Monalizumab and MEDI5752 in patients with MSI and/or dMMR metastatic cancer (MONAMI)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Assistance Publique Hopitaux De Paris

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Pathological Conditions, Signs and Symptoms [C23]

Trial duration

completed 13 Nov 2025

Decision date (initial)

2024-11-14

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2024-511857-23-00

EudraCT number

2022-004122-22

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety

The primary objective of the phase II study is to 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.

Secondary objectives 4

1. To 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);
2. To assess ORR per RECIST v.1.1 at 48 and 96 weeks and iRECIST at 24, 48 and 96 weeks with MEDI5752 and monalizumab
3. To assess progression-free survival per RECIST v.1.1 and iRECIST at 24, 48 and 96 weeks with MEDI5752 and monalizumab
4. To assess overall survival at 24, 48 and 96 weeks with MEDI5752 and monalizumab

Conditions and MedDRA coding

cancerology

Regulatory references

Plan to share IPD

Yes

IPD plan description

All of the individual participant data collected during the trial, subject to compliance to regulations, will be available. Document (Study protocol, statistical analysis plan, informed consent form, clinical study report, analytic code) will be also available. Data will be available immediately following publication ending 2 years after publication, with investigators whose proposed use of the data has been approved by the PI and / or the review commitee if relevant. Proposals should be directed to [email protected]. To gain access, data requestors will need to sign a data access agreement.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 17

1. Signed and dated patient informed consent form (ICF) and willingness to comply with all study procedures and availability for the study duration
2. Age ≥ 18 years
3. Body weight > 35 kg
4. Eastern Cooperative Oncology Group performance status of 0 or 1
5. Life expectancy ≥ 12 weeks
6. Histologically confirmed carcinoma
7. 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
8. Documented advanced or metastatic disease not suitable for complete surgical resection
9. Patients with unresectable or metastatic MSI cancer, intolerant to or progressive under or after at least one line of therapy, with no satisfactory alternative option.
10. 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
11. Availability of a representative tumor specimen for exploratory translational research; tumor tissue specimens, either formalin-fixed, paraffin-embedded (FFPE) tissue block or unstained tumor tissue sections (minimum of 30 positively charged slides) from primary or metastatic site must be submitted to the central laboratory
12. Baseline-corrected QT interval < 470 ms
13. Adequate hematologic and end-organ function, defined by the following laboratory test results, obtained within 14 days prior to initiation of study treatment: - Hematological status: o White blood cell > 2000/μL; o Neutrophils > 1500/μL; o Platelets > 100.000/μL; o Hemoglobin > 9.0 g/dL; - Adequate renal function: Serum creatinine level < 150 μM and calculated creatinine clearance (Cockcroft-Gault) ≥ 45 mL/minute, - Adequate liver function: MONAMI protocol, version 2.0 of 23/05/2024 13/93 This document is the property of DRCI/AP-HP. All reproduction is strictly prohibited. Version 2.0 dated 25/01/2024 o Serum bilirubin ≤ 1.5 x upper normal limit (ULN) or direct bilirubin ≤ULN for participants with total bilirubin levels >1.5 × ULN; o Alkaline phosphatase (ALP) ≤ 3 x ULN; o Alanine aminotransferase (ALT) ≤ 3.0 x ULN; o Aspartame aminotransferase (AST) ≤ 3.0 x ULN; o Prothrombin time (PT)/International normalized ratio (INR) and partial PT (PTT) ≤ 1.5 x ULN unless participants are receiving anticoagulant therapy and their INR is stable and within the recommended range for the desired level of anticoagulation
14. Females of childbearing potential: - Must have negative pregnancy test at screening , prior to each administration of investigational product and at each follow-up visit until 140 days after last treatment; - If sexually active with a nonsterilized male partner, must use at least one highly effective method of birth control from screening to 140 days after the last dose of MEDI5752 and monalizumab; - IT IS STRONGLY RECOMMENDED THAT nonsterilized male partners of female subjects of childbearing potential use a male condom plus spermicide from screening to 140 days after the last dose of MEDI5752 (Note: Male condoms are not reliable as a sole contraception method) - Refer to APPENDIX 18.1 : Definition of Women of Childbearing Potential for definitions of females of childbearing potential
15. Female subjects must not breastfeed and must not donate, or retrieve for their own use, ova from screening to 140 days after the last dose of MEDI5752 and monalizumab
16. Nonsterilized male subjects who are sexually active with a female partner of childbearing potential must use a condom with spermicide from screening to 140 days after the last dose of MEDI5752 and monalizumab (Note: Male condoms are not reliable as a sole contraception method). IT IS STRONGLY RECOMMENDED THAT female partners of a male subject also use at least one highly effective method of contraception throughout this period. In addition, male subjects must refrain from fathering a child or donating sperm during the study and for 140 days after the last dose of MEDI5752 and monalizumab.
17. Registration in a national health care system (AME are not allowed).

Exclusion criteria 21

1. Active brain metastases or known leptomeningeal metastases
2. History of interstitial lung disease or pneumonitis
3. 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.,
4. History of another primary malignancy except for: - Malignancy treated with curative intent and with no known active disease ≥ 5 years before the first dose of study treatment and of low potential risk for recurrence - Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease - Adequately treated carcinoma in situ without evidence of disease - Participants with a history of prostate cancer (tumor/node/metastasis stage) of Stage ≤ T2cN0M0 without biochemical recurrence or progression and who in the opinion of the investigator are not deemed to require active intervention
5. Evidence of the following infections: - Active infection including tuberculosis (TB) (clinical evaluation that includes clinical history, physical examination, and radiographic findings and TB testing in line with local practice), - or human immunodeficiency virus (HIV) (positive for HIV-1 or HIV-2 antibodies), - or active or uncontrolled hepatitis B (HBV) or hepatitis C (HCV). Participants are eligible if they: o Have controlled hepatitis C viral load defined as undetectable hepatitis C RNA by PCR either spontaneously or in response to a successful prior course of anti-hepatitis C therapy, o Have received HBV vaccination with only anti-HBs positivity and no clinical signs of hepatitis, o Are HBsAg- and anti-HBc+ (ie, those who have cleared HBV after infection) and meet conditions i-iii below: o Are HBsAg+ with chronic HBV infection (lasting 6 months or longer) and meet conditions i-iii below: ▪ HBV DNA viral load <100 IU/mL ▪ Have normal transaminase values, or, if liver metastases are present, abnormal transaminases, with a result of AST/ALT <3 × ULN, which are not attributable to HBV infection ▪ Start or maintain antiviral treatment if clinically indicated as per the investigator. - or active hepatitis A (refer to Section 5.7 for screening tests)
6. Prior allogeneic bone marrow transplantation or prior solid organ transplantation
7. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, cardiomyopathy of any etiology, symptomatic congestive heart failure (as defined by New York Heart Association class > 2), uncontrolled hypertension, unstable angina pectoris, history of myocardial infarction within the past 12 months, cardiac arrhythmia, ILD, MONAMI protocol, version 2.0 of 23/05/2024 15/93 This document is the property of DRCI/AP-HP. All reproduction is strictly prohibited. Version 2.0 dated 25/01/2024 serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the subject to give written informed consent
8. Any condition that, in the opinion of the investigator, would interfere with evaluation of the investigational product or interpretation of the subject’s safety or study results
9. Known allergy/hypersensitivity to any component or excipients of study agents
10. Administration of a (attenuated) live vaccine within 30 days of planned start of study therapy of known need for this vaccine during treatment
11. Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 140 days after the last dose of Monalizumab and MEDI5752
12. 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)
13. Patient on tutelage or guardianship
14. Other anti-cancer drugs and treatments: -Chemotherapy, targeted therapies, and immunotherapies - Radiofrequency, radiotherapy
15. Major surgical procedure within 4 weeks prior to initiation of study treatment
16. More than 3 prior lines of chemotherapy for metastatic disease
17. 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
18. Patients receiving any investigational drug within the previous 21 days before study treatment
19. Impossibility of submitting to the medical follow-up of the study for geographical, social or psychic reasons
20. 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
21. Mean QT interval corrected for heart rate using Fridericia’s formula (QTcF) ≥ 500 ms calculated from 3 ECGs

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Of the safety lead-in : - Incidence of dose-limiting toxicities, - Incidence and severity of adverse events graded according to the NCI CTCAE version 5.0, - Incidence and severity of adverse events of special interest graded according to the NCI CTCAE version 5.0 - Incidence of dose interruptions, dose modifications and discon
2. Of the phase II study: - 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

Secondary endpoints 4

1. Safety : Safety assessments will consist of monitoring and recording adverse events (AEs), including serious AEs (SAEs), performing protocol specified safety laboratory assessments, measuring protocol-specified vital signs, and conducting other protocol-specified tests (e.g., electrocardiogram) that are deemed critical to the safety evaluation of the study. The severity of AEs will be graded by Investigators according to NCI-CTCAE v5.0.
2. Tumor response and progression : Tumor response will be assessed using RECIST v.1.1 and iRECIST criteria
3. Progression-free survival (PFS) : Death event will be assessed until the initiation of the subsequent anti-cancer therapy.
4. Overall survival (OS) OS is defined as the time between beginning of treatment and death from any cause. Survival data will be censored at the last follow-up.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Assistance Publique Hopitaux De Paris

Sponsor organisation

Assistance Publique Hopitaux De Paris

Address

Porte 23, 1 Avenue Claude Vellefaux 1 Avenue Claude Vellefaux

City

Paris Cedex 10

Postcode

75475

Country

France

Scientific contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Investigateur coordonnateur

Public contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Investigateur coordonnateur

Locations

1 EU/EEA country · 4 investigational sites

By country

Investigational sites

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 4 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications