Clinical Trials /

Pembrolizumab + Poly-ICLC in MRP Colon Cancer

NCT02834052

Description:

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.

Related Conditions:
  • Colon Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Pembrolizumab + Poly-ICLC in MRP Colon Cancer
  • Official Title: A Phase I/II Trial of Pembrolizumab (MK-3475) and Poly-ICLC in Patients With Metastatic Mismatch Repair-proficient (MRP) Colon Cancer

Clinical Trial IDs

  • ORG STUDY ID: GCC-16047
  • NCT ID: NCT02834052

Conditions

  • Metastatic Colon Cancer
  • Solid Tumor

Interventions

DrugSynonymsArms
pembrolizumabMK-3475, KeytrudaPhase 1
Poly-ICLCpolyinosinic-polycytidylic acid-polylysine-carboxymethylcellulose, HiltonolPhase 1

Purpose

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.

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.
    

Trial Arms

NameTypeDescriptionInterventions
Phase 1ExperimentalThis "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).
  • pembrolizumab
  • Poly-ICLC
Phase 2ExperimentalIn 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).
  • pembrolizumab
  • Poly-ICLC

Eligibility 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Phase 1: Determine the maximum tolerated dose of poly-ICLC that can be combined with pembrolizumab
Time Frame:12 months
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Determine the adverse event profile and dose limiting toxicities of the combination of pembrolizumab and poly-ICLC
Time Frame:12 months
Safety Issue:
Description:The adverse event profile will be presented by dose level of the combination treatment for the phase I portion
Measure: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)
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description: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.
Measure: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)
Safety Issue:
Description: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.
Measure: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)
Safety Issue:
Description: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.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Asha Nayak

Trial Keywords

  • Immunotherapy
  • Anti-programmed death 1 (PD-1) inhibitor
  • Immunostimulant
  • monoclonal antibody
  • TLR3 agonist
  • Immunologic factors

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