Description:
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).
Title
- Brief Title: Azacitidine and Pembrolizumab in Pancreatic Cancer
- 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
Clinical Trial IDs
- ORG STUDY ID:
AAAR3554
- NCT ID:
NCT03264404
Conditions
Interventions
| Drug | Synonyms | Arms |
|---|
| Pembrolizumab | Keytruda | Pembrolizumab |
| Azacitidine | Vidaza | Pembrolizumab |
Purpose
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.
Trial Arms
| Name | Type | Description | Interventions |
|---|
| Pembrolizumab | Experimental | Patients with advanced pancreatic cancer will receive pembrolizumab with the hypomethylating agent azacitidine. | |
Eligibility Criteria
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.
| Maximum Eligible Age: | N/A |
| Minimum Eligible Age: | 18 Years |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
Primary Outcome Measures
| Measure: | Progression-Free Survival (PFS) |
| Time Frame: | 24 months |
| Safety Issue: | |
| Description: | 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
| Measure: | Objective Response Rate (ORR) |
| Time Frame: | 24 months |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Duration of Response (DOR) |
| Time Frame: | 24 months |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Disease Control Rate (DCR) |
| Time Frame: | 24 months |
| Safety Issue: | |
| Description: | DCR is defined as the percentage of subjects who have achieved CR, PR, or stable disease (SD) based on assessments per RECIST 1.1. |
Details
| Phase: | Phase 2 |
| Primary Purpose: | Interventional |
| Overall Status: | Recruiting |
| Lead Sponsor: | Rachael A Safyan, MD |
Trial Keywords
- Pancreas
- pembrolizumab
- azacitidine
- metastatic pancreatic cancer
- first-line
Last Updated
February 9, 2021
