A Study of MGC018 in Combination With MGD019 in Participants With Advanced Solid Tumors

Study Overview
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Brief Summary
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Study CP-MGC018-02 is a study of vobramitamab duocarmazine (MGC018) in combination with lorigerlimab. The study is designed to characterize safety, tolerability, pharmacokinetics (PK), immunogenicity, pharmacodynamics, and preliminary antitumor activity. Participants with relapsed or refractory, unresectable, locally advanced or metastatic solid tumors including, but not limited to, mCRPC, melanoma, pancreatic cancer, hepatocellular carcinoma (HCC), ovarian cancer, and renal cell carcinoma (RCC) will be enrolled. Vobramitamab duocarmazine and lorigerlimab are administered separately on Day 1 of every 4-week (28-day) cycle at the assigned dose for each cohort. Participants who do not meet criteria for study drug discontinuation may receive study drugs for up to 2 years. Tumor assessments are performed every 8 weeks for the initial 6 months on study drugs, then every 12 weeks (± 21 days) until progressive disease (PD). Participants will be followed for safety throughout the study. .

Official Title
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A Phase 1/1b Dose Escalation and Cohort Expansion Study of MGC018 in Combination With Checkpoint Inhibitor in Participants With Advanced Solid Tumors

Conditions
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Advanced Solid Tumor, Castration-Resistant Prostatic Cancer, Malignant Melanoma, Pancreatic Ductal Carcinoma, Hepatocellular Cancer, Epithelial Ovarian Cancer, Renal Cell Carcinoma

Intervention / Treatment
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* Biological: vobramitamab duocarmazine
* Biological: lorigerlimab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1. Ability to provide and document informed consent and willing and able to comply with all study procedures. Participants diagnosed with advanced solid tumors including but not limited to metastatic castration-resistant prostate cancer, melanoma, pancreatic cancer, hepatocellular carcinoma, ovarian cancer and renal cell carcinoma. Participants have received approved therapies according to their diagnosis. Participants must have an available tumor tissue sample. A fresh tumor biopsy may be performed if no archival sample is available. Eastern Cooperative Oncology Group performance status of less than or equal to 2. Life expectancy of at least 12 weeks. Evidence of measurable tumor for evaluation Acceptable end organ function according to laboratory results. Patients must agree to use highly-effective contraception during the study, and not donate sperm or ova. Exclusion Criteria: Any underlying medical or psychiatric condition impairing participant's ability to receive, tolerate, or comply with the planned treatment or study procedures. Another malignancy that required treatment within the past 2 years. Participants who have had curative therapy for non-melanomatous skin cancer, localized prostate cancer (Gleason score < 6), or carcinoma in situ are eligible for the study. Active viral, bacterial, or fungal infection requiring systemic treatment within 1 week of initiation of study drug. Participants are eligible after SARS CoV 2-related symptoms have fully recovered for ≥ 72 hours. History of immunodeficiency. Participants with HIV are eligible if they have a CD4+ count ≥ 300/µL, undetectable viral load, and maintained on antiretroviral therapy for a minimum of 4 weeks. Prior autologous/allogeneic stem cell or tissue/solid organ transplant Prior treatment with MGD009, enoblituzumab, or other B7-H3 targeted agents for cancer. Clinically significant cardiovascular disease, lung compromise, venous insufficiency, or gastrointestinal disorders. Participants with greater than Grade 1 peripheral neuropathy. Participants who have a history of severe adverse events (AEs) from immune checkpoint inhibitors (anti-PD-1, anti-PD-L1, or CTLA-4 inhibitors). All other AEs from prior immune checkpoint inhibitors must be resolved to Grade 1 or less. Participants with any grade neurologic toxicity from prior immune checkpoint inhibitors are excluded. Pleural effusion or ascites. Trace pleural or peritoneal fluid is not exclusionary. History of Guillain-Barre syndrome, myasthenia gravis, or other autoimmune sensory or motor neuropathies.

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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort -1<br>vobramitamab duocarmazine at dose level -1 and lorigerlimab intravenously (IV) every 4 weeks | Biological: vobramitamab duocarmazine<br>* Vobramitamab duocarmazine is an antibody drug conjugate (ADC) targeted against B7-H3.<br>* Other names: MGC018;Biological: lorigerlimab<br>* Lorigerlimab is a bispecific DART® molecule that binds PD-1 and CTLA-4.<br>* Other names: MGD019;|
| Experimental: Cohort 1<br>vobramitamab duocarmazine at dose level 1 and lorigerlimab IV every 4 weeks | Biological: vobramitamab duocarmazine<br>* Vobramitamab duocarmazine is an antibody drug conjugate (ADC) targeted against B7-H3.<br>* Other names: MGC018;Biological: lorigerlimab<br>* Lorigerlimab is a bispecific DART® molecule that binds PD-1 and CTLA-4.<br>* Other names: MGD019;|
| Experimental: Cohort 2<br>vobramitamab duocarmazine at dose level 1 and lorigerlimab IV every 4 weeks | Biological: vobramitamab duocarmazine<br>* Vobramitamab duocarmazine is an antibody drug conjugate (ADC) targeted against B7-H3.<br>* Other names: MGC018;Biological: lorigerlimab<br>* Lorigerlimab is a bispecific DART® molecule that binds PD-1 and CTLA-4.<br>* Other names: MGD019;|
| Experimental: Cohort 3<br>vobramitamab duocarmazine at dose level 2 and lorigerlimab IV every 4 weeks | Biological: vobramitamab duocarmazine<br>* Vobramitamab duocarmazine is an antibody drug conjugate (ADC) targeted against B7-H3.<br>* Other names: MGC018;Biological: lorigerlimab<br>* Lorigerlimab is a bispecific DART® molecule that binds PD-1 and CTLA-4.<br>* Other names: MGD019;|
| Experimental: Cohort 4<br>vobramitamab duocarmazine at dose level 3 and lorigerlimab IV every 4 weeks | Biological: vobramitamab duocarmazine<br>* Vobramitamab duocarmazine is an antibody drug conjugate (ADC) targeted against B7-H3.<br>* Other names: MGC018;Biological: lorigerlimab<br>* Lorigerlimab is a bispecific DART® molecule that binds PD-1 and CTLA-4.<br>* Other names: MGD019;|
| Experimental: Cohort 5<br>vobramitamab duocarmazine at dose level 4 and lorigerlimab IV every 4 weeks | Biological: vobramitamab duocarmazine<br>* Vobramitamab duocarmazine is an antibody drug conjugate (ADC) targeted against B7-H3.<br>* Other names: MGC018;Biological: lorigerlimab<br>* Lorigerlimab is a bispecific DART® molecule that binds PD-1 and CTLA-4.<br>* Other names: MGD019;|
| Experimental: Cohort Expansion<br>maximum tolerated dose of vobramitamab duocarmazine and lorigerlimab IV every 4 weeks | Biological: vobramitamab duocarmazine<br>* Vobramitamab duocarmazine is an antibody drug conjugate (ADC) targeted against B7-H3.<br>* Other names: MGC018;Biological: lorigerlimab<br>* Lorigerlimab is a bispecific DART® molecule that binds PD-1 and CTLA-4.<br>* Other names: MGD019;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with adverse events (AEs) |  | Up to 2 years | 
| Number of participants with serious adverse events (SAEs) |  | Up to 2 years | 
| Number of participants with AEs leading to study treatment discontinuation |  | Up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum observed concentration (Cmax) of vobramitamab duocarmazine | Peak concentration of vobramitamab duocarmazine | Cycle 1 Day 1 Preinfusion, end of infusion (EOI [1-hour]), 2 hours and 5 hours after EOI, Day 8; Day 15; Cycle 2 Day 1 Preinfusion, EOI, 1 hour after EOI; Day 8; Day 15; Day 1 of subsequent cycles pre-infusion and EOI (every 4 weeks) up to 2 years | 
| Maximum observed concentration (Cmax) of lorigerlimab | Peak concentration of lorigerlimab | Cycle 1 Day 1 Preinfusion, end of infusion (EOI [1-hour]), 1 hour and 4 hours after EOI, Day 8, Day 15; Cycle 2 Day 1 Preinfusion, EOI, 1 hour after EOI; Day 8, Day 15; Day 1 of subsequent cycles pre-infusion and EOI (every 4 weeks) up to 2 years | 
| Time to maximum concentration (Tmax) of vobramitamab duocarmazine | Time at which peak concentration of vobramitamab duocarmazine is observed | Cycle 1 Day 1 Preinfusion, end of infusion (EOI [1-hour]), 2 hours and 5 hours after EOI, Day 8; Day 15; Cycle 2 Day 1 Preinfusion, EOI, 1 hour after EOI; Day 8, Day 15; Day 1 of subsequent cycles pre-infusion and EOI (every 4 weeks) up to 2 years. | 
| Time to maximum concentration (Tmax) of lorigerlimab | Time at which peak concentration of lorigerlimab is observed | Cycle 1 Day 1 Preinfusion, end of infusion (EOI [1-hour]), 1 hour and 4 hours after EOI, Day 8; Day 15; Cycle 2 Day 1 Preinfusion, EOI, 1 hour after EOI; Day 8, Day 15; Day 1 of subsequent cycles pre-infusion and EOI (every 4 weeks) up to 2 years. | 
| Area under the concentration-time curve during the dosing interval (AUCtau) of vobramitamab duocarmazine | Concentration of vobramitamab duocarmazine in the bloodstream during the 28-day dosing interval after dose administration | Cycle 1 Day 1 Preinfusion, end of infusion (EOI [1-hour)], 2 hours and 5 hours after EOI, Day 8; Day 15; Cycle 2 Day 1 Preinfusion, EOI, 1 hour after EOI; Day 8, Day 15; Day 1 of subsequent cycles pre-infusion and EOI (every 4 weeks) up to 2 years. | 
| Area under the concentration-time curve during the dosing interval (AUCtau) of lorigerlimab | Concentration of lorigerlimab in the bloodstream during the 28-day dosing interval after dose administration | Cycle 1 Day 1 Preinfusion, end of infusion (EOI [1-hour]), 1 hours and 4 hours after EOI, Day 8; Day 15; Cycle 2 Day 1 Preinfusion, EOI, Day 8, Day 15; Day 1 of subsequent cycles pre-infusion and EOI (every 4 weeks) up to 2 years. | 
| Trough concentration of vobramitamab duocarmazine | Concentration of vobramitamab duocarmazine at the end of a dosing interval | Day 1 of each cycle (every 4 weeks) up to 2 years. | 
| Trough concentration of lorigerlimab | Concentration of lorigerlimab at the end of a dosing interval | Day 1 of each cycle (every 4 weeks) up to 2 years. | 
| Number of participants who develop anti-drug antibodies (ADA) to vobramitamab duocarmazine |  | Assessed every 4 weeks up to 2 years | 
| Number of participants who develop ADA to lorigerlimab |  | Assessed every 4 weeks up to 2 years | 
| Objective response rate (ORR) |  | Assessed every 8 weeks for the first 6 months, then every 12 weeks for up to 2 years. | 
| Progression free survival (PFS) | PFS is defined as the time from the first dose date to the date of first documented PD or death from any cause, whichever occurs first. | Assessed every 8 weeks for the first 6 months, then every 12 weeks. Survival status is assessed approximately every 12 weeks after the last dose of study treatment until withdrawal of consent, lost to follow up, death, or end of the study, up to 2 years. | 
| Duration of response (DoR) | DoR is defined as the time from the date of initial response (CR or PR) to the date of first documented PD or death from any cause, whichever occurs first. | Assessed every 8 weeks for the first 6 months, then every 12 weeks for up to 2 years. | 
| Overall survival (OS) | OS is defined as the time from the first dose date to the date of death from any cause. | Survival status is assessed approximately every 12 weeks after the last dose of study treatment until withdrawal of consent, lost to follow up, death, or end of the study, up to 2 years | 
| Radiographic PFS (rPFS) for mCRPC | rPFS is defined as the time from the first dose of study drug to the first occurrence of radiographic PD of soft tissue lesions using RECIST v1.1, or appearance of ≥ 2 new bone lesions, or death from any cause | Assessed every 8 weeks for the first 6 months, then every 12 weeks for up to 2 years. | 
| Prostate-specific antigen (PSA) response rate for mCRPC | PSA response is defined as ≥ 50% decline from baseline in PSA with confirmation at least 3 weeks later. | PSA is assessed every 4 weeks, up to 2 years while on treatment, then every 12 weeks for up to an additional 2 years in follow-up. | 
| Best PSA percent change for mCRPC |  | PSA is assessed every 4 weeks, up to 2 years while on treatment, then every 12 weeks for up to an additional 2 years in follow-up. | 
| PSA progression for mCRPC | PSA progression is defined as an increase that is ≥ 25% and ≥ 2 ng/mL the baseline or lowest value observed, and which confirmed by a second value at least 3 weeks later. | PSA is assessed every 4 weeks, up to 2 years while on treatment, then every 12 weeks for up to an additional 2 years in follow-up. | 
| Duration of PSA response for mCRPC | DoR of PSA is defined as the time from the date of initial PSA response to the date of first documented PSA progression or death from any cause, whichever occurs first. | PSA is assessed every 4 weeks, up to 2 years while on treatment, then every 12 weeks for up to an additional 2 years in follow-up. |