MGC018 With or Without MGA012 in Advanced Solid Tumors

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to evaluate the safety and tolerability, pharmacokinetics (PK) pharmacodynamics and preliminary antitumor activity of vobramitamab duocarmazine (MGC018) in patients with advanced solid tumors. Patients with solid tumors will be enrolled in the Dose Escalation Phase; Cohort Expansion will include metastatic castrate-resistant prostate cancer (mCRPC), non-small cell lung cancer (NSCLC), triple-negative breast cancer (TNBC), squamous cell carcinoma of the head and neck (SCCHN), and melanoma. Patients who do not experience unacceptable toxicity or meet criteria for permanent discontinuation may undergo additional cycles for up to two years. Patients in Cohort Expansion will be followed for survival every 3 months for 2 years following last dose.

Official Title
-----------------
A Phase 1/2, First-in-Human, Open-Label, Dose-Escalation Study of MGC018 (Anti-B7-H3 Antibody Drug Conjugate) Alone and in Combination With MGA012 (Anti-PD-1 Antibody) in Patients With Advanced Solid Tumors

Conditions
-----------------
Squamous Cell Carcinoma of Head and Neck, Triple Negative Breast Cancer, Melanoma, Advanced Solid Tumor, Adult, Metastatic Castrate Resistant Prostate Cancer, Non Small Cell Lung Cancer

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


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Tissue specimen available for retrospective analysis of B7-H3 and PD-L1 expression. Eastern Cooperative Oncology Group performance status of ≤2 Life expectancy ≥ 12 weeks for dose escalation phase and ≥ 24 weeks for cohort expansion phase Measurable disease. Prostate cancer patients with bone only disease are eligible. Acceptable laboratory parameters and adequate organ reserve. Dose Escalation Phase: Patients with histologically proven, unresectable, locally advanced or metastatic solid tumors for whom no therapy with demonstrated clinical benefit is available. Module A Cohort Expansion: mCRPC that has progressed with one prior line of chemotherapy for metastatic disease and no more than two prior lines of anti-hormonal therapy. NSCLC: metastatic disease after standard cytotoxic, targeted, and biologic or checkpoint inhibitor therapy. No more than 2 prior lines of chemotherapy. TNBC: Locally advance or metastatic disease that has progressed following at least one systemic therapy. SCCHN that has progressed during or following at least one systemic therapy for metastatic or recurrent unresectable disease. No more than 2 prior lines of chemotherapy. Melanoma that has progressed during or following at least one systemic treatment for unresectable locally advanced or metastatic disease. Patients who are intolerant of or refused standard therapy are eligible. Exclusion Criteria: Patients with history of prior central nervous system (CNS) metastasis must have been treated, be asymptomatic, and not have concurrent treatment for CNS disease, progression of CNS metastases on MRI, CT or PET within 6 months, or history of leptomeningeal disease or cord compression at the time of enrollment. Prior treatment with B7-H3 targeted agents for cancer. Treatment with systemic cancer therapy, biologic agents, or anti-hormonal therapy (mCRPC) within 4 weeks, prior small molecule targeted or kinase inhibitors within 14 days or 5 half-lives, prior radioligand within 6 months Clinically significant cardiovascular disease. Clinically significant pulmonary compromise or requirement for supplemental oxygen. History of clinically-significant cardiovascular disease, including but not limited to pericarditis or pericardial effusion. Active viral (including confirmed or presumed COVID-19), bacterial, or systemic fungal infection requiring parenteral treatment within 7 days of first study drug administration. Known history of hepatitis B or C infection or known positive test for hepatitis B surface antigen or core antigen, or hepatitis C polymerase chain reaction. Known positive testing for human immunodeficiency virus or history of acquired immune deficiency syndrome. Major trauma or major surgery within 4 weeks of first study drug administration. Clinically significant venous insufficiency. > Grade 1 peripheral neuropathy. Evidence of pleural effusion. Evidence of ascites. Serum testosterone >50 ng/dl or >1.7 nmol/L in mCRPC in Module A Cohort Expansion Phase

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Dose escalation will use a 3+3+3 design to identify an MAD or MTD, followed by a Cohort Expansion.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>0.5 mg/kg IV every 3 weeks | Biological: vobramitamab duocarmazine<br>* Anti-B7H3 antibody drug conjugate<br>* Other names: MGC018;|
| Experimental: Cohort 2<br>1.0 mg/kg IV every 3 weeks | Biological: vobramitamab duocarmazine<br>* Anti-B7H3 antibody drug conjugate<br>* Other names: MGC018;|
| Experimental: Cohort 3<br>2.0 mg/kg IV every 3 weeks | Biological: vobramitamab duocarmazine<br>* Anti-B7H3 antibody drug conjugate<br>* Other names: MGC018;|
| Experimental: Cohort 4<br>3.0 mg/kg IV every 3 weeks | Biological: vobramitamab duocarmazine<br>* Anti-B7H3 antibody drug conjugate<br>* Other names: MGC018;|
| Experimental: Cohort 5<br>4.0 mg/kg IV every 3 weeks | Biological: vobramitamab duocarmazine<br>* Anti-B7H3 antibody drug conjugate<br>* Other names: MGC018;|
| Experimental: mCRPC expansion<br>3.0 mg/kg IV every 3 weeks | Biological: vobramitamab duocarmazine<br>* Anti-B7H3 antibody drug conjugate<br>* Other names: MGC018;|
| Experimental: NSCLC expansion<br>3.0 mg/kg IV every 3 weeks | Biological: vobramitamab duocarmazine<br>* Anti-B7H3 antibody drug conjugate<br>* Other names: MGC018;|
| Experimental: TNBC expansion<br>3.0 mg/kg IV every 3 weeks | Biological: vobramitamab duocarmazine<br>* Anti-B7H3 antibody drug conjugate<br>* Other names: MGC018;|
| Experimental: Melanoma expansion<br>3.0 mg/kg IV every 3 weeks | Biological: vobramitamab duocarmazine<br>* Anti-B7H3 antibody drug conjugate<br>* Other names: MGC018;|
| Experimental: SCCHN expansion<br>3.0 mg/kg IV every 3 weeks | Biological: vobramitamab duocarmazine<br>* Anti-B7H3 antibody drug conjugate<br>* Other names: MGC018;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with Adverse Events of vobramitamab duocarmazine as assessed by CTCAE v4.03 | Safety is based on evaluation of adverse events (AEs) and serious adverse events (SAEs) from the time of study drug administration through the End of Study visit. | Throughout the study up to 24 months | 
| Number of patients with dose limiting toxicities (DLT) | Maximum tolerated or maximum administered dose of vobramitamab duocarmazine | up to 42 days from first dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best overall response (BOR) of vobramitamab duocarmazine | The best response recorded from the start of the study treatment until the end of treatment with vobramitamab duocarmazine, taking into account any requirement for confirmation of response. | Throughout the study for up to 24 months | 
| Objective response rate (ORR) of vobramitamab duocarmazine | The percentage of participants who achieve a complete response (CR or partial response (PR) to treatment with vobramitamab duocarmazine | Efficacy evaluations every 9 weeks throughout the study for up to 24 months | 
| Progression free survival (PFS) of vobramitamab duocarmazine | Efficacy assessed as the first dose date to the date of first documented progression using Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1), or death from any cause, whichever occurs first. | Every 9 weeks for up to 24 months | 
| Duration of response (DoR) of vobramitamab duocarmazine | Efficacy assessed as the time from the date of initial objective response to the date of first documented progression RECIST v1.1, or the date of death from any cause, whichever occurs first. | Throughout the study for up to 48 months | 
| Overall survival (OS) of vobramitamab duocarmazine | Efficacy assessed as the time from the first dose date to the date of death from any cause. | Every 9 weeks for up to 24 months | 
| PSA response rate | Percent of prostate cancer patients with at least 50% reduction in prostate-specific antigen (PSA) with confirmation at least 3 weeks later | Every 3 weeks up to 24 months | 
| Best PSA response | For prostate cancer patients, the greatest change from baseline in PSA. | Every 3 weeks up to 24 months | 
| Area under the curve | Area under the plasma concentration versus time curve of vobramitamab duocarmazine | Cycle 1 (each cycle is 21 days) and Cycle 2: Predose, end of infusion (EOI), 1, 4, 24, 72 hours post-infusion and predose on Days 8, 15 and 22; Predose and EOI samples collected at Day 1 Cycle 3 and afterwards for up to 24 months | 
| Cmax | Maximum Plasma Concentration of vobramitamab duocarmazine | Cycle 1 (each cycle is 21 days) and Cycle 2: Predose, end of infusion (EOI), 1, 4, 24, 72 hours post-infusion and predose on Days 8, 15 and 22; Predose and EOI samples collected at Day 1 Cycle 3 and afterwards for up to 24 months | 
| Tmax | Time to reach maximum (peak) plasma concentration of vobramitamab duocarmazine | Cycle 1 (each cycle is 21 days) and Cycle 2: Predose, end of infusion (EOI), 1, 4, 24, 72 hours post-infusion and predose on Days 8, 15 and 22; Predose and EOI samples collected at Day 1 Cycle 3 and afterwards for up to 24 months | 
| Ctrough | Trough plasma concentration of vobramitamab duocarmazine | Cycle 1 (each cycle is 21 days) and Cycle 2: Predose, end of infusion (EOI), 1, 4, 24, 72 hours post-infusion and predose on Days 8, 15 and 22; Predose and EOI samples collected at Day 1 Cycle 3 and afterwards for up to 24 months | 
| CL | Total body clearance of the drug from plasma of vobramitamab duocarmazine and vobramitamab duocarmazine+retifanlimab | Cycle 1 (each cycle is 21 days) and Cycle 2: Predose, end of infusion (EOI), 1, 4, 24, 72 hours post-infusion and predose on Days 8, 15 and 22; Predose and EOI samples collected at Day 1 Cycle 3 and afterwards for up to 24 months | 
| Vss | Apparent volume of distribution at steady state of vobramitamab duocarmazine | Cycle 1 (each cycle is 21 days) and Cycle 2: Predose, end of infusion (EOI), 1, 4, 24, 72 hours post-infusion and predose on Days 8, 15 and 22; Predose and EOI samples collected at Day 1 Cycle 3 and afterwards for up to 24 months | 
| t1/2 | Terminal half life of vobramitamab duocarmazine | Cycle 1 (each cycle is 21 days) and Cycle 2: Predose, end of infusion (EOI), 1, 4, 24, 72 hours post-infusion and predose on Days 8, 15 and 22; Predose and EOI samples collected at Day 1 Cycle 3 and afterwards for up to 24 months . | 
| Immunogenicity | Percent of patients with anti-drug antibodies against vobramitamab duocarmazine | Every 3 weeks through end of treatment, up to 24 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
antibody-drug conjugate (ADC), B7-H3