A study of PF-05082566, a 4-1BB agonist monoclonal antibody (mAb), in patients with solid tumors or b-cell lymphomas, and in combination with rituximab in patients with CD20 positive Non-Hodgkin's Lymphoma (NHL).
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
190
Intravenous, Dose escalation, once per month
Intravenous, 375 mg/m2, once per week for 4 weeks
IV, Dose escalation, once per month
Number of Participants With Dose-Limiting Toxicities (DLTs) in First 2 Cycles of Portion A
DLT: Any of the following adverse events (AEs) occurred in the first 2 cycles of treatment (up to 28 days post second dose) which was attributed to PF-05082566 alone for Portion A and not related to progressive disease. Hematologic: Grade 4 neutropenia lasting more than (\>)7 days; febrile neutropenia; neutropenic infection; Grade ≥3 thrombocytopenia with bleeding; Grade 4 thrombocytopenia; Grade ≥3 hemolysis. Non-Hematologic: Grade ≥3 toxicities, except those Grade 3 events that responded to treatment (eg, Grade 3 nausea, vomiting, diarrhea responding to standard medical supportive care within 48 hours would not be considered a DLT). Severity of AEs were graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (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). Each cycle=28 days.
Time frame: Cycle 1 Day 1 to Cycle 2 Day 29 in Portion A (up to 57 days, each cycle = 28 days)
Number of Participants With DLTs in First 2 Cycles of Portion B
DLT: Any of the following AEs occurred in the first 2 cycles of treatment (up to 28 days post second dose) which was attributed to PF-05082566 in combination with rituximab for Portion B and not related to progressive disease. Hematologic: Grade 4 neutropenia lasting more than (\>)7 days; febrile neutropenia; neutropenic infection; Grade ≥3 thrombocytopenia with bleeding; Grade 4 thrombocytopenia; Grade ≥3 hemolysis. Non-Hematologic: Grade ≥3 toxicities, except those Grade 3 events that responded to treatment (eg, Grade 3 nausea, vomiting, diarrhea responding to standard medical supportive care within 48 hours would not be considered a DLT). Severity of AEs were graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (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). Each cycle=28 days.
Time frame: Cycle 1 Day 1 to Cycle 2 Day 29 in Portion B (up to 57 days, each cycle = 28 days)
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City of Hope
Duarte, California, United States
UC San Diego Moores Cancer Center-Investigational Drug Services
La Jolla, California, United States
UC San Diego Medical Center-La Jolla (Jacobs Medical Center/Thornton Hospital)
La Jolla, California, United States
UC San Diego Moores Cancer Center
La Jolla, California, United States
Research Administration Office: Clinical Research Unit
Los Angeles, California, United States
Ronald Reagan UCLA Medical Center, Drug Information Center
Los Angeles, California, United States
UCLA Bowyer Clinic
Los Angeles, California, United States
UCLA Hematology-Oncology Clinic
Los Angeles, California, United States
Stanford University Medical Center
Palo Alto, California, United States
Stanford University Medical Center
Palo Alto, California, United States
...and 32 more locations
Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) in Portion A
An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; life-threatening experience (immediate risk of dying); initial or prolonged inpatient hospitalization; persistent or significant disability/incapacity; congenital anomaly/birth defect. AEs included both non-serious AEs and SAEs. Treatment-emergent AEs were those with initial onset or increasing in severity after the first dose of study treatment. Causality of AEs was determined by the investigator.
Time frame: Up to approximately 2 years
Number of Participants With Treatment-Emergent AEs by Maximum National Cancer Institute Common Terminology Criteria for Adverse Event (NCI CTCAE) Grade in Portion A
An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Treatment-emergent AEs were those with initial onset or increasing in severity after the first dose of study treatment. Severity of AEs were graded 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).
Time frame: Up to approximately 2 years
Number of Participants With Hematology Laboratory Abnormalities by Maximum NCI CTCAE Grade in Portion A
Following hematology laboratory abnormalities were graded per NCI CTCAE version 4.03: anemia, hemoglobin increased, lymphocyte count increased, lymphopenia, neutrophils (absolute), platelets, white blood cells. The abnormalities with at least 1 participant are presented here.
Time frame: Up to approximately 2 years
Number of Participants With Chemistries Laboratory Abnormalities by Maximum NCI CTCAE Grade in Portion A
Following chemistries laboratory abnormalities were graded per NCI CTCAE version 4.03: alanine aminotransferase (ALT), Alkaline phosphatase, Aspartate aminotransferase (AST), bilirubin (total), creatinine, gamma glutamyl transferase (GGT), hypercalcemia, hyperglycemia, hyperkalemia, hypermagnesemia, hypernatremia, hypoalbuminemia, hypocalcemia, hypoglycemia, hypokalemia, hypomagnesemia, hyponatremia, hypophosphatemia. The abnormalities with at least 1 participant are presented here.
Time frame: Up to approximately 2 years
Number of Participants With Clinically Significant Vital Sign Abnormalities in Portion A
For vital signs in Portion A, blood pressure and pulse rate were measured. Clinical significance was determined by the investigator.
Time frame: Up to approximately 2 years
PF-05082566 Maximum Observed Serum Concentration (Cmax) in Portion A
Cmax of PF-05082566 was observed directly from data.
Time frame: Day 1 of Cycle 1 and Cycle 2 at pre-dose, and 1, 1.5, 2, 6, 24, 48, 168, 336 and 504 hours post-dose
PF-05082566 Pre-dose Trough Concentration During Multiple Dosing (Ctrough) in Portion A
Ctrough of PF-05082566 was observed directly from data.
Time frame: Day 1 pre-dose of Cycle 2
PF-05082566 Time for Maximum Observed Serum Concentration (Tmax) in Portion A
Tmax of PF-05082566 was observed directly from data as time of Cmax.
Time frame: Day 1 of Cycle 1 and Cycle 2 at pre-dose, and 1, 1.5, 2, 6, 24, 48, 168, 336 and 504 hours post-dose.
PF-05082566 Area Under the Serum Concentration-Time Profile (AUC) From Time 0 to the Time of the Last Measurable Concentration (AUClast) in Portion A
AUClast of PF-05082566 was determined by linear/log trapezoidal method.
Time frame: Day 1 of Cycle 1 and Cycle 2 at pre-dose, and 1, 1.5, 2, 6, 24, 48, 168, 336 and 504 hours post-dose.
PF-05082566 AUC From Time 0 to Infinity (AUCinf) in Portion A
AUCinf = AUClast + (Clast\*/kel), where Clast\* is the estimated concentration at the time of the last measurable concentration and kel is the terminal phase rate constant calculated as the absolute value of the slope of a linear regression during the terminal phase of the natural log-transformed concentration time profile.
Time frame: Day 1 of Cycle 1 and Cycle 2 at pre-dose, and 1, 1.5, 2, 6, 24, 48, 168, 336 and 504 hours post-dose.
PF-05082566 AUC From Time 0 to Time of Dosing Interval (AUCtau) in Portion A
AUCtau of PF-05082566 was determined using linear/log trapezoidal method.
Time frame: Day 1 of Cycle 1 and Cycle 2 at pre-dose, and 1, 1.5, 2, 6, 24, 48, 168, 336 and 504 hours post-dose.
PF-05082566 Clearance (CL) in Portion A
CL = Dose/AUCinf for Cycle 1 and Dose/AUCtau for Cycle 2. It was reported in units of milliliter per hour per kilogram (mL/hr/kg).
Time frame: Day 1 of Cycle 1 and Cycle 2 at pre-dose, and 1, 1.5, 2, 6, 24, 48, 168, 336 and 504 hours post-dose.
PF-05082566 Volume of Distribution at Steady State (Vss) in Portion A
Vss = CL × MRT, where CL is clearance and MRT is the mean residence time after intravenous administration.
Time frame: Day 1 of Cycle 1 and Cycle 2 at pre-dose, and 1, 1.5, 2, 6, 24, 48, 168, 336 and 504 hours post-dose.
Number of Participants With Positive Anti-Drug Antibody (ADA) for PF-05082566 in Portion A
ADA for PF-05082566 was detected using electrochemiluminescence assay. Positive ADA for PF-05082566: titer\>=6.23.
Time frame: Up to approximately 2 years
Number of Participants With QTc Interval Meeting Categorical Summarization Criteria in Portion A
Categorical summarization criteria for QTc interval (time from ECG Q wave to the end of the T wave corresponding to electrical systole corrected for heart rate): 1) absolute value of \>450 to \<=480 milliseconds (msec), \>480 to \<=500 msec, \>500 msec; 2) a maximum change from baseline of \>30 to \<=60 msec or \>60 msec.
Time frame: Up to approximately 2 years
Percentage of Participants Achieving Objective Response Per Response Evaluation Criteria in Solid Tumor (RECIST) Version 1.1 in Portion A
Objective response: confirmed best overall response (BOR) of complete response (CR) or partial response (PR) per RECIST version 1.1. BOR of CR: target lesions and non-target diseases achieved CR, without new lesions. BOR of PR: target lesions achieved CR or PR while non-target diseases were non-CR/non-progression of disease (non-PD), indeterminate or missing, and without new lesions. For target lesions, CR: complete disappearance of all target lesions except nodal disease (target nodes must decrease to normal size); PR: \>=30% decrease under baseline of the sum of diameters of all target measurable lesions. For non-target diseases, CR: disappearance of all non-target lesions and normalization of tumor marker levels; non-CR/non-PD: persistence of any non-target lesions and/or tumor marker level above the normal limits; Indeterminate: progression had not been determined and \>=1 non-target sites were not assessed or assessment methods were inconsistent with those used at baseline.
Time frame: Every 8 weeks from Cycle 1 Day 1 for the first 10 months on study treatment, then every 16 weeks till follow-up visit (assessed up to approximately 2 years)
Duration of Response in Portion A
Duration of response: the time from first documentation of objective response (confirmed BOR of CR or PR per RECIST version 1.1) to the date of first documentation of objective progression of disease (PD) or death due to any cause. Objective PD per RECIST version 1.1: \>=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 millimeters (mm); or unequivocal progression of pre-existing lesions for non-target disease; or appearance of new lesions. This outcome measure reports the individual values for evaluable participants (instead of medians etc) due to the limited number of events.
Time frame: Every 8 weeks from Cycle 1 Day 1 for the first 10 months on study treatment, then every 16 weeks till follow-up visit (assessed up to approximately 2 years)
Time to Response in Portion A
Time to response: the time from Cycle 1 Day 1 to the first documentation of objective response (confirmed BOR of CR or PR per RECIST version 1.1). BOR of CR: target lesions and non-target diseases achieved CR, without new lesions. BOR of PR: target lesions achieved CR or PR while non-target diseases were non-CR/non-PD, indeterminate or missing, and without new lesions. For target lesions, CR: complete disappearance of all target lesions except nodal disease (target nodes decreased to normal size); PR: \>=30% decrease under baseline of the sum of diameters of all target measurable lesions. For non-target diseases, CR: disappearance of all non-target lesions and normalization of tumor marker levels; non-CR/non-PD: persistence of any non-target lesions and/or tumor marker level above the normal limits; Indeterminate: progression had not been determined and \>=1 non-target sites were not assessed or assessment methods were inconsistent with those used at baseline.
Time frame: Every 8 weeks from Cycle 1 Day 1 for the first 10 months on study treatment, then every 16 weeks till follow-up visit (assessed up to approximately 2 years)
Progression-Free Survival in Portion A
Progression-free survival: the time from Cycle 1 Day 1 to the date of the first documentation of objective PD or death due to any cause, whichever occurred first. Objective PD per RECIST version 1.1: \>=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; or unequivocal progression of pre-existing lesions for non-target disease; or appearance of new lesions.
Time frame: Every 8 weeks from Cycle 1 Day 1 for the first 10 months on study treatment, then every 16 weeks till follow-up visit (assessed up to approximately 2 years)
Overall Survival in Portion A
Overall survival was defined as the time from Cycle 1 Day 1 to the date of death due to any cause.
Time frame: Every 8 weeks from Cycle 1 Day 1 for the first 10 months on study treatment, then every 16 weeks till follow-up visit (assessed up to approximately 2 years)
Number of Participants With Treatment-Emergent AEs and SAEs in Portion B
An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; life-threatening experience (immediate risk of dying); initial or prolonged inpatient hospitalization; persistent or significant disability/incapacity; congenital anomaly/birth defect. AEs included both non-serious AEs and SAEs. Treatment-emergent AEs were those with initial onset or increasing in severity after the first dose of study treatment. Causality of AEs was determined by the investigator.
Time frame: Up to approximately 4 years
Number of Participants With Treatment-Emergent AEs by Maximum NCI CTCAE Grade in Portion B
An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Treatment-emergent AEs were those with initial onset or increasing in severity after the first dose of study treatment. Severity of AEs were graded 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).
Time frame: Up to approximately 4 years
Number of Participants With Hematology Laboratory Abnormalities by Maximum NCI CTCAE Grade in Portion B
Following hematology laboratory abnormalities were graded per NCI CTCAE version 4.03: anemia, hemoglobin increased, lymphocyte count increased, lymphopenia, neutrophils (absolute), platelets, white blood cells. The abnormalities with at least 1 participant are presented here.
Time frame: Up to approximately 2 years
Number of Participants With Chemistries Laboratory Abnormalities by Maximum NCI CTCAE Grade in Portion B
Following chemistries laboratory abnormalities were graded per NCI CTCAE version 4.03: alanine aminotransferase (ALT), Alkaline phosphatase, Aspartate aminotransferase (AST), bilirubin (total), creatinine, gamma glutamyl transferase (GGT), hypercalcemia, hyperglycemia, hyperkalemia, hypermagnesemia, hypernatremia, hypoalbuminemia, hypocalcemia, hypoglycemia, hypokalemia, hypomagnesemia, hyponatremia, hypophosphatemia. The abnormalities with at least 1 participant are presented here.
Time frame: Up to approximately 2 years
Number of Participants With Clinically Significant Vital Sign Abnormalities in Portion B
For vital signs in Portion B, blood pressure, pulse rate, and body temperature were measured. Clinical significance was determined by the investigator.
Time frame: Up to approximately 2 years
PF-05082566 Cmax in Portion B
Cmax of PF-05082566 was observed directly from data.
Time frame: Cycle 1 Day 1 pre-dose, 1.5, 2, 6, 24, 48, 144, 312, and 504 hours post-dose; Cycle 2 Day 1 pre-dose, 1.5, 2, 6, 24, 48, 168, 336, and 504 hours post-dose.
PF-05082566 Ctrough in Portion B
Ctrough of PF-05082566 was observed directly from data.
Time frame: Day 1 pre-dose of Cycle 2
PF-05082566 Tmax in Portion B
Tmax of PF-05082566 was observed directly from data as time of Cmax.
Time frame: Cycle 1 Day 1 pre-dose, 1.5, 2, 6, 24, 48, 144, 312, and 504 hours post-dose; Cycle 2 Day 1 pre-dose, 1.5, 2, 6, 24, 48, 168, 336, and 504 hours post-dose.
PF-05082566 AUClast in Portion B
AUClast of PF-05082566 was determined by linear/log trapezoidal method.
Time frame: Cycle 1 Day 1 pre-dose, 1.5, 2, 6, 24, 48, 144, 312, and 504 hours post-dose; Cycle 2 Day 1 pre-dose, 1.5, 2, 6, 24, 48, 168, 336, and 504 hours post-dose.
PF-05082566 AUCinf in Portion B
AUCinf = AUClast + (Clast\*/kel), where Clast\* is the estimated concentration at the time of the last measurable concentration and kel is the terminal phase rate constant calculated as the absolute value of the slope of a linear regression during the terminal phase of the natural log-transformed concentration time profile.
Time frame: Cycle 1 Day 1 pre-dose, 1.5, 2, 6, 24, 48, 144, 312, and 504 hours post-dose.
PF-05082566 AUCtau in Portion B
AUCtau of PF-05082566 was determined using linear/log trapezoidal method.
Time frame: Cycle 1 Day 1 pre-dose, 1.5, 2, 6, 24, 48, 144, 312, and 504 hours post-dose; Cycle 2 Day 1 pre-dose, 1.5, 2, 6, 24, 48, 168, 336, and 504 hours post-dose.
PF-05082566 CL in Portion B
CL = Dose/AUCinf for Cycle 1 and Dose/AUCtau for Cycle 2.
Time frame: Cycle 1 Day 1 pre-dose, 1.5, 2, 6, 24, 48, 144, 312, and 504 hours post-dose; Cycle 2 Day 1 pre-dose, 1.5, 2, 6, 24, 48, 168, 336, and 504 hours post-dose.
PF-05082566 Vss in Portion B
Vss = CL × MRT, where CL is clearance and MRT is the mean residence time after intravenous administration.
Time frame: Cycle 1 Day 1 pre-dose, 1.5, 2, 6, 24, 48, 144, 312, and 504 hours post-dose; Cycle 2 Day 1 pre-dose, 1.5, 2, 6, 24, 48, 168, 336, and 504 hours post-dose.
Rituximab Cmax and Ctrough in Portion B
Cmax and Ctrough of rituximab were observed directly from data.
Time frame: Day 1 pre-dose of Cycle 2
Number of Participants With Positive ADA for PF-05082566 and Rituximab in Portion B
ADA for PF-05082566 and rituximab was detected using electrochemiluminescence assay. Positive ADA for PF-05082566: titer\>=6.23. Positive ADA for rituximab: titer\>=1.88.
Time frame: Up to approximately 2 years
Number of Participants With QTc Interval Meeting Categorical Summarization Criteria in Portion B
Categorical summarization criteria for QTc interval: 1) absolute value of \>450 to \<=480 milliseconds (msec), \>480 to \<=500 msec, \>500 msec; 2) a maximum change from baseline of \>30 to \<=60 msec or \>60 msec.
Time frame: Up to approximately 2 years
Percentage of Participants Achieving Objective Response Per Cheson 2007 Criteria in Portion B
Objective Response in Portion B was defined as BOR of CR or PR according to Cheson 2007 criteria. BOR of CR or PR per Cheson 2007: CR or PR of index lesions (complete disappearance of all detectable clinical and radiographic evidence of disease, all lymph nodes returned to normal size, spleen and/or liver if enlarged prior to therapy became normal or no longer palpable; or \>=50% decrease in the sum of the product diameters \[SPD\] of up to 6 index lesions, no increase in size of other nodes, liver or spleen), without PD of non-index lesions (ie, without: new nonnodal lesion, new nodal lesion \>=15 mm in greatest transverse diameter \[GTD\], unequivocal progression of existing non index lesions, bone marrow that was negative and is now positive, new circulating lymphoma cells in blood cell count and/or pleural fluid, new circulating blasts in the blood cell count), and without any new lesions.
Time frame: Every 8 weeks from Cycle 1 Day 1 for the first 10 months on study treatment, then every 16 weeks till follow-up visit (assessed up to approximately 2 years)
Duration of Response in Portion B
Duration of Response in Portion B was defined, for participants with an objective response (BOR of CR or PR per Cheson 2007 criteria), as the time from first documentation of objective response to the date of first documentation of objective PD or death due to any cause. Objective PD per Cheson 2007 was defined as: PD of index lesions (\>=50% increase in SPD of previously involved sites from nadir), or PD of non-index lesions (new nonnodal lesion, new nodal lesion \>=15 mm in GTD, unequivocal progression of existing non index lesions, bone marrow that was negative and is now positive, new circulating lymphoma cells in blood cell count and/or pleural fluid, new circulating blasts in the blood cell count), or appearance of new lesions.
Time frame: Every 8 weeks from Cycle 1 Day 1 for the first 10 months on study treatment, then every 16 weeks till follow-up visit (assessed up to approximately 2 years)
Time to Response in Portion B
Time to response in Portion B was defined, for participants with an objective response (BOR of CR or PR per Cheson 2007 criteria), as the time from Cycle 1 Day 1 to the first documentation of objective response. BOR of CR or PR per Cheson 2007: CR or PR of index lesions (complete disappearance of all detectable clinical and radiographic evidence of disease, all lymph nodes returned to normal size, spleen and/or liver if enlarged prior to therapy became normal or no longer palpable; or \>=50% decrease in the SPD of up to 6 index lesions, no increase in size of other nodes, liver or spleen), without PD of non-index lesions (ie, without: new nonnodal lesion, new nodal lesion \>=15 mm in GTD, unequivocal progression of existing non index lesions, bone marrow that was negative and is now positive, new circulating lymphoma cells in blood cell count and/or pleural fluid, new circulating blasts in the blood cell count), and without any new lesions.
Time frame: Every 8 weeks from Cycle 1 Day 1 for the first 10 months on study treatment, then every 16 weeks till follow-up visit (assessed up to approximately 2 years)
Progression-Free Survival in Portion B
Progression-free survival in Portion B was defined as the time from Cycle 1 Day 1 to the date of the first documentation of objective PD (per Cheson 2007) or death due to any cause, whichever occurred first. Objective PD per Cheson 2007 was defined as: PD of index lesions (\>=50% increase in SPD of previously involved sites from nadir), or PD of non-index lesions (new nonnodal lesion, new nodal lesion \>=15 mm in GTD, unequivocal progression of existing non index lesions, bone marrow that was negative and is now positive, new circulating lymphoma cells in blood cell count and/or pleural fluid, new circulating blasts in the blood cell count), or appearance of new lesions.
Time frame: Every 8 weeks from Cycle 1 Day 1 for the first 10 months on study treatment, then every 16 weeks till follow-up visit (assessed up to approximately 2 years)
Overall Survival in Portion B
Overall survival was defined as the time from Cycle 1 Day 1 to the date of death due to any cause.
Time frame: Every 8 weeks from Cycle 1 Day 1 for the first 10 months on study treatment, then every 16 weeks till follow-up visit (assessed up to approximately 2 years)