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

NCT03832621 · Status: COMPLETED · Phase: PHASE2 · Type: INTERVENTIONAL · Enrollment: 135

Last updated 2022-04-04

No results posted yet for this study

Summary

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.

Conditions

Interventions

DRUG

Temozolomide

temozolomide 150 mg/sqm daily on days 1-5 every 4 weeks

DRUG

Nivolumab

nivolumab 480 mg i.v. every 4 weeks

DRUG

Ipilimumab

low-dose ipilimumab 1 mg/Kg i.v. every 8 weeks

Sponsors & Collaborators

  • Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

    lead OTHER

Principal Investigators

  • Filippo Pietrantonio, MD · Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

Study Design

Allocation
NA
Purpose
TREATMENT
Masking
NONE
Model
SINGLE_GROUP

Eligibility

Min Age
18 Years
Max Age
99 Years
Sex
ALL
Healthy Volunteers
No

Timeline & Regulatory

Start
2019-03-25
Primary Completion
2021-09-30
Completion
2021-09-30

Countries

  • Italy

Study Locations

More Related Trials

Entities

Drugs
Diseases

Read the full study record

This page highlights key information. For complete eligibility criteria, study locations, investigator contacts, and the full protocol, visit the original record on ClinicalTrials.gov.

View NCT03832621 on ClinicalTrials.gov