A Study of Vobramitamab Duocarmazine in Participants With Metastatic Castration Resistant Prostate Cancer and Other Solid Tumors

• vobramitamab duocarmazine 2.0 mg (Arm A) (Biological), also known as MGC018: 2.0 mg/kg intravenous (IV) every 4 weeks
• vobramitamab duocarmazine 2.7 mg (Arm B) (Biological), also known as MGC018: 2.7 mg.kg IV every 4 weeks
• vobramitamab duocarmazine (Biological), also known as MGC018: 2.7 mg.kg IV every 4 weeks
• Abiraterone (Drug): 1000 mg once daily
• Enzalutamide (Drug): 160 mg daily

Primary outcomes

• Part 1: Six-month Radiographic Progression Free Survival (rPFS) as Determined by the Investigator [Assessed every 8 weeks for six months. Six month data reported.]: The landmark analysis for 6 month rPFS rate will occur when all participants on Part 1 have been on study for at least 6 months.
• Part 2: Objective Response Rate (ORR) Per Investigator Assessment of Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 Criteria [Every 8 weeks for the first 24 weeks, then every 12 weeks. Average duration of participation, 10 months.]: The ORR is defined as the percentage of participants in the response evaluable population who achieve a best overall response of complete response (CR) or partial response (PR), per RECIST version 1.1 criterial CR is defined as disappearance of all target and non-target lesions. PR is defined as at least a 30% decrease from baseline in the sum of diameters of target lesions.

Secondary outcomes

• Part 1: ORR Per PCWG3 Criteria as Determined by the Investigator [Every 8 weeks for the first 24 weeks, then every 12 weeks. Average duration of participation, 10 months,]: To qualify as an objective response, CR and PR require confirmation at least 4 weeks after initial observation of complete response (CR) or partial response (PR). CR + PR = ORR
• Part 1: Median Duration of Response (DoR) Per PCWG3 Criteria as Determined by the Investigator [Every 8 weeks for the first 24 weeks, then every 12 weeks. Average duration of participation, 10 months.]: The DoR will be calculated as the time from the date of initial tumor response (CR or PR) to the date of first documented PD or death from any cause, whichever occurs first.
• Part 1: Mean Best Tumor Size Change Over Time [Every 8 weeks for the first 24 weeks, then every 12 weeks. Average duration of participation, 10 months.]
• Part 1: Prostate-specific Cancer Antigen (PSA) Response Rate Per PCWG3 Criteria [Every 4 weeks throughout study participation. Average duration 10 months.]: PSA response is defined as a ≥ 50% decline in PSA from baseline with PSA confirmation ≥ 3 weeks after the first documented reduction in PSA of ≥ 50%.
• Part 1: Time to PSA Progression Per PCWG3 Criteria [Every 4 weeks throughout study participation. Average duration of participation, 10 months.]: In participants with a decrease in PSA from baseline, PSA progression is defined as a ≥ 25% increase and an absolute increase of ≥ 2 ng/mL above the nadir value, which is confirmed by a consecutive second value obtained ≥ 3 weeks later. In participants with no decrease in PSA from baseline, PSA progression is defined as a ≥ 25% increase and an absolute increase of ≥ 2 ng/mL above the baseline value after 12 weeks. Time to PSA progression is defined as the time from the date of randomization to the first PSA progression.
• Part 1: Duration of PSA Response Per PCWG3 Criteria [Every 4 weeks throughout study participation. Average duration of participation, 10 months.]: Duration of PSA response is defined as the time from the date of first documented PSA response to the earliest date of PSA progression.
• Part 1: Best PSA Percent Change [Every 4 weeks throughout study participation. Average duration of participation, 10 months.]
• Part 1: Time to First Symptomatic Skeletal Event (SSE) [Every 4 weeks throughout the study. Average duration of participation, 10 months.]: An SSE is defined as any of the following events: new symptomatic pathological fracture, requirement for radiation therapy to relieve bone pain, spinal cord compression, or tumor-related orthopedic surgical intervention. The time to first SSE is defined as the time from the date of randomization to the first occurrence of SSE.
• Number of Participants With Adverse Event (AEs), Serious AEs (SAEs), and AEs Leading to Study Treatment Discontinuation. [Throughout the study, average duration of participation, 10 months.]
• Number of Participants Who Develop Anti-drug Antibodies (ADA) [Every 4 weeks throughout the study, average duration of participation was 10 months.]: Participant specimens were evaluated for the presence of ADA beginning a baseline and throughout the study. If at any time during the study, the results show evidence of ADA, they were counted as ADA positive. There was no time-to- event analysis nor by visit analysis of the data.
• Part 2: Median DoR Per Investigator Assessment of RECIST 1.1 Criteria [Every 8 weeks for the first 24 weeks, then every 12 weeks. Average duration of participation, 10 months.]: The DoR will be calculated as the time from the date of initial tumor response (CR or PR) to the date of first documented progressive disease (PD) or death from any cause, whichever occurs first.
• Part 2: Median Progression Free Survival (PFS) Per Investigator Assessment of RECIST 1.1 Criteria [Every 8 weeks for the first 24 weeks, then every 12 weeks. Average duration of participation, 10 months.]: PFS is defined as the time from the date of the first dose to the date of first PD per RECIST 1.1 criteria or death from any cause, whichever occurs first.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Part 1 only: Histologically confirmed adenocarcinoma of the prostate without evidence of neuroendocrine differentiation, signet cell, or small cell features.
* Part 2 only: Histologically confirmed SCC or the anus, melanoma, HNSCC, squamous NSCLC, or SCLC.
* Part 1 only: Received 1 prior ARAT for metastatic or non-metastatic, castration-sensitive or castration-resistant prostate cancer. A second ARAT regimen of <60 days used as bridging to lutetium-177 is permitted. Up to 3 total prior lines of therapy for mCRPC are permitted..
* Part 2 only: At least 1 prior line of systemic therapy for unresectable or metastatic disease and no more than 2 prior lines of cytotoxic chemotherapy. Participants with HNSCC or melanoma must have received prior PD-1 or PD-L1 inhibitor for advanced or metastatic disease.
* All participants must have ≥ 1 metastatic lesion, according to RECIST 1.1 or PCWG3 criteria, that is present on magnetic resonance imaging (MRI), computed tomography (CT), or bone scan obtained ≤ 28 days prior to initiation of study treatment.
* All participants must have tumor progression, according to disease-specific criteria, following their most recent anti-cancer therapy.
* All participants must have and available archival or formalin-fixed paraffin-embedded (FFPE) tumor tissue sample for participants with metastasis to internal organs
* All participants have acceptable physical condition and laboratory values.
* All participants of childbearing potential must agree to use highly effective methods of birth control.
* All participants must not be pregnant, planning to be pregnant, or breastfeeding.

Exclusion Criteria:

* Any underlying medical or psychiatric condition impairing participant's ability to receive, tolerate, or comply with the planned treatment or study procedures.
* Part 1 only: Received >1 prior taxane-containing regimen for prostate cancer. A second taxane regimen of <60 days used as bridging for lutetium-177 is permitted.
* Part 1 only: Received >3 total prior therapies for mCRPC
* Part 1 only: Participants with known BRCA or ATM mutation (germline or somatic) are not eligible unless they received prior treatment with a PARP inhibitor where available, indicated and tolerated.
* Another hematologic or solid tumor ≥ stage 1 malignancy that completed surgery, last dose of radiotherapy, or last dose of systemic anti-cancer therapy ≤ 2 years from first dose of study treatment. Participants who had curative therapy for non-melanomatous skin cancer or for localized malignancy are eligible.
* Untreated, symptomatic central nervous system (CNS) metastasis.
* Prior treatment with any B7-H3 targeted agent for cancer,
* Contradictions to the use of corticosteroid treatment
* Prior stem cell, tissue, or solid organ transplant.
* Part 1 only: Use of products that have published anti-prostate cancer activity or are known to decrease PSA.

Participant flow

Outcome results

• Part 1: Six-month Radiographic Progression Free Survival (rPFS) as Determined by the Investigator (Primary), Number, proportion of participants: Part 1: MGC018 2.0 mg (Arm A) 0.69 (0.57 to 0.78); Part 1: MGC018 2.7 mg (Arm B) 0.70 (0.46 to 0.79); Part 1: Control Arm 0.47 (0.021 to NA); Part 2
• Part 2: Objective Response Rate (ORR) Per Investigator Assessment of Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 Criteria (Primary), Number, percentage of participants: Part 2 0
• Part 1: ORR Per PCWG3 Criteria as Determined by the Investigator (Secondary), Number, percentage of participants: Part 1: MGC018 2.0 mg (Arm A) 13.6; Part 1: MGC018 2.7 mg (Arm B) 30.6; Part 1: Control Arm 0; Part 2
• Part 1: Median Duration of Response (DoR) Per PCWG3 Criteria as Determined by the Investigator (Secondary), Median, months: Part 1: MGC018 2.0 mg (Arm A) 9.4 (3.68 to NA); Part 1: MGC018 2.7 mg (Arm B) 9.1 (5.78 to 9.92); Part 1: Control Arm ; Part 2
• Part 1: Mean Best Tumor Size Change Over Time (Secondary), Mean, percent change from baseline: Part 1: MGC018 2.0 mg (Arm A) -13.0 +/- 59.70; Part 1: MGC018 2.7 mg (Arm B) -29.0 +/- 33.92; Part 1: Control Arm -7.44 +/- 7.16; Part 2
• Part 1: Prostate-specific Cancer Antigen (PSA) Response Rate Per PCWG3 Criteria (Secondary), Number, percent: Part 1: MGC018 2.0 mg (Arm A) 45.8 (34.8 to 57.1); Part 1: MGC018 2.7 mg (Arm B) 38.0 (26.8 to 50.3); Part 1: Control Arm ; Part 2
• Part 1: Time to PSA Progression Per PCWG3 Criteria (Secondary), Median, months: Part 1: MGC018 2.0 mg (Arm A) 5.9 (4.63 to 6.97); Part 1: MGC018 2.7 mg (Arm B) 6.9 (4.83 to NA); Part 1: Control Arm 4.6 (NA to NA); Part 2
• Part 1: Duration of PSA Response Per PCWG3 Criteria (Secondary), Median, months: Part 1: MGC018 2.0 mg (Arm A) 6.1 (4.63 to NA); Part 1: MGC018 2.7 mg (Arm B) NA (5.13 to NA); Part 1: Control Arm ; Part 2
• Part 1: Best PSA Percent Change (Secondary), Mean, percent change from baseline: Part 1: MGC018 2.0 mg (Arm A) -28.7 +/- 67.05; Part 1: MGC018 2.7 mg (Arm B) -33.1 +/- 70.89; Part 1: Control Arm ; Part 2
• Part 1: Time to First Symptomatic Skeletal Event (SSE) (Secondary), Mean, days: Part 1: MGC018 2.0 mg (Arm A) 3.71 +/- 1.984; Part 1: MGC018 2.7 mg (Arm B) 2.80 +/- 2.142; Part 1: Control Arm ; Part 2
• Number of Participants With Adverse Event (AEs), Serious AEs (SAEs), and AEs Leading to Study Treatment Discontinuation. (Secondary), Count of participants, Participants: Part 1: MGC018 2.0 mg (Arm A) 89; Part 1: MGC018 2.7 mg (Arm B) 86; Part 1: Control Arm 3; Part 2 4
• Number of Participants Who Develop Anti-drug Antibodies (ADA) (Secondary), Number, participants: Part 1: MGC018 2.0 mg (Arm A) 0; Part 1: MGC018 2.7 mg (Arm B) 0; Part 1: Control Arm ; Part 2 0
• Part 2: Median DoR Per Investigator Assessment of RECIST 1.1 Criteria (Secondary)
• Part 2: Median Progression Free Survival (PFS) Per Investigator Assessment of RECIST 1.1 Criteria (Secondary), Median, months: Part 2 NA (NA to NA)

Adverse events

Time frame: Adverse events were collected for each participant from the time of first dose through 28 days after the last dose of study treatment or until the start of another anti-cancer treatment, up to average duration of participation, 10 months months. All-cause mortality was assessed from the time of first dose until death, or participant withdrawal of consent, or the end of the study, whichever was earlier, up to average duration of participation, 10 months.

Serious adverse events by term

23 more terms not shown.

Other adverse events by term

• Study Protocol (PDF, 2024-08-19)
• Statistical Analysis Plan (PDF, 2024-04-18)

• Liudmila Schafer, M.D., Study director, MacroGenics