Ignite Creation Date:
2024-05-06 @ 7:49 PM
Last Modification Date:
2024-10-26 @ 3:15 PM
Study NCT ID:
NCT06152523
Status:
NOT_YET_RECRUITING
Last Update Posted:
2023-11-30
First Post:
2023-09-05
Brief Title:
Monalizumab and MEDI5752 in Patients With MSI andor dMMR Metastatic Cancer
Sponsor:
Assistance Publique - Hôpitaux de Paris
Organization:
Assistance Publique - Hôpitaux de Paris
Study Overview
Official Title:
Monalizumab and MEDI5752 in Patients With MSI andor dMMR Metastatic Cancer
Status:
NOT_YET_RECRUITING
Status Verified Date:
2023-11
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
MONAMI
Brief Summary:
MSI is a molecular indicator of defective DNA mismatch repair dMMR The MSIdMMR 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
MSIdMMR cancers are highly immunogenic MSIdMMR 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 MSIdMMR cancers are highly sensitive to ICIs whatever the tumor location MSIdMMR 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 MSIdMMR mCRC and gastric cancer The phase III KEYNOTE-177 trial evaluating first-line treatment of pembrolizumab in patients with MSIdMMR 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 445 months Median PFS was 165 versus 82 months HR 059 95CI 045-079 The hazard ratio favored pembrolizumab versus chemotherapy with a trend toward reduction in the risk of death HR 074 95 CI 053-103 P00359 despite a 60 effective crossover rate Pembrolizumab has been approved by the FDA and the EMA for patients with newly diagnosed MSIdMMR 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 MSIdMMR gastric cancer patients N 44 Indeed the unstratified hazard ratio for OS with nivolumab plus chemotherapy versus chemotherapy alone was 033 95 CI 012-087 for patients with MSIdMMR 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-1CTLA-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 NKG2AHLA-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 NKG2AHLA-E axis play a crucial role in MSIdMMR tumors Therefore a combined blockade of non-redundant checkpoint pathways to unleash NK and T cells seems particularly promising for MSIdMMR 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 NKG2AHLA-E axis with a bispecific monoclonal antibody targeting both PD1 and CTLA4 for patients with metastatic MSIdMMR cancers
MSIdMMR cancers are highly immunogenic MSIdMMR 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 MSIdMMR cancers are highly sensitive to ICIs whatever the tumor location MSIdMMR 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 MSIdMMR mCRC and gastric cancer The phase III KEYNOTE-177 trial evaluating first-line treatment of pembrolizumab in patients with MSIdMMR 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 445 months Median PFS was 165 versus 82 months HR 059 95CI 045-079 The hazard ratio favored pembrolizumab versus chemotherapy with a trend toward reduction in the risk of death HR 074 95 CI 053-103 P00359 despite a 60 effective crossover rate Pembrolizumab has been approved by the FDA and the EMA for patients with newly diagnosed MSIdMMR 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 MSIdMMR gastric cancer patients N 44 Indeed the unstratified hazard ratio for OS with nivolumab plus chemotherapy versus chemotherapy alone was 033 95 CI 012-087 for patients with MSIdMMR 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-1CTLA-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 NKG2AHLA-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 NKG2AHLA-E axis play a crucial role in MSIdMMR tumors Therefore a combined blockade of non-redundant checkpoint pathways to unleash NK and T cells seems particularly promising for MSIdMMR 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 NKG2AHLA-E axis with a bispecific monoclonal antibody targeting both PD1 and CTLA4 for patients with metastatic MSIdMMR cancers
Detailed Description:
MONAMI is a multicenter 4 French hospitals single-arm phase II trial according to AHerns 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 v11 may not be indicative of true disease progression During the study participants who meet criteria for disease progression per RECIST v11 unconfirmed disease progression per iRECIST criteria iuPD and show evidence of clinical benefit may continue study treatment at the Investigators 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 eg cord compression requiring urgent alternative medical intervention For participants receiving treatment beyond progression an additional radiographic assessmentscan 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
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 v11 may not be indicative of true disease progression During the study participants who meet criteria for disease progression per RECIST v11 unconfirmed disease progression per iRECIST criteria iuPD and show evidence of clinical benefit may continue study treatment at the Investigators 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 eg cord compression requiring urgent alternative medical intervention For participants receiving treatment beyond progression an additional radiographic assessmentscan 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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 2022-004122-22 | EUDRACT_NUMBER | None | None |