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

NCT02732938 | Terminated Phase 2 Results FDA Drug

• 2 other identifiers: A94210182015-003767-11
• Study Type: interventional
• Target: 22
• Locations: 1 country
• Sites: 18

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.

Conditions

Metastatic Pancreatic Ductal Adenocarcinoma

Keywords

CCR2i, nab-paclitaxel, Abraxane, gemcitabine, pancreas

Outcome Measures

Primary Outcomes (7)

• 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 Outcomes (22)

• 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)

• 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)

• 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)

• 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)

• 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)

Other Outcomes (1)

• Objective Response Rate (ORR) [Phase 1b]

  1 year

Study Arms (1)

PF-04136309 + Nab-p + Gem

EXPERIMENTAL

PF-04136309 oral dosing Nab-paclitaxel IV dosing Gemcitabine IV dosing

Drug: PF-04136309; Drug: Nab-paclitaxel; Drug: Gemcitabine

Interventions

PF-04136309 DRUG

PF-04136309 oral dosing

PF-04136309 + Nab-p + Gem

Nab-paclitaxel DRUG

Nab-paclitaxel IV dosing

Also known as: Abraxane

PF-04136309 + Nab-p + Gem

Gemcitabine DRUG

Gemcitabine IV dosing

Also known as: Gemzar

PF-04136309 + Nab-p + Gem

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Pfizer: lead

Study Sites (18)

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Brigham and Women's Hospital

Boston, Massachusetts, 02115, United States

Location

Beth Israel Deaconess Medical Center

Boston, Massachusetts, 02215, United States

Location

Dana Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10022, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

University of Rochester Cancer Center Pharmacy

Rochester, New York, 14642, United States

Location

University of Rochester Medical Center

Rochester, New York, 14642, United States

Location

Sampson Regional Medical Center

Clinton, North Carolina, 28328, United States

Location

Southeastern Medical Oncology Center

Clinton, North Carolina, 28328, United States

Location

Southeastern Medical Oncology Center

Goldsboro, North Carolina, 27534, United States

Location

Wayne Memorial Hospital

Goldsboro, North Carolina, 27534, United States

Location

Onslow Memorial Hospital

Jacksonville, North Carolina, 28546, United States

Location

Southeastern Medical Oncology Center

Jacksonville, North Carolina, 28546, United States

Location

Medical University of South Carolina

Charleston, South Carolina, 29425, United States

Location

MUSC Hollings Cancer Center

Charleston, South Carolina, 29425, United States

Location

MUSC Health East Cooper

Mt. Pleasant, South Carolina, 29464, United States

Location

MUSC Health North Charleston

North Charleston, South Carolina, 29406, United States

Location

Related Publications (1)

• 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.

  PMID: 31297636 DERIVED

Related Links

• To obtain contact information for a study center near you, click here.
• To obtain contact information for a study center near you, click here.

MeSH Terms

Interventions

PF-04136309; 130-nm albumin-bound paclitaxel; Albumin-Bound Paclitaxel; Gemcitabine

Intervention Hierarchy (Ancestors)

Paclitaxel; Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Diterpenes; Terpenes; Albumins; Proteins; Amino Acids, Peptides, and Proteins; Heterocyclic Compounds; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring

Limitations and Caveats

The study was terminated prematurely based on the company's change in prioritization for the portfolio and was not due to any safety concerns or regulatory interactions.

Results Point of Contact

• Title: Pfizer ClinicalTrials.gov Call Center
• Organization: Pfizer, Inc.

ClinicalTrials.gov_Inquiries@pfizer.com

1-800-718-1021

Study Officials

• Pfizer CT.gov Call Center

  Pfizer

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Masking: NONE
• Purpose: TREATMENT
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 29, 2016
• First Posted: April 11, 2016
• Study Start: May 4, 2016
• Primary Completion: September 15, 2017
• Study Completion: October 10, 2017
• Last Updated: February 4, 2019
• Results First Posted: February 4, 2019

Record last verified: 2018-12

Data Sharing

• IPD Sharing: Will share

Locations

US (18)