Clinical trial NCT05005728: XmAb®20717 (Vudalimab) Alone or in Combination With Chemotherapy or Targeted Therapy in Patients With Metastatic Castration-Resistant Prostate Cancer
Official title: 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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Metastatic Castration-Resistant Prostate Cancer
Keywords: Prostate cancer
Metastatic castration resistant
Aggressive variant
Anaplastic
Neuroendocrine
Homologous recombination deficiency
MSI-H
CDK12
XmAb20717
Vudalimab
Lead sponsor: Xencor, Inc.
Sponsor class: INDUSTRY
First posted: 2021-08-13
Enrollment: 72
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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

Eligibility criteria: 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
  * Soft-tissue progression per RECIST 1.1
  * Progression of bone disease (evaluable disease) or 2 or more new bone lesions by bone scan
* Prostate cancer must have progressed following treatment including at least 1 androgen receptor signaling inhibitor (ARSI) agent
* 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 Cohort 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
* 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 HBsAg or HBcAb (a subject whose HBsAg is negative and HBcAb is positive may be enrolled if a HBV DNA test is negative and the subject is retested for HBsAg and HBV DNA every 2 months)

Primary outcomes:
measure: Incidence of treatment-emergent adverse events (safety and tolerability of vudalimab)
timeFrame: 8 weeks
Secondary outcomes:
measure: Objective response rate (RECIST 1.1, as modified by PCWG3)
timeFrame: 8 weeks
measure: Prostate-specific antigen (PSA) response
timeFrame: 8 weeks
measure: Bone scans based on PCWG3 criteria
timeFrame: 8 weeks
measure: Radiographic progression-free survival (PCWG3)
timeFrame: 8 weeks
measure: Duration of response (RECIST 1.1, as modified by PCWG3)
timeFrame: 8 weeks
Other outcomes:
Locations:
city: Anchorage
country: United States
facility: Alaska Oncology and Hematology
state: Alaska
city: Glendale
country: United States
facility: Palo Verde Hematology Oncology
state: Arizona
city: Phoenix
country: United States
facility: Mayo Clinic Hospital
state: Arizona
city: Duarte
country: United States
facility: City of Hope
state: California
city: Los Angeles
country: United States
facility: VA Greater Los Angeles
state: California
city: San Diego
country: United States
facility: University of California, San Diego
state: California
city: Lone Tree
country: United States
facility: Rocky Mountain Cancer Centers
state: Colorado
city: Jacksonville
country: United States
facility: Mayo Clinic
state: Florida
city: Chicago
country: United States
facility: The University of Chicago Medical Center
state: Illinois
city: Iowa City
country: United States
facility: University of Iowa Hospitals & Clinics
state: Iowa
city: Fairway
country: United States
facility: University of Kansas Clinical Research Center
state: Kansas
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Omaha
country: United States
facility: GU Research Network/Urology Cancer Center
state: Nebraska
city: Las Vegas
country: United States
facility: Comprehensive Cancer Centers of Nevada
state: Nevada
city: Albuquerque
country: United States
facility: XCancer New Mexico Oncology Hematology Consultants, Ltd.
state: New Mexico
city: Bronx
country: United States
facility: Montefiore Medical Center
state: New York
city: New York
country: United States
facility: Columbia University
state: New York
city: Tigard
country: United States
facility: Northwest Cancer Specialists
state: Oregon
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Pittsburgh
country: United States
facility: UPMC Hillman Cancer Center
state: Pennsylvania
city: Myrtle Beach
country: United States
facility: Carolina Urologic Research Center
state: South Carolina
city: Nashville
country: United States
facility: SCRI Oncology Partners
state: Tennessee
city: Weslaco
country: United States
facility: Texas Oncology-Central South
state: Texas
city: Fairfax
country: United States
facility: Virginia Cancer Specialists
state: Virginia
city: Norfolk
country: United States
facility: Virginia Oncology Associates
state: Virginia
city: Seattle
country: United States
facility: University of Washington/Seattle Cancer Care/Alliance
state: Washington
Study officials:
affiliation: Xencor, Inc.
name: Jolene Shorr
role: STUDY_DIRECTOR
References: