Ph1b/2 Study of PF-04136309 in Combination With Gem/Nab-P in First-line Metastatic Pancreatic Patients

Study Overview
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Brief Summary
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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
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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.

Official Title
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PHASE 1B/2 STUDY OF PF-04136309 IN COMBINATION WITH GEMCITABINE AND NAB-PACLITAXEL IN PATIENTS WITH PREVIOUSLY UNTREATED METASTATIC PANCREATIC DUCTAL ADENOCARCINOMA

Conditions
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Metastatic Pancreatic Ductal Adenocarcinoma

Intervention / Treatment
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* Drug: PF-04136309
* Drug: Nab-paclitaxel
* Drug: Gemcitabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Histologically or cytologically proven diagnosis of metastatic ductal adenocarcinoma of the pancreas. All patients must provide a baseline tumor sample at registration. If an archival sample is not available, patients must have a metastatic biopsy collected at the screening visit. Patient must have received no previous radiotherapy, surgery, chemotherapy or investigational therapy for the treatment of metastatic disease. Measurable disease as per RECIST v. 1.1. Resolved acute effects of any prior therapy to baseline severity or Grade ≤1 NCI CTCAE. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1. Age ≥18 years. Adequate Bone Marrow, Renal and liver Functions. Exclusion Criteria Patients with known symptomatic brain metastases requiring steroids. Prior therapy with modulators of monocyte or TAM function. Participation in other studies involving investigational drug(s) (Phases 1-4) within 4 weeks of registering for the current study and/or during study participation. Diagnosis of any second malignancy within the last 3 years, except for adequately treated basal cell carcinoma, or squamous cell skin carcinoma or in situ cervical carcinoma. Known hypersensitivity to nab-paclitaxel or to gemcitabine or to any of the excipients. Any one of the following currently or in the previous 6 months: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident, transient ischemic attack; symptomatic pulmonary embolism; congenital long QT syndrome, torsades de points, arrhythmias (including sustained ventricular tachyarrhythmia and ventricular fibrillation), right bundle branch block and left anterior hemiblock (bifascicular block), ongoing cardiac dysrhythmias of NCI CTCAE Grade >=2, atrial fibrillation of any grade, or QTc interval >470 msec at screening. Concurrent administration of herbal preparations. Use of oral anticoagulants. Use of subcutaneous anti coagulation is allowed. Concurrent use of potent or moderate inhibitors or inducers of CYP3A4 and/or CYP2C8. Active and clinically significant bacterial, fungal or viral infection including hepatitis B (HBV), hepatitis C (HCV), known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) related illness. History of interstitial lung disease, or slowly progressive dyspnea and unproductive cough, sarcoidosis, silicosis, idiopathic pulmonary fibrosis, pulmonary hypersensitivity pneumonitis or multiple allergies. Other severe acute or chronic medical or psychiatric condition, including recent (within the past year) or active suicidal ideation or behavior) or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the patient inappropriate for entry into this study. Pregnant female patients; breastfeeding female patients; males patients with partners currently pregnant, male patients able to father children and female patients of childbearing potential who are unwilling or unable to use two (2) highly effective methods of contraception as outlined in this protocol for the duration of the study and for 28 days after last dose of PF-04136309, and for 6 months after last dose of nab-paclitaxel, gemcitabine, or both. Patients who are investigational site staff members directly involved in the conduct of the trial and their family members, site staff members otherwise supervised by the Investigator, or patients who are Pfizer employees directly involved in the conduct of the trial.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PF-04136309 + Nab-p + Gem<br>PF-04136309 oral dosing Nab-paclitaxel IV dosing Gemcitabine IV dosing | Drug: PF-04136309<br>* PF-04136309 oral dosing<br>Drug: Nab-paclitaxel<br>* Nab-paclitaxel IV dosing<br>* Other names: Abraxane;Drug: Gemcitabine<br>* Gemcitabine IV dosing<br>* Other names: Gemzar;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Dose-Limiting Toxicities (DLTs) [Phase 1b] | 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. | Day 1 to Day 28 | 
| Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) [Phase 1b] | 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. | 1 year | 
| Number of Participants With Treatment-Emergent Adverse Events (AEs) by Severity [Phase 1b] | 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. | 1 year | 
| Number of Participants With Hematology Laboratory Abnormalities by Maximum National Cancer Institute Common Terminology Criteria for Adverse Event (NCI CTCAE) Grade [Phase 1b] | 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. | 1 year | 
| Number of Participants With Chemistries Laboratory Abnormalities by Maximum NCI CTCAE Grade [Phase 1b] | 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. | 1 year | 
| Number of Participants With Urinalysis Laboratory Abnormalities by Maximum NCI CTCAE Grade [Phase 1b] | 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. | 1 year | 
| Progression Free Survival (PFS) [Phase 2] | 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. | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PF-04136309 Maximum Observed Plasma Concentration (Cmax) for Cycle 1 Day 15 in the 750 mg BID Group [Phase 1b] | 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. | 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) | 
| PF-04136309 Maximum Observed Plasma Concentration (Cmax) for Cycle 1 Day 15 in the 500 mg BID Group [Phase 1b] | 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. | 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) | 
| PF-04136309 Time to Reach Maximum Observed Plasma Concentration (Tmax) for Cycle 1 Day 15 in the 750 mg BID Group [Phase 1b] | 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. | 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) | 
| PF-04136309 Time to Reach Maximum Observed Plasma Concentration (Tmax) for Cycle 1 Day 15 in the 500 mg BID Group [Phase 1b] | 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. | 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) | 
| 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] | 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. | 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) | 
| 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] | 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. | 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) | 
| PF-04136309 Minimum Observed Plasma Concentration (Cmin) for Cycle 1 Day 15 in the 750 mg BID Group [Phase 1b] | 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. | 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) | 
| PF-04136309 Minimum Observed Plasma Concentration (Cmin) for Cycle 1 Day 15 in the 500 mg BID Group [Phase 1b] | 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. | 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) | 
| PF-04136309 Apparent Oral Clearance (CL/F) for Cycle 1 Day 15 in the 750 mg BID Group [Phase 1b] | 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. | 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) | 
| PF-04136309 Apparent Oral Clearance (CL/F) for Cycle 1 Day 15 in the 500 mg BID Group [Phase 1b] | 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. | 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) | 
| PF-04136309 Plasma Decay Half-Life (t1/2) for Cycle 1 Day 15 [Phase 1b] | 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. | 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) | 
| PF-04136309 Apparent Volume of Distribution (Vz/F) for Cycle 1 Day 15 [Phase 1b] | 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. | 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) | 
| Ex Vivo Inhibition of Chemokine Ligand 2 (CCL2)-Induced Extracellular Signal Regulated Kinase (ERK) Phosphorylation in the Peripheral Blood [Phase 1b] | A drop in the CCL2-induced ERK kinase phosphorylation (pERK) biomarker level indicates target engagement (TE). | 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 | 
| Number of Participants With Overall Survival (OS) [Phase 2] | 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. | Up to approximately 13.5 months | 
| Number of Participants With Treatment-Emergent Adverse Events (AEs) [Phase 2] | 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. | Up to approximately 1 year | 
| Number of Participants With Laboratory Abnormalities by Severity [Phase 2] | Hematology, chemistry, and urinalysis laboratory parameters were to be analyzed and graded by NCI CTCAE version 4.03. | Up to approximately 1 year | 
| Objective Response Rate (ORR) [Phase 2] | 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. | Up to approximately 1 year | 
| Duration of Objective Response (DR) [Phase 2] | 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. | Up to approximately 1 year | 
| Time to Progression (TTP) With the Double Combination PF-04136309 and Gemcitabine (Maintenance Therapy) After Interruption of Nab-paclitaxel [Phase 2] | 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. | Up to approximately 1 year | 
| Trough PF-04136309 Concentrations [Phase 2] | The minimum plasma concentration of PF-04136309. | 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 | 
| Change From Baseline in Pharmacodynamic (PD) Markers in Metastatic Tumors and Bone Marrow [Phase 2] | 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. | Baseline, Cycle 1 Day 28 or Cycle 2 Day 28; EOT visit (optional) for CNB | 
| Number of Participants With Peripheral Neurological Adverse Events [Phase 2] | 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. | Up to approximately 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CCR2i, nab-paclitaxel, Abraxane, gemcitabine, pancreas