MGC018 Versus Androgen Receptor Axis-targeted Therapy in Participants With Metastatic Castration Resistant Prostate Cancer

Overview

Study CP-MGC018-03 is a randomized, open-label, seamless, Phase 2/3 study. The study will enroll participants with metastatic castration-resistant prostate cancer (mCRPC) previously treated with one prior androgen receptor axis-targeted therapy (ARAT) and one prior taxane-containing regimen. ARAT includes abiraterone, enzalutamide, or apalutamide. Participants may have received up to 1 prior cabazitaxel regimen, but no other chemotherapy agents. The Phase 2 stage will assess efficacy and tolerability of two MGC018 experimental arms (2.0 mg/kg Q4W and 2.7 mg/kg Q4W) compared to the control arm (abiraterone or enzalutamide). Approximately 150 participants will be randomized 1:1:1 in Phase 2 among the three study treatment arms (two MGC018 experimental arms and one control arm). An interim analysis will be performed to select the Phase 3 dose regimen for the MGC018 experimental arm for Phase 3 after approximately 150 participants enrolled in Phase 2 have been followed for at least 2 months (60 days). The Phase 3 stage will assess efficacy of the selected dose regimen for the MGC018 experimental arm versus the control arm (abiraterone or enzalutamide). Approximately 270 additional participants will be randomized 1:1 between each study treatment arm in Phase 3 (one MGC018 experimental arm and the control arm).

Full Title of Study: “A Phase 2/3, Randomized, Open-label, Study of MGC018 Versus Androgen Receptor Axis-targeted Therapy (Abiraterone or Enzalutamide) in Participants With Metastatic Castration-resistant Prostate Cancer”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: November 2024

Interventions

  • Drug: ARAT
    • androgen receptor axis-targeted therapy
  • Biological: Arm A: MGC018
    • MGC018 2.0 mg/kg administered every 4 weeks
  • Biological: Arm B MGD018
    • MGC018 2.7 mg.kg administered every 4 weeks

Arms, Groups and Cohorts

  • Experimental: Control Arm
    • ARAT: either abiraterone or enzalutamide
  • Experimental: Arm A
    • MGC018 2.0 mg/kg every 4 weeks
  • Experimental: Arm B
    • MGC018 2.7 mg/kg every 4 weeks

Clinical Trial Outcome Measures

Primary Measures

  • Radiographic progression free survival (rPFS) using blinded independent central review (BICR) in Phase 2
    • Time Frame: Every 8 weeks for the first 24 weeks, then every 12 weeks, up to 2 years
    • The rPFS is defined as the time from the date of randomization to the date of first documented progressive disease (PD) per Prostate Cancer Working Group 3 (PCWG3) or death from any cause, whichever occurs first. Three arms will be compared: Arm A, Arm B, and control.
  • rPFS) using BICR in Phase 3
    • Time Frame: Every 8 weeks for the first 24 weeks, then every 12 weeks, up to 2 years
    • The rPFS is defined as the time from the date of randomization to the date of first documented PD per PCWG3 or death from any cause, whichever occurs first. Two arms will be compared: Arm A or Arm B, and control

Secondary Measures

  • Prostate-specific Cancer Antigen (PSA) response rate per PCWG3 criteria in Phase 2
    • Time Frame: Every 4 weeks throughout study participation, up to 2 years
    • 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%.
  • Time to PSA progression per PCWG3 criteria In Phase 2
    • Time Frame: Every 4 weeks throughout study participation, up to 2 years
    • In participants with a decrease in PSA from baseline: ≥ 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: ≥ 25% increase and an absolute increase of ≥ 2 ng/mL above the baseline value after 12 weeks.
  • Overall response rate (ORR) in Phase 2
    • Time Frame: Every 8 weeks for the first 24 weeks, then every 12 weeks, up to 2 years
    • The number of participants experiencing a complete response (CR) or partial response (PR) to treatment.
  • Duration of response (DoR) per PCWG3 criteria and BICR in Phase 2
    • Time Frame: Every 8 weeks throughout study participation, up to 2 years
    • 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.
  • ORR per PCWG3 in Phase 3
    • Time Frame: Every 8 weeks throughout study participation, up to 2 years
    • The number of participants experiencing a CR or PR to treatment according to PCWG3 criteria using BICR. Three arms will be compared: Arm A, Arm B, and control.
  • Best Overall Response (BOR) in Phase 3
    • Time Frame: Every 8 weeks throughout study participation, up to 2 years.
    • BOR is categorized using PCWG3 as CR, PR, stable disease (SD, progressive disease (PD), or not evaluable (NE). Two arms will be compared: Arm A or Arm B, and control.
  • DoR in Phase 3
    • Time Frame: Every 8 weeks throughout study participation, up to 2 years.
    • 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. Two arms will be compared: Arm A or Arm B, and control.
  • Disease Control Rate (DCR) in Phase 3
    • Time Frame: Every 8 weeks throughout study participation, up to 2 years.
    • DCR is defined as the percentage of participants with a response of CR, PR, or SD for at least 3 months. Two arms will be compared: Arm A or Arm B, and control.
  • Overall survival (OS) in Phase 3
    • Time Frame: Every 12 weeks up to 4 years
    • The time from the date of randomization to date of death from any cause.
  • rPFS per PCWG3 using investigator review
    • Time Frame: Every 8 weeks throughout study participation, up to 2 years.
    • The rPFS is defined as the time from the date of randomization to the date of first Investigator-documented PD per PCWG3 or death from any cause, whichever occurs first.
  • ORR per PCWG3 using investigator review
    • Time Frame: Every 8 weeks throughout study participation, up to 2 years.
    • The number of participants experiencing a complete response or partial response to treatment.
  • DoR per PCWG3 using investigator review
    • Time Frame: Every 8 weeks throughout study participation, up to 2 years.
    • 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.
  • Duration of PSA response per PCWG3 criteria
    • Time Frame: Every 4 weeks throughout study participation, up to 2 years
    • Duration of PSA response is defined as the time from the date of first documented PSA response to the earliest date of PSA progression.
  • PSA percent change over time
    • Time Frame: Every 4 weeks throughout study participation, up to 2 years
  • Best PSA percent change
    • Time Frame: Every 4 weeks throughout study participation, up to 2 years
  • Time to pain progression based on BPI-sf worst pain severity in Phase 3
    • Time Frame: Every 4 weeks throughout study participation, up to 2 years
    • Pain progression is defined as an increase of ≥ 30% from baseline in the BPI-sf worst pain intensity score (item 3) observed at 2 consecutive evaluations ≥ 4 weeks apart. Time to pain progression is defined as the time interval from randomization to the first date a participant experiences pain progression.
  • Number of participants with pain progression based on BPI-sf worst pain severity in Phase 3
    • Time Frame: Every 4 weeks throughout study participation, up to 2 years
    • Pain progression is defined as an increase of ≥ 30% from baseline in the BPI-sf worst pain intensity score (item 3) observed at 2 consecutive evaluations ≥ 4 weeks apart.
  • Change from baseline in Functional Assessment of Cancer Therapy – Prostate (FACT-P) score In Phase 3
    • Time Frame: Every 4 weeks throughout the study, up to 2 years
    • Mean values and change from baseline of FACT-P total scale/subscale scores at each scheduled visit will be summarized by study treatment arm.
  • Time to first symptomatic skeletal event (SSE) in Phase 3
    • Time Frame: Every 4 weeks throughout the study, up to 2 years
    • 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.
    • Time Frame: Throughout the study, up to 2 years
  • Number of participants who develop anti-drug antibodies
    • Time Frame: Throughout the study, up to 2 years
  • maximum concentration or concentration at the end of infusion (Cmax)
    • Time Frame: Cycle 1, Day 1: Predose, end of infusion (EOI), 2-4 hours, 6-8 hours after start of infusion, Pre-infusion and EOI on Cycle 1 Day 15 and Cycle 2 Days 1 and 15; Pre-infusion and EOI on Day 1 of Cycles 3, 4, 5, 6, 9 and 12 (each cycle is 28 days)
    • The highest measured concentration of MGC018 in the bloodstream.
  • area under the concentration time curve (AUC)
    • Time Frame: Cycle 1, Day 1: Predose, end of infusion (EOI), 2-4 hours, 6-8 hours after start of infusion, Pre-infusion and EOI on Cycle 1 Day 15 and Cycle 2 Days 1 and 15; Pre-infusion and EOI on Day 1 of Cycles 3, 4, 5, 6, 9 and 12 (each cycle is 28 days)
    • AUC is the total amount of MGC018 in bloodstream after drug administration
  • Trough drug concentration (Ctrough or Cmin)
    • Time Frame: Cycle 1, Day 1: Predose, end of infusion (EOI), 2-4 hours, 6-8 hours after start of infusion, Pre-infusion and EOI on Cycle 1 Day 15 and Cycle 2 Days 1 and 15; Pre-infusion and EOI on Day 1 of Cycles 3, 4, 5, 6, 9 and 12 (each cycle is 28 days)
    • Trough concentration is the concentration measured before a subsequent dose of MGC018
  • Clearance (CL)
    • Time Frame: Cycle 1, Day 1: Predose, end of infusion (EOI), 2-4 hours, 6-8 hours after start of infusion, Pre-infusion and EOI on Cycle 1 Day 15 and Cycle 2 Days 1 and 15; Pre-infusion and EOI on Day 1 of Cycles 3, 4, 5, 6, 9 and 12 (each cycle is 28 days)
    • Drug clearance is the amount of drug removed from the bloodstream by the body per unit of time
  • Volume of distribution (Vz)
    • Time Frame: Cycle 1, Day 1: Predose, end of infusion (EOI), 2-4 hours, 6-8 hours after start of infusion, Pre-infusion and EOI on Cycle 1 Day 15 and Cycle 2 Days 1 and 15; Pre-infusion and EOI on Day 1 of Cycles 3, 4, 5, 6, 9 and 12 (each cycle is 28 days)
    • The volume of distribution is related to how much drug is distributed to body tissues, or remains in the bloodstream.
  • Terminal half-life
    • Time Frame: Cycle 1, Day 1: Predose, end of infusion (EOI), 2-4 hours, 6-8 hours after start of infusion, Pre-infusion and EOI on Cycle 1 Day 15 and Cycle 2 Days 1 and 15; Pre-infusion and EOI on Day 1 of Cycles 3, 4, 5, 6, 9 and 12 (each cycle is 28 days)
    • Terminal elimination half-life is the time it takes for the concentration of the drug in plasma or serum to be reduced by 50%

Participating in This Clinical Trial

Inclusion Criteria

  • Histologically confirmed adenocarcinoma of the prostate without evidence of neuroendocrine differentiation, signet cell, or small cell features. – Participants must have ≥ 1 metastatic lesion that is present on magnetic resonance imaging (MRI), computed tomography (CT), or bone scan obtained ≤ 28 days prior to initiation of study treatment. – Tumor progression at study entry documented by PSA or imaging per PCWG3 criteria – Received 1 prior ARAT for metastatic prostate cancer (mPC) with lack of progression for at least 12 months – Received 1 prior taxane-containing regimen for mPC. – May have received up to 1 prior cabazitaxel regiment for mPC. – Availability of archival or formalin-fixed paraffin-embedded (FFPE) tumor tissue sample for participants with metastasis to internal organs – Acceptable physical condition and laboratory values. Exclusion Criteria:

  • Any underlying medical or psychiatric condition impairing participant's ability to receive, tolerate, or comply with the planned treatment or study procedures. – Prior chemotherapy other than docetaxel or cabazitaxel. Prior immunotherapy and radiopharmaceutical therapy is allowed. – Known history of documented BRCA or ATM mutation (germline or somatic). Participants with known BRCA or ATM mutation who had disease progression or unacceptable toxicity on a PARP inhibitor are eligible. – 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.

Gender Eligibility: Male

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • MacroGenics
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Stephen L Eck, M.D., Study Director, MacroGenics
  • Overall Contact(s)
    • Global Trial Manager, 301-251-5172, info@macrogenics.com

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