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

NCT06152523 | Not Yet Recruiting Phase 2 DMC

• 2 other identifiers: APHP2200972022-004122-22
• Study Type: interventional
• Target: 43
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

MSI; dMMR Colorectal Cancer

Keywords

Cancer; MSI/dMMR tumors; Monalizumab; MEDI5257; Efficacy; Safety/tolerability; Pharmacokinetic; MSI phenotype; Immune Checkpoint Inhibitors; Immunotherapy; Cytotoxic chemotherapy

Outcome Measures

Primary Outcomes (2)

• Incidence of dose-limiting toxicities

  Day 42 / 3 years

• Assess the objective response rate (ORR) per RECIST v.1.1 criteria at 24 weeks of monalizumab and MEDI5752 in combination in patients with MSI/dMMR metastatic cancer (Phase II study)

  Week 24

Secondary Outcomes (18)

• Incidence and severity of adverse events graded according to the NCI CTCAE version 5.0

  3 Years

• Incidence and severity of adverse events of special interest graded according to the NCI CTCAE version 5.0, version

  3 Years

• Incidence of dose interruptions, dose modifications and discontinuations due to adverse events

  3 Years

• Objective response rate per RECIST v.1.1 criteria at 24 weeks since the initiation of the treatment, defined by the number of patients with partial or complete response at 24 weeks (Phase II Study)

  Week 24

• Assess the safety profile of MEDI5752 plus monalizumab (adverse events per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v.5.0) ( (Phase II Study)

  Week 24

Study Arms (1)

MSI/dMMR tumors across all solid tumor types in adult patients

EXPERIMENTAL

Drug: Monalizumab/MEDI5257

Interventions

Monalizumab/MEDI5257 DRUG

Phase II trial using an A'Hern design with a safety lead-in cohort to assess the safety/tolerability of the combination of monalizumab and MEDI5752 in patients with metastatic MSI/dMMR cancer

MSI/dMMR tumors across all solid tumor types in adult patients

Eligibility Criteria

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

You may qualify if:

• Signed and dated patient informed consent form (ICF) and willingness to comply with all study procedures and availability for the study duration,
• Age ≥ 18 years,
• Body weight \> 35 kg,
• Eastern Cooperative Oncology Group performance status of 0 or 1,
• Life expectancy ≥ 12 weeks,
• Histologically confirmed carcinoma,
• dMMR and/or MSI tumor status defined by:
• Loss of MMR protein expression using immunohistochemistry with four (anti-MLH1, anti-MSH2, anti-MSH6, and anti-PMS2) antibodies,
• and/or ≥ two instable markers by polymerase chain reaction using standard panels; if two instable markers in the pentaplex panel, it is required to present confirmation of the dMMR status by immunohistochemistry or a comparison of the tumor PCR test with matched to normal tissue.
• Documented advanced or metastatic disease not suitable for complete surgical resection,
• Prior treatment for metastatic disease: patients are eligible if they have progressed on or following prior treatment and who have no satisfactory alternative treatment options , except for patients :
• with MSI/dMMR colorectal or oesogastric cancer who are eligible for study enrollment even if they did not receive prior treatment for metastatic disease,
• with advanced or recurrent endometrial carcinoma, who are eligible for study enrollment if they have disease progression on or following prior treatment with a platinum-containing therapy in any setting and who are not candidates for curative surgery or radiation
• with unresectable or metastatic small intestine or biliary cancer, who are eligible for the study enrolment if they have disease progression on or following at least one prior therapy
• At least one measurable lesion as assessed by CT-scan or magnetic resonance imaging (MRI) according to RECIST v1.1 and feasibility of repeated radiological assessments. Participants 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,

You may not qualify if:

• Active brain metastases or known leptomeningeal metastases.
• Persistence of toxicities related to prior chemotherapies grade \> 1 (NCI CTCAE v5.0; except alopecia, fatigue, or peripheral sensory neuropathy, which can be grade 2),
• Concomitant unplanned antitumor therapy (e.g. chemotherapy, molecular targeted therapy, radiotherapy, immunotherapy),
• Major surgical procedure within 4 weeks prior to initiation of study treatment,
• More than 3 prior lines of chemotherapy,
• Prior treatment with an anti-PD1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways, including prior therapy with anti-tumor vaccines or other immuno-stimulatory antitumor agents,
• Patients receiving any investigational drug within the previous 21 days before study treatment,
• Impossibility of submitting to the medical follow-up of the study for geographical, social or psychic reasons,
• Patients with an active, known or suspected autoimmune disease. Can be enrolled: Patients with type I diabetes mellitus, hypothyroidism requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger,
• History of interstitial lung disease or pneumonitis,
• Patients with a condition requiring systemic treatment with either corticosteroids (\> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days prior to treatment initiation.
• Treatment permitted in the absence of active autoimmune disease: Inhaled or topical steroids, and adrenal replacement steroid doses \> 10 mg daily prednisone equivalent.,
• Prior malignancy active within the previous 3 years except for except for:
• Locally curable cancers that have been apparently cured (e.g. squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast),
• Lynch syndrome-related cancer in complete remission for \> 1 year;

Sponsors & Collaborators

• Assistance Publique - Hôpitaux de Paris: lead

Study Sites (1)

Department of medical oncology - Saint-Antoine Hospital

Paris, 75012, France

Location

MeSH Terms

Conditions

Neoplasms

Interventions

monalizumab

Study Officials

• Romain COHEN, Dr

  Assistance Publique - Hôpitaux de Paris

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Romain COHEN, Dr

CONTACT

+33 1 49 28 23 36; romain.cohen@aphp.fr

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: September 5, 2023
• First Posted: November 30, 2023
• Study Start: December 1, 2023
• Primary Completion (Estimated): December 1, 2028
• Study Completion (Estimated): December 1, 2028
• Last Updated: November 30, 2023

Record last verified: 2023-11

Locations

FR (1)