A Study of PF-05082566 In Combination With Mogamulizumab In Patients With Advanced Solid Tumors

Study Overview
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Brief Summary
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This study is a Phase 1b, open label, multi center, multi-dose trial designed to estimate the maximum tolerated dose (MTD) and select the recommended dose for phase 2 (RP2D) investigations of PF- 05082566 in combination with KW-0761 (mogamulizumab) in patients with advanced solid tumors. Once the MTD of PF-05082566 administered in combination with KW-0761 is estimated (dose finding), one or more expansion cohorts of patients with selected advanced solid tumors (dose-expansion ) will be enrolled to further characterize the combination in term of safety profile, anti tumor activity, pharmacokinetics, pharmacodynamics and biomarkers modulation.

Official Title
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A PHASE 1B STUDY OF PF-05082566 IN COMBINATION WITH MOGAMULIZUMAB (KW-0761) IN PATIENTS WITH ADVANCED SOLID TUMORS

Conditions
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Advanced/Metastatic Solid Tumors

Intervention / Treatment
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* Drug: PF-05082566
* Drug: KW-0761


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histological or cytological diagnosis of advanced/metastatic solid tumor malignancy. Dose Finding Cohorts: Tumor types will be limited to CRC, SCCHN, squamous NSCLC, bladder, or ovarian carcinomas which have progressed on standard therapy, or for which no standard therapy is available. Measurable disease by RECIST version 1.1. For Expansion Cohorts only: patients must have tumor accessible for biopsies (core needle biopsy or excision preferred). Age 18 years. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Adequate bone marrow, renal and liver function. Serum/urine pregnancy test (for females of childbearing potential) negative at screening and before the patient will receive the study treatment. Male and female patients of childbearing potential and at risk for pregnancy must agree to use two (2) highly effective methods of contraception throughout the study and for 60 days after the last dose of assigned study treatment. Exclusion Criteria: Active central nervous system primary or secondary malignancies, active seizure disorder, spinal cord compression, or carcinomatous meningitis. Therapeutic or experimental monoclonal antibodies in last 60 days prior registration. Systemic anticancer therapy or major surgery within 28 days prior to registration. In absence of toxicity from prior systemic anticancer therapy, 5 half-lives since completion of prior systemic anticancer therapy is allowed. Systemic steroids, any other form of immunosuppressive therapy or radiation therapy within 14 days prior to registration. Live vaccine within 30 days prior to registration. Severe hypersensitivity reaction to treatment with another monoclonal antibody, known or suspected hypersensitivity to study drugs or any component of their formulation. History of autoimmune disease or known inflammatory bowel disease. Uncontrolled hypertension (blood pressure >150/100 mmHg despite optimal medical therapy) or any of the following within 12 months prior to registration: myocardial infarction, congenital long QT syndrome, torsade de points, arrhythmias, right bundle branch block and left anterior hemiblock uncontrolled angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack, pulmonary embolism, ongoing NCICTCAE Grade 2 cardiac dysrhythmias, atrial fibrillation or QTcF interval >470 msec.

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 + KW-0761<br>During Parts 1 & 2 Mogamulizumab and PF-05082566 will be administered at appropriate intervals. Part 1: PF-05082566 dose escalation; increased doses of PF-05082566 IV are administered with mogamulizumab IV. Part 2: patients will be treated with the maximum tolerated dose established in Phase 1 for the combination. | Drug: PF-05082566<br>* Part 1: PF-05082566 dose escalation; Increased doses of PF-05082566 IV are administered at appropriate intervals. Part 2: MTD of PF-05082566 IV established in Part 1 is administered.<br>Drug: KW-0761<br>* Part 1: KW-0761 IV administered at appropriate intervals. Part 2: KW-0761 IV administered at appropriate intervals at the MTD dose for the combination.<br>* Other names: KW-0761= Mogamulizumab or POTELIGEO®;|

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) | DLTs was defined as any of the following adverse events (AEs) according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 at first 2 Cycles. Hematologic: (1) Grade 4 neutropenia lasting >7 days; (2) Febrile neutropenia, defined as absolute neutrophil count (ANC) <1000/mm3 with a single temperature of >38.3 degrees C (101 degrees F) or a sustained temperature of >=38 degrees C (100.4 degrees F) for more than 1 hour; (3) Grade >=3 neutropenic infection; (4) Grade >=3 thrombocytopenia with bleeding; (5) Grade 4 thrombocytopenia. Non-Hematologic: (1) Grade >=3 non laboratory toxicities (excluding infusion reactions), except those that had not been maximally treated (eg, nausea, vomiting, diarrhea); (2) Grade >=3 laboratory abnormalities (other than aspartate aminotransferase [AST]/alanine aminotransferase [ALT]) if: Medical intervention was required to treat the participant, or The abnormality led to hospitalization; (3) Grade 4 AST and ALT increase. | First 2 Cycles (28 days in each cycle) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-Emergent Adverse Events (All Causalities) | An AE was any untoward medical occurrence in a participant administered a product or medical device without regard to possibility of causal relationship. Serious AEs (SAEs) were defined as any untoward medical occurrence at any dose that resulted in death; was life-threatening (immediate risk of death); required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity (substantial disruption of the ability to conduction normal life functions); resulted in congenital anomaly/birth defect. Treatment-emergent AEs were those with initial onset or increasing in severity after the first dose of study treatment. AEs were graded by the investigator according to NCI CTCAE version 4.03 (Grade 1: mild AE; Grade 2: moderate AE; Grade 3: severe AE; Grade 4: life-threatening consequences, urgent intervention indicated; Grade 5: death related to AE). AEs included non-serious AEs and SAEs. | Day 1 up to 60 days after last dose of study treatment | 
| Number of Participants With Treatment-Emergent Adverse Events (PF-05082566 Related) | An AE was any untoward medical occurrence in a participant administered a product or medical device has a causal relationship with PF-05082566. SAEs were defined as any untoward medical occurrence at any dose that resulted in death; was life-threatening (immediate risk of death); required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity (substantial disruption of the ability to conduction normal life functions); resulted in congenital anomaly/birth defect. Treatment-emergent AEs were those with initial onset or increasing in severity after the first dose of study treatment. AEs were graded by the investigator according to NCI CTCAE version 4.03 (Grade 1: mild AE; Grade 2: moderate AE; Grade 3: severe AE; Grade 4: life-threatening consequences, urgent intervention indicated; Grade 5: death related to AE). AEs included non-serious AEs and SAEs. | Day 1 up to 60 days after last dose of study treatment | 
| Number of Participants With Treatment-Emergent Adverse Events (Mogamulizumab Related) | An AE was any untoward medical occurrence in a participant administered a product or medical device has a causal relationship with Mogamulizumab. SAEs were defined as any untoward medical occurrence at any dose that resulted in death; was life-threatening (immediate risk of death); required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity (substantial disruption of the ability to conduction normal life functions); resulted in congenital anomaly/birth defect. Treatment-emergent AEs were those with initial onset or increasing in severity after the first dose of study treatment. AEs were graded by the investigator according to NCI CTCAE version 4.03 (Grade 1: mild AE; Grade 2: moderate AE; Grade 3: severe AE; Grade 4: life-threatening consequences, urgent intervention indicated; Grade 5: death related to AE). AEs included non-serious AEs and SAEs. | Day 1 up tp 60 days after last dose of study treatment | 
| Number of Participants With Hematology Laboratory Abnormalities as Characterized by Type, Frequency, Severity (as Graded by NCI CTCAE) -Grades 3 or 4 | The hematology laboratory tests include: Anemia, Hemoglobin increased, Lymphocyte count increased, Lymphopenia, Neutrophils (absolute), Platelets, White blood cells. | Screening (within 28 days prior to registration) up to 28 days (+7 days) after the last dose of study treatment | 
| Number of Participants With Chemistries Laboratory Abnormalities as Characterized by Type, Frequency, Severity (as Graded by NCI CTCAE) -Grades 3 or 4 | The chemistry laboratory tests included: Alanine aminotransferase, Aspartate Aminotransferase, Alkaline Phosphatase, Lactate Dehydrogenase, Sodium, Potassium, Magnesium, Total Calcium, Phosphorus or Phosphate, Total bilirubin, Creatinine or creatinine clearance, Albumin, Total proteins, Uric Acid, BUN or Urea, Immunoglobulin G, Glucose (fasted). | Screening (within 28 days prior to registration) up to 28 days (+7 days) after the last dose of study treatment | 
| Number of Participants With Clinical Significant Observations in Vital Signs | Blood pressure (BP) and pulse rate were recorded in supine or sitting position. | Screening (within 28 days prior to registration) up to 28 days (+7 days) after the last dose of study treatment | 
| Number of Participants With Significant Changes From Baseline in Physical Examination | Physical examination included an examination of major body systems, including general, head, ears, eyes, nose, mouth, throat, neck, lungs, heart, abdomen, musculoskeletal, lymph nodes, neurological and external genitalia. Significant changes from baseline were reported in each category. | Cycle 2 Day 1; End of the treatment. | 
| Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status Shift to Grades 2, 3, 4 or 5 | ECOG performance status was classified as 5 grades: 0 (Fully active, able to carry on all predisease performance without restriction); 1 (Restricted in physically strenuous activity, but ambulatory and able to carry out work of a light or sedentary nature, ie, light house work, office work); 2 (Ambulatory and capable of all self care but unable to carry out any work activities. Up and about more than 50% of waking hours); 3 (Capable of only limited self care, confined to bed or chair more than 50% of waking hours); 4 (Completely disabled. Cannot carry on any self care. Totally confined to bed or chair); 5 (Death). On-study shifts to ECOG performance statuses of 2, 3, 4 or 5 were reported. | Screening (within 28 days prior to registration) up to 28 days (+7 days) after the last dose of study treatment | 
| Maximum Observed Serum Concentration (Cmax) of PF-05082566-Cycle 5 | Maximum Observed Serum Concentration (Cmax) was observed directly from the data. | Cycle 5: Day 1 at pre-dose, at the end of PF-05082566 infusion, and at 2, 6, 168 hours (Day 8) and 336 hours (Day 15) after the start of PF-05082566 infusion. | 
| Dose Normalized Cmax of PF-05082566-Cycle 5 | Dose normalized Cmax was calculated by Cmax / Dose | Cycle 5: Day 1 at pre-dose, at the end of PF-05082566 infusion, and at 2, 6, 168 hours (Day 8) and 336 hours (Day 15) after the start of PF-05082566 infusion. | 
| Cmax of Mogamulizumab-Cycles 1 and 5 | Maximum Observed Serum Concentration (Cmax) was observed directly from the data. | Cycle 1: pre-dose and at the end of mogamulizumab infusion on Days 1, 8, 15 and 22; Cycle 5: Pre-dose, at the end of mogamulizumab infusion, and at 6 hours, 168 hours (Day 8) after the start of the mogamulizumab infusion; Pre-dose on Day 15 | 
| Pre-dose Concentration During Multiple Dosing (Ctrough) of PF-05082566-Cycle 5 | Pre-dose Concentration during Multiple Dosing (Ctrough) was observed directly from data | Cycle 5: Day 1 at pre-dose, at the end of PF-05082566 infusion, and at 2, 6, 168 hours (Day 8) and 336 hours (Day 15) after the start of PF-05082566 infusion. | 
| Ctrough of Mogamulizumab- Cycle 5 | Pre-dose Concentration during Multiple Dosing (Ctrough) was observed directly from data. | Cycle 5: Pre-dose, at the end of mogamulizumab infusion, and at 6 hours, 168 hours (Day 8) after the start of the mogamulizumab infusion; Pre-dose on Day 15 | 
| Time for Cmax (Tmax) of PF-05082566-Cycle 5 | Time for Cmax (Tmax) was observed directly from the data. | Cycle 5: Day 1 at pre-dose, at the end of PF-05082566 infusion, and at 2, 6, 168 hours (Day 8) and 336 hours (Day 15) after the start of PF-05082566 infusion. | 
| Time of Last Measurable Concentration (Tlast) of PF-05082566-Cycle 5 | Time of last measurable concentration was observed directly from data. | Cycle 5: Day 1 at pre-dose, at the end of PF-05082566 infusion, and at 2, 6, 168 hours (Day 8) and 336 hours (Day 15) after the start of PF-05082566 infusion. | 
| Tmax of Mogamulizumab-Cycles 1 and 5 | Time for Cmax (Tmax) was observed directly from the data. | Cycle 1: pre-dose and at the end of mogamulizumab infusion on Days 1, 8, 15 and 22; Cycle 5: Pre-dose, at the end of mogamulizumab infusion, and at 6 hours, 168 hours (Day 8) after the start of the mogamulizumab infusion; Pre-dose on Day 15 | 
| Tlast of Mogamulizumab-Cycles 1 and 5 | Time of last measurable concentration was observed directly from the data. | Cycle 1: pre-dose and at the end of mogamulizumab infusion on Days 1, 8, 15 and 22; Cycle 5: Pre-dose, at the end of mogamulizumab infusion, and at 6 hours, 168 hours (Day 8) after the start of the mogamulizumab infusion; Pre-dose on Day 15 | 
| Area Under the Serum Concentration-time Profile From Time 0 to the Time of the Last Measurable Concentration (AUClast) of PF-05082566-Cycle 5 | AUClast was area under the serum concentration-time profile from time 0 to the time of the last measurable concentration (Clast), which was measured by Linear/Log trapezoidal method. | Cycle 5: Day 1 at pre-dose, at the end of PF-05082566 infusion, and at 2, 6, 168 hours (Day 8) and 336 hours (Day 15) after the start of PF-05082566 infusion. | 
| Dose Normalized AUClast of PF-05082566-Cycle 5 | Dose normalized AUClast was calculated by AUClast / Dose | Cycle 5: Day 1 at pre-dose, at the end of PF-05082566 infusion, and at 2, 6, 168 hours (Day 8) and 336 hours (Day 15) after the start of PF-05082566 infusion. | 
| AUClast of Mogamulizumab-Cycles 1 and 5 | AUClast was area under the serum concentration-time profile from time 0 to the time of the last measurable concentration (Clast), which was measured by Linear/Log trapezoidal method. | Cycle 1: pre-dose and at the end of mogamulizumab infusion on Days 1, 8, 15 and 22; Cycle 5: Pre-dose, at the end of mogamulizumab infusion, and at 6 hours, 168 hours (Day 8) after the start of the mogamulizumab infusion; Pre-dose on Day 15 | 
| Area Under the Serum Concentration-time Profile From Time 0 to 168 Hours (AUC168) of Mogamulizumab-Cycle 1 | AUC168 was area under the serum concentration-time profile from time 0 to 168 hours post dose (Cycle 1 only where dosing was once a week), which was measured by Linear/Log trapezoidal method. | Cycle 1: pre-dose and at the end of mogamulizumab infusion on Days 1, 8, 15 and 22 | 
| Area Under the Serum Concentration-time Profile From Time 0 to Time Tau (AUCtau) of Mogamulizumab-Cycle 5 | AUCtau was area under the serum concentration-time profile from time 0 to time tau, the dosing interval, where tau=336 hours | Cycle 5: Pre-dose, at the end of mogamulizumab infusion, and at 6 hours, 168 hours (Day 8) after the start of the mogamulizumab infusion; Pre-dose on Day 15 | 
| Clearance (CL) of Mogamulizumab-Cycle 5 | Clearance (CL) was measured by Dose / AUCtau | Cycle 5: Pre-dose, at the end of mogamulizumab infusion, and at 6 hours, 168 hours (Day 8) after the start of the mogamulizumab infusion; Pre-dose on Day 15 | 
| Anti-Drug Antibody (ADA) Titer for PF-05082566 | Serum samples were assayed for ADA using a validated analytical method. | Pre-dose on Day 1 of Cycles 1, 3, 5, 8, 12, 16, 20, 24 up to 24 months | 
| Neutralizing Antibodies (NAb) Titers for PF-05082566 | ADA positive samples were further analyzed for NAb using a validated assay. | Pre-dose on Day 1 of Cycles 1, 3, 5, 8, 12, 16, 20, 24 up to 24 months | 
| Anti-Drug Antibody (ADA) Titers for Mogamulizumab | Serum samples were assayed for ADA using a validated analytical method. | Pre-dose on Day 1 of Cycles 1, 3, 5, 8, 12, 16, 20, 24 up to 24 months | 
| Neutralizing Antibodies (NAb) Titers for Mogamulizumab | ADA positive samples were further analyzed for NAb using a validated assay | Pre-dose on Day 1 of Cycles 1, 3, 5, 8, 12, 16, 20, 24 up to 24 months | 
| Number of Participants With Objective Response (OR) and Immune-related Objective Response (irOR) | OR was defined as best overall response (BOR) of complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumor (RECIST) version 1.1. Immune-related OR (irOR) was defined as immune-related BOR (irBOR) of immune-related CR (irCR) and immune-related PR (irPR) according to immune-related RECIST. CR: Complete disappearance of all target lesions with the exception of nodal disease; PR: Greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions. | Every 8 weeks up to 24 months | 
| Time to Response (TTR) and Immue-related Time to Response (irTTR)-Dose Expansion Portion | TTR was defined, for participants with an OR, as the time from the date of first dose of study treatment to the first documentation of OR (CR or PR), which was subsequently confirmed. irTTR was defined, for participants with an irOR, as the time from the first dose of study treatment to the first documentation of irOR (irCR or irPR) which was subsequently confirmed. CR: Complete disappearance of all target lesions with the exception of nodal disease; PR: Greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions. | Every 8 weeks up to 24 months | 
| Duration of Response (DR) and Immune-related DR (irDR) -Dose Expansion Portion | DR was defined, for participants with an OR, as the time from first documentation of OR (CR or PR) to the date of first documentation of objective progression disease (PD) or death due to any cause. irDR was defined, for participants with an irOR, as the time from the first documentation of irOR (irCR or irPR) to the date of first documentation of immune-related PD (irPD) (which was subsequently confirmed) or death due to any cause. CR: Complete disappearance of all target lesions with the exception of nodal disease; PR: Greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions; PD: 20% increase in the sum of diameters of target measurable lesions above the smallest sum observed (over baseline if no decrease in the sum is observed during therapy), with a minimum absolute increase of 5 mm. | Every 8 weeks from the first occurrence of CR or PR, until disease progression or death up to 24 months | 
| Progression Free Survival (PFS) and Immune-related PFS (irPFS) - Dose Expansion Portion | PFS was defined as the time from the date of first dose of study treatment to the date of the first documentation of PD or death due to any cause, whichever occurred first. irPFS was defined as the time from the first dose of study treatment to the date of first documentation of irPD (which was subsequently confirmed) or death due to any cause, whichever occurred first. PD:20% increase in the sum of diameters of target measurable lesions above the smallest sum observed (over baseline if no decrease in the sum is observed during therapy), with a minimum absolute increase of 5 mm. | Every 8 weeks up to 24 months |