Monalizumab and MEDI5752 in Patients With MSI and/or dMMR Metastatic Cancer — MONAMI  

dMMR Colorectal Cancer Clinical Trial

Official title: Monalizumab and MEDI5752 in Patients With MSI and/or dMMR Metastatic Cancer

Status Not yet recruiting

Clinical Trial Summary

MSI is a molecular indicator of defective DNA mismatch repair (dMMR). The MSI/dMMR status is observed in all tumor types, representing notably 5% of metastatic colorectal cancers (mCRC), 25% of advanced endometrial cancer and 8% of metastatic gastric cancer.

MSI/dMMR cancers are highly immunogenic. MSI/dMMR tumors are characterized by a high tumor mutational burden with highly immunogenic neoantigens. These tumors are associated with an upregulation of immune checkpoints (PD1, PDL1, CTLA4, etc.) that protects MSI cancer cells from their hostile immune micro-environment, characterized by a high infiltration of activated cytotoxic T CD8+ and NK lymphocytes. Consequently, MSI/dMMR cancers are highly sensitive to ICIs, whatever the tumor location. MSI/dMMR status is a predictive biomarker for the efficacy of immunotherapy, regardless of the tumor type. Then, by several phase II and III studies The efficacy of immunotherapy has been demonstrated as front-line treatment for patients with chemotherapy-naive MSI/dMMR mCRC and gastric cancer. The phase III KEYNOTE-177 trial evaluating first-line treatment of pembrolizumab in patients with MSI/dMMR mCRC demonstrated its superiority over first-line chemotherapy, with a significant improvement of health-related quality of life. At final analysis, the median follow-up was 44.5 months. Median PFS was 16.5 versus 8.2 months (HR = 0.59; 95%CI 0.45-0.79). The hazard ratio favored pembrolizumab versus chemotherapy with a trend toward reduction in the risk of death (HR 0.74; 95% CI, 0.53-1.03; P=0.0359), despite a 60% effective crossover rate. Pembrolizumab has been approved by the FDA and the EMA for patients with newly diagnosed MSI/dMMR mCRC and is now the standard of care for this population. Also, the phase III CHECKMATE-649 trial reveal that the Combination of immunotherapy and cytotoxic chemotherapy is the new standard of care for patients with newly diagnosed metastatic oesogastric cancer. Importantly, results of the CHECKMATE-649 are outstanding for the subgroup population of MSI/dMMR gastric cancer patients (N = 44). Indeed, the unstratified hazard ratio for OS with nivolumab plus chemotherapy versus chemotherapy alone was 0.33 (95% CI 0.12-0.87) for patients with MSI/dMMR tumors. All in all, ICIs are the standard of care in first-line setting for patients with mCRC or metastatic oesogastric cancer. Besides, several phase II studies suggest that ICI combinations might overcome primary resistance to anti-PD1 monotherapy These data justify the development of bispecific monoclonal antibodies targeting both PD1 and CTLA4 such as MEDI5752. MEDI5752 has been developed based on the observation that there is a higher expression of PD-1/CTLA-4 on tumor resident versus peripheral T cells. Preclinical data show MEDI5752 fully suppresses PD-1 and preferentially inhibits CTLA-4 in the tumor versus the periphery, which is meant to uncouple CTLA-4 dependant peripheral toxicity from antitumor activity Natural killer cells are integral to the functioning of the innate immune system and play an important role in innate antitumor immunity. There is a growing body of evidence for targeting the NKG2A/HLA-E axis in combination with other ICIs to sensitize tumors to ICI therapy. NKG2A recognizes the non-classical HLA class I molecule HLA-E. The NKG2A receptor is found on peripheral NK cells and subsets of T cells in cancer patients. It is also present in tumor-infiltrating NK and cytotoxic T cells. Importantly, NK cells and the NKG2A/HLA-E axis play a crucial role in MSI/dMMR tumors. Therefore, a combined blockade of non-redundant checkpoint pathways to unleash NK and T cells seems particularly promising for MSI/dMMR neoplasms. Monalizumab specifically binds and blocks the inhibitory receptor NKG2A. Monalizumab has been investigated in combination with ibrutinib (in chronic lymphoid leukemia), cetuximab +/- durvalumab (in squamous cell carcinoma of the head and neck, and in solid tumors), durvalumab +/- FOLFOX (in solid tumors). In the first-in-human dose escalation of monalizumab plus durvalumab, a manageable toxicity profile was shown.

Taken together, these data provide a strong rational to combine an inhibitor of the NKG2A/HLA-E axis with a bispecific monoclonal antibody targeting both PD1 and CTLA4 for patients with metastatic MSI/dMMR cancers.

Clinical Trial Description

MONAMI is a multicenter (4 French hospitals) single-arm phase II trial according to A'Hern's design with a safety lead-in. For the achievement of the main objectif and primary endpoint, the tumor measurements using CT-scan (preferred option) or MRI will be performed at baseline, 6 weeks, 12 weeks, 18 weeks and 24 weeks. The same type of imaging (CT or MRI) as the one used at baseline will have to be performed for all tumor imaging evaluation.

The study contains a safety lead-in (N = 9) in which the safety and tolerability of monalizumab plus MEDI5752 will be assessed after the second cycle (the first 42 days of treatment).

The Data Safety Monitoring Board (DSMB) will evaluate the safety data at pre-specified intervals (every 4 weeks and at the end of the safety lead-in) and at additional points during the conduct of the safety lead-in, if necessary. The tolerability assessment will be based upon occurrence of dose-limiting toxicities. Additional patients will be enrolled based on assessments of the safety data by the DSMB during the safety lead-in Enrollment will be put on hold after the inclusion of the first patient in the safety lead-in until the end of the DLT period and until a discussion with the DSMB can occur. After every 3 new included patients in the safety lead-in until the end of the DLT period of the last included patient and until a discussion with the DSMB can occur. During this period, if 3 patients experience dose-limiting toxicities until a discussion with the DSMB can occur and after the inclusion of all the patients of the safety lead-in, until the end of the DLT period of the last patient and until a discussion with the DSMB can occur for the authorization to initiate the second part of the phase II study.

Patients will be treated with monalizumab 750 mg and MEDI5752 750 mg every 3 weeks intravenously, for 32 infusions (or less in case of RECIST disease progression or limiting toxicity, whichever occurs first).

Monalizumab will be supplied by AstraZeneca as a lyophilized product for concentrate for solution for infusion MEDI5752 will be supplied by AstraZeneca as a lyophilized product for concentrate for solution for infusion

Because of the possibility of an initial increase in tumor burden caused by immune-cell infiltration in the setting of a T-cell response (termed "pseudoprogression") with cancer immunotherapy, radiographic progression per RECIST v1.1 may not be indicative of true disease progression. During the study, participants who meet criteria for disease progression per RECIST v1.1 (unconfirmed disease progression per iRECIST criteria: iuPD) and show evidence of clinical benefit may continue study treatment at the Investigator's discretion provided that the participants meet all of the following criteria:

• Absence of clinically important symptoms and signs (including worsening of laboratory values) indicative of disease progression

• Investigator-assessed potential clinical benefit for the participant

• The participant is tolerating study drugs

• No decline in ECOG Performance Status

• Absence of rapid progression of disease or of progressive tumor at critical anatomical sites (e.g., cord compression) requiring urgent alternative medical intervention For participants receiving treatment beyond progression, an additional radiographic assessment/scan should be performed within 6 weeks of initial progression to determine whether there has been a stabilization or decrease in the tumor size or continued PD (confirmed disease progression per iRECIST criteria; icPD). Study treatment should be discontinued permanently upon documentation of further progression.

Safety lead-in cohort : 9 Phase II study : 29 Total : 43 patients maximum

• 38 evaluable patients

• If necessary, inclusions may be continued to reach the required number of evaluable patients within the limit of 5 additional participants

Duration of enrolment period (including safety lead-in cohort with interruption of inclusion after the first 9 participants): 2 years

The length of participation for participants, of which:

• Maximum period between screening and treatment initiation: 21 days

• Treatment duration: 2 years maximum

• Duration of follow-up period: 3 years from inclusion in the study Total study duration:

5 years and 21 days

Patients included in the safety lead-in will be analyzed as part of the overall population of the phase II study ;

Related Conditions & MeSH terms

• dMMR Colorectal Cancer
• MSI
• Neoplasm Metastasis

• NCT number: NCT06152523
• Study type: Interventional
• Source: Assistance Publique - Hôpitaux de Paris
• Contact: Romain COHEN, Dr
• Phone: +33 1 49 28 23 36
• Email: romain.cohen@aphp.fr
• Status: Not yet recruiting
• Phase: Phase 2
• Start date: December 2023
• Completion date: December 2028