Clinical trial NCT02732938: Ph1b/2 Study of PF-04136309 in Combination With Gem/Nab-P in First-line Metastatic Pancreatic Patients
Official title: PHASE 1B/2 STUDY OF PF-04136309 IN COMBINATION WITH GEMCITABINE AND NAB-PACLITAXEL IN PATIENTS WITH PREVIOUSLY UNTREATED METASTATIC PANCREATIC DUCTAL ADENOCARCINOMA
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Metastatic Pancreatic Ductal Adenocarcinoma
Keywords: CCR2i, nab-paclitaxel, Abraxane, gemcitabine, pancreas
Lead sponsor: Pfizer
Sponsor class: INDUSTRY
First posted: 2016-04-11
Enrollment: 22
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Primary purpose: TREATMENT

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.

Eligibility criteria: Inclusion Criteria

1. Histologically or cytologically proven diagnosis of metastatic ductal adenocarcinoma of the pancreas.
2. 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.
3. Patient must have received no previous radiotherapy, surgery, chemotherapy or investigational therapy for the treatment of metastatic disease.
4. Measurable disease as per RECIST v. 1.1.
5. Resolved acute effects of any prior therapy to baseline severity or Grade ≤1 NCI CTCAE.
6. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1.
7. Age ≥18 years.
8. Adequate Bone Marrow, Renal and liver Functions.

Exclusion Criteria

1. Patients with known symptomatic brain metastases requiring steroids.
2. Prior therapy with modulators of monocyte or TAM function.
3. 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.
4. 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.
5. Known hypersensitivity to nab-paclitaxel or to gemcitabine or to any of the excipients.
6. 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.
7. Concurrent administration of herbal preparations.
8. 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.
9. 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.
10. History of interstitial lung disease, or slowly progressive dyspnea and unproductive cough, sarcoidosis, silicosis, idiopathic pulmonary fibrosis, pulmonary hypersensitivity pneumonitis or multiple allergies.
11. 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.
12. 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.
13. 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.

Primary outcomes:
measure: Number of Participants With Dose-Limiting Toxicities (DLTs) [Phase 1b]
timeFrame: Day 1 to Day 28
measure: Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) [Phase 1b]
timeFrame: 1 year
measure: Number of Participants With Treatment-Emergent Adverse Events (AEs) by Severity [Phase 1b]
timeFrame: 1 year
measure: Number of Participants With Hematology Laboratory Abnormalities by Maximum National Cancer Institute Common Terminology Criteria for Adverse Event (NCI CTCAE) Grade [Phase 1b]
timeFrame: 1 year
measure: Number of Participants With Chemistries Laboratory Abnormalities by Maximum NCI CTCAE Grade [Phase 1b]
timeFrame: 1 year
measure: Number of Participants With Urinalysis Laboratory Abnormalities by Maximum NCI CTCAE Grade [Phase 1b]
timeFrame: 1 year
measure: Progression Free Survival (PFS) [Phase 2]
timeFrame: 1 year
Secondary outcomes:
measure: PF-04136309 Maximum Observed Plasma Concentration (Cmax) for Cycle 1 Day 15 in the 750 mg BID Group [Phase 1b]
timeFrame: 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)
measure: PF-04136309 Maximum Observed Plasma Concentration (Cmax) for Cycle 1 Day 15 in the 500 mg BID Group [Phase 1b]
timeFrame: 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)
measure: PF-04136309 Time to Reach Maximum Observed Plasma Concentration (Tmax) for Cycle 1 Day 15 in the 750 mg BID Group [Phase 1b]
timeFrame: 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)
measure: PF-04136309 Time to Reach Maximum Observed Plasma Concentration (Tmax) for Cycle 1 Day 15 in the 500 mg BID Group [Phase 1b]
timeFrame: 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)
measure: 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]
timeFrame: 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)
measure: 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]
timeFrame: 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)
measure: PF-04136309 Minimum Observed Plasma Concentration (Cmin) for Cycle 1 Day 15 in the 750 mg BID Group [Phase 1b]
timeFrame: 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)
measure: PF-04136309 Minimum Observed Plasma Concentration (Cmin) for Cycle 1 Day 15 in the 500 mg BID Group [Phase 1b]
timeFrame: 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)
measure: PF-04136309 Apparent Oral Clearance (CL/F) for Cycle 1 Day 15 in the 750 mg BID Group [Phase 1b]
timeFrame: 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)
measure: PF-04136309 Apparent Oral Clearance (CL/F) for Cycle 1 Day 15 in the 500 mg BID Group [Phase 1b]
timeFrame: 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)
measure: PF-04136309 Plasma Decay Half-Life (t1/2) for Cycle 1 Day 15 [Phase 1b]
timeFrame: 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)
measure: PF-04136309 Apparent Volume of Distribution (Vz/F) for Cycle 1 Day 15 [Phase 1b]
timeFrame: 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)
measure: Ex Vivo Inhibition of Chemokine Ligand 2 (CCL2)-Induced Extracellular Signal Regulated Kinase (ERK) Phosphorylation in the Peripheral Blood [Phase 1b]
timeFrame: 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
measure: Number of Participants With Overall Survival (OS) [Phase 2]
timeFrame: Up to approximately 13.5 months
measure: Number of Participants With Treatment-Emergent Adverse Events (AEs) [Phase 2]
timeFrame: Up to approximately 1 year
measure: Number of Participants With Laboratory Abnormalities by Severity [Phase 2]
timeFrame: Up to approximately 1 year
measure: Objective Response Rate (ORR) [Phase 2]
timeFrame: Up to approximately 1 year
measure: Duration of Objective Response (DR) [Phase 2]
timeFrame: Up to approximately 1 year
measure: Time to Progression (TTP) With the Double Combination PF-04136309 and Gemcitabine (Maintenance Therapy) After Interruption of Nab-paclitaxel [Phase 2]
timeFrame: Up to approximately 1 year
measure: Trough PF-04136309 Concentrations [Phase 2]
timeFrame: 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
measure: Change From Baseline in Pharmacodynamic (PD) Markers in Metastatic Tumors and Bone Marrow [Phase 2]
timeFrame: Baseline, Cycle 1 Day 28 or Cycle 2 Day 28; EOT visit (optional) for CNB
measure: Number of Participants With Peripheral Neurological Adverse Events [Phase 2]
timeFrame: Up to approximately 1 year
Other outcomes:
measure: Objective Response Rate (ORR) [Phase 1b]
timeFrame: 1 year
Locations:
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Rochester
country: United States
facility: University of Rochester Cancer Center Pharmacy
state: New York
city: Rochester
country: United States
facility: University of Rochester Medical Center
state: New York
city: Clinton
country: United States
facility: Sampson Regional Medical Center
state: North Carolina
city: Clinton
country: United States
facility: Southeastern Medical Oncology Center
state: North Carolina
city: Goldsboro
country: United States
facility: Southeastern Medical Oncology Center
state: North Carolina
city: Goldsboro
country: United States
facility: Wayne Memorial Hospital
state: North Carolina
city: Jacksonville
country: United States
facility: Onslow Memorial Hospital
state: North Carolina
city: Jacksonville
country: United States
facility: Southeastern Medical Oncology Center
state: North Carolina
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Charleston
country: United States
facility: MUSC Hollings Cancer Center
state: South Carolina
city: Mount Pleasant
country: United States
facility: MUSC Health East Cooper
state: South Carolina
city: North Charleston
country: United States
facility: MUSC Health North Charleston
state: South Carolina
Study officials:
affiliation: Pfizer
name: Pfizer CT.gov Call Center
role: STUDY_DIRECTOR
References:
citation: Noel M, O'Reilly EM, Wolpin BM, Ryan DP, Bullock AJ, Britten CD, Linehan DC, Belt BA, Gamelin EC, Ganguly B, Yin D, Joh T, Jacobs IA, Taylor CT, Lowery MA. Phase 1b study of a small molecule antagonist of human chemokine (C-C motif) receptor 2 (PF-04136309) in combination with nab-paclitaxel/gemcitabine in first-line treatment of metastatic pancreatic ductal adenocarcinoma. Invest New Drugs. 2020 Jun;38(3):800-811. doi: 10.1007/s10637-019-00830-3. Epub 2019 Jul 12.