Clinical trial NCT02315066: Study Of OX40 Agonist PF-04518600 Alone And In Combination With 4-1BB Agonist PF-05082566
Official title: A PHASE 1, OPEN-LABEL, DOSE ESCALATION STUDY OF PF-04518600 AS A SINGLE AGENT AND IN COMBINATION WITH PF-05082566 IN PATIENTS WITH SELECTED LOCALLY ADVANCED OR METASTATIC CANCERS
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Neoplasms
Keywords: Immunotherapy
PF-04518600
PF-05082566
solid tumors
tumors
neoplasm metastasis
Phase 1
hepatocellular carcinoma
HCC
liver cancer
ocular melanoma
melanoma
clear cell renal cell carcinoma
RCC
kidney cancer
head and neck squamous cell carcinoma
HNSCC
head and neck cancer
cervical cancer
cancer of the cervix
gastric cancer
stomach cancer
non small cell lung cancer
NSCLC
lung cancer
urothelial bladder carcinoma
bladder cancer
OX40
4-1BB
Lead sponsor: Pfizer
Sponsor class: INDUSTRY
First posted: 2014-12-11
Enrollment: 174
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: To assess the safety and tolerability at increasing dose levels of PF-04518600 alone or in combination wtih PF-05082566 in patients with select advanced or metastatic carcinoma in order to determine the maximum tolerated dose and select the recommended Phase 2 dose.


Eligibility criteria: Inclusion Criteria:

* Part A1 only: Patients with histological or cytological diagnosis of HNSCC, HCC, melanoma, or clear cell RCC who progressed on or are intolerant to standard therapy, for which no standard therapy is available or who decline standard therapy.
* Part A2 only: Patients with histological or cytological diagnosis of advanced/metastatic HCC who are treatment naïve and have declined standard of care, or have had at least 1 prior line of systemic therapy. Prior anti PD L1/PD 1 therapy is allowed.
* Part B1 only: Patients with histological or cytological diagnosis of NSCLC, HNSCC, melanoma, urothelial bladder carcinoma (including renal pelvis, ureters, urinary bladder, and urethra), gastric or squamous cell carcinoma of the uterine cervix who progressed on or are intolerant to standard therapy, for which no standard therapy is available, or who decline standard therapy.
* Part B2

Arm 1 only:

1. Ocular melanoma patients with advanced/metastatic disease, or
2. Cutaneous/acral melanoma patients with advanced/metastatic disease who have received checkpoint inhibitor (anti PD L1, anti PD 1, or anti CTLA4) based treatment on which disease progressed. \[Note: Checkpoint inhibitor may have been part of a combination therapy, as long as the combination did not contain OX40 or 4 1BB agonist.\] Any questions on prior treatment may be discussed with the Sponsor.

Arm 2 only:

* Histological or cytological diagnosis of NSCLC with advanced/metastatic disease. Patients must have previously received prior anti PD L1 or anti PD 1 mAb on which disease progressed. \[Note: Previous anti PD L1 or anti PD 1 mAb may have been part of a combination therapy, eg, in combination with chemotherapy, as long as the combination did not contain OX40 or 4 1BB agonist.\]
* Performance Status of 0 or 1 - Adequate bone marrow, kidney and liver function

Exclusion Criteria:

* Brain metastases requiring steroids
* Major surgery, Radiation therapy within 4 weeks of starting study treatment (except: palliative radiotherapy to a limited field is allowed after consultation with sponsor's medical monitor at any time during study participation, including during screening), or systemic anti-cancer therapy within 4 weeks of study treatment start (6 weeks for mitomycin C or nitrosoureas)
* Active and clinically significant bacterial, fungal, or viral infection
* History of active autoimmune disorders
* History of immune-mediated adverse events requiring immunosuppressive therapy or were grade 3 or higher related to prior immune-modulatory therapy
* Prior treatment with an OX40 agonist and 4-1BB agonist (for Part B1/B2)
* Prior anthracycline treatment and at risk of cardiac failure (New York Heart Association Class 2)

Primary outcomes:
measure: Number of Participants With Dose Limiting Toxicities (DLTs) in Part A1
timeFrame: The first 2 cycles of treatment (Day 1 up to Day 28)
measure: Number of Participants With All-Causality Treatment Emergent Adverse Events(TEAEs) and Serious Adverse Event(SAEs), Treatment-Related TEAEs and SAEs in Part A
timeFrame: AEs: The informed consent date up to the last dosing date + 28 days or all drug-related toxicities resolved date. SAEs: The informed consent date through first dosing date + 98 days or up to the last dosing date + 60 days, and any post-reporting period.
measure: Number of Participants With Laboratory Test Abnormalities in Part A
timeFrame: The first dosing date to the earlier date between the last dosing date + 35 days and the first new anti-cancer therapy date (if applicable)
measure: Number of Participants With DLTs in Part B1
timeFrame: The First 2 Cycles of Treatment (Day 1 up to Day 28)
measure: Number of Participants With All-causality TEAEs and SAEs, and Treatment-Related TEAEs and SAEs in Part B
timeFrame: AEs: The informed consent date up to the last dosing date + 60 days or all drug-related toxicities resolved date. SAEs: The informed consent date through first dosing date + 98 days or up to the last dosing date + 60 days, and any post-reporting period.
measure: Number of Participants With Laboratory Test Abnormalities in Part B
timeFrame: The first dosing date to the earlier date between the last dosing date + 35 days and the first new anti-cancer therapy date (if applicable)
Secondary outcomes:
measure: Objective Response Rate (ORR) Assessed by Response Evaluation Criteria in Solid Tumor (RECIST) Version 1.1 and Immune Related Response Evaluation Criteria in Solid Tumors (irRECIST) in Part A
timeFrame: Baseline up to 24 months post first dose.
measure: Kaplan-Meier Estimate of Median Progression-Free Survival (PFS) in Part A
timeFrame: Baseline up to 24 months post first dose
measure: Kaplan-Meier Estimate of Median Time to Progression (TTP) in Part A
timeFrame: Baseline up to 24 months post first dose
measure: Number of Participants Having Stable Disease (SD) in Part A
timeFrame: Baseline up to 24 months post first dose.
measure: Kaplan-Meier Estimate of Median Duration of Response (DoR) in Part A
timeFrame: Baseline up to 24 months post first dose.
measure: Kaplan-Meier Estimate of Median Overall Survival (OS) in Part A
timeFrame: Baseline up to 24 months post first dose.
measure: Overall Survival Rates at Months 6, 12, and 24 in Part A
timeFrame: Baseline up to 24 months post first dose.
measure: Maximum Serum Concentration (Cmax) of PF-04518600 Following Single Dose on Cycle 1 Day 1 (C1D1) and Steady-State Maximum Serum Concentration(Css,Max) Following Multiple Doses on Cycle 3 Day 1 (C3D1) in Part A
timeFrame: For Part A1, pre-dose, 1, 4, and 24 hours post dose on C1D1, pre-dose, 1, and 4 hours post dose on Day 1 of Cycles 3; For Par A2, pre-dose, 1, and 4 hours post dose on C1D1, pre-dose and 1 hour post dose on Day 1 of Cycles 3.
measure: Area Under the Concentration-Time Profile From Time 0 to Time Tau (AUCtau) of PF-04518600 Following Single Dose on C1D1 and Following Multiple Doses on C3D1 in Part A
timeFrame: For Part A1, pre-dose, 1, 4, and 24 hours post dose on C1D1, pre-dose, 1, and 4 hours post dose on Day 1 of Cycles 3; For Par A2, pre-dose, 1, and 4 hours post dose on C1D1, pre-dose and 1 hour post dose on Day 1 of Cycles 3.
measure: Area Under the Concentration-Time Profile From Time 0 Extrapolated to Infinite Time (AUCinf) of PF-04518600 Following Single Dose on C1D1 and Following Multiple Doses on C3D1 in Part A
timeFrame: For Part A1, pre-dose, 1, 4, and 24 hours post dose on C1D1, pre-dose, 1, and 4 hours post dose on Day 1 of Cycles 3; For Par A2, pre-dose, 1, and 4 hours post dose on C1D1, pre-dose and 1 hour post dose on Day 1 of Cycles 3.
measure: Terminal Half-Life (t1/2) of PF-04518600 Following Single Dose on C1D1 and Following Multiple Doses on C3D1 in Part A
timeFrame: For Part A1, pre-dose, 1, 4, and 24 hours post dose on C1D1, pre-dose, 1, and 4 hours post dose on Day 1 of Cycles 3; For Par A2, pre-dose, 1, and 4 hours post dose on C1D1, pre-dose and 1 hour post dose on Day 1 of Cycles 3.
measure: Lowest Serum Concentration Observed During the Dosing Interval (Cmin) of PF-04518600 Following Multiple Doses on C3D1 in Part A.
timeFrame: For Part A1, pre-dose, 1, 4, and 24 hours post dose on C1D1, pre-dose, 1, and 4 hours post dose on Day 1 of Cycles 3; For Par A2, pre-dose, 1, and 4 hours post dose on C1D1, pre-dose and 1 hour post dose on Day 1 of Cycles 3.
measure: Average Serum Concentration Over the Dosing Interval (Cav) of PF-04518600 Following Multiple Doses on C3D1 in Part A
timeFrame: For Part A1, pre-dose, 1, 4, and 24 hours post dose on C1D1, pre-dose, 1, and 4 hours post dose on Day 1 of Cycles 3; For Par A2, pre-dose, 1, and 4 hours post dose on C1D1, pre-dose and 1 hour post dose on Day 1 of Cycles 3.
measure: Clearance (CL) of PF-04518600 Following Multiple Doses on C3D1 in Part A
timeFrame: For Part A1, pre-dose, 1, 4, and 24 hours post dose on C1D1, pre-dose, 1, and 4 hours post dose on Day 1 of Cycles 3; For Par A2, pre-dose, 1, and 4 hours post dose on C1D1, pre-dose and 1 hour post dose on Day 1 of Cycles 3.
measure: Apparent Volume of Distribution at Steady State (Vss) of PF-04518600 Following Multiple Doses on C3D1 in Part A.
timeFrame: For Part A1, pre-dose, 1, 4, and 24 hours post dose on C1D1, pre-dose, 1, and 4 hours post dose on Day 1 of Cycles 3; For Par A2, pre-dose, 1, and 4 hours post dose on C1D1, pre-dose and 1 hour post dose on Day 1 of Cycles 3.
measure: Accumulation Ratio (Rac) of PF-04518600 at C3D1 Following Multiple Doses on C3D1 in Part A
timeFrame: For Part A1, pre-dose, 1, 4, and 24 hours post dose on C1D1, pre-dose, 1, and 4 hours post dose on Day 1 of Cycles 3; For Par A2, pre-dose, 1, and 4 hours post dose on C1D1, pre-dose and 1 hour post dose on Day 1 of Cycles 3.
measure: Number of Participants With Anti Drug Antibody (ADA) and Neutralizing Antibody (NAb) Against PF-04518600 in Part A
timeFrame: Baseline up to end of treatment (maximum of 14 weeks).
measure: Mean Unbound Cell Surface OX40 in Part A1
timeFrame: Pre-dose, 4 and 24 hours post dose on Cycle 1 Day 1, and Day 8 on Cycles 1 to 3, then pre-dose on Cycles 4 and 7 and end of treatment in Part A1
measure: ORR Assessed by RECIST Version 1.1 and irRECIST in Part B
timeFrame: Baseline up to 24 months post first dose.
measure: Kaplan-Meier Estimate of Median PFS in Part B
timeFrame: Baseline up to 24 months post first dose.
measure: Kaplan-Meier Estimate of Median TTP in Part B
timeFrame: Baseline up to 24 months post first dose.
measure: Number of Participants Having SD in Part B
timeFrame: Baseline up to 24 months post first dose.
measure: Kaplan-Meier Estimate of Median DoR in Part B
timeFrame: Baseline up to 24 months post first dose.
measure: Kaplan-Meier Estimate of Median OS in Part B
timeFrame: Baseline up to 24 months post first dose.
measure: Overall Survival Rates at Months 6, 12, and 24 in Part B
timeFrame: Baseline up to 24 months post first dose.
measure: Cmax of PF-04518600 Following Single Dose on C1D1 and Css,Max Following Multiple Doses on C3D1 in Part B
timeFrame: For Part B1, pre-dose, 1, 4, and 24 hours post dose on C1D1, pre-dose, 1 hour post dose on Day 1 of Cycles 3; For Part B2, pre-dose, 1, and 4 hours post dose on C1D1, pre-dose and 1 hour post dose on Day 1 of Cycles 3.
measure: AUCtau of PF-04518600 Following Single Dose on C1D1 and Following Multiple Doses on C3D1 in Part B
timeFrame: For Part B1, pre-dose, 1, 4, and 24 hours post dose on C1D1, pre-dose, 1 hour post dose on Day 1 of Cycles 3; For Part B2, pre-dose, 1, and 4 hours post dose on C1D1, pre-dose and 1 hour post dose on Day 1 of Cycles 3.
measure: AUCinf of PF-04518600 Following Single Dose on C1D1 and Following Multiple Doses on C3D1 in Part B
timeFrame: For Part B1, pre-dose, 1, 4, and 24 hours post dose on C1D1, pre-dose, 1 hour post dose on Day 1 of Cycles 3; For Part B2, pre-dose, 1, and 4 hours post dose on C1D1, pre-dose and 1 hour post dose on Day 1 of Cycles 3.
measure: t1/2 of PF-04518600 Following Single Dose on C1D1 and Following Multiple Doses on C3D1 in Part B
timeFrame: For Part B1, pre-dose, 1, 4, and 24 hours post dose on C1D1, pre-dose, 1 hour post dose on Day 1 of Cycles 3; For Part B2, pre-dose, 1, and 4 hours post dose on C1D1, pre-dose and 1 hour post dose on Day 1 of Cycles 3.
measure: Cmin of PF-04518600 Following Multiple Doses on C3D1 in Part B
timeFrame: For Part B1, pre-dose, 1, 4, and 24 hours post dose on C1D1, pre-dose, 1 hour post dose on Day 1 of Cycles 3; For Part B2, pre-dose, 1, and 4 hours post dose on C1D1, pre-dose and 1 hour post dose on Day 1 of Cycles 3.
measure: Cav of PF-04518600 Following Multiple Doses on C3D1 in Part B
timeFrame: For Part B1, pre-dose, 1, 4, and 24 hours post dose on C1D1, pre-dose, 1 hour post dose on Day 1 of Cycles 3; For Part B2, pre-dose, 1, and 4 hours post dose on C1D1, pre-dose and 1 hour post dose on Day 1 of Cycles 3.
measure: CL of PF-04518600 Following Multiple Doses on C3D1 in Part B
timeFrame: For Part B1, pre-dose, 1, 4, and 24 hours post dose on C1D1, pre-dose, 1 hour post dose on Day 1 of Cycles 3; For Part B2, pre-dose, 1, and 4 hours post dose on C1D1, pre-dose and 1 hour post dose on Day 1 of Cycles 3.
measure: Vss of PF-04518600 Following Multiple Doses on C3D1 in Part B
timeFrame: For Part B1, pre-dose, 1, 4, and 24 hours post dose on C1D1, pre-dose, 1 hour post dose on Day 1 of Cycles 3; For Part B2, pre-dose, 1, and 4 hours post dose on C1D1, pre-dose and 1 hour post dose on Day 1 of Cycles 3.
measure: Rac of PF-04518600 Following Multiple Doses on C3D1 in Part B
timeFrame: For Part B1, pre-dose, 1, 4, and 24 hours post dose on C1D1, pre-dose, 1 hour post dose on Day 1 of Cycles 3; For Part B2, pre-dose, 1, and 4 hours post dose on C1D1, pre-dose and 1 hour post dose on Day 1 of Cycles 3.
measure: Cmax of Utomilumab Following Single Dose on C1D1 and Css,Max Following Multiple Doses on C3D1 in Part B
timeFrame: For Part B1, pre-dose, 1, 4, and 24 hours post dose on C1D1, pre-dose, 1 hour post dose on Day 1 of Cycles 3; For Part B2, pre-dose, 1, and 4 hours post dose on C1D1, pre-dose and 1 hour post dose on Day 1 of Cycles 3.
measure: AUCtau of Utomilumab Following Single Dose on C1D1 and Following Multiple Doses on C3D1 in Part B
timeFrame: For Part B1, pre-dose, 1, 4, and 24 hours post dose on C1D1, pre-dose, 1 hour post dose on Day 1 of Cycles 3; For Part B2, pre-dose, 1, and 4 hours post dose on C1D1, pre-dose and 1 hour post dose on Day 1 of Cycles 3.
measure: AUCinf of Utomilumab Following Single Dose on C1D1 and Following Multiple Doses on C3D1 in Part B
timeFrame: For Part B1, pre-dose, 1, 4, and 24 hours post dose on C1D1, pre-dose, 1 hour post dose on Day 1 of Cycles 3; For Part B2, pre-dose, 1, and 4 hours post dose on C1D1, pre-dose and 1 hour post dose on Day 1 of Cycles 3.
measure: t1/2 of Utomilumab Following Single Dose on C1D1 and Following Multiple Doses on C3D1 in Part B
timeFrame: For Part B1, pre-dose, 1, 4, and 24 hours post dose on C1D1, pre-dose, 1 hour post dose on Day 1 of Cycles 3; For Part B2, pre-dose, 1, and 4 hours post dose on C1D1, pre-dose and 1 hour post dose on Day 1 of Cycles 3.
measure: Cmin of Utomilumab Following Multiple Doses on C3D1 in Part B
timeFrame: For Part B1, pre-dose, 1, 4, and 24 hours post dose on C1D1, pre-dose, 1 hour post dose on Day 1 of Cycles 3; For Part B2, pre-dose, 1, and 4 hours post dose on C1D1, pre-dose and 1 hour post dose on Day 1 of Cycles 3.
measure: Cav of Utomilumab Following Multiple Doses on C3D1 in Part B
timeFrame: For Part B1, pre-dose, 1, 4, and 24 hours post dose on C1D1, pre-dose, 1 hour post dose on Day 1 of Cycles 3; For Part B2, pre-dose, 1, and 4 hours post dose on C1D1, pre-dose and 1 hour post dose on Day 1 of Cycles 3.
measure: CL of Utomilumab Following Multiple Doses on C3D1 in Part B
timeFrame: For Part B1, pre-dose, 1, 4, and 24 hours post dose on C1D1, pre-dose, 1 hour post dose on Day 1 of Cycles 3; For Part B2, pre-dose, 1, and 4 hours post dose on C1D1, pre-dose and 1 hour post dose on Day 1 of Cycles 3.
measure: Vss of Utomilumab Following Multiple Doses on C3D1 in Part B
timeFrame: For Part B1, pre-dose, 1, 4, and 24 hours post dose on C1D1, pre-dose, 1 hour post dose on Day 1 of Cycles 3; For Part B2, pre-dose, 1, and 4 hours post dose on C1D1, pre-dose and 1 hour post dose on Day 1 of Cycles 3.
measure: Rac of Utomilumab Following Multiple Doses on C3D1 in Part B
timeFrame: For Part B1, pre-dose, 1, 4, and 24 hours post dose on C1D1, pre-dose, 1 hour post dose on Day 1 of Cycles 3; For Part B2, pre-dose, 1, and 4 hours post dose on C1D1, pre-dose and 1 hour post dose on Day 1 of Cycles 3.
measure: Number of Participants With ADA and NAb Against PF-04518600 in Part B
timeFrame: Baseline up to end of treatment (maximum of 14 weeks).
measure: Number of Participants With ADA and NAb Against Utomilumab in Part B
timeFrame: Baseline up to end of treatment (maximum of 14 weeks).
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: The Angeles Clinic And Research Institute, A Cedars-Sinai Affiliate
state: California
city: Los Angeles
country: United States
facility: Keck Hospital of USC
state: California
city: Los Angeles
country: United States
facility: LAC+USC Medical Center
state: California
city: Los Angeles
country: United States
facility: USC/Norris Comprehensive Cancer Center
state: California
city: Los Angeles
country: United States
facility: Ronald Regan Medical Center
state: California
city: Los Angeles
country: United States
facility: UCLA Hematology & Oncology Clinic
state: California
city: Newport Beach
country: United States
facility: Hoag Memorial Hospital Presbyterian
state: California
city: Santa Monica
country: United States
facility: Medical Imaging Center of Southern California, Inc.
state: California
city: Santa Monica
country: United States
facility: Santa Monica UCLA Hematology & Oncology Clinic
state: California
city: Farmington
country: United States
facility: UConn Health, Pharmacy
state: Connecticut
city: Farmington
country: United States
facility: UConn Health, Neag Comprehensive Cancer Center
state: Connecticut
city: Tampa
country: United States
facility: H. Lee Moffitt Cancer Center & Research Institute
state: Florida
city: Boston
country: United States
facility: Massachusetts General Hospital (MGH)
state: Massachusetts
city: Boston
country: United States
facility: Brigham & Women's Hospital (BWH)
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center (BIDMC)
state: Massachusetts
city: Boston
country: United States
facility: Dana-Farber Cancer Institute (DFCI)
state: Massachusetts
city: Chelsea
country: United States
facility: Massachusetts General/Chelsea HealthCare Center
state: Massachusetts
city: Danvers
country: United States
facility: Mass General/North Shore Center for Outpatient Care
state: Massachusetts
city: Waltham
country: United States
facility: Mass General West
state: Massachusetts
city: New York
country: United States
facility: Columbia University Medical Center - Herbert Irving Pavilion
state: New York
city: Houston
country: United States
facility: Methodist Hospital-Pathology
state: Texas
city: Houston
country: United States
facility: The University of Texas MD Anderson Cancer Center
state: Texas
city: Seattle
country: United States
facility: Seattle Cancer Care Alliance
state: Washington
city: Seattle
country: United States
facility: University of Washington Medical Center
state: Washington
city: Paris
country: France
facility: Groupe hospitalier Pitie Salpetriere
city: Villejuif
country: France
facility: Institut Gustave Roussy
city: Kashiwa
country: Japan
facility: National Cancer Center Hospital East
state: Chiba
city: Amsterdam
country: Netherlands
facility: The Netherlands Cancer Institute
city: Amsterdam
country: Netherlands
facility: Slotervaart Hospital/Antoni van Leeuwenhoek
city: Rotterdam
country: Netherlands
facility: Erasmus MC
Study officials:
affiliation: Pfizer
name: Pfizer CT.gov Call Center
role: STUDY_DIRECTOR
References:
citation: Hamid O, Chiappori AA, Thompson JA, Doi T, Hu-Lieskovan S, Eskens FALM, Ros W, Diab A, Spano JP, Rizvi NA, Wasser JS, Angevin E, Ott PA, Forgie A, Yang W, Guo C, Chou J, El-Khoueiry AB. First-in-human study of an OX40 (ivuxolimab) and 4-1BB (utomilumab) agonistic antibody combination in patients with advanced solid tumors. J Immunother Cancer. 2022 Oct;10(10):e005471. doi: 10.1136/jitc-2022-005471.
citation: Diab A, Hamid O, Thompson JA, Ros W, Eskens FALM, Doi T, Hu-Lieskovan S, Klempner SJ, Ganguly B, Fleener C, Wang X, Joh T, Liao K, Salek-Ardakani S, Taylor CT, Chou J, El-Khoueiry AB. A Phase I, Open-Label, Dose-Escalation Study of the OX40 Agonist Ivuxolimab in Patients with Locally Advanced or Metastatic Cancers. Clin Cancer Res. 2022 Jan 1;28(1):71-83. doi: 10.1158/1078-0432.CCR-21-0845. Epub 2021 Oct 6.