A Dose Escalation Study Of PF-06801591 In Melanoma, Head And Neck Cancer (SCCHN), Ovarian, Sarcoma, Non-Small Cell Lung Cancer, Urothelial Carcinoma or Other Solid Tumors

Study Overview
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Brief Summary
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Protocol B8011001 is a Phase 1, open-label, multi-center, multiple-dose, dose escalation and expansion, safety, pharmacokinetics (PK), and pharmacodynamics (PD) study of PF-06801591 in previously treated adult patients with locally advanced or metastatic melanoma, SCCHN, ovarian carcinoma, sarcoma, NSCLC, urothelial carcinoma or other solid tumors. This is a 2 Part study whereby the safety and tolerability of increasing dose levels of intravenous (IV) or subcutaneous (SC) PF-06801591 was assessed in Part 1. Part 2 expansion is designed to further evaluate the safety and efficacy of SC PF-06801591 in patients with NSCLC or urothelial carcinoma as well as confirm the recommended Phase 2 dose.

Detailed Description
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Protocol B8011001 is a Phase 1, two part, open-label, multi center, multiple-dose, safety, efficacy, PK, and PD study of PF-06801591 administered intravenously (IV) or subcutaneous (SC) in previously treated adult patients with locally advanced or metastatic melanoma, squamous cell carcinoma head and neck (SCCHN), ovarian carcinoma, sarcoma, non-small cell lung carcinoma (NSCLC), urothelial carcinoma or other solid tumors. The first part of the study, Part 1 dose escalation, was designed to assess the safety and tolerability of increasing dose levels of IV or SC administered PF-06801591 to establish the maximum tolerated dose (MTD) using a modified Toxicity Probability Interval (mTPI) design. Part 2 expansion is designed to further evaluate the safety and efficacy of 300 mg of PF-06801591 administered SC once every 4 weeks in patients with NSCLC or urothelial carcinoma as well as confirm the recommended Phase 2 dose (RP2D). Part 1 enrollment has completed, enrollment will only be allowed for Part 2.

Official Title
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A PHASE 1, OPEN-LABEL, DOSE ESCALATION AND EXPANSION STUDY OF PF-06801591 IN PATIENTS WITH LOCALLY ADVANCED OR METASTATIC MELANOMA, SQUAMOUS CELL HEAD AND NECK CANCER, OVARIAN CANCER, SARCOMA, NON-SMALL CELL LUNG CANCER, UROTHELIAL CARCINOMA OR OTHER SOLID TUMORS.

Conditions
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Part 1, MELANOMA, SCCHN, OVCA, SARCOMA, OTHER SOLID TUMORS, Part 1 and 2, NSCLC, UROTHELIAL CARCINOMA

Intervention / Treatment
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* Drug: PF-06801591
* Drug: PF-06801591


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria (Part 2 Only): Histological or cytological diagnosis of locally advanced or metastatic NSCLC or urothelial carcinoma who have progressed on or were intolerant to standard of care systemic therapy, or for whom standard of care systemic therapy was refused (refusal must be documented) or unavailable. No prior treatment with anti-PD-1 or anti-PD-L1 therapy. NSCLC patients whose tumor is not known to have ALK or EGFR mutations must have progressed on or after no more than 1 prior line of platinum-containing systemic therapy or were intolerant or refused standard of care systemic therapy. NSCLC patients whose tumor is known to have ALK or EGFR mutation must have received prior systemic therapies that only include 1 or more lines of ALK or EGFR targeting drugs and chemotherapy limited to 1 line of a platinum-based regimen and they must have progressed on or after both types of therapies. Urothelial carcinoma patients must have received up to 2 lines of prior systemic therapy and progressed on or after, experienced disease recurrence within 12 months of neoadjuvant or adjuvant treatment, were intolerant to, ineligible or refused platinum-containing systemic therapy. If urothelial cancer patients are treatment naïve and eligible for platinum-containing systemic therapy but are refusing platinum chemotherapy, they must also be documented to have previous PD-L1 high status. Provide archived tumor tissue sample taken within the past 2 years or provide a fresh tumor biopsy sample. At least one measurable lesion as defined by RECIST version 1.1. Adequate renal, liver, thyroid and bone marrow function. Performance status 0 or 1. Patient is capable of receiving study treatment for at least 8 weeks. Exclusion Criteria (Part 2 Only) Active brain or leptomeningeal metastases. Active, known or suspected autoimmune disease. Patients with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll. Diagnosis of prior immunodeficiency or organ transplant requiring immunosuppressive therapy or prior allogeneic bone marrow or hematopoietic stem cell transplant. Patients with a condition requiring systemic treatment with either corticosteroids (>10mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids, and adrenal replacement doses >10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease. Patients with a history of interstitial lung disease, non-infectious pneumonitis, or active pulmonary tuberculosis. Those with active lung infections requiring treatment are also excluded. History of Grade ≥3 immune mediated AE (including AST/ALT elevations that where considered drug related and cytokine release syndrome) that was considered related to prior immune modulatory therapy (eg, immune checkpoint inhibitors, co-stimulatory agents, etc.) and required immunosuppressive therapy. Active hepatitis B or C, HIV/AIDS. Other potentially metastatic malignancy within past 5 years.

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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1 PF-06801591<br>0.5 mg/kg IV every 21 days (Part 1) | Drug: PF-06801591<br>* IV every 21 days (Part 1)<br>|
| Experimental: Arm 2 PF-06801591<br>1.0 mg/kg IV every 21 days (Part 1) | Drug: PF-06801591<br>* IV every 21 days (Part 1)<br>|
| Experimental: Arm 3 PF-06801591<br>3.0 mg/kg IV every 21 days (Part 1) | Drug: PF-06801591<br>* IV every 21 days (Part 1)<br>|
| Experimental: Arm 4 PF-06801591<br>10 mg/kg IV every 21 days (Part 1) | Drug: PF-06801591<br>* IV every 21 days (Part 1)<br>|
| Experimental: Arm 5 PF-06801591<br>300 mg SC every 28 days (Part 1 and 2) | Drug: PF-06801591<br>* 300 mg SC every 28 days (Part 1 and 2)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Dose-Limiting Toxicities (DLT) - Part 1 | DLT was defined as any of the following drug-related adverse events (AEs) occurring during the first cycle (21 days for IV dosing, 28 days for SC dosing) in Part 1: Grade 5 AE; Grade 4 neutropenia lasting >5 days from initiation of granulocyte colony stimulating factor; Grade 4 thrombocytopenia with bleeding; Platelet transfusion requirement or a platelet count <10,000/uL; Grade 4 non-hematologic AE; Grade 3 AE lasting >7 days despite optimal supportive care; Grade 3 central nervous system AE regardless of duration; met criteria for drug induced liver injury. Severity of AEs were graded according to Common Terminology Criteria for Adverse Events (CTCAE) v4.03. Grade 3 = severe AE. Grade 4 = life-threatening consequences; urgent intervention indicated. Grade 5 = death related to AE. | Cycle 1 in Part 1 (21 days for IV administration of PF-06801591; 28 days for SC administration of PF-06801591) | 
| Number of Participants With All-Causality Treatment-Emergent Adverse Events (AEs) - Part 1 and Part 2 | AE = any untoward medical occurrence in participant who received study treatment without regard to possibility of causal relationship. Treatment-emergent events = between first dose of study treatment and up to 28 days after last dose that were absent before treatment or that worsened relative to pretreatment state. A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Grades of severity were defined by CTCAE v4.03. Grades of severity were defined by CTCAE v4.03. Grade 3 = severe AE. Grade 4 = life-threatening consequences; urgent intervention indicated. Grade 5 = death related to AE. | Baseline up to 28 days after last dose of study treatment (maximum of 1634 days) | 
| Number of Participants With Treatment-Related Treatment-Emergent Adverse Events (AEs) - Part 1 and Part 2 | Treatment-related AE was any untoward medical occurrence attributed to study treatment in a participant who received study treatment. Treatment-emergent events = between first dose of study treatment and up to 28 days after last dose that were absent before treatment or that worsened relative to pretreatment state. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-related AEs and SAEs were determined by the investigator. Grades of severity were defined by CTCAE v4.03. Grades of severity were defined by CTCAE v4.03. Grade 3 = severe AE. Grade 4 = life-threatening consequences; urgent intervention indicated. Grade 5 = death related to AE. | Baseline up to 28 days after last dose of study treatment (maximum of 1634 days) | 
| Number of Participants With Laboratory Test Abnormalities - Part 1 and Part 2 | Following parameters were analyzed for laboratory examination: hematology (anemia, hemoglobin increased, lymphocyte count decreased, lymphocyte count increased, neutrophil count decreased, platelet count decreased, white blood cell decreased); chemistries (increase of alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, blood bilirubin, CPK, creatinine, gamma-glutamyl transferase [GGT], lipase, and serum amylase); urinalysis (proteinuria); coagulation (activated partial thromboplastin time prolonged, international normalized ratio [INR] increased). Grades of severity were defined by CTCAE v4.03. Grade 0 = No Change from normal or reference range (this grade is not included in the CTCAE v4.03 document but may used in certain circumstances). Grade 1 = mild adverse event (AE). Grade 2 = moderate AE; Grade 3 = severe AE. Grade 4 = life-threatening consequences; urgent intervention indicated. Grade 5 = death related to AE. | Baseline up to 28 days after last dose of study treatment (maximum of 1634 days) | 
| Objective Response Rate (ORR) Based on RECIST Version 1.1 - Part 2 | ORR was defined as percentage of participants with confirmed objective response (OR) of complete response (CR) and partial response (PR) based on RECIST version 1.1. CR was defined as complete disappearance of all target lesions with the exception of nodal disease. All target nodes must decrease to normal size (short axis < 10 mm). All target lesions must be assessed. PR was defined as >= 30% decrease under baseline of the sum of diameters of all target measurable lesions. The short diameter was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. All target lesions must be assessed. | Baseline up to end of treatment in Part 2 (maximum of 851 days) | 
| Objective Response Rate (ORR) Based on Immune Related RECIST (irRECIST) - Part 2 | ORR was defined as percentage of participants with objective response (OR) of complete response (CR) and partial response (PR) based on irRECIST. CR was defined as complete disappearance of all target lesions with the exception of nodal disease. All target nodes must decrease to normal size (short axis < 10 mm). All target lesions must be assessed. PR was defined as >= 30% decrease under baseline of the sum of diameters of all target measurable lesions. The short diameter was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. All target lesions must be assessed. | Baseline up to end of treatment in Part 2 (maximum of 851 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Plasma Concentration (Cmax) of PF-06801591 - Part 1 | Cmax was the maximum concentration after dose administration observed directly from the data. | Pre-dose, 1 and 24 hours post dose on Cycle 1 Day 1, and pre-dose and 1 hour post dose on Cycle 4 Day 1 in Part 1 | 
| AUClast of PF-06801591 in Part 1. | Area Under the Concentration Versus Time Curve (AUC) From Time Zero to the Last Quantifiable Time Point Prior to the Next Dose (AUClast) of PF-06801591 - Part 1 | Pre-dose, 1 and 24 hours post dose on Cycle 1 Day 1 in Part 1 | 
| Clearance (CL) of PF-06801591 - Part 1 | CL for IV dosing. CL was calculated by dose / AUCtau for Cycles 1 and 4 IV dosing. AUCtau was defined as area under the serum concentration time profile from time zero to time tau, the dosing interval, where tau = 504 hours for every 3 weeks (Q3W) IV dosing reporting arm. | Pre-dose, 1 and 24 hours post dose on Cycle 1 Day 1, and pre-dose and 1 hour post dose on Cycle 4 Day 1 in Part 1 | 
| Volume of Distribution at Steady State (Vss) of PF-06801591 - Part 1 | Steady state volume of distribution of PF-0680159 for IV dosing. Vss was calculated by CL*MRT. CL was the clearance for IV dosing. MRT was the mean residence time calculated for a single IV dose as AUMCinf/AUCinf - (DOF/2). AUMCinf was the area under the moment curve from time 0 extrapolated to infinity. DOF was the duration of infusion. AUCinf was the area under the serum concentration time profile from time 0 extrapolated to infinity. | Pre-dose, 1 and 24 hours post dose on Cycle 1 Day 1, and pre-dose and 1 hour post dose on Cycle 4 Day 1 in Part 1 | 
| Accumulation Ratio (Rac) of PF-06801591 - Part 1 | Rac was calculated by (Cycle 4 AUCtau) / (Cycle 1 AUCtau). AUCtau was Area under the serum concentration time profile from time zero to time tau, the dosing interval, where tau = 504 hours for Q3W IV dosing and tau = 672 hours for every 4 weeks (Q4W) SC dosing. | Pre-dose and 1 hour post dose on Day 1 of Cycles 1 and 4 in Part 1 | 
| Terminal Elimination Half-Life (t1/2) of PF-06801591 - Part 1 | t1/2 was calculated by Loge(2)/kel. kel was the terminal phase rate constant calculated by a linear regression of the log linear concentration time curve. Only those data points judged to describe the terminal log linear decline were used in the regression. | Pre-dose and 1 hour post dose on Day 1 of Cycles 1 and 4 in Part 1 | 
| Number of Participants With Anti-Drug Antibody (ADA) Against PF-06801591 - Part 1 and Part 2 | Number of participants with ADA positive against PF-06801591 after IV and SC dosing - Part 1 and Part 2. A participant was ADA positive if (1) baseline titer was missing or negative and participant had ≥ 1 post-treatment positive titer (treatment-induced), or (2) positive titer at baseline and had a ≥ 0.602 in titer from baseline in ≥ 1 post-treatment sample (treatment-boosted). Participants who were ADA positive at baseline but did not become boosted post-treatment were considered as ADA negative. | Baseline up to end of treatment (maximum of 851 days) | 
| Number of Participants With Neutralizing Antibodies (NAb) Positive Against PF-06801591 - Part 1 and Part 2 | Number of participants with NAb positive against PF-06801591 after IV and SC dosing - Part 1 and Part 2. A participant was NAb positive if (1) baseline titer was missing or negative and participant had ≥ 1 post-treatment positive titer (treatment-induced), or (2) positive titer at baseline and had a ≥ 0.602 in titer from baseline in ≥ 1 post-treatment sample (treatment-boosted). Participants who were NAb positive at baseline but did not become boosted post-treatment were considered as NAb negative. | Baseline up to end of treatment (maximum of 851 days) | 
| Percentage of Baseline PD-1 Receptor Occupancy (RO) by PF-06801591 - Part 1 | PD-1 RO by sasanlimab was measured by the reduction of free receptor on the surface of CD8+ effector cells (CD3+, CD4-, CD8+, CD45RA+, CCR7-, CD279+) and CD8+ effector memory cells (CD3+, CD4-, CD8+, CD45RA-, CCR7-, CD279+) presented in pre- and postdose whole blood samples by flow cytometry. Percentage of baseline (ie, normalized change from baseline) PD-1 RO were calculated as [(percentage of cells at Cycle X Day X)/(percentage of cells at baseline)]*100, and are reported for this outcome measure. Baseline was defined as the most recent non-missing value prior to dosing. | Baseline, Days 1, 8, 15, 21 of Cycle 1, Day 1 of Cycles 2, 3, 5, Days 1, 15, 21 of Cycle 4, and end of treatment (EOT) in Part 1 (cycle = 21 days for IV dosing; cycle = 28 days for SC dosing) | 
| Number of Participants Achieving Objective Response (OR) Based on RECIST Version 1.1 - Part 1 | Number of participants achieving confirmed OR based on RECIST version 1.1 in Part 1. CR was defined as complete disappearance of all target lesions with the exception of nodal disease. All target nodes must decrease to normal size (short axis < 10 mm). All target lesions must be assessed. PR was defined as >= 30% decrease under baseline of the sum of diameters of all target measurable lesions. The short diameter was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. All target lesions must be assessed. | Baseline up to end of treatment in Part 1 (maximum of 1606 days) | 
| Number of Participants Achieving Objective Response (OR) Based on irRECIST - Part 1 | Number of participants achieving confirmed OR based on irRECIST in Part 1. OR = irCR + irPR. Overall immune related complete response (irCR) was defined as complete disappearance of all lesions (whether measurable or not) and no new lesions. All measurable lymph nodes also must have a reduction in short axis to <10 mm. Overall immune related partial response (irPR) was defined as sum of the diameters (longest for non nodal lesions, shortest for nodal lesions) of target and new measurable lesions decreases >=30%. | Baseline up to end of treatment in Part 1 (maximum of 1606 days) | 
| Progression-Free Survival (PFS) Based on RECIST Version 1.1 and irRECIST - Part 1 and Part 2 | PFS was defined as the time from initiation of study intervention to first documentation of tumor progression or to death due to any cause, whichever occurred first. PFS was analyzed by the Kaplan-Meier approach for each tumor type. As this outcome measure was a secondary endpoint defined in the protocol to investigate preliminary signal of efficacy, the results were analyzed and are reported for Part 1 dose-escalation groups combined to provide more statistically meaningful results, instead of results analyzed by dose level with very limited number of participants in each group. | Baseline up to end of treatment (maximum of 1606 days) | 
| Duration of Stable Disease (DOSD) Based on RECIST Version 1.1 and irRECIST - Part 1 and Part 2 | DOSD was analyzed by the Kaplan-Meier approach for each tumor type. Stable disease (SD) was defined as not qualifying for complete response (CR), partial response (PR), or progression. All target lesions must have been assessed. Stable could follow PR only in the rare case that the sum increased by less than 20% from the nadir, but enough that a previously documented 30% decrease no longer held. CR was defined as complete disappearance of all target lesions with the exception of nodal disease. All target nodes must have decreased to normal size (short axis < 10 mm). All target lesions must have been assessed. PR was defined as greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions. The short diameter was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. All target lesions must have been assessed. | Baseline up to end of treatment (maximum of 1606 days) | 
| Duration of Response (DOR) Based on RECIST Version 1.1 and irRECIST - Part 1 and Part 2 | DOR was defined as the time from start date (which was the date of first documentation of PR or CR) to date of first documentation of objective progression or death. CR was defined as complete disappearance of all target lesions with the exception of nodal disease. PR was defined as greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions. Objective progression was defined as 20% increase in the sum of diameters of target measurable lesions above the smallest sum observed (over baseline if no decrease in the sum was observed during therapy), with a minimum absolute increase of 5 mm. As this outcome measure was a secondary endpoint defined in the protocol to investigate preliminary signal of efficacy, the results were analyzed and are reported for Part 1 dose-escalation groups combined to provide more statistically meaningful results, instead of results analyzed by dose level with very limited number of participants in each group. | Baseline up to end of treatment (maximum of 1606 days) | 
| Time to Response (TTR) Based on RECIST Version 1.1 - Part 2 | TTR was the time to confirmed or unconfirmed complete response (CR) or partial response (PR) based on investigator assessment per RECIST v1.1 by tumor type. CR was defined as complete disappearance of all target lesions with the exception of nodal disease. All target nodes must have decreased to normal size (short axis < 10 mm). All target lesions must have been assessed. PR was defined as greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions. The short diameter was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. All target lesions must have been assessed. | Baseline up to end of treatment in Part 2 (maximum of 851 days) | 
| Time to Progression (TTP) Based on RECIST Version 1.1 and irRECIST - Part 2 | TTP was the time to objective progression. Objective progression was defined as 20% increase in the sum of diameters of target measurable lesions above the smallest sum observed (over baseline if no decrease in the sum was observed during therapy), with a minimum absolute increase of 5 mm. TTP was analyzed by the Kaplan-Meier approach for each tumor type. | Baseline up to end of treatment in Part 2 (maximum of 851 days) | 
| Median Time to Death - Part 2 | Median time to death was analyzed by the Kaplan-Meier approach for each tumor type. | Baseline up to end of treatment in Part 2 (maximum of 851 days) | 
| Probability of Survival at 6 Months, 1 Year, and 2 Years - Part 2 | Probability of survival was calculated from the product-limit method. | Baseline up to end of treatment in Part 2 (maximum of 851 days) | 
| Trough PF-06801591 Concentrations (Ctrough) - Part 2 | Trough PF-06801591 Concentrations (Ctrough) - Part 2. Ctrough was directly observed from data. | Pre-dose on Day 1 of Cycles 2-6, 9, 12, 15, 18, 21, 24, and Follow-up Day 28 in Part 2 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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dose response, efficacy, safety, pharmacokinetics, pharmacodynamics, open label, multiple ascending dose, immunogenicity, recommended phase 2 dose, subcutaneous