07799933, Multiple dose, accumulation ratio (Rac)(Baseline to 2 years)
- Part 1 and Part 2: Duration of response(Baseline to 2 years)
- Part 1/2/3: PK parameters of PF-07799933, Single dose, maximum observed concentration (Cmax)(Baseline to 2 years)
- Part 1/2/3: PK parameters of PF-07799933, Single dose, time to maximum plasma concentration (Tmax)(Baseline to 2 years)
- Part 1/2/3: PK parameters of PF-07799933, Single dose, area under the plasma concentration-time curve from time 0 to the last time point of quantifiable concentration (AUClast)(Baseline to 2 years)
- Part 1/2/3: PK parameters of PF-07799933, Single dose, area under plasma concentration-time curve over 24 hours (AUC24)(Baseline to 2 years)
- Part 1/2/3: PK parameters of PF-07799933, Single dose, terminal elimination half life (t½)(Baseline to 2 years)
- Part 1/2/3: PK parameters of PF-07799933, Multiple dose, time to maximum plasma concentration (Tmax)(Baseline to 2 years)
- Part 1/2/3: PK parameters of PF-07799933, Multiple dose, area under the plasma concentration-time curve over the dosing interval (AUCτ)(Baseline to 2 years)
- Part 1/2/3: PK parameters of PF-07799933, Multiple dose, CL/F(Baseline to 2 years)
- Part 3: Number of participants with clinically significant change from baseline in vital sign abnormalities(Baseline to 2 years)
- Part 3: Dose dose modifications due to AEs(Baseline to 2 years)
- Part 3: Discontinuations due to AEs(Baseline to 2 years)
- Part 3: Time to event endpoints in each combination(Baseline to 2 years)
- Part 1/2/3: PK parameters of PF-07799933, Single dose, apparent oral clearance (CL/F)(Baseline to 2 years)
- Part 1/2/3: PK parameters of PF-07799933, Single dose, apparent volume of distribution (Vz/F)(Baseline to 2 years)
- Part 1/2/3: PK parameters of PF-07799933, Multiple dose, maximum observed concentration (Cmax)(Baseline to 2 years)
- Part 1/2/3: PK parameters of PF-07799933, Multiple dose, trough plasma or serum concentration (Ctrough)(Baseline to 2 years)
- Part 1/2/3: PK parameters of PF-07799933, Multiple dose, average plasma concentration (Cav)(Baseline to 2 years)
- Part 1/2/3: PK parameters of PF-07799933, Multiple dose, peak-to-trough ratio (PTR)(Baseline to 2 years)
- Part 3: PK parameters of cytochrome P450 (CYP)3A4 probe substrate midazolam, Cmax(Baseline to 2 years)
- Part 3: PK parameters of CYP3A4 probe substrate midazolam, Tmax(Baseline to 2 years)
- Part 1/2/3: Intracranial response(Baseline to 2 years)
- Part 3: Number of participants with clinically significant change from baseline in laboratory abnormalities(Baseline to 2 years)
- Part 1/2/3: PK parameters of PF-07799933, Multiple dose, t1/2(Baseline to 2 years)
- Part 1/2/3: PK parameters of PF-07799933, Multiple dose, Vz/F(Baseline to 2 years)
- Part 3: TTR(Baseline to 2 years)
- Part 3: PFS(Baseline to 2 years)
- Number of participants with clinically significant physical exam abnormalities (Part 3)(Baseline to 28 days after last dose of study medication)
- Part 3: Number of participants with treatment-emergent adverse events (AEs)(Baseline to 2 years)
- Part 3: Dose interruptions due to AEs(Baseline to 2 years)
- Part 1/2/3: PK parameters of PF-07799933, Single dose, area under plasma concentration-time curve over 48 hours (AUC48)(Baseline to 2 years)
- Part 1/2/3: PK parameters of PF-07799933, Single dose, area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUCinf)(Baseline to 2 years)
- Part 3: PK parameters of CYP3A4 probe substrate midazolam, Vz/F(Baseline to 2 years)
- Part 3: PK parameters of CYP3A4 probe substrate midazolam, AUClast(Baseline to 2 years)
- Part 3: PK parameters of CYP3A4 probe substrate midazolam, t½(Baseline to 2 years)
- Part 3: PK parameters of CYP3A4 probe substrate midazolam, AUCinf(Baseline to 2 years)
- Part 3: PK parameters of CYP3A4 probe substrate midazolam, CL/F(Baseline to 2 years)
- Part 3: DOR(Baseline to 2 years)
- Part 3: OS(Baseline to 2 years)