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Pembrolizumab + Poly-ICLC in MRP Colon Cancer

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ClinicalTrials.gov Identifier: NCT02834052
Recruitment Status : Recruiting
First Posted : July 15, 2016
Last Update Posted : March 22, 2018
Sponsor:
Collaborators:
Oncovir, Inc.
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Asha Nayak, Augusta University

Brief Summary:
The main purpose of this study is to determine the dose of poly-ICLC that is safe and tolerable when it is combined with pembrolizumab in patients with colon cancer. This study will also evaluate how the combination of pembrolizumab and poly-ICLC activates the immune system in the patient's blood and inside the tumor; how it affects the size and number of tumor(s) in each patient; and how effective the combination is in patients with colon cancer that is unlikely to respond to pembrolizumab alone.

Condition or disease Intervention/treatment Phase
Metastatic Colon Cancer Solid Tumor Drug: pembrolizumab Drug: Poly-ICLC Phase 1 Phase 2

Detailed Description:

Mismatch repair genes normally serve to fix the small glitches that occur when DNA is copied as cells divide. In 1993, researchers discovered that mutations in human mismatch repair genes play a key role in the development of certain forms of colorectal cancer; individuals who are deficient in these mismatch repair genes are at high risk for colorectal cancer. Accumulating evidence has shown that immunotherapy may be most effective against these cancers.

Programmed cell death protein 1, also known as PD-1, functions as an immune checkpoint, down-regulating the immune system by preventing the activation of T-cells, which in turn reduces autoimmunity and promotes self-tolerance. A new class of immunotherapy drugs that block PD-1, the PD-1 inhibitors, activate the immune system to attack tumors and are therefore used with varying success to treat some types of cancer.

Current clinical trials are showing that patients whose tumors are mismatch repair deficient are more likely to respond to immune-boosting anti-PD-1 drugs—such as pembrolizumab—than those with tumors proficient in mismatch repair. The idea is that the greater the number of DNA glitches in a tumor cell, the more abnormal proteins it will produce—and the more abnormal proteins that are generated, the greater the odds that the body's immune cells will regard the tumor cells as "foreign" and target them for destruction. Thus far, PD-1 inhibitors have shown great promise for mismatch repair deficient cancer patients, but not for mismatch repair proficient (MRP) cancer patients.

In this clinical trial, the investigators hypothesize that treating MRP colon cancer patients with immunostimulating agent poly-ICLC will generate an inflammatory response, increasing epitope recognition and development of tumor reactive T-cells at the tumor site. However, interferon alpha and gamma produced by the poly-ICLC will increase PD-L1 expression and limit new T-cell development. Thus, PD1 blockade will increase the effectiveness of treatment with pembrolizumab.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 42 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I/II Trial of Pembrolizumab (MK-3475) and Poly-ICLC in Patients With Metastatic Mismatch Repair-proficient (MRP) Colon Cancer
Actual Study Start Date : January 10, 2018
Estimated Primary Completion Date : January 2020
Estimated Study Completion Date : January 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Phase 1

This "Run In" phase is aimed to determine if poly-ICLC can be safely combined with standard dosages of pembrolizumab:

i. Pembrolizumab will be administered 200 mg intravenously (IV) every 3 weeks (q3w)

ii. Poly-ICLC will be administered intramuscularly (IM) twice weekly at one of two dose levels: 1 mg or 2 mg

Each dose level will enroll 3-6 participants, up to 12 participants total, depending on the occurrence of dose limiting toxicities (DLT) at each dosing level.

Participants may receive treatment for 1 year (~17 cycles).

Drug: pembrolizumab
200mg pembrolizumab will be given intravenously on Day 1 of each 3-week cycle
Other Names:
  • MK-3475
  • Keytruda

Drug: Poly-ICLC

The maximum tolerated dose of Poly ICLC will be given twice weekly, in each 3-week cycle:

Week 1, Days 1 and 4

Week 2, Days 8 and 11

Week 3, Days 15 and 18

Other Names:
  • polyinosinic-polycytidylic acid-polylysine-carboxymethylcellulose
  • Hiltonol

Experimental: Phase 2

In Phase 2, all participants will receive the standard pembrolizumab dose (200 mg IV q3w) in addition to the maximum tolerated dose of poly-ICLC (either 1 mg or 2 mg), as determined by the Phase 1 arm.

Up to 30 participants will be treated in Phase 2. Participants may receive treatment for 1 year (~17 cycles).

Drug: pembrolizumab
200mg pembrolizumab will be given intravenously on Day 1 of each 3-week cycle
Other Names:
  • MK-3475
  • Keytruda

Drug: Poly-ICLC

The maximum tolerated dose of Poly ICLC will be given twice weekly, in each 3-week cycle:

Week 1, Days 1 and 4

Week 2, Days 8 and 11

Week 3, Days 15 and 18

Other Names:
  • polyinosinic-polycytidylic acid-polylysine-carboxymethylcellulose
  • Hiltonol




Primary Outcome Measures :
  1. Phase 1: Determine the maximum tolerated dose of poly-ICLC that can be combined with pembrolizumab [ Time Frame: 12 months ]

    A minimum of 3 participants will be treated at dose level 1 (1mg).

    • If 0 out of 3 participants experience dose limiting toxicities (DLT), then dose escalation will proceed to dose level 2 (2mg).
    • If 1 out of 3 participants experience DLT, a cohort of additional 3 participants will be assigned to the same dose level (1mg).
    • If 2 or more participants of 3 (or 6) experience DLT at dose level 1, then enrollment of participants will be stopped.

  2. Phase 1 and 2: Determine the response rate of metastatic MRP colon cancer (that has progressed following two lines of therapy in the metastatic setting) to the combination of pembrolizumab and poly-ICLC [ Time Frame: From baseline to disease progression (Expected 12-24 months) ]
    Response rate will be determined using RECIST 1.1 criteria, calculated as the number of participants with complete response (CR) or partial response (PR)


Secondary Outcome Measures :
  1. Determine the adverse event profile and dose limiting toxicities of the combination of pembrolizumab and poly-ICLC [ Time Frame: 12 months ]
    The adverse event profile will be presented by dose level of the combination treatment for the phase I portion

  2. Determine the progression free survival rate of recurrent metastatic MRP colon cancer to the combination of pembrolizumab and poly-ICLC [ Time Frame: From baseline to disease progression (up to 24 months) ]
    The progression free survival rate for the combination of pembrolizumab and poly-ICLC administered at the Recommended Phase 2 Dose (RP2D) will be estimated, including the correspondent 95% confidence interval.

  3. Determine the 20-week progression free survival rate of recurrent metastatic MRP colon cancer to the combination of pembrolizumab and poly-ICLC [ Time Frame: 20 weeks ]
    The 20-week progression free survival rate for the combination of pembrolizumab and poly-ICLC administered at the Recommended Phase 2 Dose (RP2D) will be estimated along with the correspondent 95% confidence interval.

  4. Determine the overall survival rate for recurrent metastatic MRP colon cancer response to the combination of pembrolizumab and poly-ICLC [ Time Frame: From baseline to disease progression (up to 24 months) ]
    The overall survival rate of response to the combination of pembrolizumab and poly-ICLC administered at the Recommended Phase 2 Dose (RP2D) will be estimated along with the correspondent 95% confidence interval.

  5. Determine the duration of response of recurrent metastatic MRP colon cancer to the combination of pembrolizumab and poly-ICLC [ Time Frame: From baseline to disease progression (up to 24 months) ]
    The duration of response to the combination of pembrolizumab and poly-ICLC administered at the Recommended Phase 2 Dose (RP2D) will be estimated along with the correspondent 95% confidence interval.



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

Diagnosis/Condition for Entry into the Trial Phase 1 - Presence of histologically confirmed malignancy that has progressed following at least one therapy and able to be visualized on imaging. Measurable disease is not required. Patients with known targetable mutations must have progressive disease on the appropriated targeted drug therapy.

Phase 2 - Presence of MRP colon cancer that has progressed following at least two lines of therapy. Ten patients will be included who have disease that can be biopsied pre- and post-therapy.

Inclusion Criteria:

  • Be willing and able to provide written informed consent for the trial
  • Have measurable disease based on RECIST 1.1 (Phase 2)
  • Be willing to provide tissue from a newly obtained core or excisional biopsy of a tumor lesion
  • Have a performance status of 0 or 1 on the ECOG Performance Scale
  • Have adequate organ function, according to screening labs performed within 10 days of treatment initiation
  • Subjects of childbearing potential must be willing to use an adequate method of contraception for the course of the study through 120 days after the last dose of study medication

Exclusion Criteria:

  • Currently participating/previously participated in a therapeutic study and received study therapy or used an investigational device within 4 weeks of the first dose of treatment
  • Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment
  • Has a known history of active TB (Bacillus Tuberculosis)
  • Hypersensitivity to pembrolizumab or any of its excipients
  • Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer
  • Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent
  • Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies), active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
  • Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis.
  • Has active autoimmune disease that has required systemic treatment in the past 2 years

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 ClinicalTrials.gov identifier (NCT number): NCT02834052


Contacts
Contact: Carrie McAteer, BA, CCRC 706-721-1409 mmcateer@augusta.edu
Contact: GCC Clinical Trials Office Cancer_Center_Trials@augusta.edu

Locations
United States, Georgia
Georgia Cancer Center at Augusta University Recruiting
Augusta, Georgia, United States, 30912
Contact: Sandy Wall, RN, ADN    706-721-4430    swall@augusta.edu   
Principal Investigator: Asha Nayak, MD         
Sub-Investigator: Sharad Ghamande, MD         
Sponsors and Collaborators
Asha Nayak
Oncovir, Inc.
Merck Sharp & Dohme Corp.
Investigators
Principal Investigator: Asha Nayak, MD Georgia Cancer Center at Augusta University
Study Director: Sharad Ghamande, MD Georgia Cancer Center at Augusta University

Responsible Party: Asha Nayak, Director, Inpatient Oncology Service, Augusta University
ClinicalTrials.gov Identifier: NCT02834052     History of Changes
Other Study ID Numbers: GCC-16047
First Posted: July 15, 2016    Key Record Dates
Last Update Posted: March 22, 2018
Last Verified: March 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Asha Nayak, Augusta University:
Immunotherapy
Anti-programmed death 1 (PD-1) inhibitor
Immunostimulant
monoclonal antibody
TLR3 agonist
Immunologic factors

Additional relevant MeSH terms:
Colonic Neoplasms
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Pembrolizumab
Poly ICLC
Poly I-C
Carboxymethylcellulose Sodium
Antineoplastic Agents
Interferon Inducers
Immunologic Factors
Physiological Effects of Drugs
Laxatives
Gastrointestinal Agents
Antiviral Agents
Anti-Infective Agents