Clinical Trials /

Nivolumab+Ipilimumab+RT in MSS mCRC

NCT04575922

Description:

This research is being done to study the effects of the combination of ipilimumab, nivolumab, and radiation therapy in people with metastatic microsatellite stable colorectal cancer. This research study involves the following drugs and interventions: - Ipilimumab - Nivolumab - Radiation Therapy

Related Conditions:
  • Colorectal Adenocarcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Nivolumab+Ipilimumab+RT in MSS mCRC
  • Official Title: Nivolumab and Ipilimumab and Radiation Therapy in Metastatic, Microsatellite Stable Colorectal Cancer

Clinical Trial IDs

  • ORG STUDY ID: 20-256
  • NCT ID: NCT04575922

Conditions

  • Metastatic Microsatellite Stable Colorectal Cancer

Interventions

DrugSynonymsArms
NivolumabOpdivoNivolumab+Ipilimumab+Radiation Therapy (RT)
IpilimumabYervoyNivolumab+Ipilimumab+Radiation Therapy (RT)

Purpose

This research is being done to study the effects of the combination of ipilimumab, nivolumab, and radiation therapy in people with metastatic microsatellite stable colorectal cancer. This research study involves the following drugs and interventions: - Ipilimumab - Nivolumab - Radiation Therapy

Detailed Description

      This research study is a Phase II clinical trial. Phase II clinical trials test the safety
      and effectiveness of an investigational intervention to learn whether the intervention works
      in treating a specific disease. "Investigational" means that the intervention is being
      studied.

      The U.S. Food and Drug Administration (FDA) has not approved the combination of ipilimumab
      and nivolumab for metastatic microsatellite stable colorectal cancer but they have been
      approved for other uses.

      The FDA has not approved ipilimumab for metastatic microsatellite stable colorectal cancer,
      but it has been approved for other uses.

      The FDA has not approved nivolumab for metastatic microsatellite stable colorectal cancer,
      but it has been approved for other uses.

      Ipilimumab and Nivolumab are both genetically-engineered antibodies. An antibody is a protein
      that can attach to specific molecular targets. Ipilimumab and nivolumab work by activating
      the immune system, which can help to fight certain cancers. This trial explores whether
      radiation therapy may increase the benefit from immune activation with ipilimumab and
      nivolumab.

      The research study procedures include screening for eligibility, and study treatment
      including evaluations and follow up visits.

      Participants will be in this research study for as long as the study interventions are safe
      and beneficial. Participants will then be followed for up to 5 years.

      It is expected that about 30 people will take part in this research study.

      Bristol-Myers Squibb, a pharmaceutical company, is supporting this research study by
      providing funding for this study, including the two study drugs.
    

Trial Arms

NameTypeDescriptionInterventions
Nivolumab+Ipilimumab+Radiation Therapy (RT)ExperimentalStudy cycles are 6 weeks long, participants will receive: Cycle 1: Nivolumab every 2 weeks during cycle, Ipilimumab 1x on Day 1 of cycle, and Radiation Therapy every other weekday or 2 days for a total of 3 treatments during week 1 of Cycle 1 only. Cycles 2-4: Nivolumab every 2 weeks during each cycle, Ipilimumab 1x on Day 1 of each cycle Cycles 5-Disease Progression: Nivolumab every 2 weeks during each cycle
  • Nivolumab
  • Ipilimumab

Eligibility Criteria

        Inclusion Criteria:

          -  Participants must have histologically or cytologically confirmed adenocarcinoma of
             colorectal origin

          -  Age >18 years.

          -  ECOG performance status <1

          -  Life expectancy of greater than 3 months

          -  Participants must have normal organ and marrow function as defined in Table 1, all
             screening labs should be performed within 14 days of protocol registration.

               -  Table 1 Adequate Organ Function Laboratory Values:

                    -  System Laboratory Value

                         -  Hematological

                              -  Absolute neutrophil count (ANC) ≥1000 /mcL

                              -  White blood count (WBC) ≥2000 /mcL

                              -  Platelets ≥75,000 / mcL

                              -  Hemoglobin ≥7.5 g/dL

                         -  Renal

                              -  Serum creatinine OR Measured or calculated creatinine clearance
                                 (GFR can also be used in place of creatinine or CrCl)≤ Serum
                                 creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl)

                                   -  40 mL/min (if using the Cockcroft-Gault formula below):
                                      Female CrCl = (140 - age in years) x weight in kg x 0.85 72 x
                                      serum creatinine in mg/dL Male CrCl = (140 - age in years) x
                                      weight in kg x 1.00 72 x serum creatinine in mg/dL

                         -  Hepatic

                              -  Serum total bilirubin ≤ 1.5 X ULN (subjects with Gilbert Syndrome
                                 can have a total bilirubin <3 mg/dL

                              -  AST (SGOT) and ALT (SGPT) ≤ 3 X ULN OR ≤ 5 X ULN for subjects with
                                 liver metastases

                         -  Coagulation

                              -  International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5
                                 X ULN unless subject is receiving anticoagulant therapy as long as
                                 PT is within therapeutic range of intended use of anticoagulants

                              -  Activated Partial Thromboplastin Time (aPTT) ≤2.5 X ULN unless
                                 subject is receiving anticoagulant therapy as long as PTT is
                                 within therapeutic range of intended use of anticoagulants

                                   -  Creatinine clearance should be calculated per institutional
                                      standard.

          -  Women of childbearing potential (WOCBP) must use appropriate method(s) of
             contraception. WOCBP should use an adequate method to avoid pregnancy for 5 months (30
             days plus the time required for nivolumab to undergo five half-lives) after the last
             dose of investigational drug.

          -  Women of childbearing potential must have a negative serum or urine pregnancy test
             (minimum sensitivity 25 IU/L or equivalent units of HCG).

          -  Women must not be breastfeeding.

          -  Men who are sexually active with WOCBP must use any contraceptive method with a
             failure rate of less than 1% per year. Men receiving nivolumab and who are sexually
             active with WOCBP will be instructed to adhere to contraception for a period of 7
             months after the last dose of investigational product. Women who are not of
             childbearing potential, ie, who are postmenopausal or surgically sterile as well as
             azoospermic men do not require contraception.

          -  Ability to understand and the willingness to sign a written informed consent document.

          -  If applicable, stable dose of dexamethasone 2 mg or less (or equivalent dose of
             another steroid) for 7 days prior to initiation of treatment.

          -  One previously unirradiated measurable lesion amenable to radiotherapy 8 Gy x 3 and
             can meet dose constraints, and another unirradiated measurable lesion > 1 cm in size
             (>15 mm for nodal disease) outside the radiation field that can be used as measurable
             disease.

          -  Colorectal patients must have documentation of microsatellite status: MSS or pMMR.

        Immunohistochemistry (IHC) and/or PCR is acceptable.

          -  Colorectal patients must have received any prior combination of Fluorouracil (5FU),
             Irinotecan and Oxaliplatin, or have a contraindication/intolerance to receiving these
             agents.

        Patients may have received these agents all together or sequentially.

        Exclusion Criteria:

          -  Participants who have had chemotherapy, targeted small molecule therapy or study
             therapy within 14 days of protocol treatment, or those who have not recovered (i.e., ≤
             Grade 1 or at baseline) from adverse events due to agents administered more than 2
             weeks earlier. Subjects with ≤ Grade 2 neuropathy are an exception to this criterion
             and may qualify for the study. If subject received major surgery, they must have
             recovered adequately from the toxicity and/or complications from the intervention
             prior to starting therapy.

          -  Patients who have had radiation within 8 weeks prior to protocol registration.

          -  Participants who are receiving any other investigational agents.

          -  Patients are excluded if they have an active, known or suspected autoimmune disease
             other than those listed below. Subjects are permitted to enroll if they have vitiligo,
             type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only
             requiring hormone replacement, psoriasis not requiring systemic treatment, or
             conditions not expected to recur in the absence of an external trigger.

          -  Patients are excluded if they have a condition requiring systemic treatment with
             either corticosteroids (> 12 mg daily prednisone equivalents) or other
             immunosuppressive medications within 14 days of study drug administration. Inhaled or
             topical steroids and adrenal replacement doses > 12 mg daily prednisone equivalents
             are permitted in the absence of active autoimmune disease. Subjects are permitted to
             use topical, ocular, intraarticular, intranasal, and inhalational corticosteroids
             (with minimal systemic absorption).

        Physiologic replacement doses of systemic corticosteroids are permitted, even if > 12
        mg/day prednisone equivalents. A brief course of corticosteroids for prophylaxis (e.g.,
        contrast dye allergy) or for treatment of non-autoimmune conditions (e.g., delayed-type
        hypersensitivity reaction caused by contact allergen) is permitted.

          -  Patients are excluded if they have previously received anti-CTLA-4 therapy. Prior
             anti- PD-1 or anti-PD-L1 therapy is permitted with 6-month washout period unless the
             following treatment-related toxicities are present:

               -  Any toxicity NCI CTCAE grade >/= 3 from previous immunotherapy that did not
                  resolve to grade 1 with or without immunosuppressive therapy. Patients must be
                  off all immunosuppressive therapy prior to enrollment.

               -  Myocarditis, any grade.

               -  Pneumonitis, any grade.

               -  Patients with grade 2 hepatitis or colitis will be evaluated on a case-by-case
                  basis and may be included only after consultation with a Gastroenterologist and
                  the study physician.

          -  Has a known history of active TB (Bacillus Tuberculosis).

          -  No active or chronic HBV or HCV. Patients are excluded if they have a positive test
             for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid
             (HCV antibody) indicating acute or chronic infection. Subjects with a history of HBV
             or HCV require documentation of treatment completion, further testing is not required.

          -  Patients are excluded if they have known history of testing positive for human
             immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).

        These participants are at increased risk of lethal infections when treated with marrow
        suppressive therapy. Appropriate studies will be undertaken in participants receiving
        combination antiretroviral therapy when indicated.

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

          -  Has known psychiatric or substance abuse disorders that would interfere with
             cooperation with the requirements of the trial.

          -  Is pregnant or breastfeeding, or expecting to conceive or father children within the
             projected duration of the trial, starting with the pre-screening or screening visit
             through 5 months for woman and 7 months for men, after the last dose of trial
             treatment.

          -  Has a known additional malignancy that is progressing or requires active treatment.

        Exceptions include basal cell carcinoma of the skin and squamous cell carcinoma of the skin
        that has undergone potentially curative therapy or in situ cervical cancer.

          -  Has known history of, or any evidence of active, non-infectious pneumonitis.

          -  Has an active infection requiring systemic therapy.

          -  Has received a live/attenuated vaccine within 30 days of planned start of study
             therapy.

        Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and
        are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated
        vaccines, and are not allowed.

          -  History of allergy to study drug components.

          -  History of severe hypersensitivity reaction to any monoclonal antibody.

          -  Uncontrolled brain metastases. Patients treated with radiation > 4 weeks prior with
             follow up imaging showing control are eligible
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Disease control rate (DCR)
Time Frame:From the start of the treatment until the criteria for progression are met, up to 5 years
Safety Issue:
Description:Estimate the disease control rate (DCR) for unirradiated lesions for nivolumab/ipilimumab/radiation in metastatic, microsatellite stable colorectal cancer per Response Evaluation Criteria in Solid Tumors (RECIST v1.1). Disease control is the number of patients that achieve either a CR, PR, or SD. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum diameters while on study.

Secondary Outcome Measures

Measure:Overall response rate (ORR)
Time Frame:From the start of the treatment until disease progression/recurrence, up to 5 years
Safety Issue:
Description:Estimate the overall response rate (ORR) for unirradiated lesions for nivolumab/ipilimumab/radiation in metastatic, microsatellite stable colorectal cancer by RECIST 1.1. ORR is the number of patients that achieve either a CR or PR. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Measure:Number of Participants With Treatment-Related Adverse Events as Assessed by CTCAE 5
Time Frame:6 Weeks
Safety Issue:
Description:Toxicity rates associated with the protocol treatment of nivolumab and ipilimumab combined with radiation will be summarized by category and grade.
Measure:Progression-free survival (PFS)
Time Frame:Duration from the first day of protocol treatment to the earliest date of tumor progression by RECIST or clinical criteria, appearance of new metastases, or death due to any cause, up to 5 years
Safety Issue:
Description:Duration from the first day of protocol treatment to the earliest date of tumor progression by RECIST or clinical criteria, appearance of new metastases, or death due to any cause.
Measure:Overall survival (OS)
Time Frame:Duration from the first day of protocol treatment to the date of death due to any cause, up to 5 years
Safety Issue:
Description:Duration from the first day of protocol treatment to the date of death due to any cause. Patients will be censored at the date of last follow-up.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Massachusetts General Hospital

Trial Keywords

  • metastatic microsatellite stable colorectal cancer

Last Updated

September 29, 2020