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

Sponsor

Xencor, Inc. (Industry)

Overall Status

Recruiting

CT.gov ID

NCT05005728

Collaborator

(none)

Enrollment

Locations

Arms

32.3

Anticipated Duration (Months)

8.5

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Metastatic Castration-Resistant Prostate Cancer	Combination Product: XmAb20717 + carboplatin + cabazitaxel Combination Product: XmAb20717 + olaparib Biological: XmAb20717 monotherapy	Phase 2

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 after treatment with at least 2 prior lines of anticancer therapy. It will enroll subjects into one of 5 molecularly defined cohorts based on the results of acceptable, documented prior diagnostic testing:

Cohort A: Aggressive variant (anaplastic) adenocarcinoma of the prostate (AVPCa)
Cohort B: Homologous recombination deficient (HRD)/cyclin-dependent kinase 12 (CDK12) mutation positive tumors that have progressed on poly-adenosine diphosphate ribose polymerase inhibitors (HRD/CDK12 PARP Progressors)
Cohort C: HRD/CDK12 mutation positive tumors not previously treated with PARP inhibitors (HRD/CDK12 PARP Naïve)
Cohort D: Microsatellite instability-high (MSI-H) or mismatch repair deficient (MMRD) tumors (MSI-H/MMRD)
Cohort E: No Targetable Mutations

Subjects will receive XmAb20717 alone (Cohort D) or in combination with standard therapy (XmAb20717 + carboplatin + cabazitaxel [or docetaxel if no prior treatment]: Cohorts A, B, and E; XmAb20717 + olaparib: Cohort C).

Study Design

Study Type:

Interventional

Anticipated Enrollment :

85 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Oct 22, 2021

Anticipated Primary Completion Date :

Jun 30, 2023

Anticipated Study Completion Date :

Jun 30, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cohort A - AVPCa XmAb20717 + carboplatin + cabazitaxel	Combination Product: XmAb20717 + carboplatin + cabazitaxel Subjects will receive XmAb20717 10 mg/kg IV every 2 weeks plus carboplatin target AUC 4 IV every 3 weeks and cabazitaxel 20 mg/m2 IV every 3 weeks
Experimental: Cohort B - HRD/CDK12 PARP - Progressors XmAb20717 + carboplatin + cabazitaxel	Combination Product: XmAb20717 + carboplatin + cabazitaxel Subjects will receive XmAb20717 10 mg/kg IV every 2 weeks plus carboplatin target AUC 4 IV every 3 weeks and cabazitaxel 20 mg/m2 IV every 3 weeks
Experimental: Cohort C - HRD/CDK12 PARP Naïve XmAb20717 + olaparib	Combination Product: XmAb20717 + olaparib Subjects will receive XmAb20717 10 mg/kg IV every 2 weeks plus olaparib 300 mg orally twice daily
Experimental: Cohort D - MSI-H or MMRD XmAb20717 monotherapy	Biological: XmAb20717 monotherapy Subjects will receive XmAb20717 10 mg/kg IV every 2 weeks
Experimental: Cohort E - No Targetable Mutations XmAb20717 + carboplatin + cabazitaxel	Combination Product: XmAb20717 + carboplatin + cabazitaxel Subjects will receive XmAb20717 10 mg/kg IV every 2 weeks plus carboplatin target AUC 4 IV every 3 weeks and cabazitaxel 20 mg/m2 IV every 3 weeks

Outcome Measures

Primary Outcome Measures

Incidence of treatment-emergent adverse events (safety and tolerability of XmAb20717) [8 weeks]

Secondary Outcome Measures

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]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

Male

Accepts Healthy Volunteers:

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 treatment with at least 2 prior lines of anticancer therapy approved for treatment of metastatic prostate cancer; prior treatment of subjects in Cohort D (MSI-H or MMRD) must include a checkpoint inhibitor approved by FDA for that indication
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:

Cohort A (AVPCa) - Aggressive variant prostate cancer
Cohort B or C (HRD) - Homologous recombination deficient (HRD) tumor
Cohort D (MSI-H/MMRD) - Microsatellite instability-high (MSI-H) or mismatch repair deficient (MMRD) tumors (MSI-H/MMRD)
Cohort E (No Targetable Mutations) - Not eligible for Cohorts A, B, C, or D

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

Treatment with any other anticancer therapy within 2 weeks of the start of study drug (ie, other immunotherapy, chemotherapy, radiation therapy, etc.)
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)
A 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.)
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)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	City of Hope	Duarte	California	United States	91010
2	University of Iowa Hospitals & Clinics	Iowa City	Iowa	United States	52242
3	GU Research Network/Urology Cancer Center	Omaha	Nebraska	United States	68130
4	Comprehensive Cancer Centers of Nevada	Las Vegas	Nevada	United States	89148
5	XCancer New Mexico Oncology Hematology Consultants, Ltd.	Albuquerque	New Mexico	United States	87109
6	Montefiore Medical Center	Bronx	New York	United States	10461
7	Columbia University	New York	New York	United States	10032
8	University of Pannsylvania	Philadelphia	Pennsylvania	United States	19104
9	UPMC Hillman Cancer Center	Pittsburgh	Pennsylvania	United States	15232
10	University of Washington/Seattle Cancer Care/Alliance	Seattle	Washington	United States	98109