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

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.

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.

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.

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.

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.

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.

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.

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.

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.

Maximum PF-05082566 observed serum concentration.

Maximum MK-3475 observed serum concentration.

Time to reach PF-05082566 maximum observed serum concentration.

PF-05082566 pre-dose concentration during multiple dosing

MK-3475 pre-dose concentration during multiple dosing

PF-05082566 terminal half-life

Clearance of PF-05082566

PF-05082566 volume of distribution at steady state

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)

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.

ADA blood samples were assayed for anti-MK-3475 antibodies using a validated analytical method in compliance with Merck (anti-MK-3475) SOPs.

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.