A Study Of 4-1BB Agonist PF-05082566 Plus PD-1 Inhibitor MK-3475 In Patients With Solid Tumors (B1641003/KEYNOTE-0036)

Study Overview
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Brief Summary
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This is a safety, pharmacokinetic and pharmacodynamic study designed to estimate the maximum tolerated dose (MTD), and determine the Recommended Phase 2 Dose (RP2D) of PF-05082566, a 4-1BB agonist monoclonal antibody (mAb), in combination with MK-3475, a PD-1 inhibitor in patients with solid tumors.

Official Title
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A PHASE 1B STUDY OF THE 4-1BB AGONIST PF-05082566 IN COMBINATION WITH THE PD-1 INHIBITOR MK-3475 IN PATIENTS WITH ADVANCED SOLID TUMORS

Conditions
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Advanced Solid Tumors

Intervention / Treatment
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* Drug: PF-05082566
* Drug: MK-3475


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histological or cytological diagnosis of advanced/metastatic solid tumor malignancy which has progressed on standard therapy or for which no standard therapy is available. Measurable disease per RECIST v1.1. Adequate bone marrow, renal and liver functioning Exclusion Criteria: CNS primary malignancies, active seizure disorder or spinal cord compression, or carcinomatous meningitis. History of any of the following toxicities associated with a prior immunotherapy: Grade 3 immune mediated adverse event that was considered related to previous immunotherapy and required immune suppressive therapy; Grade 2 hepatic function related adverse event that persisted more than 1 week, was considered related to immunotherapy, or required treatment discontinuation or immunosuppressive therapy Any of the following within the 12 months prior to registration: myocardial infarction, uncontrolled angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack and 6 months for deep vein thrombosis or pulmonary embolism. History of or known presence of extensive, disseminated/bilateral or Grade 3 or 4 interstitial fibrosis or interstitial lung disease, including a history of pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, interstitial lung disease, obliterative bronchiolitis, or pulmonary fibrosis, but not including a history of prior radiation pneumonitis. Patients with clinically significant lung disease requiring oxygen therapy (eg, COPD).

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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PF-05082566 +MK-3475<br>PF-05082566 +MK-3475 | Drug: PF-05082566<br>* Starting dose of 0.45 mg/kg q3wks IV, dose escalation<br>Drug: MK-3475<br>* 2 mg/kg q3wks, IV<br>* Other names: pembrolizumab;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Dose-Limiting Toxicities (DLT) of PF-05082566 in Combination With MK-3475 | Severity of adverse events (AEs) was graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. For the purpose of dose escalation, any of the following AEs occurring during the DLT observation period that were attributable to one or both study drugs were classified as DLTs. 1) Hematologic: Grade 4 neutropenia; Febrile neutropenia, defined as absolute neutrophil count (ANC) <1000/mm3 with a single temperature of >38.3C(101F) or a sustained temperature of 38C (100.4F) for more than 1 hour; Grade>=3 neutropenic infection; Grade>=3 thrombocytopenia with bleeding; Grade 4 thrombocytopenia. 2) Non hematologic: Grade>=3 toxicities (non-laboratory); Grade>=3 nausea, vomiting or diarrhea despite maximal medical therapy; Grade 4 aspartate aminotransferase (AST) and alanine aminotransferase (ALT). 3) Other (non-AST/ALT) non-hematologic Grade>=3 laboratory value. 4) Inability to complete 2 infusions of MK-3475 and PF-05082566 during the DLT observation period. | First 2 cycles of treatment up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Serious Adverse Events (SAEs) and Treatment Emergent Adverse Events (TEAEs) by Maximum CTCAE Grade (All Causalities) | An AE was any untoward medical occurrence in a clinical investigation subject administered a product or medical device, regardless of its causal relationship with study treatment. A SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; life threatening; initial or prolonged inpatient hospitalization; persistent or significant disability/incapacity; congenital anomaly/birth defect. Any events occurring following start of treatment or increasing in severity were counted as treatment emergent. The severity was graded by National Cancer Institute (NCI) CTCAE v.4.03. Grade 1 was mild AE. Grade 2 was moderate AE. Grade 3 was severe AE. Grade 4 was life-threatening consequences and urgent intervention AE. Grade 5 was indicated death related to AE. | Baseline up to 90 days after the last dose of study drug, approximately 27 months | 
| Number of Participants With Serious Adverse Events (SAEs) and Treatment Emergent Adverse Events (TEAEs) by Maximum CTCAE Grade (PF-05082566-related) | An AE was any untoward medical occurrence in a clinical investigation subject administered a product or medical device, regardless of its causal relationship with study treatment. A SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; life threatening; initial or prolonged inpatient hospitalization; persistent or significant disability/incapacity; congenital anomaly/birth defect. Any events occurring following start of treatment or increasing in severity were counted as treatment emergent. The severity was graded by NCI CTCAE v.4.03. Grade 1 was mild AE. Grade 2 was moderate AE. Grade 3 was severe AE. Grade 4 was life-threatening consequences and urgent intervention AE. Grade 5 was indicated death related to AE. | Baseline up to 90 days after the last dose of study drug, approximately 27 months | 
| Number of Participants With Serious Adverse Events (SAEs) and Treatment Emergent Adverse Events (TEAEs) by Maximum CTCAE Grade (MK-3475-related) | An AE was any untoward medical occurrence in a clinical investigation subject administered a product or medical device, regardless of its causal relationship with study treatment. A SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; life threatening; initial or prolonged inpatient hospitalization; persistent or significant disability/incapacity; congenital anomaly/birth defect. Any events occurring following start of treatment or increasing in severity were counted as treatment emergent. The severity was graded by NCI CTCAE v.4.03. Grade 1 was mild AE. Grade 2 was moderate AE. Grade 3 was severe AE. Grade 4 was life-threatening consequences and urgent intervention AE. Grade 5 was indicated death related to AE. | Baseline up to 90 days after the last dose of study drug, approximately 27 months | 
| Number of Participants With Serious Adverse Events (SAEs) and Treatment Emergent Adverse Events (TEAEs) by Maximum CTCAE Grade (Both-related) | An AE was any untoward medical occurrence in a clinical investigation subject administered a product or medical device, regardless of its causal relationship with study treatment. A SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; life threatening; initial or prolonged inpatient hospitalization; persistent or significant disability/incapacity; congenital anomaly/birth defect. Any events occurring following start of treatment or increasing in severity were counted as treatment emergent. The severity was graded by NCI CTCAE v.4.03. Grade 1 was mild AE. Grade 2 was moderate AE. Grade 3 was severe AE. Grade 4 was life-threatening consequences and urgent intervention AE. Grade 5 was indicated death related to AE. | Baseline up to 90 days after the last dose of study drug, approximately 27 months | 
| Number of Participants With Laboratory Test Values Meeting Categorical Summarization Criteria by Maximum CTCAE Grade (Hematology) | The hematology laboratory test included: absolute neutrophil count, hemoglobin, platelet count, white blood cell with differential, coagulation panel, urinalysis and pregnancy test. Laboratory results were categorical summarized according to the NCI-CTCAE criteria version 4.03. The total number of participants with hematology laboratory test was assessed. | Baseline up to 28 days after the last dose of study drug, approximately 25 months | 
| Number of Participants With Laboratory Test Values Meeting Categorical Summarization Criteria by Maximum CTCAE Grade (Chemistries) | The chemical laboratory test included: sodium, potassium, total calcium, creatinine, albumin, alanine aminotransferase, alanine aminotransferase, glucose, phosphorus, magnesium, total bilirubin, blood urea nitrogen, alkaline phosphatase, lactate dehydrogenase, immunoglobulin G, total protein, uric acid, thyroid function assessments, hepatitis B and C tests. Laboratory results were categorical summarized according to the NCI-CTCAE criteria version 4.03. The total number of participants with chemistry laboratory test was assessed. | Baseline up to 28 days after the last dose of study drug, approximately 25 months | 
| Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Criteria of Potential Clinical Concern | Vital sign summaries included all vital sign assessments from the on-treatment period. All vital sign parameters including blood pressure (BP) and weight were summarized using actual values and changes from baseline for each visit over time. The changes computed were the differences from baseline. The participants meeting criteria of potential clinical concern were judged by investigator. | Baseline up to 28 days after the last dose of study drug, approximately 25 months | 
| Number of Participants With Shift From Baseline in Eastern Cooperative Oncology Group (ECOG) Performance Status to Worst on Study | The ECOG shift from baseline to highest score during the on-treatment period was summarized by treatment group.ECOG Performance Status included 0, 1, 2, 3, and 4 grades. Grade 1 was Restricted in physically strenuous activity, but ambulatory and able to carry out work of a light or sedentary nature. Grade 2 was Ambulatory and capable of all self care but unable to carry out any work activities.Up and about more than 50% of waking hours. Grade 3 was capable of only limited self care, confined to bed or chair more than 50% of waking hours. Grade 4 was completely disabled. Cannot carry on any self care. Totally confined to bed or chair. | Baseline up to 28 days after the last dose of study drug, approximately 25 months | 
| Maximum Observed Serum Concentration (Cmax) of PF-05082566 | Maximum PF-05082566 observed serum concentration. | During Cycle 5 on Day 1 at pre-dose, end of infusion, and at 2, 6, and 24 hours after the start of infusion, day 8 (168 hours) and day 15 (336 hours) after start of infusion | 
| Maximum Observed Serum Concentration (Cmax) of MK-3475 | Maximum MK-3475 observed serum concentration. | During Cycle 5 Day 1 at pre-dose; and end of infusion. | 
| Time for Cmax (Tmax) of PF-05082566 | Time to reach PF-05082566 maximum observed serum concentration. | During Cycle 5 on Day 1 at pre-dose, end of infusion, and at 2, 6, and 24 hours after the start of infusion, day 8 (168 hours) and day 15 (336 hours) after start of infusion. | 
| Pre-dose Concentration During Multiple Dosing (Ctrough) of PF-05082566 | PF-05082566 pre-dose concentration during multiple dosing | During Cycle 5 on Day 1 at pre-dose, end of infusion, and at 2, 6, and 24 hours after the start of infusion, day 8 (168 hours) and day 15 (336 hours) after start of infusion. | 
| Pre-dose Concentration During Multiple Dosing (Ctrough) of MK-3475 | MK-3475 pre-dose concentration during multiple dosing | During Cycle 5 Day 1 at pre-dose; and end of infusion. | 
| Terminal Half-life （t½）of PF-05082566 | PF-05082566 terminal half-life | During Cycle 5 on Day 1 at pre-dose, end of infusion, and at 2, 6, and 24 hours after the start of infusion, day 8 (168 hours) and day 15 (336 hours) after start of infusion. | 
| Clearance (CL) of Study Drug of PF-05082566 | Clearance of PF-05082566 | During Cycle 5 on Day 1 at pre-dose, end of infusion, and at 2, 6, and 24 hours after the start of infusion, day 8 (168 hours) and day 15 (336 hours) after start of infusion. | 
| Volume of Distribution at Steady State (Vss) of PF-05082566 | PF-05082566 volume of distribution at steady state | During Cycle 5 on Day 1 at pre-dose, end of infusion, and at 2, 6, and 24 hours after the start of infusion, day 8 (168 hours) and day 15 (336 hours) after start of infusion. | 
| Area Under the Serum Concentration-time Curve From Time 0 to Time Tau, the Dosing Interval, Where Tau = 504 Hours (21 Days) [AUCtau] for PF-05082566 | PF-05082566 area under the serum concentration-time curve (AUC) from time 0 to time tau, the dosing interval, where tau = 504 hours (21 days) (AUCtau) | During Cycle 5 on Day 1 at pre-dose, end of infusion, and at 2, 6, and 24 hours after the start of infusion, day 8 (168 hours) and day 15 (336 hours) after start of infusion. | 
| Number of Participants With Positive Anti-Drug Antibody (ADA) of PF-05082566 | ADA blood samples were assayed for anti-PF-05082566 antibodies using a validated analytical method in compliance with Pfizer (anti-PF-05082566) standard operating procedures (SOPs). ADA data was listed and summarized for PF 05082566 by dose. Negative ADA: titer<6.23; Positive ADA: titer>=6.23.Treatment-induced ADA = ADA developed de novo (seroconversion) following biologic drug administration. Treatment-boosted ADA = pre-existing ADA that were boosted to a higher level following biologic drug administration. | Pre-dose (Day 1), Cycles 1, 3, 5, 7, and subsequently pre-dose (Day 1) every 2 cycles up to Cycle 12, and every 4 cycles thereafter | 
| Number of Participants With Positive Anti-Drug Antibody (ADA) of MK-3475 | ADA blood samples were assayed for anti-MK-3475 antibodies using a validated analytical method in compliance with Merck (anti-MK-3475) SOPs. | Pre-dose in Cycles 1, 3, 5, 7 and subsequently pre dose every 2 cycles up to Cycle 12 and every 4 cycles thereafter and 28 days, and during follow-up (3 months and 6 months after the end of MK-3475 treatment). | 
| Number of Participants With Objective Tumor Response | Objective response (OR) was defined as complete response (CR) or partial response (PR) according to RECIST version 1.1 from the date of first dose of study treatment until documented disease progression.CR = at least 2 determinations of CR at least 4 weeks apart and before progression; PR = at least 2 determinations of PR or better at least 4 weeks apart and before progression (and not qualifying for a CR); Progression of disease (PD) = progression<=12 weeks after the date of first dose of study treatment (and not qualifying for CR, PR, SD or non-CR/non-PD); Stable disease (SD) (applicable only to participants with measurable disease at baseline) = at least 1 SD assessment (or better)>=6 weeks after the date of first dose of study treatment and before progression (and not qualifying for CR or PR). Both CR and PR were confirmed by repeat assessments performed no less than 4 weeks after the criteria for response were first met. | Baseline, at Week 9, and then every 6 weeks up to 90 days after the last dose of study drug, approximately 27 months. For those patients who achieved a confirmed PR or CR, tumor assessments could be conducted as clinically indicated. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Advanced Solid Tumors