Clinical Trials /

Determining the Effects of Temozolomide Followed by Nivolumab in Patients With Colorectal Cancer

NCT03879811

Description:

The purpose of this study is to find out whether temozolomide followed by nivolumab is an effective treatment for MMR-proficient colorectal cancer, while causing few or mild side effects.

Related Conditions:
  • Colorectal Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Determining the Effects of Temozolomide Followed by Nivolumab in Patients With Colorectal Cancer
  • Official Title: Phase II Study of Temozolomide and Nivolumab in MMR-Proficient Colorectal Cancer (CA209-8JN)

Clinical Trial IDs

  • ORG STUDY ID: 18-545
  • NCT ID: NCT03879811

Conditions

  • Colorectal Cancer

Interventions

DrugSynonymsArms
TMZMMR-Proficient Colorectal Cancer
NivolumabMMR-Proficient Colorectal Cancer

Purpose

The purpose of this study is to find out whether temozolomide followed by nivolumab is an effective treatment for MMR-proficient colorectal cancer, while causing few or mild side effects.

Trial Arms

NameTypeDescriptionInterventions
MMR-Proficient Colorectal CancerExperimentalThe first 3 subjects will receive oral TMZ at 150mg/m2 day 1 to 5 during cycle 1, followed by nivolumab via IV infusion at 480 mg every four weeks (Q4W) starting 4 weeks after TMZ day 1 (i.e. Cycle 2 day 1). Nivolumab will continue for up for 2 years maximum. If confirmed that TMB increased in at least 2 of 3 subjects following 1 cycle of TMZ, then subsequent patients will continue to receive TMZ during cycle 1 only, and the original three participants will not be replaced. If it is determined that TMB did not increase following 1 cycle of TMZ, then subsequent patients will receive TMZ up to cycle 3, those first 3 patients will discontinue further Nivolumab and be replaced and an additional 6 patients will initially be enrolled. If confirmed that TMB increased in at least 1 of 6 subjects following 3 cycles of TMZ, then 12 more patients will be allowed to enroll for a total of 18 in stage I.
  • TMZ
  • Nivolumab

Eligibility Criteria

        Inclusion Criteria:

          -  Subject or legally authorized representative, is willing and able to provide written
             informed consent/assent for the trial

          -  Histologically- or cytologically- confirmed CRC

          -  Locally advanced or metastatic CRC

          -  Confirmation of MGMT promoter methylation on archived tissue by PCR analysis (any
             time).

          -  MGMT promoter methylation is determined using the ARUP laboratory assay (or similar).
             Total methylation is calculated as an average across listed CpG sites. Total
             methylation of 0-9 percent is reported as "Not detected" 10-29 percent as "Low level"
             and equal or more than 30 percent as "Detected". Patients will require MGMT promoter
             methylation to be "detected" in order to be eligible.

          -  Undergone testing for MSI/dMMR and determined to be MSS or MMR proficient

          -  Subjects must be refractory or intolerant to at least 2 lines of standard
             chemotherapy, according to NCCN guidelines for patients eligible for intensive
             therapy. At a minimum, such therapies should include regimens containing oxaliplatin
             or irinotecan in combination with a fluoropyrimidine (e.g., FOLFOX or FOLFIRI or their
             variants).

          -  At least one index lesion which is measurable based on RECIST 1.1

          -  Be >/= 18 years of age on day of signing informed consent

          -  Consent for tumor biopsies and blood draws for research purposes

          -  Have an ECOG performance status of 0 or 1

          -  Demonstrate adequate organ function as defined in Table 6.1, all screening labs should
             be performed within 28 days of treatment initiation.

        Adequate Organ Function Laboratory Values

        Hematological

          -  Absolute neutrophil count (ANC) >/= 1,500/mcl

          -  Platelets >/= 100,000/mcl

          -  WBC >/= 2000/ul

          -  Hemoglobin >/= 9.0 g/dL

        Renal

          -  Serum creatinine </= 1.5 x upper limit of normal (ULN) OR

          -  Measured or calculated creatinine clearance (GFR can also be used in place of
             creatinine of CrCl) >/= 60 mL/min for subject with creatinine levels > 1.5 x
             institutional ULN (Creatinine clearance should be calculated per institutional
             standard)

        Hepatic

          -  Serum total bilirubin </= 1.5 x ULN -OR- Direct bilirubin </= ULN for subjects with
             total bilirubin levels > 1.5 ULN

          -  AST (SGOT) and ALT (SGPT) </= 2.5 x ULN -OR- </= 5 x ULN for subjects with liver
             metastases

          -  Female subject of childbearing potential should have a negative serum pregnancy within
             2 weeks prior to starting treatment

          -  Female subjects of childbearing potential should be willing to use 2 methods of birth
             control or be surgically sterile, or abstain from heterosexual activity for the course
             of the study through 5 months after the last dose of study medication. Subjects of
             childbearing potential are those who have not been surgically sterilized or have not
             been free from menses for > 1 year

          -  Male subjects should agree to use an adequate method of contraception starting with
             the first dose of study therapy through 7 months after the last dose of study therapy
             (defined in section 7.1). In addition, male subjects must be willing to refrain from
             sperm donation during this time.

        Coagulation

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

          -  Activated Partial Thromboplastin Time (aPTT) </= 1.5 x ULN unless subject is receiving
             anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use
             of anticoagulants

        Exclusion Criteria:

          -  Subject is currently participating in or has participated in a study of an
             investigational agent or using an investigational device within 4 weeks of the first
             dose of treatment.

          -  Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy (>10
             mg/day prednisone, or equivalent) or any other form of immunosuppressive therapy
             within 7 days prior to the first dose of trial treatment. inhaled or topical steroids
             are permitted in the absence of active autoimmune disease

          -  Prior chemotherapy, targeted small molecule therapy, or biological therapy, within 2
             weeks prior to study Day 1 or who has not recovered (i.e., </= Grade 1 or at baseline)
             from adverse events due to a previously administered agent (exc. alopecia)

          -  If subject received major surgery, they must have recovered adequately prior to
             starting therapy

          -  Has a known additional malignancy that is progressing or requires active treatment.
             Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the
             skin, or in situ cervical cancer that has undergone potentially curative therapy

          -  Has known active central nervous system (CNS) metastases and/or carcinomatous
             meningitis. Subjects with previously treated brain metastases may participate provided
             they are stable (without evidence of progression by imaging for at least four weeks
             prior to the first dose of trial treatment any neurologic symptoms have returned to
             baseline), have no evidence of new or enlarging brain metastases, and are not using
             steroids for at least 7 days prior to trial treatment,

          -  Has an active, known or suspected autoimmune disease requiring systemic treatment
             within the past 3 months or a documented history of clinically severe autoimmune
             disease, or a syndrome that requires systemic steroids or immunosuppressive agents.
             Subjects with vitiligo or resolved childhood asthma/atopy, type 1 diabetes mellitus
             are permitted. Subjects that require intermittent use of bronchodilators or local
             steroid injections would not be excluded from the study. Subjects with hypothyroidism
             stable on hormone replacement or Sjorgen's syndrome will not be excluded from the
             study.

          -  Has evidence of known interstitial lung disease or active, non-infectious pneumonitis

          -  Has an active infection requiring systemic therapy

          -  Has a history or current evidence of any condition, therapy, or laboratory abnormality
             that might confound the results of the trial, interfere with the subject's
             participation for the full duration of the trial, or it is not in the best interest of
             the subject to participate, in the opinion of the treating investigator

          -  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 females, 7 months for males after the last dose of trial
             treatment

          -  Prior anti-PD-1, anti-PDL-1, anti-PDL-2, anti-Cytotixic T-lymphocyte-associated
             antigen-4 (CTLA-4) antibody or any other antibody or drug specifically targeting
             T-cell co-stimulation or checkpoint pathways

          -  Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies)

          -  Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA
             [qualitative] is detected)

          -  Has received a live vaccine within 30 days prior to the first dose of trial treatment

          -  Subjects is a prisoners or compulsory detained
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:response rate of TMZ followed by nivolumab in participants with MMR-proficient Colorectal Cancer
Time Frame:up to 2 years
Safety Issue:
Description:Response determined by RECIST 1.1

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Memorial Sloan Kettering Cancer Center

Trial Keywords

  • MMR-Proficient Colorectal Cancer
  • Temozolomide
  • Nivolumab
  • Memorial Sloan Kettering Cancer Center
  • 18-545

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