SNPMiner Trials by Shray Alag

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SNPMiner SNPMiner Trials (Home Page)


Report for Mutation D949V

Developed by Shray Alag, 2020-2021.
SNP Clinical Trial Gene

There is one clinical trial.

Clinical Trials


1 Phase 1b Trial of 5-fluorouracil, Leucovorin, Irinotecan in Combination With Temozolomide (FLIRT) and Bevacizumab for the First-line Treatment of Patients With MGMT Silenced, Microsatellite Stable Metastatic Colorectal Cancer.

An upfront-intensified treatment combining all the three active cytotoxic agents in metastatic colorectal cancer (mCRC) including fluoropyrimidines, oxaliplatin, irinotecan (FOLFOXIRI) plus antiangiogenic blockade with bevacizumab significantly improved survival. No biomarkers are available for predicting sensitivity/resistance to single chemotherapeutic drugs, the simultaneous delivery of all active chemotherapeutic agents might overcome resistance to single drugs. Temozolomide has modest but non-negligible activity (about 10%) in chemo-refractory patients with MGMT methylated mCRC. The response rate to temozolomide-based therapy in pretreated patients is increased to up to 20% when restricting the focus on those with MGMT IHC-negative/MGMT methylated and MSS cancers. Clinical and preclinical synergy has been reported for combination of temozolomide with irinotecan and fluoropyrimidines. Temozolomide could be regarded as a "targeted" chemotherapy for patients with MSS and MGMT silenced tumors. In this subgroup of patients, an intensified triplet upfront regimen including temozolomide, fluoropyrimidines, irinotecan, associated with bevacizumab, could be a novel combination in molecularly super-selected mCRC patients. Moving from this, the investigators designed this open-label, monocentric, phase 1b study evaluating the safety of the combination regimen 5-fluorouracil, leucovorin, irinotecan, temozolomide and bevacizumab in patients with MGMT silenced and MSS mCRC. The study will consist in a dose-escalation assessment of the safety of the treatment in subjects with previously untreated MGMT silenced, MSS mCRC. A 3 + 3 design will be used to assess the maximum tolerated dose (MTD) or maximum tested dose of the combination FLIRT-bevacizumab.

NCT04689347
Conditions
  1. Metastatic Colorectal Cancer
Interventions
  1. Drug: Bevacizumab
  2. Drug: Irinotecan
  3. Drug: Leucovorin
  4. Drug: 5Fluorouracil
  5. Drug: Temozolomide
MeSH:Colorectal Neoplasms
HPO:Neoplasm of the large intestine

- Presence of one of the following: DPYD2a (c.1905+1G>A); DPYD13 (c.1679 T>G); DPYD D949V (c.2846 A>T); DPYD IVS10 (c.1129-5923 C>G). --- D949V ---

Primary Outcomes

Description: The RD to be tested in a future phase 2 trial will be one dose level below the MTD or the maximum tested dose if MTD will not be reached. he MTD will be defined as the dose level at which ≥2/3 or ≥2/6 subjects experience a dose-limiting toxicity. At least 6 patients should be treated at the RD during the dose escalation.

Measure: To evaluate the safety and to determine the recommended phase 2 dose of the combination of FLIRT- bevacizumab in patients with MGMT silenced and MSS mCRC, previously untreated for advanced disease

Time: 24 months

Secondary Outcomes

Description: To assess ORR per RECIST version 1.1

Measure: ORR obtained by FLIRT bevacizumab

Time: 24 months

Description: To assess the quality of life as measured by EORTC QLQ-C30 during treatment

Measure: To assess the quality of life as measured by PROs questionnaires

Time: 24 months

Description: To assess the quality of life as measured by EORTC QLQ-CR29 during treatment

Measure: To assess the quality of life as measured by PROs questionnaires

Time: 24 months

Description: To assess the quality of life as measured by EuroQol EQ-5D during treatment

Measure: To assess the quality of life as measured by PROs questionnaires

Time: 24 months

Other Outcomes

Description: Quantification of the percentage of MGMT methylation by digital PCR methylBEAMing will be performed in archival tumor tissue. Mutational load will be assessed in archival tumor tissues by means of whole exome sequencing.

Measure: Evaluate tumor biomarkers in archival tumor tissue

Time: 24 months

Description: Digital PCR for MGMT methylation status will be performed in cell-free circulating DNA (cfDNA). Mutational load will be assessed in cfDNA by means of whole exome sequencing.

Measure: Evaluate plasma biomarkers in longitudinal blood samples (plasma and PBMCs)

Time: 24 months

Description: FS is defined as the time from enrolment to the first documentation of objective disease progression determined by investigator assessment or death due to any cause, whichever occurs first. PFS will be censored on the date of the last evaluable on study tumour assessment documenting absence of progressive disease for patients who are alive, on study and progression free at the time of the analysis. Alive patients having no tumour assessments after baseline will have time to event censored on the date of enrolment

Measure: PFS of FLIRT bevacizumab

Time: 24 months

Description: OS is defined as the time from enrolment to the date of death due to any cause. For patients still alive at the time of analysis, the OS time will be censored on the last date the patients were known to be alive.

Measure: OS of FLIRT bevacizumab

Time: 24 months


HPO Nodes