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

NCT03879811 | Withdrawn Phase 2 FDA Drug

• 1 other identifier: 18-545
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

Brief Summary

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.

Conditions

Colorectal Cancer

Keywords

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

Outcome Measures

Primary Outcomes (1)

• response rate of TMZ followed by nivolumab in participants with MMR-proficient Colorectal Cancer

  Response determined by RECIST 1.1

  up to 2 years

Study Arms (1)

MMR-Proficient Colorectal Cancer

EXPERIMENTAL

The 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.

Drug: TMZ; Drug: Nivolumab

Interventions

TMZ DRUG

Oral TMZ at 150mg/m2

MMR-Proficient Colorectal Cancer

Nivolumab DRUG

Nivolumab via IV infusion at 480 mg every four weeks (Q4W) starting 4 weeks after TMZ day 1

MMR-Proficient Colorectal Cancer

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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)

Sponsors & Collaborators

• Memorial Sloan Kettering Cancer Center: lead
• Bristol-Myers Squibb: collaborator

Related Links

• Related Info

MeSH Terms

Conditions

Colorectal Neoplasms

Interventions

Nivolumab

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Neil H Segal, MD, PhD

  Memorial Sloan Kettering Cancer Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Simon two-stage design, single arm study

Study Record Dates

• First Submitted: March 15, 2019
• First Posted: March 19, 2019
• Study Start: March 13, 2019
• Primary Completion: March 1, 2021
• Study Completion: March 1, 2021
• Last Updated: May 15, 2025

Record last verified: 2019-12

Data Sharing

• IPD Sharing: Will share