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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02444793
Recruitment Status : Terminated (The study was terminated due to marginal efficacy and change in sponsor prioritization. The combination had a manageable safety profile.)
First Posted : May 14, 2015
Results First Posted : February 15, 2019
Last Update Posted : February 27, 2019
Sponsor:
Collaborator:
Kyowa Kirin Co., Ltd.
Information provided by (Responsible Party):
Pfizer

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Advanced/Metastatic Solid Tumors Drug: PF-05082566 Drug: KW-0761 Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 24 participants
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A PHASE 1B STUDY OF PF-05082566 IN COMBINATION WITH MOGAMULIZUMAB (KW-0761) IN PATIENTS WITH ADVANCED SOLID TUMORS
Actual Study Start Date : May 2015
Actual Primary Completion Date : September 2017
Actual Study Completion Date : October 2017

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 Name: KW-0761= Mogamulizumab or POTELIGEO®




Primary Outcome Measures :
  1. Number of Participants With Dose Limiting Toxicities (DLT) [ Time Frame: First 2 Cycles (28 days in each cycle) ]
    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.


Secondary Outcome Measures :
  1. Number of Participants With Treatment-Emergent Adverse Events (All Causalities) [ Time Frame: Day 1 up to 60 days after last dose of study treatment ]
    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.

  2. Number of Participants With Treatment-Emergent Adverse Events (PF-05082566 Related) [ Time Frame: Day 1 up to 60 days after last dose of study treatment ]
    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.

  3. Number of Participants With Treatment-Emergent Adverse Events (Mogamulizumab Related) [ Time Frame: Day 1 up tp 60 days after last dose of study treatment ]
    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.

  4. Number of Participants With Hematology Laboratory Abnormalities as Characterized by Type, Frequency, Severity (as Graded by NCI CTCAE) -Grades 3 or 4 [ Time Frame: Screening (within 28 days prior to registration) up to 28 days (+7 days) after the last dose of study treatment ]
    The hematology laboratory tests include: Anemia, Hemoglobin increased, Lymphocyte count increased, Lymphopenia, Neutrophils (absolute), Platelets, White blood cells.

  5. Number of Participants With Chemistries Laboratory Abnormalities as Characterized by Type, Frequency, Severity (as Graded by NCI CTCAE) -Grades 3 or 4 [ Time Frame: Screening (within 28 days prior to registration) up to 28 days (+7 days) after the last dose of study treatment ]
    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).

  6. Number of Participants With Clinical Significant Observations in Vital Signs [ Time Frame: Screening (within 28 days prior to registration) up to 28 days (+7 days) after the last dose of study treatment ]
    Blood pressure (BP) and pulse rate were recorded in supine or sitting position.

  7. Number of Participants With Significant Changes From Baseline in Physical Examination [ Time Frame: Cycle 2 Day 1; End of the treatment. ]
    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.

  8. Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status Shift to Grades 2, 3, 4 or 5 [ Time Frame: Screening (within 28 days prior to registration) up to 28 days (+7 days) after the last dose of study treatment ]
    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.

  9. Maximum Observed Serum Concentration (Cmax) of PF-05082566-Cycle 5 [ Time Frame: 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. ]
    Maximum Observed Serum Concentration (Cmax) was observed directly from the data.

  10. Dose Normalized Cmax of PF-05082566-Cycle 5 [ Time Frame: 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 was calculated by Cmax / Dose

  11. Cmax of Mogamulizumab-Cycles 1 and 5 [ Time Frame: 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 ]
    Maximum Observed Serum Concentration (Cmax) was observed directly from the data.

  12. Pre-dose Concentration During Multiple Dosing (Ctrough) of PF-05082566-Cycle 5 [ Time Frame: 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. ]
    Pre-dose Concentration during Multiple Dosing (Ctrough) was observed directly from data

  13. Ctrough of Mogamulizumab- Cycle 5 [ Time Frame: 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) was observed directly from data.

  14. Time for Cmax (Tmax) of PF-05082566-Cycle 5 [ Time Frame: 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 for Cmax (Tmax) was observed directly from the data.

  15. Time of Last Measurable Concentration (Tlast) of PF-05082566-Cycle 5 [ Time Frame: 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 was observed directly from data.

  16. Tmax of Mogamulizumab-Cycles 1 and 5 [ Time Frame: 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 ]
    Time for Cmax (Tmax) was observed directly from the data.

  17. Tlast of Mogamulizumab-Cycles 1 and 5 [ Time Frame: 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 ]
    Time of last measurable concentration was observed directly from the data.

  18. Area Under the Serum Concentration-time Profile From Time 0 to the Time of the Last Measurable Concentration (AUClast) of PF-05082566-Cycle 5 [ Time Frame: 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 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.

  19. Dose Normalized AUClast of PF-05082566-Cycle 5 [ Time Frame: 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 was calculated by AUClast / Dose

  20. AUClast of Mogamulizumab-Cycles 1 and 5 [ Time Frame: 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 ]
    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.

  21. Area Under the Serum Concentration-time Profile From Time 0 to 168 Hours (AUC168) of Mogamulizumab-Cycle 1 [ Time Frame: Cycle 1: pre-dose and at the end of mogamulizumab infusion on Days 1, 8, 15 and 22 ]
    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.

  22. Area Under the Serum Concentration-time Profile From Time 0 to Time Tau (AUCtau) of Mogamulizumab-Cycle 5 [ Time Frame: 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 ]
    AUCtau was area under the serum concentration-time profile from time 0 to time tau, the dosing interval, where tau=336 hours

  23. Clearance (CL) of Mogamulizumab-Cycle 5 [ Time Frame: 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) was measured by Dose / AUCtau

  24. Anti-Drug Antibody (ADA) Titer for PF-05082566 [ Time Frame: Pre-dose on Day 1 of Cycles 1, 3, 5, 8, 12, 16, 20, 24 up to 24 months ]
    Serum samples were assayed for ADA using a validated analytical method.

  25. Neutralizing Antibodies (NAb) Titers for PF-05082566 [ Time Frame: Pre-dose on Day 1 of Cycles 1, 3, 5, 8, 12, 16, 20, 24 up to 24 months ]
    ADA positive samples were further analyzed for NAb using a validated assay.

  26. Anti-Drug Antibody (ADA) Titers for Mogamulizumab [ Time Frame: Pre-dose on Day 1 of Cycles 1, 3, 5, 8, 12, 16, 20, 24 up to 24 months ]
    Serum samples were assayed for ADA using a validated analytical method.

  27. Neutralizing Antibodies (NAb) Titers for Mogamulizumab [ Time Frame: Pre-dose on Day 1 of Cycles 1, 3, 5, 8, 12, 16, 20, 24 up to 24 months ]
    ADA positive samples were further analyzed for NAb using a validated assay

  28. Number of Participants With Objective Response (OR) and Immune-related Objective Response (irOR) [ Time Frame: Every 8 weeks up to 24 months ]
    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.

  29. Time to Response (TTR) and Immue-related Time to Response (irTTR)-Dose Expansion Portion [ Time Frame: Every 8 weeks up to 24 months ]
    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.

  30. Duration of Response (DR) and Immune-related DR (irDR) -Dose Expansion Portion [ Time Frame: Every 8 weeks from the first occurrence of CR or PR, until disease progression or death up to 24 months ]
    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.

  31. Progression Free Survival (PFS) and Immune-related PFS (irPFS) - Dose Expansion Portion [ Time Frame: Every 8 weeks up to 24 months ]
    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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02444793


Locations
Show Show 21 study locations
Sponsors and Collaborators
Pfizer
Kyowa Kirin Co., Ltd.
Investigators
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Study Director: Pfizer CT.gov Call Center Pfizer
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
  Study Documents (Full-Text)

Documents provided by Pfizer:
Study Protocol  [PDF] February 4, 2016
Statistical Analysis Plan  [PDF] September 21, 2017

Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT02444793    
Other Study ID Numbers: B1641004
First Posted: May 14, 2015    Key Record Dates
Results First Posted: February 15, 2019
Last Update Posted: February 27, 2019
Last Verified: February 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
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.
Additional relevant MeSH terms:
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Neoplasms
Mogamulizumab
Antineoplastic Agents