Study of Novel Immunomodulators as Monotherapy and in Combination With Anticancer Agents in Participants With Advanced Hepatobiliary Cancer

Study Overview
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Brief Summary
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GEMINI-Hepatobiliary study will assess the efficacy, safety and tolerability of novel immunomodulators alone and in combination with other anticancer drugs in participants with specified advanced solid tumors.

Detailed Description
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This Phase II, open-label, uncontrolled, multicentre study evaluating the preliminary efficacy and safety of MEDI5752 as monotherapy (MONO) and in combination with anticancer agents (COMBO) in participants with advanced hepatobiliary cancer (e.g., HCC, BTC, etc.). This study has a modular design with independent substudies. In Substudy 1, MEDI5752 will be evaluated as monotherapy and in combination with bevacizumab or lenvatinib in approximately 120 evaluable participants with advanced HCC. In Substudy 2, the efficacy and safety of AZD2936 or MEDI5752 plus gemcitabine and cisplatin are investigated in approximately 60 evaluable participants with advanced BTC who have not received previous treatment for advanced/metastatic disease.

Official Title
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A Phase II, Open-Label, Multi-Drug, Multi-Center, Master Protocol to Evaluate the Efficacy and Safety of Novel Immunomodulators as Monotherapy and in Combination With Anticancer Agents in Participants With Advanced Hepatobiliary Cancer (GEMINI-Hepatobiliary)

Conditions
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Hepatocellular Carcinoma, Biliary Tract Cancer

Intervention / Treatment
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* Drug: MEDI5752
* Drug: Bevacizumab
* Drug: Lenvatinib
* Drug: AZD2936
* Drug: Gemcitabine
* Drug: Cisplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥18 years at the time of signing the ICF. Provision of a signed and dated written ICF. Confirmed locally advanced or metastatic solid tumor specified in substudy based on histopathology. Adequate organ and bone marrow function. At least 1 measurable not previously irradiated lesion per RECIST 1.1 Life expectancy of at least 12 weeks at the time of screening. Willing and able to provide an adequate tumor sample. Exclusion Criteria: History of allogeneic organ transplantation. Active or prior documented autoimmune or inflammatory disorders. Uncontrolled intercurrent illness. History of another primary malignancy, leptomeningeal carcinomatosis, and active primary immunodeficiency. Active infection, brain metastases or spinal cord compression. Participants co-infected with HBV and hepatitis D virus (HDV). Previous treatment in the present study. For substudy 1, history of hepatic encephalopathy within 12 months prior to treatment allocation.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1A<br>MEDI5752 monotherapy | Drug: MEDI5752<br>* CTLA-4/Anti-PD-1 Bispecific Antibody<br>|
| Experimental: Cohort 1B<br>MEDI5752 combination with bevacizumab | Drug: MEDI5752<br>* CTLA-4/Anti-PD-1 Bispecific Antibody<br>Drug: Bevacizumab<br>* 15 mg/kg, IV (in the vein) on day 1 of each 21 day cycle. Number of Cycles: until disease progression or unacceptable toxicity develops.<br>|
| Experimental: Cohort 1C<br>MEDI5752 combination with lenvatinib | Drug: MEDI5752<br>* CTLA-4/Anti-PD-1 Bispecific Antibody<br>Drug: Lenvatinib<br>* Daily use per oral (8 mg capsules/day for participants < 60 kg or 12 mg/day for participants ≥ 60 kg) of 21 day cycle. Number of Cycles: until disease progression or unacceptable toxicity develops.<br>|
| Experimental: Cohort 2A<br>AZD2936 combination with Gemcitabine and Cisplatin | Drug: AZD2936<br>* anti- PD-1 and TIGIT bispecific antibody<br>Drug: Gemcitabine<br>* 1000 mg/m2, IV infusion<br>Drug: Cisplatin<br>* 25 mg/m2, IV infusion<br>|
| Experimental: Cohort 2B<br>MEDI5752 combination with Gemcitabine and Cisplatin | Drug: MEDI5752<br>* CTLA-4/Anti-PD-1 Bispecific Antibody<br>Drug: Gemcitabine<br>* 1000 mg/m2, IV infusion<br>Drug: Cisplatin<br>* 25 mg/m2, IV infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate (ORR) | ORR is defined as the proportion of participants who have a confirmed CR (complete response) or confirmed PR (partial response), determined by the Investigator at local site per RECIST 1.1 (For HCC sub-study 1) | Through study completion, an average of 2 years | 
| The number of participants with adverse events/serious adverse events | Number of participants with adverse events and with serious adverse events including abnormal clinical observations, abnormal Electrocardiogram (ECG) parameters, abnormal laboratory assessments and abnormal vital signs that changed from baseline. | Through study completion, an average of 2 years | 
| Progression free survival (PFS) | PFS is defined as the time from the start of studyintervention until progression per RECIST 1.1 as assessed by the Investigator at the local site or death due to any cause in the absence of progression, whichever occurs first. (For BTC sub-study 2) | Through study completion, an average of 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration Of Response (DOR) | DoR is defined as the time from the date of first documented confirmed response until date of documented progression per RECIST 1.1 by the Investigator at local site or death due to any cause in the absence of disease progression, whichever occurs first. | Through study completion, an average of 2 years | 
| Disease Control Rate (DCR) | DCR at 12 and 24 weeks is defined as the percentage of participants who have a Complete response (CR) or Partial response (PR) in the first 13 and 25 weeks or who have Stable disease (SD) for at least 11 and 23 weeks after the date of first dose respectively, per RECIST 1.1 as assessed by the investigator at local site and derived from the raw tumour data. | At 12 and 24 weeks | 
| Progression free survival (PFS) | PFS is defined as the time from the start of study intervention until progression per RECIST 1.1 as assessed by the Investigator at the local site or death due to any cause in the absence of progression, whichever occurs first. | Through study completion, an average of 2 years | 
| Overall Survival (OS) | OS is defined as the time from the start of study intervention until the date of death due to any cause, whichever occurs first. | Through study completion, an average of 2 years | 
| Anti Drug Antibody (ADA) | Incidences of ADAs against novel immunomodulators in serum. | Through study completion, an average of 2 years | 
| Pharmacokinetics of novel immunomodulators: Maximum plasma concentration of the study drug (Cmax) | Maximum observed plasma concentration of the study drug | From the first dose of study intervention, at predefined intervals throughout the administration of novel immunomodulators ( approx 2 years ) | 
| Pharmacokinetics of novel immunomodulators: Time to maximum plasma concentration of the study drug (T-max) | Time to maximum observed plasma concentration of the study drug | From the first dose of study intervention, at predefined intervals throughout the administration of novel immunomodulators ( approx 2 years ) | 
| lmmunogenicity of novel immunomodulators | The number and percentage of participants who develop ADAs. | From the first dose of study intervention, at predefined intervals throughout the administration of novel immunomodulators ( approx 2 years) | 
| Objective response rate (ORR) | ORR is defined as the proportion of participants who have a confirmed CR (complete response) or confirmed PR (partial response), determined by the Investigator at local site per RECIST 1.1 | Through study completion, an average of 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hepatobiliary cancer, Hepatocellular carcinoma, Biliary tract cancer, GEMINI-Hepatobiliary, MEDI5752, AZD2936, Bispecific antibody, Volrustomig, Rilvegostomig