Study to Test the Safety and Tolerability of PF-07062119 in Patients With Selected Advanced or Metastatic Gastrointestinal Tumors.
- Conditions
- Gastrointestinal TumorsColorectal AdenocarcinomasGastric AdenocarcinomasEsophageal Adenocarcinomas
- Interventions
- Registration Number
- NCT04171141
- Lead Sponsor
- Pfizer
- Brief Summary
A phase 1, open-label, dose escalation and expansion study of PF-07062119 in patients with selected advanced or metastatic gastrointestinal tumors
- Detailed Description
This is a Phase 1, open-label, multi-center, non-randomized, multiple dose, safety, tolerability, pharmacokinetic, and pharmacodynamic study of PF-07062119 administered as a single agent in sequential dose levels and then in combination with anti-programmed cell death -1 protein (anti-PD-1) and in combination with an anti-vascular endothelial growth factor (anti-VEGF). In Part 1A, successive cohorts of patients will receive escalating doses of PF-007062119 and then in dose finding (Part 1B) with PF-07062119 in combination with anti-PD-1 and in combination with anti-VEGF. This study contains 2 parts, dose escalation with single agent (Part 1A) and then dose finding with PF-007062119 in combination with ant-PD-1 and in combination with anti-VEGF (Part 1B) followed by dose expansion arms as a single agent and PF-07062119 in combination with anti-PD 1 and in combination with anti-VEGF (Part 2).
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 79
- For Part 1 and Part 2, diagnosis of advanced/metastatic colorectal, gastric or esophageal adenocarcinoma that is resistant to standard therapy or for which no local regulatory approved standard therapy is available that would confer significant benefit.
- For Part 2, diagnosis of colorectal adenocarcinoma that is resistant to standard therapy or for which no standard therapy is available
- Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1
- Measurable disease or non-measurable disease and refractory to or intolerant of existing therapies (Part 1)
- Measurable disease as defined by RECIST 1.1 is required (Part 2)
- Known active uncontrolled or symptomatic Central Nervous System (CNS) metastases
- Other active malignancy within 3 years prior to randomization, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ
- Major surgery or radiation within 3 weeks prior to study entry
- Last anti-cancer treatment within 4 weeks prior to study entry
- Active or history of clinically significant autoimmune disease that required systemic immunosuppressive medication
- Active or history of clinically significant gastrointestinal disease
- Participation in other studies involving investigational drug(s) within 2 weeks prior to study entry
- Pregnant or breastfeeding female patients
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Dose Finding Anti-PD-1 Combination PF-07062119 Part 1B PF-07062119 plus anti-PD-1 Dose Finding Anti-PD-1 Combination Anti-PD1 Part 1B PF-07062119 plus anti-PD-1 Dose Finding anti-VEGF Combination PF-07062119 Part 1B PF-07062119 plus anti-VEGF Dose Finding anti-VEGF Combination Anti-VEGF Part 1B PF-07062119 plus anti-VEGF Dose Expansion Arm A PF-07062119 PF-07062119 as a Single Agent in CRC Dose Expansion Arm B PF-07062119 PF-07062119 in Combination with anti-PD-1 in CRC Dose Expansion Arm C Anti-PD1 PF-07062119 in Combination with anti-VEGF in CRC Dose Expansion Arm C Anti-VEGF PF-07062119 in Combination with anti-VEGF in CRC Dose Expansion Arm D PF-07062119 PF-07062119 in Combination with either anti-PD-1 or anti-VEGF in various Tumor Types Dose Expansion Arm D Anti-PD1 PF-07062119 in Combination with either anti-PD-1 or anti-VEGF in various Tumor Types Dose Expansion Arm D Anti-VEGF PF-07062119 in Combination with either anti-PD-1 or anti-VEGF in various Tumor Types Dose Escalation PF-07062119 Single Agent Dose Escalation Dose Expansion Arm C PF-07062119 PF-07062119 in Combination with anti-VEGF in CRC
- Primary Outcome Measures
Name Time Method Number of Participants With Dose Limiting Toxicities (DLTs) Assessed Through Cycle 1 28 Days Hematological DLTs:
* Grade 3 neutropenia lasting \>5 days
* Febrile neutropenia defined as an ANC \<1.0 x 10 ̂9/L with a single temperature of \>38.3°C, or a sustained temperature of ≥38°C, for more than 1 hour
* Grade ≥3 Neutropenia with infection
* Grade 3 Thrombocytopenia with Grade ≥2 (clinically significant) bleeding
* any Grade 4 Thrombocytopenia
* Anemia or Thrombocytopenia requiring transfusion
Non Hematological DLTs:
* Grade ≥3 fatigue lasting ≥7 days
* for participants with liver, bone, or lung metastasis, an AST or ALT increase \>8 x ULN or ALP \>10 x ULN;
* confirmed DILI meeting Hy's law criteria
* Grade 3 Vomiting or Diarrhea lasting ≥3 days despite adequate treatment/other supportive care
* Grade 4 Vomiting or Diarrhea
* Grade ≥3 CRS regardless of duration
* Grade ≥3 QTcF prolongation irrespective of duration
* any death not clearly due to underlying disease or extraneous causes Clinically important/persistent toxicities were DLTs reviewed by investigators and sponsor.Number of Participants With All-Causality Treatment-Emergent Adverse Events (TEAEs),Treatment-Emergent Serious Adverse Events (TESAEs), Maximum Grade 3 or 4 and 5 TEAEs 4 Years An AE was any untoward medical occurrence in a participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An SAE was defined as any untoward medical occurrence that, at any dose: resulted in death; was life threatening; required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent disability/incapacity; was a congenital anomaly/birth defect, etc. Treatment-emergent events were with onset date occurring during the on-treatment period. AEs were documented and recorded at each visit using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0.
Number of Participants With Treatment-Related TEAEs, TESAEs, Maximum Grade 3 or 4 and 5 TEAEs 4 Years An AE was any untoward medical occurrence in a participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An SAE was defined as any untoward medical occurrence that, at any dose: resulted in death; was life threatening; required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent disability/incapacity; was a congenital anomaly/birth defect, etc. Treatment-emergent events were with onset date occurring during the on-treatment period. Relatedness to study treatment was determined by the investigator. AEs were documented and recorded at each visit using the NCI CTCAE version 5.0. Severe AEs were classified as Grade 3; life-threatening consequences and urgent intervention indicated were classified as Grade 4; deaths related to AEs were classified as Grade 5.
Number of Participants With CTCAE Grade 3 or 4 Hematology Laboratory Abnormalities 4 Years The investigator reviewed the laboratory report, documented this review, and recorded any clinically relevant changes occurring during the study in the AE section of the CRF. Clinically significant abnormal laboratory findings were those which were not associated with the underlying disease, unless judged by the investigator to be more severe than expected for the participant's condition. CTCAE version 5.0 was applied.
Number of Participants With CTCAE Grade 3 or 4 Chemistry Laboratory Abnormalities 4 Years The investigator reviewed the laboratory report, documented this review, and recorded any clinically relevant changes occurring during the study in the AE section of the case report form (CRF). Clinically significant abnormal laboratory findings were those which were not associated with the underlying disease, unless judged by the investigator to be more severe than expected for the participant's condition. CTCAE version 5.0 was applied.
- Secondary Outcome Measures
Name Time Method Cycle 1 and Cycle 4 PF-07062119 PK Parameters: Maximum Concentration (Cmax) - Priming Cohorts Cycle 1 Day 1, Cycle 1 Day 15 and Cycle 4 Day 1 Cmax was observed directly from data.
Cycle 1 and Cycle 4 PF-07062119 PK Parameters: Cmax - Non-Priming Cohorts Cycle 1 Day 1 and Cycle 4 Day 1 Cmax was observed directly from data.
Cycle 1 and Cycle 4 PF-07062119 PK Parameters: Time to Achieve Cmax (Tmax) - Priming Cohorts Cycle 1 Day 1, Cycle 1 Day 15 and Cycle 4 Day 1 Tmax was time at which Cmax occurred which was observed directly from data as time of first occurrence.
Cycle 1 and Cycle 4 PF-07062119 PK Parameters: Tmax - Non-Priming Cohorts Cycle 1 Day 1 and Cycle 4 Day 1 Tmax was time at which Cmax occurred which was observed directly from data as time of first occurrence.
Cycle 1 and Cycle 4 PF-07062119 PK Parameters: Area Under the Serum Concentration-Time Profile From Time 0 to Time Tau, the Dosing Interval (AUCtau) - Priming Cohorts Cycle 1 Day 1 and Cycle 4 Day 1 AUCtau was area under the serum concentration-time profile from time 0 to time tau, the dosing interval, determined using linear/Log trapezoidal method.
Cycle 1 and Cycle 4 PF-07062119 PK Parameters: AUCtau - Non-Priming Cohorts Cycle 1 Day 1 and Cycle 4 Day 1 AUCtau was area under the serum concentration-time profile from time 0 to time tau, the dosing interval, determined using linear/Log trapezoidal method.
Cycle 1 and Cycle 4 PF-07062119 PK Parameters: Area Under the Serum Concentration-Time Profile From Day 1 to Day 7 (168 Hours) (AUC168) - Priming Cohorts Cycle 1 Day 1, Cycle 1 Day 15 and Cycle 4 Day 1 AUC168 was area under the serum concentration-time profile from Day 1 to Day 7 (168 hours) determined using linear/Log trapezoidal method.
Cycle 1 and Cycle 4 PF-07062119 PK Parameters: AUC168 - Non-Priming Cohorts Cycle 1 Day 1 and Cycle 4 Day 1 AUC168 was area under the serum concentration-time profile from Day 1 to Day 7 (168 hours) determined using linear/Log trapezoidal method.
Pre-dose Trough Concentrations After Multiple Doses of PF-07062119 Cycle 1 Day 15, Cycle 2 Days 1 and 15, Cycle 3 Days 1 and 15, Cycle 4 Days 1 and 15, Cycle 5 Day 1, Cycle 8 Day 1 and Cycle 11 Day 1 PF-07062119 pre-dose trough concentrations were the serum PF-07062119 concentrations assessed at 0 min of Day 1 and Day 15 in each Cycle.
Incidence of Anti-Drug Antibody (ADA) Positive Against PF-07062119 Pre-dose on Cycle 1 Day 1 and Day 15; Day 1 of Cycles 2 to 4; Day 1 of every 3rd cycle since Cycle 5 Blood samples of approximately 4 mL, to provide a minimum of serum 2 mL, were collected for determination of ADA against PF-07062119. All samples were collected on Day 1 of a cycle (also on Day 15, in Cycle 1 only) and drawn pre-dose - within 6 hours prior to any of the drugs being administered. Starting at Cycle 5, blood samples for ADA against PF-07062119 were collected every 3rd cycle pre-dose (ie, Cycle 5 Day 1, Cycle 8 Day 1, Cycle 11 Day 1, etc.). Participants with an unresolved AE possibly related to ADA were asked to return to the clinic for ADA and drug concentration assessments at approximately 3 month intervals until the AE or its sequelae resolved or stabilized at a level acceptable to the investigator and sponsor up to a maximum of 9 months.
Titers of ADA Against PF-07062119 Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 1 and End of Treatment Blood samples of approximately 4 mL, to provide a minimum of serum 2 mL, were collected for determination of ADA against PF-07062119. ADA titers of participants with positive PF-07062119 ADA (titer ≥70) are summarized.
Incidence of Neutralizing Antibody (NAb) Positive Against PF-07062119 Pre-dose on Cycle 1 Day 1 and Day 15; Day 1 of Cycles 2 to 4; Day 1 of every 3rd cycle since Cycle 5 Blood samples of approximately 4 mL, to provide a minimum of serum 2 mL, were collected for determination of NAb against PF-07062119. All samples were collected on Day 1 of a cycle (also on Day 15, in Cycle 1 only) and will be drawn pre-dose - within 6 hours prior to any of the drugs being administered. Starting at Cycle 5, blood samples for NAb against PF-07062119 were collected every 3rd cycle pre-dose (ie, Cycle 5 Day 1, Cycle 8 Day 1, Cycle 11 Day 1, etc). An NAb sample was defined as positive when NAb titer was ≥2.
Incidence of ADA Positive Against PF-06801591 Cycle 1 Day 1 and Day 15, Cycle 2 Day 1 and Day 15, Cycle 3 Day 1 and Day 15, Cycle 4 Day 15, Cycle 5 Day 15 and End of Treatment Blood samples of approximately 4 mL, to provide a minimum of serum 2 mL, were collected for determination of ADA against PF-06801591. All samples were collected on Day 1 of a cycle (also on Day 15, in Cycle 1 only) and drawn pre-dose - within 6 hours prior to any of the drugs being administered. Starting at Cycle 5, blood samples for ADA against PF-06801591 in Part 1B were collected every 3rd cycle pre-dose (ie, Cycle 5 Day 1, Cycle 8 Day 1, Cycle 11 Day 1, etc). Participants with an unresolved AE possibly related to ADA were asked to return to the clinic for ADA and drug concentration assessments at approximately 3 month intervals until the AE or its sequelae resolved or stabilized at a level acceptable to the investigator and sponsor up to a maximum of 9 months. A participant was PF-06801591 ADA positive when ADA titer was ≥99.
Percent Change From Baseline in Immune Biomarkers (CD3+ and CD8+ Cells/mm2 CT+, PD-L1 Tumor Cell Membrane Staining and PD-L1 Positive Immune Cells Per Tumor Area) in Pre-treatment and On-Treatment Paired Tumor Biopsies Baseline (Baseline was defined as the time closest to, but prior to, the start of study drug administration in the first cycle), Cycle 3 Day 1 Tumor biospecimens from archival and/de novo biopsies were used to analyze candidate nucleic acid and protein and cellular biomarkers for their ability to inform those participants who were most likely to benefit from treatment with the study interventions. De novo tumor biopsies obtained during therapy and upon disease progression could be used to help confirm pharmacodynamic effects of treatment and investigate potential acquired mechanisms of resistance (ie, presence of but not limited to regulatory T-cells or myeloid derived suppressor cells and other immune suppressive cells or proteins).
Number of Participants With Confirmed Objective Response Baseline up to maximum of 4 years Tumor assessments included all known or suspected disease sites. Imaging included contrast enhanced chest, abdomen and pelvis CT or MRI scans; brain CT or MRI scan for participants with known or suspected brain metastases; bone scan and/or bone x rays for participants with known or suspected bone metastases. For participants with known CT contrast allergy, a non-contrast CT of the chest with contrast enhanced abdominal and pelvic MRI could be used. The same imaging technique used to characterize each identified and reported lesion at baseline was employed in the tumor assessments. Assessment of response used Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Objective Response was defined as complete response (CR) + partial response (PR).
Trial Locations
- Locations (19)
The Royal Melbourne Hospital
🇦🇺Parkville, Victoria, Australia
UCLA Department of Medicine: Hematology-Oncology
🇺🇸Los Angeles, California, United States
UCLA Hematology Oncology - Santa Monica
🇺🇸Santa Monica, California, United States
University of Colorado Hospital - Anschutz Outpatient Pavilion (AOP)
🇺🇸Aurora, Colorado, United States
University of Texas MD Anderson Cancer Center
🇺🇸Houston, Texas, United States
Christus Santa Rosa Hospital
🇺🇸San Antonio, Texas, United States
NEXT Oncology
🇺🇸San Antonio, Texas, United States
University of Colorado Hospital - Anschutz Cancer Pavilion (ACP)
🇺🇸Aurora, Colorado, United States
City of Hope IDS Pharmacy
🇺🇸Duarte, California, United States
University of Colorado Hospital - Anschutz Inpatient Pavilion (AIP)
🇺🇸Aurora, Colorado, United States
START Midwest
🇺🇸Grand Rapids, Michigan, United States
Memorial Sloan Kettering Cancer Center Rockefeller Outpatient Pavillion
🇺🇸New York, New York, United States
Evelyn H. Lauder Breast and Imaging Center
🇺🇸New York, New York, United States
Memorial Sloan Kettering Cancer Center - Main Campus
🇺🇸New York, New York, United States
University Hospitals Cleveland Medical Center
🇺🇸Cleveland, Ohio, United States
Peter MacCallum Cancer Centre
🇦🇺Melbourne, Victoria, Australia
National Cancer Center Hospital East
🇯🇵Kashiwa, Chiba, Japan
City of Hope (City of Hope National Medical Center, City of Hope Medical Center)
🇺🇸Duarte, California, United States
National Cancer Center Hospital
🇯🇵Chuo-ku, Tokyo, Japan