Study of PF-07265807 in Participants With Metastatic Solid Tumors.

Study Overview
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Brief Summary
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A First-in-Human Pharmacokinetic, Safety, and Tolerability Study of PF-07265807 as Monotherapy and in Combination in Participants with Advanced or Metastatic Solid Tumors

Official Title
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A PHASE 1, OPEN-LABEL, MULTI-CENTER, DOSE-FINDING, PHARMACOKINETIC, SAFETY AND TOLERABILITY STUDY OF PF 07265807 IN PARTICIPANTS WITH SELECTED ADVANCED OR METASTATIC SOLID TUMOR MALIGNANCIES

Conditions
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Neoplasm Metastasis

Intervention / Treatment
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* Drug: PF-07265807
* Drug: Sasanlimab
* Drug: Axitinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: At least one measurable (Parts 1-4) or non-measurable lesion (Parts 1-3), not previously irradiated, as defined by RECIST 1.1 ECOG Performance Status 0 or 1, 2 with approval Adequate Bone Marrow Function Adequate Renal Function Adequate Liver Function Resolved acute effects of any prior therapy Able to provide adequate archival tumor tissue or freshly obtained tumor tissue (some participants will require mandatory pre- and on-treatment biopsy is part of the biomarker cohort). Life expectancy of at least 3 months. Part 1 and Part 2: Participants who are intolerant or resistant to standard treatment for selected solid tumors. Part 3: Participants with advanced/metastatic RCC with a clear cell component and progressed with no standard therapy available. Part 4, Cohort 1: Participants with NSCLC with METex14-skipping alteration(s) and progressed on at least 1 prior therapy. Part 4, Cohort 2: Participants with MSS CRC with intermediate TMB and progressed with no satisfactory alternative treatment available, but has not received prior treatment with an anti-PD-(L)1 therapy. Part 4, Cohort 3: Participants with metastatic gastric or GEJ adenocarcinoma that is PD-L1 positive that has progressed on at least 2 but no more than 3 prior chemotherapy regiments, but has not received prior treatment with an anti-PD-(L)1 therapy. Part 4, Cohort 4: Participants with metastatic RCC with a clear cell component with IMDC intermediate or poor risk that have not received any prior systemic therapy for metastatic disease. Exclusion Criteria: Known active uncontrolled or symptomatic CNS metastases. Any other active malignancy within 2 years prior to enrollment. Major surgery within 6 weeks, radiation therapy within 4 weeks, systemic anti-cancer therapy within 2 week or 5 half-lives (4 weeks or 5 half-lives for antibody therapies or investigational drug(s) taken on another study) prior to study entry. Active or history of autoimmune disease requiring >10mg/day prednisone or other concurrent immunosuppressive therapy. Active, uncontrolled infection (controlled HBV, HCV, HIV/AIDS may be allowed) as defined in protocol. Retinal or other serious ophthalmic disorders as defined in protocol. Clinically significant cardiac disease as defined in protocol. Uncontrolled HTN that cannot be controlled by medications. Inability to consume or absorb study drug. Known or suspected hypersensitivity to PF-07265807. Prohibited concomitant medications as defined in protocol. Active inflammatory GI disease, uncontrollable chronic diarrhea, or previous gastric resection or lap band surgery affecting absorption. Active bleeding disorder. Discontinuation of prior checkpoint inhibitor for treatment-related toxicity. Experienced >= G3 treatment-related irAE with prior PD-(L)1 agent. Prior treatment with selective AXL/MERTK inhibitors For participants receiving sasanlimab: - Known history of non-infectious pneumonitis that required steroid treatment or current pneumonitis.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Dose escalation and expansion
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Monotherapy Dose Escalation: Part 1<br>Monotherapy dose escalation of PF-07265807 in participants with select tumor types. | Drug: PF-07265807<br>* Given 2 weeks on/1 week off<br>* Other names: ARRY-067;|
| Experimental: Doublet Dose Escalation: Part 2<br>Doublet combination dose escalation of PF-07265807 with sasanlimab in participants with select tumor types. PF-07265807 will dose escalate. Sasanlimab dose will stay constant. | Drug: PF-07265807<br>* Given 2 weeks on/1 week off<br>* Other names: ARRY-067;Drug: Sasanlimab<br>* Given SC Q3W<br>* Other names: PF-06801591; RN-888;|
| Experimental: Triplet Dose Escalation: Part 3<br>Triplet combination dose escalation of PF-07265807 with sasanlimab plus axitinib in participants with select tumor types. PF-07265807 will dose escalate. Sasanlimab dose will stay constant. Axitinib dose will follow label. | Drug: PF-07265807<br>* Given 2 weeks on/1 week off<br>* Other names: ARRY-067;Drug: Sasanlimab<br>* Given SC Q3W<br>* Other names: PF-06801591; RN-888;Drug: Axitinib<br>* Dosed per package label starting with 5 mg PO BID<br>* Other names: AG-013736; Inlyta;|
| Experimental: Expansion Phase: Part 4, Cohort 1<br>PF-07265807 monotherapy in participants with METex14 mutant NSCLC. | Drug: PF-07265807<br>* Given 2 weeks on/1 week off<br>* Other names: ARRY-067;|
| Experimental: Expansion Phase: Part 4, Cohort 2<br>PF-07265807 with sasanlimab in participants with MSS CRC | Drug: PF-07265807<br>* Given 2 weeks on/1 week off<br>* Other names: ARRY-067;Drug: Sasanlimab<br>* Given SC Q3W<br>* Other names: PF-06801591; RN-888;|
| Experimental: Expansion Phase: Part 4, Cohort 3<br>PF-07265807 with sasanlimab in participants with PD-L1+ gastric cancer/GEJ | Drug: PF-07265807<br>* Given 2 weeks on/1 week off<br>* Other names: ARRY-067;Drug: Sasanlimab<br>* Given SC Q3W<br>* Other names: PF-06801591; RN-888;|
| Experimental: Expansion Phase: Part 4, Cohort 4<br>PF-07265807 with sasanlimab plus axitinib in participants with RCC | Drug: PF-07265807<br>* Given 2 weeks on/1 week off<br>* Other names: ARRY-067;Drug: Sasanlimab<br>* Given SC Q3W<br>* Other names: PF-06801591; RN-888;Drug: Axitinib<br>* Dosed per package label starting with 5 mg PO BID<br>* Other names: AG-013736; Inlyta;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Parts 1, 2, and 3: Number of participants with dose limiting toxicities (DLTs) | DLTs will be evaluated during the first cycle (day 21) or two cycles (day 42). The number of DLTs will be used to determine the maximum tolerated dose (MTD) | Baseline through day 21 or 42 | 
| Parts 1, 2 and 3: Number of participants with treatment emergent adverse events (AEs) | AEs as characterized by type, frequency, severity, timing, seriousness, and relationship to study therapy | Baseline through approximately 2 years | 
| Parts 1, 2, and 3: Number of participants with laboratory abnormalities | Laboratory abnormalities as characterized by type, frequency, severity, and timing. | Baseline through approximately 2 years | 
| Part 4: Overall Response Rate (ORR) | Response will be evaluable via radiographical tumor assessment by RECIST v1.1 | Baseline through approximately 2 years | 
| Part 4, Cohort 4: Complete Response (CR) | Response will be evaluated via radiographical tumor assessment by RECIST v1.1 | Baseline through approximately 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Parts 1, 2, and 3: Maximum plasma concentration (Cmax) of PF-07265807 and its metabolite | Single dose (Cmax) and multiple dose (assuming steady state is achieved; Cmax,ss) pharmacokinetic (PK) parameters of PF-07265807 and its metabolite | Each cycle is 21 days. Cycle 1 Days 1 and 14, predose, 0.5,1,2,4,8 and 24 (if daily dosing) hours post dose; Cycle 1 Day 7, Cycle 2 Days 1 and 14 predose and 2 hours post dose; Cycle 3 Days 1 and 14 predose | 
| Parts 2 and 3: Maximum plasma concentration (Cmax) of sasanlimab | Single dose (Cmax) pharmacokinetic (PK) parameters of sasanlimab | Through study completion, an average of 1 year | 
| Part 3: Maximum plasma concentration at steady state (Cmax,ss) of axitinib | Multiple dose (assuming steady state is achieved; Cmax,ss) pharmacokinetic (PK) parameters of axitinib | Each cycle is 21 days. Cycle 1 Day 1 predose; Cycle 1 Day 14 predose, 0.5,1,2,4, and 8 hours post dose | 
| Parts 1, 2, and 3: Time to reach maximum plasma concentration (Tmax) of PF-07265807 and its metabolite | Single dose (Tmax) and multiple dose (assuming steady state is achieved; Tmax,ss) pharmacokinetic parameters of PF-07265807 and its metabolite | Each cycle is 21 days. Cycle 1 Days 1 and 14, predose, 0.5,1,2,4,8 and 24 (if daily dosing) hours post dose; Cycle 1 Day 7, Cycle 2 Days 1 and 14 predose and 2 hours post dose; Cycle 3 Days 1 and 14 predose | 
| Parts 2 and 3: Time to reach maximum plasma concentration (Tmax) of sasanlimab | Single dose (Tmax) pharmacokinetic parameters of sasanlimab | Through study completion, an average of 1 year | 
| Part 3: Time to reach maximum plasma concentration at steady state (Tmax,ss) of axitinib | Multiple dose (assuming steady state is achieved; Tmax,ss) pharmacokinetic parameters of axitinib | Each cycle is 21 days. Cycle 1 Day 1 predose; Cycle 1 Day 14 predose, 0.5,1,2,4, and 8 hours post dose | 
| Parts 1, 2, and 3: Area under the curve from the time of dose to the last measurable concentration (AUClast) of PF-07265807 and its metabolite | Single dose (AUClast) pharmacokinetic parameters of PF-07265807 and its metabolite | Each cycle is 21 days. Cycle 1 Days 1 and 14, predose, 0.5,1,2,4,8 and 24 (if daily dosing) hours post dose; Cycle 1 Day 7, Cycle 2 Days 1 and 14 predose and 2 hours post dose; Cycle 3 Days 1 and 14 predose | 
| Parts 2 and 3: Area under the curve from the time of dose to the last measurable concentration (AUClast) of sasanlimab | Single dose (AUClast) pharmacokinetic parameters of sasanlimab | Through study completion, an average of 1 year | 
| Parts 1, 2, and 3: Area under the curve from the time of dose to the time of the subsequent dose (AUCtau) at steady state of PF-07265807 and its metabolite | Multiple dose assuming steady state is achieved (AUCtau,ss) pharmacokinetic parameters of PF-07265807 and its metabolite | Each cycle is 21 days. Cycle 1 Days 1 and 14, predose, 0.5,1,2,4,8 and 24 (if daily dosing) hours post dose; Cycle 1 Day 7, Cycle 2 Days 1 and 14 predose and 2 hours post dose; Cycle 3 Days 1 and 14 predose | 
| Part 3: Area under the curve from the time of dose to the time of the subsequent dose (AUCtau) at steady state of axitinib | Multiple dose assuming steady state is achieved (AUCtau,ss) pharmacokinetic parameters of axitinib | Each cycle is 21 days. Cycle 1 Day 1 predose; Cycle 1 Day 14 predose, 0.5,1,2,4, and 8 hours post dose | 
| Parts 1, 2, and 3: Terminal elimination half-life (t1/2) of PF-07265807 and its metabolite | As data permits, single dose (t1/2) pharmacokinetic parameters of PF-07265807 and its metabolite | Each cycle is 21 days. Cycle 1 Days 1 and 14, predose, 0.5,1,2,4,8 and 24 (if daily dosing) hours post dose; Cycle 1 Day 7, Cycle 2 Days 1 and 14 predose and 2 hours post dose; Cycle 3 Days 1 and 14 predose | 
| Parts 2 and 3: Terminal elimination half-life (t1/2) of sasanlimab | As data permits, single dose (t1/2) pharmacokinetic parameters of sasanlimab | Through study completion, an average of 1 year | 
| Parts 1, 2, and 3: Area under the curve from the time of dose extrapolated to infinity (AUCinf) of PF-07265807 and its metabolite | As data permits, single dose (AUCinf) pharmacokinetic parameters of PF-07265807 and its metabolite | Each cycle is 21 days. Cycle 1 Days 1 and 14, predose, 0.5,1,2,4,8 and 24 (if daily dosing) hours post dose; Cycle 1 Day 7, Cycle 2 Days 1 and 14 predose and 2 hours post dose; Cycle 3 Days 1 and 14 predose | 
| Parts 2 and 3: Area under the curve from the time of dose extrapolated to infinity (AUCinf) of sasanlimab | As data permits, single dose (AUCinf) pharmacokinetic parameters of sasanlimab | Through study completion, an average of 1 year | 
| Parts 1, 2, and 3: Apparent oral clearance (CL/F) of PF-07265807 | As data permits, single dose (CL/F) and multiple dose pharmacokinetic parameters of PF-07265807 | Each cycle is 21 days. Cycle 1 Days 1 and 14, predose, 0.5,1,2,4,8 and 24 (if daily dosing) hours post dose; Cycle 1 Day 7, Cycle 2 Days 1 and 14 predose and 2 hours post dose; Cycle 3 Days 1 and 14 predose | 
| Parts 2 and 3: Apparent clearance (CL/F) of sasanlimab | As data permits, single dose (CL/F) pharmacokinetic parameters of sasanlimab | Through study completion, an average of 1 year | 
| Parts 1, 2, and 3: Apparent terminal volume of distribution (Vz/F) of PF-07265807 | As data permits, single dose (Vz/F) and multiple dose (Vss/F) pharmacokinetic parameters of PF-07265807 | Each cycle is 21 days. Cycle 1 Days 1 and 14, predose, 0.5,1,2,4,8 and 24 (if daily dosing) hours post dose; Cycle 1 Day 7, Cycle 2 Days 1 and 14 predose and 2 hours post dose; Cycle 3 Days 1 and 14 predose | 
| Parts 2 and 3: Apparent terminal volume of distribution (Vz/F) of sasanlimab | As data permits, single dose (Vz/F) pharmacokinetic parameters of sasanlimab | Through study completion, an average of 1 year | 
| Parts 1, 2, and 3: ORR | Response will be evaluable via radiographical tumor assessment by RECIST v1.1 | Baseline through approximately 2 years | 
| Part 4: Number of participants with treatment emergent AEs | AEs as characterized by type, frequency, severity, timing, seriousness, and relationship to study therapy | Baseline through approximately 2 years | 
| Part 4: Number of participants with laboratory abnormalities | Laboratory abnormalities as characterized by type, frequency, severity, and timing | Baseline through approximately 2 years | 
| Part 4: Trough concentration (Ctrough) of PF-07265807 and its metabolite | Predose (Ctrough) pharmacokinetic (PK) parameter of PF-07265807 and its metabolite | Each cycle is 21 days. Cycle 1 Days 1 and 14 predose, 2, 4 hours post dose; Cycle 1 Day 7 predose and 2 hours post dose; Cycle 2 Days 1 and 14 predose | 
| Part 4: Post dose concentration (Cmax) of PF-07265807 and its metabolite | Post dose (Cmax) pharmacokinetic (PK) parameter of PF-07265807 and its metabolite | Each cycle is 21 days. Cycle 1 Days 1 and 14 predose, 2, 4 hours post dose; Cycle 1 Day 7 predose and 2 hours post dose; Cycle 2 Days 1 and 14 predose | 
| Part 4, Cohorts 2, 3 and 4: Trough concentration (Ctrough) of sasanlimab | Predose (Ctrough) pharmacokinetic (PK) parameter of sasanlimab | Each cycle is 21 days. Cycle 1 Days 1, 7, and 14, Cycle 2 Day 1, Cycle 7 Day 1, and every 6 cycles thereafter predose | 
| Part 4, Cohort 4: Trough concentration (Ctrough) of axitinib | Predose (Ctrough) pharmacokinetic (PK) parameter of axitinib | Each cycle is 21 days. Cycle 1 Day 1 predose; Cycle 1 Day 14 predose, 2, and 4 hours post dose | 
| Parts 2, 3, and 4 Cohorts 2-4: Immunogenicity of sasanlimab when given in combination | Incidence and titer of anti-sasanlimab ADA response | Through study completion, an average of 1 year | 
| Duration of Response | Response will be evaluable via radiographical tumor assessment by RECIST v1.1 | Baseline through approximately 2 years | 
| Disease Control Rate | Response will be evaluable via radiographical tumor assessment by RECIST v1.1 | Baseline through approximately 2 years | 
| Progression Free Survival | Response will be evaluable via radiographical tumor assessment by RECIST v1.1 | Baseline through approximately 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cervical Cancer, TAMK (TAM kinase), MER (mer proto-oncogene), MERTK (mer proto-oncogene tyrosine kinase), AXL (AXL receptor tyrosine kinase), AXL/MER, Selective kinase inhibitor, PD-1 (programmed cell death protein 1), PD-L1 (programmed cell death ligand 1), Immune modulator, Advanced Cancer, Metastatic Cancer, Solid Tumor Cancer, Metastatic Solid Tumor, Gastric Cancer, Esophageal Cancer, Endometrial Cancer, Hepatocellular carcinoma (HCC), Melanoma, Merkel Cell Carcinoma, High levels of MicroSatellite Instability deficient MisMatch Repair (MSI-H-dMMR) tumor, Non-small cell lung cancer (NSCLC), Small cell lung cancer (SCLC), Renal cell carcinoma (RCC), Urothelial carcinoma, Colorectal cancer (CRC)