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NCT03832621: MAYA

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

Completed Phase 2 Last updated 4 April 2022
What this trial tests

Phase 2 trial testing Temozolomide in Metastatic Colorectal Cancer in 135 participants. Completed in 30 September 2021.

Timeline
25 March 2019
Primary endpoint
30 September 2021
30 September 2021

Quick facts

Lead sponsorFondazione IRCCS Istituto Nazionale dei Tumori, Milano
PhasePhase 2
StatusCompleted
Study typeINTERVENTIONAL
Allocationna
Designsingle group
Maskingnone
Primary purposetreatment
Enrollment135
Start date25 March 2019
Primary completion30 September 2021
Estimated completion30 September 2021
Sites1 location across Italy

Drugs / interventions tested

Conditions studied

Sponsor

Fondazione IRCCS Istituto Nazionale dei Tumori, Milano — full company profile →

Who can join

Adults 18 to 99, any sex, with Metastatic Colorectal Cancer. Patients with the condition only — healthy volunteers not accepted.

Sponsor's own description

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.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

  1. Neoantigens: promising targets for cancer therapy.
    Xie N, Shen G, Gao W, Huang Z, et al · · 2023 · cited 713× · PMID 36604431 · DOI 10.1038/s41392-022-01270-x
  2. Advances in immunotherapy for colorectal cancer: a review.
    Golshani G, Zhang Y. · · 2020 · cited 170× · PMID 32536977 · DOI 10.1177/1756284820917527
  3. Immunotherapy efficacy on mismatch repair-deficient colorectal cancer: From bench to bedside.
    Lizardo DY, Kuang C, Hao S, Yu J, et al · · 2020 · cited 160× · PMID 33035640 · DOI 10.1016/j.bbcan.2020.188447
  4. Temozolomide Treatment Alters Mismatch Repair and Boosts Mutational Burden in Tumor and Blood of Colorectal Cancer Patients.
    Crisafulli G, Sartore-Bianchi A, Lazzari L, Pietrantonio F, et al · · 2022 · cited 103× · PMID 35522273 · DOI 10.1158/2159-8290.cd-21-1434
  5. Temozolomide Followed by Combination With Low-Dose Ipilimumab and Nivolumab in Patients With Microsatellite-Stable, O<sup>6</sup>-Methylguanine-DNA Methyltransferase-Silenced Metastatic Colorectal Cancer: The MAYA Trial.
    Morano F, Raimondi A, Pagani F, Lonardi S, et al · · 2022 · cited 102× · PMID 35258987 · DOI 10.1200/jco.21.02583
  6. Combination of Ipilimumab and Nivolumab in Cancers: From Clinical Practice to Ongoing Clinical Trials.
    Kooshkaki O, Derakhshani A, Hosseinkhani N, Torabi M, et al · · 2020 · cited 95× · PMID 32580338 · DOI 10.3390/ijms21124427
  7. Resistance to immune checkpoint inhibitors in non-small cell lung cancer: biomarkers and therapeutic strategies.
    Walsh RJ, Soo RA. · · 2020 · cited 77× · PMID 32670423 · DOI 10.1177/1758835920937902
  8. Immunotherapy in microsatellite instability metastatic colorectal cancer: Current status and future perspectives.
    Motta R, Cabezas-Camarero S, Torres-Mattos C, Riquelme A, et al · · 2021 · cited 66× · PMID 34541365

Verify or expand the search:

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