NIVOLUMAB Plus IPILIMUMAB and TEMOZOLOMIDE in Microsatellite Stable, MGMT Silenced Metastatic Colorectal Cancer

Sponsor
Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
Study ID
NCT03832621
Phase
PHASE2
Status
Completed

Conditions

  • Metastatic Colorectal Cancer

Eligibility Criteria

Sex
ALL
Age
18 Years - 99 Years
Healthy Volunteers
Not accepted

Interventions

  • Temozolomide — DRUG
    temozolomide 150 mg/sqm daily on days 1-5 every 4 weeks
  • Nivolumab — DRUG
    nivolumab 480 mg i.v. every 4 weeks
  • Ipilimumab — DRUG
    low-dose ipilimumab 1 mg/Kg i.v. every 8 weeks

Study Details

This is a Phase II, multicenter, single-arm trial designed to evaluate the efficacy and safety of nivolumab (NIVO), ipilimumab (IPI) and temozolomide (TMZ) combination in 27 patients with MSS, MGMT-silenced mCRC with initial clinical benefit following lead-in treatment with single-agent TMZ. Immune checkpoint inhibitors have been shown to trigger durable antitumor effects in a subset of patients. A high number of tumor mutations (so called 'tumor mutational burden') has recently been found associated with increased immunogenicity (due to a high number of neoantigens) and improved treatment efficacy across several different solid tumors. In mCRCs, only a small fraction of tumors (\<5%) display a high mutational load and are usually associated with inactivation of mismatch repair genes such as MLH1, MSH2 and MSH6. Checkpoint inhibitors may have increased activity in dMMR/microsatellite instability-high (MSI-H) tumors, a hypothesis which was tested in various Phase II trials with positive results. On the opposite, mismatch repair proficient colorectal cancer is unresponsive to immune checkpoint inhibitors. Previous reports indicate that acquired resistance to TMZ may emerge through the induction of a microsatellite-instability-positive phenotype and recent data showed that inactivation of MMR, driven by acquired resistance to the clinical agent temozolomide, increased mutational load, promoted continuous renewal of neoantigens in human colorectal cancers and triggered immune surveillance in mouse models. On all of the above grounds, the investigators hypothesize that treatment of microsatellite stable MGMT hypermethylated CRCs with alkylating agents could reshape the tumor genetic landscape by increasing the tumor mutational burden, leading to achieve potential sensitization to immunotherapy.

Key Dates

Start date
Mar 25, 2019
Status verified
Sep 2021
Primary completion
Sep 30, 2021
Completion
Sep 30, 2021

Study Design

Enrollment
135 participants (actual)
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT

Arms

  • Experimental: temozolomide + nivolumab + ipilimumab
    Temozolomide 150 mg/sqm daily on days 1-5 every 4 weeks, for two cycles followed by TC scan assessment: if SD/PR/CR second treatment phase with nivolumab 480 mg i.v. every 4 weeks, low-dose ipilimumab 1 mg/Kg i.v. every 8 weeks and temozolomide at the previously adopted schedule

Primary Outcome Measure

Evaluate the efficacy, measured as 8-month PFS rate, of the combination of temozolomide, nivolumab and ipilimumab in patients achieving disease control following 2-month lead-in treatment with single agent TMZ [ Time Frame: 8 months from the last patient enrolled ]

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