Clinical Trials /

Rintatolimod and Pembrolizumab for the Treatment of Refractory Metastatic or Unresectable Colorectal Cancer

NCT04119830

Description:

This phase IIa trial studies how well rintatolimod and pembrolizumab works in treating patients with colorectal cancer that does not respond to treatment (refractory), has spread to other places in the body (metastatic), or otherwise cannot be removed by surgery (unresectable). Rintatolimod is an immuno-oncology agent that can stimulate the immune system. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving rintatolimod and pembrolizumab together may work better than standard of care in treating patients with colorectal cancer.

Related Conditions:
  • Colorectal Adenocarcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Rintatolimod and Pembrolizumab for the Treatment of Refractory Metastatic or Unresectable Colorectal Cancer
  • Official Title: A Phase IIa Study of Rintatolimod Plus Pembrolizumab in Refractory Metastatic Colorectal Cancer

Clinical Trial IDs

  • ORG STUDY ID: I 74118
  • SECONDARY ID: NCI-2019-06440
  • SECONDARY ID: I 74118
  • SECONDARY ID: P30CA016056
  • NCT ID: NCT04119830

Conditions

  • Metastatic Colorectal Adenocarcinoma
  • Microsatellite Stable
  • Mismatch Repair Proficient
  • Refractory Colorectal Adenocarcinoma
  • Stage III Colorectal Cancer AJCC v8
  • Stage IIIA Colorectal Cancer AJCC v8
  • Stage IIIB Colorectal Cancer AJCC v8
  • Stage IIIC Colorectal Cancer AJCC v8
  • Stage IV Colorectal Cancer AJCC v8
  • Stage IVA Colorectal Cancer AJCC v8
  • Stage IVB Colorectal Cancer AJCC v8
  • Stage IVC Colorectal Cancer AJCC v8
  • Unresectable Colorectal Carcinoma

Interventions

DrugSynonymsArms
PembrolizumabKeytruda, Lambrolizumab, MK-3475, SCH 900475Treatment (rintatolimod, pembrolizumab)
RintatolimodAmpligen, AtvogenTreatment (rintatolimod, pembrolizumab)

Purpose

This phase IIa trial studies how well rintatolimod and pembrolizumab works in treating patients with colorectal cancer that does not respond to treatment (refractory), has spread to other places in the body (metastatic), or otherwise cannot be removed by surgery (unresectable). Drugs used in chemotherapy, such as rintatolimod, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving rintatolimod and pembrolizumab together may work better than standard of care in treating patients with colorectal cancer.

Detailed Description

      PRIMARY OBJECTIVE:

      I. Determine the objective response rate of patients with metastatic colorectal cancer (mCRC)
      treated with rintatolimod + pembrolizumab.

      SECONDARY OBJECTIVES:

      I. Establish the adverse event profile of combining rintatolimod and pembrolizumab.

      II. Estimate the median progression free survival and overall survival of patients with mCRC
      treated with rintatolimod and pembrolizumab.

      III. Determine the immune objective response rate of patients with mCRC treated with
      rintatolimod + pembrolizumab.

      EXPLORATORY OBJECTIVES:

      I. Assess modulation of the levels of CD8alpha expression and cytotoxic T-lymphocyte (CTL)
      density pre- and post-therapy.

      II. Assess chemokine levels in the tumor microenvironment and peripheral blood, including
      effector T cell (Teff)-attracting and regulatory T cell (Treg)-favoring chemokines.

      III. Characterize the fecal microbiotic profile and correlate those results with antitumor
      immune responses.

      OUTLINE:

      Patients receive rintatolimod intravenously (IV) over 30 minutes on days 1-3 and
      pembrolizumab IV over 30 minutes on day 3. Treatment repeats every 21 days for up to 3 cycles
      in the absence of disease progression or unacceptable toxicity. Beginning in cycle 4,
      patients receive rintatolimod IV over 30 minutes and pembrolizumab IV over 30 minutes on day
      1. Cycles repeat every 21 days for up to 24 months from the first dose in the absence of
      disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up at 30 and 90 days, and every 6
      months for up to 2 years.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (rintatolimod, pembrolizumab)ExperimentalPatients receive rintatolimod IV over 30 minutes on days 1-3 and pembrolizumab IV over 30 minutes on day 3. Treatment repeats every 21 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Beginning in cycle 4, patients receive rintatolimod IV over 30 minutes and pembrolizumab IV over 30 minutes on day 1. Cycles repeat every 21 days for up to 24 months from the first dose in the absence of disease progression or unacceptable toxicity.
  • Pembrolizumab
  • Rintatolimod

Eligibility Criteria

        Inclusion Criteria:

          -  Biopsy proven colorectal adenocarcinoma which is metastatic or otherwise unresectable

          -  Microsatellite stable/mismatch-repair proficient (by immunohistochemistry [IHC] and/or
             polymerase chain reaction [PCR])

          -  Progression following: a fluoropyrimidine, oxaliplatin, irinotecan, and anti-EGFR
             targeted therapy (if anti-EGFR therapy is appropriate), bevacizumab (if appropriate)

               -  NOTE: Patients who could not tolerate standard agents because of unacceptable,
                  but reversible, toxicity necessitating their discontinuation will be allowed to
                  participate

          -  Amenable to undergoing serial tumor biopsy (x 2). NOTE: patients with inaccessible
             lesions, where the investigator deems biopsy to be unsafe or where biopsy is otherwise
             contraindicated, are still eligible to enroll, with review and approval of the
             principal investigator (PI)

          -  Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

          -  Absolute neutrophil (ANC) count >= 1500/uL

          -  Platelets >= 100,000/uL

          -  Hemoglobin >= 9 g/dL

          -  Serum creatinine =< 1.5 X upper limit of normal (ULN) or measured or calculated
             creatinine clearance by Cockcroft Gault Equation >= 30 ml/min for subjects with
             creatinine levels > 1.5 x ULN

          -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
             [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
             =< 2.5 x ULN or (=< 5 x ULN if the patient has liver metastases)

          -  Bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN for participants with total
             bilirubin levels > 1.5 x ULN

          -  International normalized ratio (INR) or prothrombin time (PT): =< 1.5 unless
             participant is receiving anticoagulant therapy as long as PT or partial thromboplastin
             time (PTT) is within therapeutic range of intended use of anticoagulants

          -  Activated partial thromboplastin time (aPTT): =< 1.5 x ULN unless participant is
             receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of
             intended use of anticoagulants

          -  Have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
             criteria present

          -  Female participants of childbearing potential are to have a negative serum pregnancy
             test

          -  A female participant is eligible to participate if she is not pregnant, not
             breastfeeding, and at least one of the following conditions applies:

               -  Not a woman of childbearing potential (WOCBP) OR

               -  A WOCBP who agrees to follow the contraceptive guidance during the treatment
                  period and for at least 120 days after the last dose of study treatment

          -  A male participant must agree to use an adequate method of contraception during the
             treatment period and for at least 120 days after the last dose of study treatment and
             refrain from donating sperm during this period

          -  Participant or legal representative must understand the investigational nature of this
             study and sign an Independent Ethics Committee/Institutional Review Board approved
             written informed consent form prior to receiving any study related procedure

        Exclusion Criteria:

          -  Has received prior systemic anti-cancer therapy including investigational agents
             within 4 weeks prior to start of study treatment

          -  Has received a live vaccine within 30 days prior to the first dose of study drug.
             Examples of live vaccines include, but are not limited to, the following: measles,
             mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus
             Calmette?Guerin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection
             are generally killed virus vaccines and are allowed; however, intranasal influenza
             vaccines (e.g., FluMist) are live attenuated vaccines and are not allowed

          -  Has received prior radiotherapy within 2 weeks of start of study treatment.
             Participants must have recovered from all radiation-related toxicities, not require
             corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted
             for palliative radiation (=< 2 weeks of radiotherapy) to non-central nervous system
             (CNS) disease

          -  Is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of
             prednisone equivalent) or any other form of systemic immunosuppressive therapy within
             7 days prior to the first dose of study drug

          -  Has a known additional malignancy that is progressing or in the opinion of the
             investigator is likely to interfere with properly assessing treatment efficacy. Note:
             Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the
             skin, and carcinoma in situ (e.g. breast carcinoma, cervical cancer in situ) that have
             undergone potentially curative therapy are not excluded

          -  Has known active CNS metastases and/or carcinomatous meningitis. Participants with
             previously treated brain metastases may participate provided they are radiologically
             stable, i.e., without evidence of progression for at least 4 weeks by repeat imaging
             (note that the repeat imaging should be performed during study screening), clinically
             stable and without requirement of steroid treatment for at least 14 days prior to
             first dose of study treatment

          -  Has a history of (non-infectious) pneumonitis that required steroids or has current
             pneumonitis

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, unstable angina pectoris, unstable
             cardiac arrhythmia, or psychiatric illness/social situations that would limit
             compliance with study requirements

          -  Have a severe hypersensitivity (>= grade 3) to pembrolizumab and/or any of its
             excipients

          -  Has previously received rintatolimod, poly-ICLC or derivatives

          -  Has active autoimmune disease that has required systemic treatment in the past 2 years
             (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive
             drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid
             replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
             form of systemic treatment

          -  Woman of childbearing potential who has a positive urine pregnancy test within 72
             hours prior to start of study treatment. If the urine test is positive or cannot be
             confirmed as negative, a serum pregnancy test will be required

          -  Has an active infection requiring systemic therapy

          -  Has a known history of human immunodeficiency virus (HIV), unless on highly active
             antiretroviral therapy (HAART) with undetectable viral load

          -  Has a known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg]
             reactive) or known active hepatitis C virus (defined as hepatitis C virus [HCV]
             ribonucleic acid [RNA] [qualitative] is detected) infection

          -  Pregnant or nursing female participants

          -  Unwilling or unable to follow protocol requirements

          -  Any condition which in the investigator?s opinion deems the participant an unsuitable
             candidate to receive study drug
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective response rate
Time Frame:At 6 months following completion of enrollment (at 24 months)
Safety Issue:
Description:Determined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and estimated using a 90% confidence interval obtained using Jeffrey?s prior method.

Secondary Outcome Measures

Measure:Incidence of adverse events
Time Frame:Up to 2 years
Safety Issue:
Description:Toxicities and adverse events (according to Common Terminology Criteria in Adverse Events [CTCAE] version 5.0) will be summarized by attribution and grade using frequencies and relative frequencies.
Measure:Median progression free survival
Time Frame:From the time of first dosing of study treatment combination to documented disease progression by RECIST 1.1, assessed up to 2 years
Safety Issue:
Description:Will be summarized using standard Kaplan-Meier methods; where estimates of median survival and 6/12-month survival rates will be obtained with 95% confidence intervals.
Measure:Overall survival
Time Frame:From the time of first dosing of study treatment combination to time of death or initiation of a new therapy, whichever occurs first, assessed up to 2 years
Safety Issue:
Description:Will be summarized using standard Kaplan-Meier methods; where estimates of median survival and 6/12-month survival rates will be obtained with 95% confidence intervals.
Measure:Objective response rate
Time Frame:Up to 2 years
Safety Issue:
Description:Determined by immune-modified (i)RECIST and estimated using a 90% confidence interval obtained using Jeffrey?s prior method.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Roswell Park Cancer Institute

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