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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

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).

Condition or disease Intervention/treatment Phase
Pancreas Cancer Drug: Pembrolizumab Drug: Azacitidine Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 31 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : October 1, 2017
Estimated Primary Completion Date : March 2020
Estimated Study Completion Date : September 2020

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: Pembrolizumab
Patients with advanced pancreatic cancer will receive pembrolizumab with the hypomethylating agent azacitidine.
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

Primary Outcome Measures :
  1. 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.

Secondary Outcome Measures :
  1. 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.

  2. 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.

  3. 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.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03264404

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Contact: Lisa Olmos, RN (212) 342-5162

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United States, New York
Columbia University Irving Medical Center Recruiting
New York, New York, United States, 10032
Contact: Rachael A. Safyan, MD   
Principal Investigator: Rachael A. Safyan, MD         
Sponsors and Collaborators
Rachael A Safyan, MD
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Principal Investigator: Rachael A. Safyan, MD Columbia University
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Responsible Party: Rachael A Safyan, MD, Assistant Professor of Medicine, Columbia University Identifier: NCT03264404    
Other Study ID Numbers: AAAR3554
First Posted: August 29, 2017    Key Record Dates
Last Update Posted: October 3, 2019
Last Verified: October 2019

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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
Keywords provided by Rachael A Safyan, MD, Columbia University:
metastatic pancreatic cancer
Additional relevant MeSH terms:
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Pancreatic Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Endocrine Gland Neoplasms
Digestive System Diseases
Pancreatic Diseases
Endocrine System Diseases
Antineoplastic Agents, Immunological
Antineoplastic Agents
Antimetabolites, Antineoplastic
Molecular Mechanisms of Pharmacological Action
Enzyme Inhibitors