Ph1b/2 Study of PF-04136309 in Combination With Gem/Nab-P in First-line Metastatic Pancreatic Patients
- Conditions
- Metastatic Pancreatic Ductal Adenocarcinoma
- Interventions
- Registration Number
- NCT02732938
- Lead Sponsor
- Pfizer
- Brief Summary
The purpose of this Phase 1b/2 study is to evaluate the safety and tolerability of PF-04136309 in combination with nab-paclitaxel and gemcitabine, characterize the dose-limiting toxicities (DLTs) and overall safety profile of escalated doses of PF-04136309 and the associated schedule, determine the maximum tolerated dose (MTD), and to assess the enhancement of efficacy of PF-04136309 in combination with nab-paclitaxel and gemcitabine versus nab-paclitaxel + gemcitabine + placebo in terms of Progression Free Survival.
- Detailed Description
The study has 2 parts:
Phase 1b (dose-finding cohorts) will be open label as patients will receive ascending doses of PF-04136309 in combination with nab-paclitaxel + gemcitabine. The observation period for dose-limiting toxicities (DLTs) will be from Day 1 to Day 28. Pharmacokinetic (PK) and pharmacodynamic (PD) properties of PF-04136309 will also be assessed. The criteria for dose escalation will be based on a modified toxicity probability interval (mTPI) method. After evaluating the safety and other results (eg, PK) from patients enrolled in the dose escalation cohorts, a dose level will be selected to be further evaluated as the Recommended Phase 2 Dose (RP2D). A minimum of 6 patients, up to 12 patients, will be treated at this dose level to establish it as the RP2D. To further evaluate safety and pharmacodynamics, the number of patients enrolled during this part of the study (Phase 1b) may be N up to 20. The study will stop if all PF-04136309 doses explored appear to be overly toxic.
Phase 2 randomized double blinded placebo control. Approximately 92 patients will be randomized 1:1 to receive the RP2D of PF-04136309 in combination with nab-paclitaxel + gemcitabine (ARM A; n=46) versus nab-paclitaxel + gemcitabine + placebo (ARM B; n=46). The primary objective will be the enhancement of efficacy in terms of PFS.
Patients will be treated as long as they are clinically benefiting from investigational product without unacceptable toxicity, objective disease progression, or withdrawal of consent.
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 22
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- Not specified
- Arm && Interventions
Group Intervention Description PF-04136309 + Nab-p + Gem PF-04136309 PF-04136309 oral dosing Nab-paclitaxel IV dosing Gemcitabine IV dosing PF-04136309 + Nab-p + Gem Nab-paclitaxel PF-04136309 oral dosing Nab-paclitaxel IV dosing Gemcitabine IV dosing PF-04136309 + Nab-p + Gem Gemcitabine PF-04136309 oral dosing Nab-paclitaxel IV dosing Gemcitabine IV dosing
- Primary Outcome Measures
Name Time Method Number of Participants With Dose-Limiting Toxicities (DLTs) [Phase 1b] Day 1 to Day 28 DLT: Any of the following events occurred in the first treatment cycle and was attributed to the combination of PF-04136309 with nab-paclitaxel and gemcitabine where relationship with the combination could not be ruled out. Hematologic: Grade (Gr) 4 neutropenia lasting more than (\>)5 days; febrile neutropenia; Gr≥3 neutropenic infection; Gr≥3 thrombocytopenia with Gr≥2 bleeding; Gr4 thrombocytopenia. Non-Hematologic: Gr3 toxicities (except: nausea and vomiting responding to prophylaxis and/or treatment and lasting less than (\<)7 days from each chemotherapy infusion period; diarrhea responding to treatment and lasting \<7 days; Gr3 QTc prolongation \[QTc \>500 milliseconds\] \[a DLT only if persisting after correction of any reversible causes\]; Gr3 aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) increase lasting less than or equal to (≤)7 days); all Gr4 toxicities; delay of \>2 weeks in receiving the next scheduled cycle due to persisting treatment-related toxicities.
Number of Participants With Hematology Laboratory Abnormalities by Maximum National Cancer Institute Common Terminology Criteria for Adverse Event (NCI CTCAE) Grade [Phase 1b] 1 year Following parameters were analyzed for hematology laboratory test: hemoglobin, hematocrit, red blood cell (RBC) count, mean corpuscular volume (MCV); mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), platelet count, white blood cell (WBC) count, total neutrophils, eosinophils, monocytes, basophils, lymphocytes. Laboratory abnormalities were graded per NCI CTCAE version 4.03 and those with at least 1 participant are presented here.
Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) [Phase 1b] 1 year 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. Treatment-emergent AEs were those with initial onset or increasing in severity after the first dose of study treatment.
Number of Participants With Treatment-Emergent Adverse Events (AEs) by Severity [Phase 1b] 1 year 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 the 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.
Number of Participants With Chemistries Laboratory Abnormalities by Maximum NCI CTCAE Grade [Phase 1b] 1 year Following parameters were analyzed for chemistry laboratory test: blood urea nitrogen (BUN), creatinine, glucose (fasting), calcium, sodium, potassium, chloride, total bicarbonate, AST, ALT, total bilirubin, alkaline phosphatase, uric acid, albumin, total protein, Magnesium, phosphorous or phosphate. For potential Hy's Law cases, in addition to repeating AST and ALT, laboratory tests should have included albumin, creatine kinase, total bilirubin, direct and indirect bilirubin, gamma-glutamyl transferase (GGT), prothrombin time / international normalized ratio (PT/INR), alkaline phosphatase, total bile acids, and acetaminophen drug and/or protein adduct levels. Laboratory abnormalities were graded per NCI CTCAE version 4.03 and those with at least 1 participant are presented here.
Number of Participants With Urinalysis Laboratory Abnormalities by Maximum NCI CTCAE Grade [Phase 1b] 1 year Following parameters were analyzed for urinalysis laboratory test: pH, glucose, protein, blood, ketones, nitrites, leukocyte esterase, urobilinogen, urine bilirubin, microscopy (only if urine dipstick was positive for blood, protein, nitrites or leukocyte esterase), urine dipstick for urine protein (if positive collected 24 hour and microscopic \[reflex testing\]), urine dipstick for urine blood (if positive collected a microscopic \[reflex testing\]). Laboratory abnormalities were graded per NCI CTCAE version 4.03 and those with at least 1 participant are presented here.
Progression Free Survival (PFS) [Phase 2] 1 year PFS was defined as the time from randomization to first documentation of objective tumor progression or to death due to any cause, whichever occurred first.
- Secondary Outcome Measures
Name Time Method PF-04136309 Maximum Observed Plasma Concentration (Cmax) for Cycle 1 Day 15 in the 750 mg BID Group [Phase 1b] Cycle 1 Day 15 pre-dose (within 30 minutes), and 0.5, 1, 2, 3, 4, and 6 hours after the morning dose; Cycle 1 Day 16 pre-dose (within 30 minutes; as the 12-hour sample for evening dose on Day 15) Cmax of PF-04136309 was observed directly from data. This outcome measure reports individual values for the participants in the Phase 1b PF-04136309 750 mg BID +Nab-paclitaxel +Gemcitabine treatment group as summary statistics were not generated when fewer than 3 participants had reportable data.
PF-04136309 Apparent Oral Clearance (CL/F) for Cycle 1 Day 15 in the 750 mg BID Group [Phase 1b] Cycle 1 Day 15 pre-dose (within 30 minutes), and 0.5, 1, 2, 3, 4, and 6 hours after the morning dose; Cycle 1 Day 16 pre-dose (within 30 minutes; as the 12-hour sample for evening dose on Day 15) CL/F was determined by Dose/AUCtau. AUCtau is the area under the curve from time 0 to end of dosing interval. This outcome measure reports individual values for the participants in the Phase 1b PF-04136309 750 mg BID +Nab-paclitaxel +Gemcitabine treatment group as summary statistics were not generated when fewer than 3 participants had reportable data.
PF-04136309 Time to Reach Maximum Observed Plasma Concentration (Tmax) for Cycle 1 Day 15 in the 500 mg BID Group [Phase 1b] Cycle 1 Day 15 pre-dose (within 30 minutes), and 0.5, 1, 2, 3, 4, and 6 hours after the morning dose; Cycle 1 Day 16 pre-dose (within 30 minutes; as the 12-hour sample for evening dose on Day 15) Tmax of PF-04136309 was observed directly from data as time of first occurrence. This outcome measure reports summary statistics for the participants in the Phase 1b PF-04136309 500 mg BID +Nab-paclitaxel +Gemcitabine treatment group.
PF-04136309 Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) for Cycle 1 Day 15 in the 750 mg BID Group [Phase 1b] Cycle 1 Day 15 pre-dose (within 30 minutes), and 0.5, 1, 2, 3, 4, and 6 hours after the morning dose; Cycle 1 Day 16 pre-dose (within 30 minutes; as the 12-hour sample for evening dose on Day 15) The dosing interval was 12 hours for PF-04136309 BID dosing. AUCtau was determined by linear/log trapezoidal method. This outcome measure reports individual values for the participants in the Phase 1b PF-04136309 750 mg BID +Nab-paclitaxel +Gemcitabine treatment group as summary statistics were not generated when fewer than 3 participants had reportable data.
PF-04136309 Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) for Cycle 1 Day 15 in the 500 mg BID Group [Phase 1b] Cycle 1 Day 15 pre-dose (within 30 minutes), and 0.5, 1, 2, 3, 4, and 6 hours after the morning dose; Cycle 1 Day 16 pre-dose (within 30 minutes; as the 12-hour sample for evening dose on Day 15) The dosing interval was 12 hours for PF-04136309 BID dosing. AUCtau was determined by linear/log trapezoidal method. This outcome measure reports summary statistics for the participants in the Phase 1b PF-04136309 500 mg BID +Nab-paclitaxel +Gemcitabine treatment group. Arithmetic CV was the intended method of dispersion for reporting but system only has geometric CV option, hence geometric CV data were reported for this parameter.
PF-04136309 Minimum Observed Plasma Concentration (Cmin) for Cycle 1 Day 15 in the 750 mg BID Group [Phase 1b] Cycle 1 Day 15 pre-dose (within 30 minutes), and 0.5, 1, 2, 3, 4, and 6 hours after the morning dose; Cycle 1 Day 16 pre-dose (within 30 minutes; as the 12-hour sample for evening dose on Day 15) Cmin of PF-04136309 was observed directly from data. This outcome measure reports individual values for the participants in the Phase 1b PF-04136309 750 mg BID +Nab-paclitaxel +Gemcitabine treatment group as summary statistics were not generated when fewer than 3 participants had reportable data.
PF-04136309 Minimum Observed Plasma Concentration (Cmin) for Cycle 1 Day 15 in the 500 mg BID Group [Phase 1b] Cycle 1 Day 15 pre-dose (within 30 minutes), and 0.5, 1, 2, 3, 4, and 6 hours after the morning dose; Cycle 1 Day 16 pre-dose (within 30 minutes; as the 12-hour sample for evening dose on Day 15) Cmin of PF-04136309 was observed directly from data. This outcome measure reports summary statistics for the participants in the Phase 1b PF-04136309 500 mg BID +Nab-paclitaxel +Gemcitabine treatment group.
PF-04136309 Maximum Observed Plasma Concentration (Cmax) for Cycle 1 Day 15 in the 500 mg BID Group [Phase 1b] Cycle 1 Day 15 pre-dose (within 30 minutes), and 0.5, 1, 2, 3, 4, and 6 hours after the morning dose; Cycle 1 Day 16 pre-dose (within 30 minutes; as the 12-hour sample for evening dose on Day 15) Cmax of PF-04136309 was observed directly from data. This outcome measure reports summary statistics for the participants in the Phase 1b PF-04136309 500 mg BID +Nab-paclitaxel +Gemcitabine treatment group. Arithmetic coefficient of variation (CV) was the intended method of dispersion for reporting but system only has geometric CV option, hence geometric CV data were reported for this parameter.
PF-04136309 Time to Reach Maximum Observed Plasma Concentration (Tmax) for Cycle 1 Day 15 in the 750 mg BID Group [Phase 1b] Cycle 1 Day 15 pre-dose (within 30 minutes), and 0.5, 1, 2, 3, 4, and 6 hours after the morning dose; Cycle 1 Day 16 pre-dose (within 30 minutes; as the 12-hour sample for evening dose on Day 15) Tmax of PF-04136309 was observed directly from data as time of first occurrence. This outcome measure reports individual values for the participants in the Phase 1b PF-04136309 750 mg BID +Nab-paclitaxel +Gemcitabine treatment group as summary statistics were not generated when fewer than 3 participants had reportable data.
PF-04136309 Plasma Decay Half-Life (t1/2) for Cycle 1 Day 15 [Phase 1b] Cycle 1 Day 15 pre-dose (within 30 minutes), and 0.5, 1, 2, 3, 4, and 6 hours after the morning dose; Cycle 1 Day 16 pre-dose (within 30 minutes; as the 12-hour sample for evening dose on Day 15) t1/2 was determined by Loge(2)/kel, where kel is 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.
PF-04136309 Apparent Volume of Distribution (Vz/F) for Cycle 1 Day 15 [Phase 1b] Cycle 1 Day 15 pre-dose (within 30 minutes), and 0.5, 1, 2, 3, 4, and 6 hours after the morning dose; Cycle 1 Day 16 pre-dose (within 30 minutes; as the 12-hour sample for evening dose on Day 15) Vz/F was determined by Dose/(AUCtau×kel). AUCtau is the area under the curve from time 0 to end of dosing interval and kel is the terminal phase rate constant.
PF-04136309 Apparent Oral Clearance (CL/F) for Cycle 1 Day 15 in the 500 mg BID Group [Phase 1b] Cycle 1 Day 15 pre-dose (within 30 minutes), and 0.5, 1, 2, 3, 4, and 6 hours after the morning dose; Cycle 1 Day 16 pre-dose (within 30 minutes; as the 12-hour sample for evening dose on Day 15) CL/F was determined by Dose/AUCtau. AUCtau is the area under the curve from time 0 to end of dosing interval. This outcome measure reports summary statistics for the participants in the Phase 1b PF-04136309 500 mg BID +Nab-paclitaxel +Gemcitabine treatment group. Arithmetic CV was the intended method of dispersion for reporting but system only has geometric CV option, hence geometric CV data were reported for this parameter.
Ex Vivo Inhibition of Chemokine Ligand 2 (CCL2)-Induced Extracellular Signal Regulated Kinase (ERK) Phosphorylation in the Peripheral Blood [Phase 1b] Cycle 1 Day 1 pre-dose, 2 and 6 hours post-dose, and 12 hours (pre-second BID dose-optional collection); Cycle 1 Days 2, 3 and 4 pre-dose A drop in the CCL2-induced ERK kinase phosphorylation (pERK) biomarker level indicates target engagement (TE).
Number of Participants With Overall Survival (OS) [Phase 2] Up to approximately 13.5 months OS was defined as the time from date of randomization to date of death due to any cause. For participants not expiring, their survival times were to be censored at the last date they were known to be alive. Participants lacking data beyond the day of randomization were to have their survival times censored at the date of randomization with duration of 1 day.
Number of Participants With Treatment-Emergent Adverse Events (AEs) [Phase 2] Up to approximately 1 year An AE was any untoward medical occurrence in a participant administered a product or medical device 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. Treatment-emergent AEs were those with initial onset or increasing in severity after the first dose of study treatment.
Number of Participants With Laboratory Abnormalities by Severity [Phase 2] Up to approximately 1 year Hematology, chemistry, and urinalysis laboratory parameters were to be analyzed and graded by NCI CTCAE version 4.03.
Objective Response Rate (ORR) [Phase 2] Up to approximately 1 year ORR was defined as the percentage of participants with confirmed complete response (CR) or confirmed partial response (PR) according to the Response Evaluation Criteria in Solid Tumor (RECIST) version 1.1, relative to all randomized participants who had baseline measurable disease. Confirmed responses were those that persisted on repeat imaging study ≥4 weeks after initial documentation of response.
Duration of Objective Response (DR) [Phase 2] Up to approximately 1 year DR was defined as the time from the first documentation of objective tumor response to the first documentation of objective tumor progression or to death due to any cause, whichever occurs first. DR data were to be censored on the day following the date of the last on treatment (including 28 day follow-up period after last dose) tumor assessment documenting absence of progressive disease for participants who did not have objective tumor progression and who did not die due to any cause while on treatment or who were given anti-tumor treatment other than the study treatment prior to observing objective tumor progression. Participants who achieved a PR and then a CR were to have times calculated using the date of the PR as the first day. DR was only to be calculated for the subgroup of participants with objective response.
Time to Progression (TTP) With the Double Combination PF-04136309 and Gemcitabine (Maintenance Therapy) After Interruption of Nab-paclitaxel [Phase 2] Up to approximately 1 year This type of TTP was defined as the time from interruption of nab-paclitaxel to the first documentation of objective tumor progression. This TTP was to be only calculated for the subgroup of participants who were treated with the maintenance therapy.
Trough PF-04136309 Concentrations [Phase 2] Cycle 1 Day 1 pre-dose, Cycle 1 Days 2, 8 and 15 pre-dose; Day 1 of Cycle 2 and subsequent cycles pre-dose, and EOT visit The minimum plasma concentration of PF-04136309.
Change From Baseline in Pharmacodynamic (PD) Markers in Metastatic Tumors and Bone Marrow [Phase 2] Baseline, Cycle 1 Day 28 or Cycle 2 Day 28; EOT visit (optional) for CNB Collections of core needle biopsy (CNB) from a metastatic site or fine-needle aspirate (FNA) from the primary tumor tissue were optional but at least 12 paired biopsies would have to be available and fully assessable in each treatment arm to allow the comparison.
Number of Participants With Peripheral Neurological Adverse Events [Phase 2] Up to approximately 1 year To evaluate the improvement of peripheral neurotoxicity induced by nab-paclitaxel by the addition of PF-04136309 to the combination therapy of nab-paclitaxel plus gemcitabine.
Trial Locations
- Locations (15)
Wayne Memorial Hospital
🇺🇸Goldsboro, North Carolina, United States
Southeastern Medical Oncology Center
🇺🇸Jacksonville, North Carolina, United States
MUSC Health North Charleston
🇺🇸North Charleston, South Carolina, United States
Massachusetts General Hospital
🇺🇸Boston, Massachusetts, United States
Dana Farber Cancer Institute
🇺🇸Boston, Massachusetts, United States
Memorial Sloan Kettering Cancer Center
🇺🇸New York, New York, United States
Beth Israel Deaconess Medical Center
🇺🇸Boston, Massachusetts, United States
Sampson Regional Medical Center
🇺🇸Clinton, North Carolina, United States
University of Rochester Cancer Center Pharmacy
🇺🇸Rochester, New York, United States
MUSC Hollings Cancer Center
🇺🇸Charleston, South Carolina, United States
MUSC Health East Cooper
🇺🇸Mount Pleasant, South Carolina, United States
Medical University of South Carolina
🇺🇸Charleston, South Carolina, United States
Brigham and Women's Hospital
🇺🇸Boston, Massachusetts, United States
University of Rochester Medical Center
🇺🇸Rochester, New York, United States
Onslow Memorial Hospital
🇺🇸Jacksonville, North Carolina, United States