XmAb®20717 (Vudalimab) Alone or in Combination With Chemotherapy or Targeted Therapy in Patients With Metastatic Castration-Resistant Prostate Cancer

Phase 2 Multiple-Dose, Multiple-Arm, Parallel Assignment Study to Evaluate the Safety, Tolerability, and Preliminary Efficacy of XmAb®20717 Alone or in Combination With Chemotherapy or Targeted Therapies in Selected Subjects With Metastatic Castration-Resistant Prostate Cancer

This Phase 2 study will investigate the safety and clinical activity of vudalimab (XmAb20717) alone or in combination with standard of care anticancer therapies in patients with metastatic castration-resistant prostate cancer (mCRPC) who have progressed on prior therapy.

Study Overview

• Status: Recruiting
• Conditions: Metastatic Castration-Resistant Prostate Cancer
• Intervention / Treatment: Combination product: vudalimab + cabazitaxel or docetaxel; Combination product: vudalimab + olaparib; Biological: vudalimab monotherapy; Combination product: vudalimab + carboplatin + cabazitaxel; Combination product: vudalimab + docetaxel

Detailed Description

Detailed Description:

This is a Phase 2, open-label, multiple-dose, multiple-arm, parallel assignment study in patients with mCRPC who have progressed on prior therapy. It will enroll subjects into 1 of 5 molecularly defined cohorts based on the results of acceptable, documented prior diagnostic testing:

• Cohort A: Aggressive variant prostate cancer (AVPCa)
• Cohort B: Homologous recombination deficient (HRD)/cyclin-dependent kinase 12 (CDK12) biallelic loss tumors that have progressed on poly-adenosine diphosphate ribose polymerase inhibitors (HRD/CDK12 PARP Progressors) - Closed to Enrollment
• Cohort C: HRD/CDK12 biallelic loss tumors, naive to PARP inhibitors (HRD/CDK12 PARP Naïve) - Closed to Enrollment
• Cohort D: Microsatellite instability-high (MSI-H) or mismatch repair deficient (MMRD), or tumor mutational burden-high (TMB-H) tumors - Closed to Enrollment
• Cohort E: No Targetable Mutations

• Study Type: Interventional
• Enrollment (Estimated): 85
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Jolene Shorr; Phone Number: 858-275-0004; Email: jshorr@xencor.com
• Study Contact Backup: Name: Ginger Lee; Email: glee@xencor.com

Study Locations

• United States
  • Arizona
    • Phoenix, Arizona, United States, 85054
      • Recruiting
      • Mayo Clinic Hospital
  • California
    • Duarte, California, United States, 91010
      • Active, not recruiting
      • City of Hope
    • Los Angeles, California, United States, 90064
      • Active, not recruiting
      • VA Greater Los Angeles
    • San Diego, California, United States, 92093
      • Recruiting
      • University of California, San Diego
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Recruiting
      • Mayo Clinic
  • Illinois
    • Chicago, Illinois, United States, 60637
      • Recruiting
      • The University of Chicago Medical Center
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • Recruiting
      • University of Iowa Hospitals & Clinics
  • Kansas
    • Fairway, Kansas, United States, 66205
      • Recruiting
      • University of Kansas Clinical Research Center
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Recruiting
      • Mayo Clinic
  • Nebraska
    • Omaha, Nebraska, United States, 68130
      • Active, not recruiting
      • GU Research Network/Urology Cancer Center
  • Nevada
    • Las Vegas, Nevada, United States, 89148
      • Recruiting
      • Comprehensive Cancer Centers of Nevada
  • New Mexico
    • Albuquerque, New Mexico, United States, 87109
      • Active, not recruiting
      • XCancer New Mexico Oncology Hematology Consultants, Ltd.
  • New York
    • Bronx, New York, United States, 10461
      • Recruiting
      • Montefiore Medical Center
    • New York, New York, United States, 10032
      • Recruiting
      • Columbia University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Recruiting
      • University of Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15232
      • Recruiting
      • UPMC Hillman Cancer Center
  • Washington
    • Seattle, Washington, United States, 98109
      • Recruiting
      • University of Washington/Seattle Cancer Care/Alliance

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Able to provide written informed consent
• Adult (age ≥ 18 years)
• Histologically confirmed diagnosis of carcinoma of the prostate

• Documented progressive mCRPC based on at least one of the following criteria:

  • PSA progression, defined as at least 2 rises in PSA with a minimum of a 1-week interval (1.0 ng/mL is the minimal starting value if confirmed rise is the only indication of progression)
  • Soft-tissue progression per RECIST 1.1
  • Progression of bone disease (evaluable disease) or 2 or more new bone lesions by bone scan
• Progression after prior therapy
• Subjects who did not have a surgical orchiectomy must be on androgen suppression treatment (eg, luteinizing hormone-releasing hormone agonist) with castrate level of testosterone (≤ 50 ng/dL) and be willing to continue the treatment throughout the study

• Prior targeted or whole exome sequencing panel performed by CLIA-certified laboratory documenting:

  1. Cohort A (AVPCa) - Aggressive variant prostate cancer
  2. Cohort B or C (HRD) - Homologous recombination deficient (HRD) tumor
  3. Cohort D (MSI-H/MMRD) - Microsatellite instability-high (MSI-H) or mismatch repair deficient (MMRD) tumors (MSI-H/MMRD) or TMB-H (≥ 10 mut/Mb)
  4. Cohort E (No Targetable Mutations)

NOTE: Cohorts B, C, and D are no longer open for enrollment

• Evaluable disease according to PCWG3 criteria
• Adequate archival metastatic tumor tissue or agree to undergo a biopsy of at least 1 metastatic site (fresh biopsy of primary prostate is only allowed if there is clear local disease and no other measurable disease site or biopsiable bone lesion)
• ECOG performance status of 0 or 1
• Able and willing to complete the study according to the study schedule

Exclusion Criteria:

• Currently receiving anticancer therapies other than androgen deprivation therapy
• Prior treatment with docetaxel (Cohort E only)
• Treatment with any other anticancer therapy within 2 weeks of the start of study drug (ie, other immunotherapy, chemotherapy, radiation therapy, etc.)
• Disease progression on prior treatment with cabazitaxel plus carboplatin (applicable to subjects eligible for Cohort A) or cabazitaxel alone (applicable to subjects eligible for Cohorts B and E)
• Prior treatment with any cytotoxic T-lymphocyte-associated protein (CTLA4), PD1, PDL1, or programmed cell death ligand 2 (PDL2) directed immunotherapy, except subjects in Cohort D, who will have had prior FDA-approved checkpoint inhibitor therapy
• Grade 4 immune-mediated adverse events related to prior immunotherapy (applicable to subjects eligible for Cohort D)
• Failure to recover from any toxicity related to previous anticancer treatment to ≤ Grade 2
• Have known active central nervous system metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are radiologically stable, ie, are without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), are clinically stable, and are without requirement of steroid treatment for at least 14 days prior to first dose of study treatment.
• Platelet count < 100 × 109/L
• Hemoglobin level ≤ 9.0 g/dL
• Absolute neutrophil count ≤ 1.7 × 109 for subjects who will receive cabazitaxel; < 1.0 × 109/L for all others
• Aspartate aminotransferase at screening > 3 × upper limit of normal (ULN) for subjects without known liver involvement by tumor or > 5 × ULN for subjects with known liver involvement by tumor
• Alanine aminotransferase at screening > 3 × ULN for subjects without known liver involvement by tumor or > 5 × ULN for subjects with known liver involvement by tumor
• Bilirubin ≥ 1.5 × ULN (unless prior diagnosis and documentation of ongoing hemolysis or Gilbert's syndrome has been made)
• Estimated creatinine clearance < 50 mL/minute calculated by the Cockcroft Gault or Modification of Diet in Renal Disease formulas
• Active known or suspected autoimmune disease (except vitiligo; type 1 diabetes mellitus or residual hypothyroidism due to an autoimmune condition that is treatable with hormone replacement therapy only; psoriasis, atopic dermatitis, or another autoimmune skin condition that is managed without systemic therapy; or arthritis that is managed without systemic therapy beyond oral acetaminophen and nonsteroidal anti-inflammatory drugs)
• Have any condition requiring systemic treatment with corticosteroids, prednisone equivalents, or other immunosuppressive medications within 14 days prior to first dose of study drug (except inhaled or topical corticosteroids or brief courses of corticosteroids given for prophylaxis of contrast dye allergic response). Subjects who are currently taking prednisone from a previous prostate cancer therapy will be permitted to enroll in the study.
• Receipt of an organ allograft
• Known history of left ventricular ejection fraction ≤ 40%
• History or evidence of any other clinically unstable/uncontrolled disorder, condition, or disease other than their primary malignancy that, in the opinion of the Investigator, would pose a risk to patient safety or interfere with study evaluations, procedures, or completion
• Evidence of any serious bacterial, viral, parasitic, or systemic fungal infections within the 30 days prior to the first dose of study drug
• Receipt of a live-virus vaccine within 30 days prior to the first dose of study drug (seasonal flu vaccines that do not contain live virus are permitted)
• Known human immunodeficiency virus (HIV) positive subject with CD4+ T-cell (CD4+) counts < 350 cells/μL, or an HIV viral load greater than 400 copies/mL, or a history of an AIDS (acquired immunodeficiency syndrome)-defining opportunistic infection within the past 12 months, or who has not been on established antiretroviral therapy (ART) for at least 4 weeks prior to initiation of study drug dosing. (Effective ART is defined as a drug, dosage, and schedule associated with reduction and control of the viral load.) (HIV positive subjects who do not meet any of these exclusion criteria are eligible)
• Positive test for hepatitis C RNA (a subject who is hepatitis C virus [HCV] antibody positive but HCV RNA negative due to documented, curative prior antiviral treatment or natural resolution is eligible)
• Positive test for hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb; a subject whose HBsAg is negative and HBcAb is positive may be enrolled if a hepatitis B virus [HBV] DNA test is negative and the subject is retested for HBsAg and HBV DNA every 2 months)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort A - AVPCa	Combination product: vudalimab + carboplatin + cabazitaxel; Vudalimab IV, carboplatin IV, cabazitaxel IV
Experimental: Cohort B - HRD/CDK12 PARP - Progressors	Combination product: vudalimab + cabazitaxel or docetaxel; Vudalimab IV, cabazitaxel or docetaxel IV
Experimental: Cohort C - HRD/CDK12 PARP Naïve	Combination product: vudalimab + olaparib; Vudalimab IV, olaparib oral
Experimental: Cohort D - MSI-H, MMRD or TMB-H	Biological: vudalimab monotherapy; Vudalimab IV
Experimental: Cohort E - No Targetable Mutations	Combination product: vudalimab + docetaxel; Vudalimab IV, docetaxel IV

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Incidence of treatment-emergent adverse events (safety and tolerability of vudalimab)	8 weeks

Secondary Outcome Measures

Outcome Measure	Time Frame
Objective response rate (RECIST 1.1, as modified by PCWG3)	8 weeks
Prostate-specific antigen (PSA) response	8 weeks
Bone scans based on PCWG3 criteria	8 weeks
Radiographic progression-free survival (PCWG3)	8 weeks
Duration of response (RECIST 1.1, as modified by PCWG3)	8 weeks

Collaborators and Investigators

• Sponsor: Xencor, Inc.
• Investigators: Study Director: Jolene Shorr, Xencor, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): October 22, 2021
• Primary Completion (Estimated): March 31, 2025
• Study Completion (Estimated): September 30, 2025

Study Registration Dates

• First Submitted: August 5, 2021
• First Submitted That Met QC Criteria: August 11, 2021
• First Posted (Actual): August 13, 2021

Study Record Updates

• Last Update Posted (Actual): March 5, 2024
• Last Update Submitted That Met QC Criteria: March 1, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Prostate cancer; Neuroendocrine; CDK12; Anaplastic; Homologous recombination deficiency; MSI-H; Metastatic castration resistant; Aggressive variant; XmAb20717; Vudalimab
• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Genital Neoplasms, Male; Prostatic Diseases; Urogenital Diseases; Male Urogenital Diseases; Genital Diseases, Male; Genital Diseases; Prostatic Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Poly(ADP-ribose) Polymerase Inhibitors; Docetaxel; Carboplatin; Olaparib
• Other Study ID Numbers: XmAb20717-04

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No