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

NCT03832621 | Completed Phase 2

• 1 other identifier: INT202-18
• Study Type: interventional
• Target: 135
• Locations: 1 country
• Sites: 1

Brief 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

Metastatic Colorectal Cancer

Keywords

nivolumab; ipilimumab; temozolomide; microsatellite stable; MSS; MGMT

Outcome Measures

Primary Outcomes (1)

• 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

  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

  8 months from the last patient enrolled

Secondary Outcomes (8)

• Estimate the overall response rates (ORR) of the combination regimen of temozolomide, nivolumab and ipilimumab

  36 months

• Estimate duration of response (DoR) of the combination regimen of temozolomide, nivolumab and ipilimumab

  36 months

• Estimate overall survival (OS) of the combination regimen of temozolomide, nivolumab and ipilimumab

  36 months

• Estimate ORR according to an Imaging Independent Central Review, using RECIST 1.1 and modified RECIST criteria

  36 moths

• Evaluate the adverse events encountered by patients treated with the combination of temozolomide, nivolumab and ipilimumab

  36 months

Other Outcomes (2)

• Evaluate the relationship between tumor and plasma MGMT methylation

  36 months

• Evaluate the tumor mutational load

  36 months

Study Arms (1)

temozolomide + nivolumab + ipilimumab

EXPERIMENTAL

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

Drug: Temozolomide; Drug: Nivolumab; Drug: Ipilimumab

Interventions

Temozolomide DRUG

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

temozolomide + nivolumab + ipilimumab

Nivolumab DRUG

nivolumab 480 mg i.v. every 4 weeks

temozolomide + nivolumab + ipilimumab

Ipilimumab DRUG

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

temozolomide + nivolumab + ipilimumab

Eligibility Criteria

• Age: 18 Years - 99 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Have provided written informed consent prior to any study specific procedures
• Willing and able to comply with the protocol
• ≥18 years of age
• ECOG status 0 - 1
• At least 12 weeks of life expectancy at time of entry into the study
• Histologically confirmed metastatic or inoperable adenocarcinoma of the colon and/or rectum, with centrally confirmed mismatch repair proficiency (microsatellite stable \[MSS\]) by multiplex polymerase chain reaction (PCR), MGMT promoter methylation by methylation-specific PCR (MSP) and MGMT low expression by IHC
• Patients with progressive disease or that are not candidate for oxaliplatin irinotecan fluoropirimidin based chemotherapy and anti EGFR mAbs (in RAS/BRAF wild type tumors) in the metastatic setting
• Patients with documented disease relapsed within 6 months from the completion of adjuvant oxaliplatin-based chemotherapy are considered eligible
• Measureable, unresectable disease according to RECIST 1.1. Subjects with lesions in a previously irradiated field as the sole site of measurable disease will be permitted to enroll provided the lesion(s) have demonstrated clear progression and can be measured accurately.
• Is willing and able to provide an adequate archival tumor sample (FFPE) available for tissue screening for central tissue screening. If the tumour block is not available, a minimum of twenty 3-micron unstained sections on charged slides of tumor will be required.

You may not qualify if:

• Requirement for treatment with any medicinal product that contraindicates the use of any of the study medications, may interfere with the planned treatment, affects patient compliance or puts the patient at high risk for treatment-related complications
• Inability to swallow pills
• Refractory nausea and vomiting, malabsorption, external biliary shunt or significant bowel resection that would preclude adequate absorption
• Inadequate haematological function indicated by all of the following:
• White Blood Cell (WBC) count \< 2 x 109/L
• Absolute neutrophil count (ANC) \< 1.5 x 109/L
• Platelet count \< 100 x 109/L
• Haemoglobin \< 9 g/dL (patients may have transfusions and/or growth factors to attain adequate Hb)
• Inadequate liver function indicated by all of the following:
• Total bilirubin ≥ 1.5 x upper limit of normal (ULN)
• Aspartate transaminase (AST) and alanine aminotransferase (ALT) ≥ 3 x ULN (≥ 5 x ULN in patients with known liver metastases)
• Alkaline phosphatase (ALP) ≥ 2 x ULN (≥ 5 x ULN in patients with known liver metastases)
• Inadequate renal function indicated by all of the following:
• \- Serum creatinine \> 1.5 x ULN or calculated creatinine clearance \< 40 ml/min
• INR \> 1.5 and aPTT \> 1.5 x ULN within 7 days prior to the start of study treatment for patients not receiving anti-coagulation

Sponsors & Collaborators

• Fondazione IRCCS Istituto Nazionale dei Tumori, Milano: lead

Study Sites (1)

Fondazione IRCCS Istituto Nazionale dei Tumori

Milan, MI, 20133, Italy

Location

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MeSH Terms

Conditions

Colorectal Neoplasms

Interventions

Temozolomide; Nivolumab; Ipilimumab

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Dacarbazine; Triazenes; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Filippo Pietrantonio, MD

  Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 31, 2019
• First Posted: February 6, 2019
• Study Start: March 25, 2019
• Primary Completion: September 30, 2021
• Study Completion: September 30, 2021
• Last Updated: April 4, 2022

Record last verified: 2021-09

Locations

IT (1)