A Dose Escalation Study Of PF-06801591 In Melanoma, Head And Neck Cancer (SCCHN), Ovarian, Sarcoma, Non-Small Cell Lung Cancer, Urothelial Carcinoma or Other Solid Tumors
- Conditions
- Part 1MELANOMASCCHNSARCOMAOVCAOTHER SOLID TUMORSPart 1 and 2NSCLCUROTHELIAL CARCINOMA
- Interventions
- Registration Number
- NCT02573259
- Lead Sponsor
- Pfizer
- Brief Summary
Protocol B8011001 is a Phase 1, open-label, multi-center, multiple-dose, dose escalation and expansion, safety, pharmacokinetics (PK), and pharmacodynamics (PD) study of PF-06801591 in previously treated adult patients with locally advanced or metastatic melanoma, SCCHN, ovarian carcinoma, sarcoma, NSCLC, urothelial carcinoma or other solid tumors. This is a 2 Part study whereby the safety and tolerability of increasing dose levels of intravenous (IV) or subcutaneous (SC) PF-06801591 was assessed in Part 1. Part 2 expansion is designed to further evaluate the safety and efficacy of SC PF-06801591 in patients with NSCLC or urothelial carcinoma as well as confirm the recommended Phase 2 dose.
- Detailed Description
Protocol B8011001 is a Phase 1, two part, open-label, multi center, multiple-dose, safety, efficacy, PK, and PD study of PF-06801591 administered intravenously (IV) or subcutaneous (SC) in previously treated adult patients with locally advanced or metastatic melanoma, squamous cell carcinoma head and neck (SCCHN), ovarian carcinoma, sarcoma, non-small cell lung carcinoma (NSCLC), urothelial carcinoma or other solid tumors.
The first part of the study, Part 1 dose escalation, was designed to assess the safety and tolerability of increasing dose levels of IV or SC administered PF-06801591 to establish the maximum tolerated dose (MTD) using a modified Toxicity Probability Interval (mTPI) design. Part 2 expansion is designed to further evaluate the safety and efficacy of 300 mg of PF-06801591 administered SC once every 4 weeks in patients with NSCLC or urothelial carcinoma as well as confirm the recommended Phase 2 dose (RP2D). Part 1 enrollment has completed, enrollment will only be allowed for Part 2.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 147
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- Not specified
- Arm && Interventions
Group Intervention Description Arm 2 PF-06801591 PF-06801591 1.0 mg/kg IV every 21 days (Part 1) Arm 3 PF-06801591 PF-06801591 3.0 mg/kg IV every 21 days (Part 1) Arm 4 PF-06801591 PF-06801591 10 mg/kg IV every 21 days (Part 1) Arm 5 PF-06801591 PF-06801591 300 mg SC every 28 days (Part 1 and 2) Arm 1 PF-06801591 PF-06801591 0.5 mg/kg IV every 21 days (Part 1)
- Primary Outcome Measures
Name Time Method Number of Participants With Treatment-Related Treatment-Emergent Adverse Events (AEs) - Part 1 and Part 2 Baseline up to 28 days after last dose of study treatment (maximum of 1634 days) Treatment-related AE was any untoward medical occurrence attributed to study treatment in a participant who received study treatment. Treatment-emergent events = between first dose of study treatment and up to 28 days after last dose that were absent before treatment or that worsened relative to pretreatment state. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-related AEs and SAEs were determined by the investigator. Grades of severity were defined by CTCAE v4.03. Grades of severity were defined by CTCAE v4.03. Grade 3 = severe AE. Grade 4 = life-threatening consequences; urgent intervention indicated. Grade 5 = death related to AE.
Number of Participants With Laboratory Test Abnormalities - Part 1 and Part 2 Baseline up to 28 days after last dose of study treatment (maximum of 1634 days) Following parameters were analyzed for laboratory examination: hematology (anemia, hemoglobin increased, lymphocyte count decreased, lymphocyte count increased, neutrophil count decreased, platelet count decreased, white blood cell decreased); chemistries (increase of alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, blood bilirubin, CPK, creatinine, gamma-glutamyl transferase \[GGT\], lipase, and serum amylase); urinalysis (proteinuria); coagulation (activated partial thromboplastin time prolonged, international normalized ratio \[INR\] increased). Grades of severity were defined by CTCAE v4.03. Grade 0 = No Change from normal or reference range (this grade is not included in the CTCAE v4.03 document but may used in certain circumstances). Grade 1 = mild adverse event (AE). Grade 2 = moderate AE; Grade 3 = severe AE. Grade 4 = life-threatening consequences; urgent intervention indicated. Grade 5 = death related to AE.
Objective Response Rate (ORR) Based on Immune Related RECIST (irRECIST) - Part 2 Baseline up to end of treatment in Part 2 (maximum of 851 days) ORR was defined as percentage of participants with objective response (OR) of complete response (CR) and partial response (PR) based on irRECIST. CR was defined as complete disappearance of all target lesions with the exception of nodal disease. All target nodes must decrease to normal size (short axis \< 10 mm). All target lesions must be assessed. PR was defined as \>= 30% decrease under baseline of the sum of diameters of all target measurable lesions. The short diameter was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. All target lesions must be assessed.
Objective Response Rate (ORR) Based on RECIST Version 1.1 - Part 2 Baseline up to end of treatment in Part 2 (maximum of 851 days) ORR was defined as percentage of participants with confirmed objective response (OR) of complete response (CR) and partial response (PR) based on RECIST version 1.1. CR was defined as complete disappearance of all target lesions with the exception of nodal disease. All target nodes must decrease to normal size (short axis \< 10 mm). All target lesions must be assessed. PR was defined as \>= 30% decrease under baseline of the sum of diameters of all target measurable lesions. The short diameter was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. All target lesions must be assessed.
Percentage of Participants With Dose-Limiting Toxicities (DLT) - Part 1 Cycle 1 in Part 1 (21 days for IV administration of PF-06801591; 28 days for SC administration of PF-06801591) DLT was defined as any of the following drug-related adverse events (AEs) occurring during the first cycle (21 days for IV dosing, 28 days for SC dosing) in Part 1: Grade 5 AE; Grade 4 neutropenia lasting \>5 days from initiation of granulocyte colony stimulating factor; Grade 4 thrombocytopenia with bleeding; Platelet transfusion requirement or a platelet count \<10,000/uL; Grade 4 non-hematologic AE; Grade 3 AE lasting \>7 days despite optimal supportive care; Grade 3 central nervous system AE regardless of duration; met criteria for drug induced liver injury. Severity of AEs were graded according to Common Terminology Criteria for Adverse Events (CTCAE) v4.03. Grade 3 = severe AE. Grade 4 = life-threatening consequences; urgent intervention indicated. Grade 5 = death related to AE.
Number of Participants With All-Causality Treatment-Emergent Adverse Events (AEs) - Part 1 and Part 2 Baseline up to 28 days after last dose of study treatment (maximum of 1634 days) AE = any untoward medical occurrence in participant who received study treatment without regard to possibility of causal relationship. Treatment-emergent events = between first dose of study treatment and up to 28 days after last dose that were absent before treatment or that worsened relative to pretreatment state. A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Grades of severity were defined by CTCAE v4.03. Grades of severity were defined by CTCAE v4.03. Grade 3 = severe AE. Grade 4 = life-threatening consequences; urgent intervention indicated. Grade 5 = death related to AE.
- Secondary Outcome Measures
Name Time Method Maximum Plasma Concentration (Cmax) of PF-06801591 - Part 1 Pre-dose, 1 and 24 hours post dose on Cycle 1 Day 1, and pre-dose and 1 hour post dose on Cycle 4 Day 1 in Part 1 Cmax was the maximum concentration after dose administration observed directly from the data.
AUClast of PF-06801591 in Part 1. Pre-dose, 1 and 24 hours post dose on Cycle 1 Day 1 in Part 1 Area Under the Concentration Versus Time Curve (AUC) From Time Zero to the Last Quantifiable Time Point Prior to the Next Dose (AUClast) of PF-06801591 - Part 1
Median Time to Death - Part 2 Baseline up to end of treatment in Part 2 (maximum of 851 days) Median time to death was analyzed by the Kaplan-Meier approach for each tumor type.
Terminal Elimination Half-Life (t1/2) of PF-06801591 - Part 1 Pre-dose and 1 hour post dose on Day 1 of Cycles 1 and 4 in Part 1 t1/2 was calculated by Loge(2)/kel. kel was the terminal phase rate constant calculated by a linear regression of the log linear concentration time curve. Only those data points judged to describe the terminal log linear decline were used in the regression.
Number of Participants With Anti-Drug Antibody (ADA) Against PF-06801591 - Part 1 and Part 2 Baseline up to end of treatment (maximum of 851 days) Number of participants with ADA positive against PF-06801591 after IV and SC dosing - Part 1 and Part 2. A participant was ADA positive if (1) baseline titer was missing or negative and participant had ≥ 1 post-treatment positive titer (treatment-induced), or (2) positive titer at baseline and had a ≥ 0.602 in titer from baseline in ≥ 1 post-treatment sample (treatment-boosted). Participants who were ADA positive at baseline but did not become boosted post-treatment were considered as ADA negative.
Percentage of Baseline PD-1 Receptor Occupancy (RO) by PF-06801591 - Part 1 Baseline, Days 1, 8, 15, 21 of Cycle 1, Day 1 of Cycles 2, 3, 5, Days 1, 15, 21 of Cycle 4, and end of treatment (EOT) in Part 1 (cycle = 21 days for IV dosing; cycle = 28 days for SC dosing) PD-1 RO by sasanlimab was measured by the reduction of free receptor on the surface of CD8+ effector cells (CD3+, CD4-, CD8+, CD45RA+, CCR7-, CD279+) and CD8+ effector memory cells (CD3+, CD4-, CD8+, CD45RA-, CCR7-, CD279+) presented in pre- and postdose whole blood samples by flow cytometry. Percentage of baseline (ie, normalized change from baseline) PD-1 RO were calculated as \[(percentage of cells at Cycle X Day X)/(percentage of cells at baseline)\]\*100, and are reported for this outcome measure. Baseline was defined as the most recent non-missing value prior to dosing.
Trough PF-06801591 Concentrations (Ctrough) - Part 2 Pre-dose on Day 1 of Cycles 2-6, 9, 12, 15, 18, 21, 24, and Follow-up Day 28 in Part 2 Trough PF-06801591 Concentrations (Ctrough) - Part 2. Ctrough was directly observed from data.
Clearance (CL) of PF-06801591 - Part 1 Pre-dose, 1 and 24 hours post dose on Cycle 1 Day 1, and pre-dose and 1 hour post dose on Cycle 4 Day 1 in Part 1 CL for IV dosing. CL was calculated by dose / AUCtau for Cycles 1 and 4 IV dosing. AUCtau was defined as area under the serum concentration time profile from time zero to time tau, the dosing interval, where tau = 504 hours for every 3 weeks (Q3W) IV dosing reporting arm.
Number of Participants With Neutralizing Antibodies (NAb) Positive Against PF-06801591 - Part 1 and Part 2 Baseline up to end of treatment (maximum of 851 days) Number of participants with NAb positive against PF-06801591 after IV and SC dosing - Part 1 and Part 2. A participant was NAb positive if (1) baseline titer was missing or negative and participant had ≥ 1 post-treatment positive titer (treatment-induced), or (2) positive titer at baseline and had a ≥ 0.602 in titer from baseline in ≥ 1 post-treatment sample (treatment-boosted). Participants who were NAb positive at baseline but did not become boosted post-treatment were considered as NAb negative.
Number of Participants Achieving Objective Response (OR) Based on RECIST Version 1.1 - Part 1 Baseline up to end of treatment in Part 1 (maximum of 1606 days) Number of participants achieving confirmed OR based on RECIST version 1.1 in Part 1. CR was defined as complete disappearance of all target lesions with the exception of nodal disease. All target nodes must decrease to normal size (short axis \< 10 mm). All target lesions must be assessed. PR was defined as \>= 30% decrease under baseline of the sum of diameters of all target measurable lesions. The short diameter was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. All target lesions must be assessed.
Number of Participants Achieving Objective Response (OR) Based on irRECIST - Part 1 Baseline up to end of treatment in Part 1 (maximum of 1606 days) Number of participants achieving confirmed OR based on irRECIST in Part 1. OR = irCR + irPR. Overall immune related complete response (irCR) was defined as complete disappearance of all lesions (whether measurable or not) and no new lesions. All measurable lymph nodes also must have a reduction in short axis to \<10 mm. Overall immune related partial response (irPR) was defined as sum of the diameters (longest for non nodal lesions, shortest for nodal lesions) of target and new measurable lesions decreases \>=30%.
Progression-Free Survival (PFS) Based on RECIST Version 1.1 and irRECIST - Part 1 and Part 2 Baseline up to end of treatment (maximum of 1606 days) PFS was defined as the time from initiation of study intervention to first documentation of tumor progression or to death due to any cause, whichever occurred first. PFS was analyzed by the Kaplan-Meier approach for each tumor type. As this outcome measure was a secondary endpoint defined in the protocol to investigate preliminary signal of efficacy, the results were analyzed and are reported for Part 1 dose-escalation groups combined to provide more statistically meaningful results, instead of results analyzed by dose level with very limited number of participants in each group.
Volume of Distribution at Steady State (Vss) of PF-06801591 - Part 1 Pre-dose, 1 and 24 hours post dose on Cycle 1 Day 1, and pre-dose and 1 hour post dose on Cycle 4 Day 1 in Part 1 Steady state volume of distribution of PF-0680159 for IV dosing. Vss was calculated by CL\*MRT. CL was the clearance for IV dosing. MRT was the mean residence time calculated for a single IV dose as AUMCinf/AUCinf - (DOF/2). AUMCinf was the area under the moment curve from time 0 extrapolated to infinity. DOF was the duration of infusion. AUCinf was the area under the serum concentration time profile from time 0 extrapolated to infinity.
Accumulation Ratio (Rac) of PF-06801591 - Part 1 Pre-dose and 1 hour post dose on Day 1 of Cycles 1 and 4 in Part 1 Rac was calculated by (Cycle 4 AUCtau) / (Cycle 1 AUCtau). AUCtau was Area under the serum concentration time profile from time zero to time tau, the dosing interval, where tau = 504 hours for Q3W IV dosing and tau = 672 hours for every 4 weeks (Q4W) SC dosing.
Duration of Stable Disease (DOSD) Based on RECIST Version 1.1 and irRECIST - Part 1 and Part 2 Baseline up to end of treatment (maximum of 1606 days) DOSD was analyzed by the Kaplan-Meier approach for each tumor type. Stable disease (SD) was defined as not qualifying for complete response (CR), partial response (PR), or progression. All target lesions must have been assessed. Stable could follow PR only in the rare case that the sum increased by less than 20% from the nadir, but enough that a previously documented 30% decrease no longer held. CR was defined as complete disappearance of all target lesions with the exception of nodal disease. All target nodes must have decreased to normal size (short axis \< 10 mm). All target lesions must have been assessed. PR was defined as greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions. The short diameter was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. All target lesions must have been assessed.
Time to Response (TTR) Based on RECIST Version 1.1 - Part 2 Baseline up to end of treatment in Part 2 (maximum of 851 days) TTR was the time to confirmed or unconfirmed complete response (CR) or partial response (PR) based on investigator assessment per RECIST v1.1 by tumor type. CR was defined as complete disappearance of all target lesions with the exception of nodal disease. All target nodes must have decreased to normal size (short axis \< 10 mm). All target lesions must have been assessed. PR was defined as greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions. The short diameter was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. All target lesions must have been assessed.
Time to Progression (TTP) Based on RECIST Version 1.1 and irRECIST - Part 2 Baseline up to end of treatment in Part 2 (maximum of 851 days) TTP was the time to objective progression. Objective progression was defined as 20% increase in the sum of diameters of target measurable lesions above the smallest sum observed (over baseline if no decrease in the sum was observed during therapy), with a minimum absolute increase of 5 mm. TTP was analyzed by the Kaplan-Meier approach for each tumor type.
Duration of Response (DOR) Based on RECIST Version 1.1 and irRECIST - Part 1 and Part 2 Baseline up to end of treatment (maximum of 1606 days) DOR was defined as the time from start date (which was the date of first documentation of PR or CR) to date of first documentation of objective progression or death. CR was defined as complete disappearance of all target lesions with the exception of nodal disease. PR was defined as greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions. Objective progression was defined as 20% increase in the sum of diameters of target measurable lesions above the smallest sum observed (over baseline if no decrease in the sum was observed during therapy), with a minimum absolute increase of 5 mm. As this outcome measure was a secondary endpoint defined in the protocol to investigate preliminary signal of efficacy, the results were analyzed and are reported for Part 1 dose-escalation groups combined to provide more statistically meaningful results, instead of results analyzed by dose level with very limited number of participants in each group.
Probability of Survival at 6 Months, 1 Year, and 2 Years - Part 2 Baseline up to end of treatment in Part 2 (maximum of 851 days) Probability of survival was calculated from the product-limit method.
Trial Locations
- Locations (55)
Communal Non-profit Institution "City Clinical Hospital #4" of Dnipro City Council, Department of
🇺🇦Dnipro, Ukraine
University of Rochester
🇺🇸Rochester, New York, United States
Tennessee Oncology, PLLC
🇺🇸Smyrna, Tennessee, United States
Ronald Reagan UCLA Medical Center, Drug Information Center
🇺🇸Los Angeles, California, United States
University Malaya Medical Centre
🇲🇾Lembah Pantai, Kuala Lumpur, Malaysia
Europejskie Centrum Zdrowia Otwock Szpital im. Fryderyka Chopina
🇵🇱Otwock, Poland
Communal noncommercial enterprise Sumy regional Rada Sumy regional clinical oncologic dispensary,
🇺🇦Sumy, Ukraine
Vinnytsia Regional Clinical Oncological Hospital
🇺🇦Vinnytsia, Ukraine
Clinical Research Unit
🇺🇸Los Angeles, California, United States
Norton Cancer Institute, Multidisciplinary Clinic
🇺🇸Louisville, Kentucky, United States
SBHI ¨Saint-Petersburg clinical scientific practical center of specialized types of
🇷🇺Pesochny Village, Saint-petersburg, Russian Federation
National Cancer Center
🇰🇷Goyang-si, Gyeonggi-do, Korea, Republic of
Joint Stock Company Current medical technologies
🇷🇺Saint-Petersburg, Russian Federation
MROI n.a. P.A. Gertsen, filiation of FSBI "NMRC of radiology" MoH Russia
🇷🇺Moscow, Russian Federation
Norton Hospital
🇺🇸Louisville, Kentucky, United States
Ronald Reagan Medical Center, Department of Radiological Sciences
🇺🇸Los Angeles, California, United States
Mazowiecki Szpital Specjalistyczny im. Dr. Jozefa Psarskiego w Ostrolece, Osrodek Onkologiczny
🇵🇱Ostroleka, Poland
Centrum Onkologii-Instytut im.Marii Sklodowskiej-Curie
🇵🇱Warszawa, Poland
Grigoriev Radiological Institute of the National Academy of Medical Sciences of Ukraine,
🇺🇦Kharkiv, Ukraine
Communal Non-profit Institution of Kharkiv Regional Council "Regional Clinical Specialized Health
🇺🇦Kharkiv, Ukraine
Norton Cancer Institute, Norton Healthcare Pavilion
🇺🇸Louisville, Kentucky, United States
Clinical Research Centre(Crc), Hospital Umum Sarawak
🇲🇾Kuching, Sarawak, Malaysia
Communal Non-profit Institution "Central City Clinical Hospital" of Uzhhorod City Council,
🇺🇦Uzhhorod, Ukraine
Regionalny Szpital Specjalistyczny im. dr. Wl. Bieganskiego w Grudziadzu
🇵🇱Grudziadz, Poland
Centrum Badan Klinicznych JCI Life Science Park
🇵🇱Krakow, Poland
Hospital Tengku Ampuan Afzan
🇲🇾Kuantan, Pahang, Malaysia
Asan Medical Center
🇰🇷Seoul, Korea, Republic of
Non-governmental Healthcare Institution ¨Railway Clinical Hospital of JSC ¨Russian Railways¨
🇷🇺Saint-Petersburg, Russian Federation
SHATOD "Dr. Marko Antonov Markov - Varna" EOOD
🇧🇬Varna, Bulgaria
Complex Oncology Center - Plovdiv EOOD
🇧🇬Plovdiv, Bulgaria
SPb SBHI "City Clinical Oncology Dispensary"
🇷🇺Saint-Petersburg, Russian Federation
Szpitale Pomorskie Sp. z.o.o., Oddzial Onkologii i Radioterapii
🇵🇱Gdynia, Poland
Communal non-Commercial Enterprise "Prykarpatski Clinical Oncological Center of Ivano-
🇺🇦Ivano-Frankivsk, Ukraine
Sbhi "Lrcod"
🇷🇺Vsevolozhsky District, Leningrad Region, Russian Federation
Severance Hospital Yonsei University Health System
🇰🇷Seoul, Korea, Republic of
Hospital Sultan Ismail
🇲🇾Johor Bahru, Johor, Malaysia
Joint-Stock Company Current medical technologies
🇷🇺St. Petersburg, Russian Federation
SBHI YaR ¨Regional clinical oncology hospital¨
🇷🇺Yaroslavl, Russian Federation
The Sarah Cannon Research Institute
🇺🇸Nashville, Tennessee, United States
"MHAT for Women Health - Nadezhda" OOD
🇧🇬Sofia, Bulgaria
MHAT Uni Hospital OOD
🇧🇬Panagyurishte, Pazardzhik, Bulgaria
Gachon University Gil Medical Center
🇰🇷Incheon, Korea, Republic of
Severance Hospital, Yonsei University Health System
🇰🇷Seoul, Korea, Republic of
Seoul National University Bundang Hospital
🇰🇷Seongnam-si, Gyeonggi-do, Korea, Republic of
SBHI "ChRCCO and NM"
🇷🇺Chelyabinsk, Russian Federation
Comprehensive Cancer Centers of Nevada
🇺🇸Las Vegas, Nevada, United States
BHI of Omsk Region "Clinical Oncology Dispensary"
🇷🇺Omsk, Russian Federation
UNC Hospitals, The University of North Carolina at Chapel Hill
🇺🇸Chapel Hill, North Carolina, United States
UCLA Hematology & Oncology Clinic
🇺🇸Los Angeles, California, United States
Santa Monica UCLA Hematology & Oncology Clinic
🇺🇸Santa Monica, California, United States
Division of Medical Oncology, Severance Hospital, Yonsei University Health System
🇰🇷Seoul, Korea, Republic of
The Catholic University of Korea, St. Vincent's Hospital
🇰🇷Suwon, Gyeonggi-do, Korea, Republic of
Ulsan University Hospital
🇰🇷Ulsan, Korea, Republic of
"Specialized Clinic "Prognosis Optima" LLC
🇺🇦Kyiv, Ukraine
Communal Institution ¨Zaporizhzhya Regional Clinical Oncological Dispensary¨
🇺🇦Zaporizhzhya, Ukraine