NIVOLUMAB Plus IPILIMUMAB and TEMOZOLOMIDE in Microsatellite Stable, MGMT Silenced Metastatic Colorectal Cancer (MAYA)
|The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.|
|ClinicalTrials.gov Identifier: NCT03832621|
Recruitment Status : Completed
First Posted : February 6, 2019
Last Update Posted : April 4, 2022
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.
|Condition or disease||Intervention/treatment||Phase|
|Metastatic Colorectal Cancer||Drug: Temozolomide Drug: Nivolumab Drug: Ipilimumab||Phase 2|
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||135 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||NIVOLUMAB Plus IPILIMUMAB and TEMOZOLOMIDE in Combination in Microsatellite Stable (MSS), MGMT Silenced Metastatic Colorectal Cancer (mCRC): the MAYA Study|
|Actual Study Start Date :||March 25, 2019|
|Actual Primary Completion Date :||September 30, 2021|
|Actual Study Completion Date :||September 30, 2021|
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
temozolomide 150 mg/sqm daily on days 1-5 every 4 weeks
nivolumab 480 mg i.v. every 4 weeks
low-dose ipilimumab 1 mg/Kg i.v. every 8 weeks
- 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 ]
The primary efficacy endpoint of this study is 8-month PFS rate, defined as the proportion of patients alive and progression-free at 8 months from the enrollment.
Investigator-assessed PFS according to RECIST v1.1 Investigator-assessed PFS according to modified RECIST
- Estimate the overall response rates (ORR) of the combination regimen of temozolomide, nivolumab and ipilimumab [ Time Frame: 36 months ]ORR measured by response rate according to RECIST 1.1 and modified RECIST criteria
- Estimate duration of response (DoR) of the combination regimen of temozolomide, nivolumab and ipilimumab [ Time Frame: 36 months ]DoR assessed per RECIST 1.1 and modified RECIST
- Estimate overall survival (OS) of the combination regimen of temozolomide, nivolumab and ipilimumab [ Time Frame: 36 months ]overall survival
- Estimate ORR according to an Imaging Independent Central Review, using RECIST 1.1 and modified RECIST criteria [ Time Frame: 36 moths ]CD-ROM copies of the CT scans performed at baseline and during treatment until disease progression according to RECIST 1.1 and modified RECIST criteria will be collected at the Coordinating Center (S.C. Oncologia Medica 1, Fondazione IRCCS Istituto Nazionale dei Tumori) for central review
- Evaluate the adverse events encountered by patients treated with the combination of temozolomide, nivolumab and ipilimumab [ Time Frame: 36 months ]Number of participants with treatment-related adverse events graded according to the NCI CTCAE v4.0
- Estimate DoR of the combination regimen of temozolomide, nivolumab and ipilimumab according to an Imaging Independent Central Review [ Time Frame: 36 months ]DoR calculated after the Imaging Independent Central Review
- Estimate PFS of the combination regimen of temozolomide, nivolumab and ipilimumab according to an Imaging Independent Central Review [ Time Frame: 36 months ]PFS calculated after the Imaging Independent Central Review
- Assess quality of life [ Time Frame: 36 months ]Quality of life will be assessed through Patient reported outcomes (PRO) instrument. PRO will be assessed by EORTC QLQ-C30 EORTC QLQ-CR29 and EuroQol EQ-5D
- Evaluate the relationship between tumor and plasma MGMT methylation [ Time Frame: 36 months ]Quantification of the percentage of MGMT methylation with digital PCR for MGMT methylation status will be performed in archival tumor tissue, tumor re-biopsies and cell-free circulating DNA (cfDNA) (cfDNA)
- Evaluate the tumor mutational load [ Time Frame: 36 months ]Mutational load will be assessed in archival tumor tissues, tumor biopsies and cfDNA by means of whole exome sequencing
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03832621
|Fondazione IRCCS Istituto Nazionale dei Tumori|
|Milan, MI, Italy, 20133|
|Principal Investigator:||Filippo Pietrantonio, MD||Fondazione IRCCS Istituto Nazionale dei Tumori, Milano|