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

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

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.

Study Overview

• Status: Terminated
• Conditions: Advanced/Metastatic Solid Tumors
• Intervention / Treatment: Drug: PF-05082566; Drug: KW-0761

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • La Jolla, California, United States, 92093
      • University of California San Diego Moores Cancer Center
    • La Jolla, California, United States, 92037-0845
      • UC San Diego Moores Cancer Center
    • La Jolla, California, United States, 92037
      • UC San Diego Medical Center - La Jolla(Thornton Hospital)
    • La Jolla, California, United States, 92093
      • University Of California / San Diego Moores Cancer Center
    • San Diego, California, United States, 92103
      • UC San Diego Medical Center - Hillcrest
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • Georgetown University Medical Center
    • Washington, District of Columbia, United States, 20007
      • MedStar Georgetown University Hospital
    • Washington, District of Columbia, United States, 20007
      • Georgetown University
  • Florida
    • Tampa, Florida, United States, 33612
      • Moffitt Cancer Center and Research Institute
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Hospital
    • Detroit, Michigan, United States, 48202
      • Henry Ford Hospital Research Pharmacy
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27514
      • UNC Cancer Hospital Infusion Pharmacy
    • Chapel Hill, North Carolina, United States, 27599-7600
      • UNC Hospitals, University of North Carolina at Chapel Hill
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Taussig Cancer Institute
  • South Dakota
    • Sioux Falls, South Dakota, United States, 57104
      • Sanford Cancer Center
    • Sioux Falls, South Dakota, United States, 57105
      • Sanford USD Medical Center
    • Sioux Falls, South Dakota, United States, 57104
      • Sanford Research
  • Tennessee
    • Gallatin, Tennessee, United States, 37066
      • Tennessee Oncology, PLLC
    • Nashville, Tennessee, United States, 37203
      • Tennessee Oncology, PLLC
    • Nashville, Tennessee, United States, 37203
      • The Sarah Cannon Research Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: PF-05082566 + KW-0761; 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; 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.; Drug: KW-0761; 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.; Other Names: KW-0761= Mogamulizumab or POTELIGEO®

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Pfizer
• Collaborators: Kyowa Kirin Co., Ltd.
• Investigators: Principal Investigator: Michael J Pishvaian, Md, PhD, Georgetown University; Principal Investigator: Esra E Cohen, MD, University of California, San Diego; Principal Investigator: Dale R Shepard, MD, PhD, The Cleveland Clinic

Publications and helpful links

General Publications

• Cohen EEW, Pishvaian MJ, Shepard DR, Wang D, Weiss J, Johnson ML, Chung CH, Chen Y, Huang B, Davis CB, Toffalorio F, Thall A, Powell SF. A phase Ib study of utomilumab (PF-05082566) in combination with mogamulizumab in patients with advanced solid tumors. J Immunother Cancer. 2019 Dec 4;7(1):342. doi: 10.1186/s40425-019-0815-6.

Helpful Links

• To obtain contact information for a study center near you, click here.
• To obtain contact information for a study center near you, click here.

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2015
• Primary Completion (Actual): September 1, 2017
• Study Completion (Actual): October 1, 2017

Study Registration Dates

• First Submitted: May 12, 2015
• First Submitted That Met QC Criteria: May 12, 2015
• First Posted (Estimate): May 14, 2015

Study Record Updates

• Last Update Posted (Actual): February 27, 2019
• Last Update Submitted That Met QC Criteria: February 13, 2019
• Last Verified: February 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Antineoplastic Agents; Mogamulizumab
• Other Study ID Numbers: B1641004

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.