MGC018 With or Without MGA012 in Advanced Solid Tumors

Phase 2TerminatedNCT03729596

MacroGenics143 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

143

Conditions

Squamous Cell Carcinoma of Head and Neck Triple Negative Breast Cancer Melanoma Advanced Solid Tumor, Adult

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Locations (21)

UCLA Department of Medicine - Hematology/Oncology

Santa Monica, California, United States

Sibley Memorial Hospital

Washington D.C., District of Columbia, United States

The Johns Hopkins Kimmel Cancer Center

Baltimore, Maryland, United States

START Midwest

Grand Rapids, Michigan, United States

Nebraska Methodist Hospital

Omaha, Nebraska, United States

Comprehensive Cancer Centers of Nevada

Las Vegas, Nevada, United States

Carolina Biooncology Institute

Huntersville, North Carolina, United States

Inova Schar Cancer Institute

Fairfax, Virginia, United States

Virginia Cancer Specialist

Fairfax, Virginia, United States

St Vincent's Health Network (Kinghorn Cancer Centre)

Darlinghurst, Australia

...and 11 more locations

Outcomes

Primary Outcomes

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.

Time frame: Throughout the study up to 24 months

Number of Participants With Dose Limiting Toxicities (DLT)

Number of participants with severe side effects from study treatment during the DLT evaluation period (6 weels)

Time frame: up to 42 days from first dose

Secondary Outcomes

Best Overall Response (BOR) of Vobramitamab Duocarmazine

The best response recorded from the start of the study treatment until the end of treatment according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria version 1.1, taking into account any requirement for confirmation of response. Complete response (CR) is defined as disappearance of all target and non-target lesions. Partial response (PR) is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters, no progression of non-target lesions, and no new lesions. Progressive disease (PD) is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, or unequivocal progression of non-target lesions, or appearance of new lesions. Stable disease (SD) is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify as progression. Not evaluable (NE) is where the response cannot be determined.

Time frame: 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

Time frame: Efficacy evaluations every 9 weeks throughout the study for up to 24 months

Progression Free Survival (PFS) of Vobramitamab Duocarmazine

PFS is calculated from the first dose date until the date of first documented PD using RECIST v1.1, or death from any cause, whichever occurs first. Progressive disease (PD) is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, or unequivocal progression of non-target lesions, or appearance of new lesions. Median PFS and 95% CI is estimated using the Kaplan-Meier method.

Time frame: Every 9 weeks for up to 24 months

Median Duration of Response (DoR) of Vobramitamab Duocarmazine

Median DoR assessed as the time from the date of initial objective response to the date of first documented PD, per RECIST v1.1, or the date of death from any cause, whichever occurs first. Median DoR and 95% CI is estimated using the Kaplan-Meier method.

Time frame: Throughout the study for up to 48 months

Median Overall Survival (OS) of Vobramitamab Duocarmazine

Median OS assessed as the time from the first dose date to the date of death from any cause, using the Kaplan-Meier method for estimating median and confidence interval. .

Time frame: 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

Time frame: Every 3 weeks up to 24 months

Best PSA Response

For prostate cancer patients, the greatest change from baseline in PSA.

Time frame: Every 3 weeks up to 24 months

Mean Area Under the Curve (AUC) of Vobramitamab Duocarmazine Antibody Drug Conjugate (ADC)

Area under the plasma concentration versus time curve of vobramitamab duocarmazine

Time frame: At baseline, Cycle 1, Day 1: 1 hour, 4 hours after the first dose, Day 2, Day 3, Day 7, Day 14 and Cycle 2 Day 1 (approximately 21 days after the first dose).

Mean AUC of Duocarmycin

Area under the plasma concentration versus time curve of duocarmycin (unconjugated payload) in the bloodstream

Time frame: At baseline, Cycle 1, Day 1: 1 hour, 4 hours after the first dose, Day 2, Day 3, Day 7, Day 14 and Cycle 2 Day 1 (approximately 21 days after the first dose).

Mean Maximum Concentration Vobramitamab Duocarmazine ADC

Maximum Plasma Concentration of vobramitamab duocarmazine ADC in the bloodstream

Time frame: At baseline, Cycle 1, Day 1, 1 and 4 hours after the end of infusion, Day 2, and Day 3.

Mean Maximum Concentration Duocarmycin

Maximum Plasma Concentration of vobramitamab duocarmazine ADC in the bloodstream

Time frame: At baseline, Cycle 1, Day 1, 1 and 4 hours after the end of infusion, Day 2, and Day 3.

Mean Trough Concentration of Vobramitamab Duocarmazine ADC

Average trough plasma concentration of vobramitamab duocarmazine ADC in the bloodstream.

Time frame: At baseline, and before subsequent infusion Cycle 2, Day 1 (Study Day 22).

Mean Trough Concentration of Duocarmycin

Average trough plasma concentration of duocarmycin unconjugated payload in the bloodstream.

Time frame: At baseline, and before subsequent infusion Cycle 2, Day 1 (Study Day 22).

Number of Participants Who Develop MGC018 Anti-drug Antibodies

Shifts in MGC018 anti-drug antibodies after treatment with vobramitamab duocarmazine

Time frame: Every 3 weeks through end of treatment, up to 24 months