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Azacitidine and Pembrolizumab in Pancreatic Cancer

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03264404
Recruitment Status : Recruiting
First Posted : August 29, 2017
Last Update Posted : October 3, 2019
Information provided by (Responsible Party):
Rachael A Safyan, MD, Columbia University

Tracking Information
First Submitted Date  ICMJE August 22, 2017
First Posted Date  ICMJE August 29, 2017
Last Update Posted Date October 3, 2019
Actual Study Start Date  ICMJE October 1, 2017
Estimated Primary Completion Date March 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 28, 2017)
Progression-Free Survival (PFS) [ Time Frame: 24 months ]
PFS is defined as the time from the first day of trial treatment to the first documented disease progression per RECIST 1.1 or death due to any cause, whichever occurs first.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03264404 on Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: August 28, 2017)
  • Objective Response Rate (ORR) [ Time Frame: 24 months ]
    ORR is defined as the proportion of the subjects in the analysis population who have a complete response (CR) or partial response (PR). Responses are based on assessments per RECIST 1.1.
  • Duration of Response (DOR) [ Time Frame: 24 months ]
    For subjects who demonstrate CR or PR, based on assessments per RECIST 1.1, DOR is defined as the time from first documented evidence of CR or PR until disease progression or death due to any cause, whichever occurs first.
  • Disease Control Rate (DCR) [ Time Frame: 24 months ]
    DCR is defined as the percentage of subjects who have achieved CR, PR, or stable disease (SD) based on assessments per RECIST 1.1.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title  ICMJE Azacitidine and Pembrolizumab in Pancreatic Cancer
Official Title  ICMJE Phase II Open-Label, Single-Center Study Evaluating Safety and Efficacy of Pembrolizumab Following Induction With the Hypomethylating Agent Azacitidine in Patients With Advanced Pancreatic Cancer After Failure of First-Line Therapy
Brief Summary

The purpose of this study is to determine the effectiveness of combining immune therapy, pembrolizumab, with a hypomethylating agent, azacitidine, for pancreatic cancer. People who have advanced pancreatic cancer with disease progression on first-line therapy are usually treated with a second chemotherapy regimen. However, there is no single accepted chemotherapy regimen and national guidelines recommend chemotherapy or clinical trial participation. In this study, all study subjects will receive a combination of immune therapy (every 3 weeks) and a hypomethylating agent (every 4 weeks).To date, studies have shown that combining a hypomethylating agent with chemotherapy or immune therapy may benefit patients across different solid tumor types including pancreatic cancer. Preclinical data in a mouse model of pancreatic cancer demonstrates improvement in survival with the combination of a hypomethylating agent and immune therapy. However, the use of single agent hypomethylating agent or immune therapy has not been shown to be effective in patients with pancreatic cancer. The one exception, to date, is the use of immune therapy in those individuals with a particular genetic feature known as mismatch repair deficiency and microsatellite instability. The combination of immune therapy and a hypomethylating agent has not been studied in human subjects and is not approved by the FDA for use in pancreatic cancer.

This is a non-randomized, single-center, open-label trial of pembrolizumab and azacitidine in subjects with locally advanced or metastatic pancreatic adenocarcinoma. Approximately 31 individuals will be asked to participate in this study.

Primary objective: To evaluate the progression-free survival per RECIST 1.1.

Secondary Objectives:

  1. Safety Objective: To determine the safety and tolerability of induction therapy with azacitidine followed by pembrolizumab in advanced pancreatic cancer.
  2. To evaluate the objective response rate (ORR), duration of response (DOR), disease control rate (DCR), and time to progression (TTP) per RECIST 1.1, and overall survival (OS).
Detailed Description

Pancreatic ductal adenocarcinoma (PDA) has the worst prognosis of any major malignancy in the United States and, unlike other common cancers, annual deaths from PDA are rising. Despite recent advances, cytotoxic chemotherapy for PDA has been disappointing. Even among the small subset of patients who are suitable for surgical resection at the time of diagnosis, complete resection is followed by recurrence in majority of patients without further systemic therapy. Thus all PDA patients require systemic chemotherapy and more effective regimens are urgently needed.

Combination chemotherapy is effective in controlling disease and prolonging survival in patients with advanced pancreatic cancer. Despite recent successful phase 3 studies in the first-line setting, there is no defined second-line treatment for patients who experience disease progression following first-line therapy. Consensus guidelines (such as the National Comprehensive Cancer Network (NCCN) guidelines) recommend clinical trial participation in this setting.

The investigators' pre-clinical data suggests that decitabine treatment in the KPC model of pancreatic cancer leads to a significant up-regulation of interferon-related genes and a polarization of the infiltrating immune cells. Based on these results, the investigators have evaluated the effect of single agent decitabine or anti-PD1H (a homologue of PD1 with very similar function and expression pattern) compared to combination therapy (treatment with decitabine followed by PD1H blockade). The investigators' preliminary results showed minimal effect of either agent alone on tumor growth but marked decrease in tumor progression in the combination arm. These results form the foundation of this phase II study.

This study will treat patients with the combination of azacitidine and pembrolizumab. A direct comparison between azacitidine and decitabine in terms of efficacy within a controlled clinical trial has not been performed thus far. In randomized myelodysplastic syndrome (MDS) trials, the remission rates were similar for azacitidine and decitabine but the overall survival in the experimental arm was significantly shorter in the decitabine trial compared to the azacitidine trial. A primary reason to utilize azacitidine in this setting is our desire to amply reduced dose therapy with the goal of maintaining subjects on therapy Low-dose azacitidine is being tested in phase I/II clinical trials for advanced solid tumors—mainly colorectal cancer, small-cell lung carcinomas, ovarian cancer, and breast cancer.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Pancreas Cancer
Intervention  ICMJE
  • Drug: Pembrolizumab
    Pembrolizumab 200 mg IV every 3 weeks until progression
    Other Name: Keytruda
  • Drug: Azacitidine
    50 mg/m2 subcutaneous daily for 5 days every 28 days
    Other Name: Vidaza
Study Arms  ICMJE Experimental: Pembrolizumab
Patients with advanced pancreatic cancer will receive pembrolizumab with the hypomethylating agent azacitidine.
  • Drug: Pembrolizumab
  • Drug: Azacitidine
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: August 28, 2017)
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE September 2020
Estimated Primary Completion Date March 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Be willing and able to provide written informed consent for the trial.
  • Age ≥18 years of age on day of signing informed consent.
  • Have confirmed diagnosis of pancreatic ductal adenocarcinoma
  • Have a predicted life expectancy of greater than 3 months.
  • Have measurable disease based on RECIST 1.1.
  • Have a performance status of 0 or 1 using the Eastern Cooperative Oncology Group (ECOG) Performance Scale within 3 days of first dose of study drug.
  • Have documented radiographic progression to or documented intolerance of first line systemic chemotherapy which included either gemcitabine or Fluorouracil (5-FU) based regimen (including capecitabine).
  • Subjects who have documented disease recurrence within 6 months of completing neoadjuvant or adjuvant chemotherapy for limited disease will be eligible for study. Subjects who recur greater than 6 months after completing adjuvant or neoadjuvant chemotherapy will not be eligible unless they receive additional chemotherapy for advanced disease.

Exclusion Criteria:

  • Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy, or herbal/complementary oral or IV medicine within 2 weeks of the first dose of treatment.
  • Has received chemotherapy or radiotherapy within 14 days of first dose of study medication.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Lisa Olmos, RN (212) 342-5162
Listed Location Countries  ICMJE United States
Removed Location Countries  
Administrative Information
NCT Number  ICMJE NCT03264404
Other Study ID Numbers  ICMJE AAAR3554
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Rachael A Safyan, MD, Columbia University
Study Sponsor  ICMJE Rachael A Safyan, MD
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Rachael A. Safyan, MD Columbia University
PRS Account Columbia University
Verification Date October 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP