Platform Study for Prostate Researching Translational Endpoints Correlated to Response to Inform Use of Novel Combinations

Phase 1

Completed

• Conditions: Metastatic Castration-resistant Prostate Cancer
• Interventions: Drug: NKTR-214 (Cohort A); Drug: CDX-301 (Cohort B and C); Radiation: Stereotactic body radiation therapy (SBRT) (Cohort B); Drug: Nivolumab (Cohort A, B and C); Drug: INO-5151 (Cohort C); Device: Cellectra 2000; Drug: Poly-ICLC (Cohort B)

• Registration Number: NCT03835533
• Lead Sponsor: Parker Institute for Cancer Immunotherapy

Brief Summary

This study is designed to evaluate multiple clinical hypotheses and mechanistically-defined combinations to evaluate the safety and efficacy of immunotherapy combinations in participants with mCRPC who have received prior secondary androgen receptor signaling inhibitor therapy (eg, abiraterone, enzalutamide, apalutamide).

Detailed Description

This is an open-label, non-randomized, exploratory platform protocol designed to assess the safety and antitumor activity of multiple immunotherapy combinations in participants with mCRPC who have received prior therapy. The platform study will consist of 2 stages: Stage 1, an initial stage to evaluate safety, biomarkers, and clinical activity of a combination and Stage 2, an expanded cohort, when warranted, based on the safety, clinical activity, and/or biomarker results from Stage 1. The Sponsor intends to modify and/or add new combinations to the protocol as data emerge from this and other trials.

Participants must provide consent for archival tissue from a prior biopsy or surgery for prostate cancer and must consent to baseline and on-treatment biopsies, if medically feasible. Participants will be assigned to receive one of the enrolling combination study interventions and will be monitored for safety and response.

Study Timeline

• Study First Submitted: 2019-02-07
• Study First Submitted QC: 2019-02-07
• Study First Posted: 2019-02-08
• Study Start: 2019-06-21
• Primary Completion: 2022-10-03
• Study Completion: 2022-10-03
• Results First Submitted: 2022-12-21
• Status Verified: 2023-10
• Results First Submitted QC: 2023-10-24
• Last Update Submitted: 2023-10-24
• Results First Posted: 2024-04-12
• Last Update Posted: 2024-04-12

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Male
• Target Recruitment: 43

Inclusion Criteria

1. Metastatic castration resistant prostate cancer with castrate-level testosterone (< 50 ng/dL) at screening.

2. Disease progression per Prostate Cancer Working Group 3 (PCWG3) criteria.

3. Provide fresh pre-treatment core needle or incisional biopsy of a metastatic tumor lesion not previously irradiated. Fine needle aspiration is not acceptable.

   1. Additionally, if a pre-treatment biopsy is not medically feasible for participants with bone only disease, formalin-fixed paraffin-embedded (FFPE) tumor specimen in a paraffin block (preferred) or at least 10 slides containing unstained, freshly cut, serial sections must be provided.
   2. For all participants, in addition to fresh pre-treatment biopsy, consent for archival tissue is required.

4. Must be willing to undergo tumor biopsy(ies) on treatment, if medically feasible.

5. Have received and progressed on prior secondary androgen receptor signaling inhibitor therapy (eg, abiraterone, enzalutamide, apalutamide).

6. Participants must discontinue antiandrogen therapy (ie, bicalutamide, flutamide, nilutamide) at least 4-6 weeks prior to registration with no evidence of prostate-specific antigen (PSA) decline after washout.

   1. Bicalutamide: Washout period at least 6 weeks
   2. Flutamide and nilutamide: Washout period at least 4 weeks

7. Participants must discontinue therapies for mCRPC for 5 half-lives or 28 days, whichever is shorter.

   1. Participants will remain on gonadotropin-releasing hormone (GnRH) agents throughout this study.
   2. Prior chemotherapy is allowed if no progression of disease on chemotherapy as defined by PCWG3-modified RECIST 1.1.
   3. Prior treatment with sipuleucel-T, radium-223, or poly ADP ribose polymerase (PARP) inhibitor (eg, olaparib) is allowed.
   4. Tissue biopsy may be performed during washout period.

Key

Exclusion Criteria

1. Has a diagnosis of immunodeficiency or conditions that need systemic corticosteroid replacement therapy > 10 mg/day prednisone (or equivalent) or other immunosuppressive medications within 28 days prior to the first dose of study intervention. Inhaled steroids are permitted if necessary.

2. Has any active known or suspected autoimmune disease. Participants with vitiligo, type I diabetes mellitus, controlled autoimmune hypothyroidism, psoriasis not requiring systemic treatment, or other conditions under control are permitted to enroll.

3. Has a known history of active TB (Bacillus Tuberculosis).

4. Has known history of, or any evidence of active, non-infectious pneumonitis.

5. Known history of testing positive for human immunodeficiency virus (HIV), known acquired immunodeficiency syndrome (AIDS), or any positive test for hepatitis B or hepatitis C virus representing acute or chronic disease.

6. Has received a live vaccine within 30 days of planned start of study intervention.

   Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (eg, Flu-Mist®) are live attenuated vaccines, and are not allowed.

7. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least 4 weeks prior to the first dose of study intervention and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to study intervention. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Cohort A: NKTR-214 + Nivolumab	NKTR-214 (Cohort A)	-
Cohort C: CDX-301 + INO-5151 + Nivolumab	CDX-301 (Cohort B and C)	-
Cohort B: SBRT + CDX-301 + Poly-ICLC + Nivolumab	Stereotactic body radiation therapy (SBRT) (Cohort B)	-
Cohort B: SBRT + CDX-301 + Poly-ICLC + Nivolumab	CDX-301 (Cohort B and C)	-
Cohort C: CDX-301 + INO-5151 + Nivolumab	INO-5151 (Cohort C)	-
Cohort C: CDX-301 + INO-5151 + Nivolumab	Cellectra 2000	-
Cohort A: NKTR-214 + Nivolumab	Nivolumab (Cohort A, B and C)	-
Cohort B: SBRT + CDX-301 + Poly-ICLC + Nivolumab	Poly-ICLC (Cohort B)	-
Cohort B: SBRT + CDX-301 + Poly-ICLC + Nivolumab	Nivolumab (Cohort A, B and C)	-
Cohort C: CDX-301 + INO-5151 + Nivolumab	Nivolumab (Cohort A, B and C)	-

Primary Outcome Measures

Name	Time	Method
Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE)	For AEs, from initiation of study drug through 100 days after last dose, up to 24 months. For SAEs, from signing informed consent (prior to Screening) through 100 days after last dose, up to 24 months.	An AE is any event that either occurs after the initiation of study drug, having been absent at baseline, or, if present at baseline, appears to have worsened in severity or frequency, regardless of its relation to the drug. An SAE is any AE that suggests a significant hazard, contraindication, side effect, or untoward medical occurrence that results in death, is life threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.; Investigators recorded AEs during each participant interaction. Prior to initiation of study drug, only SAEs that were related to a protocol-mandated intervention were recorded.; The AE row includes all participants who experienced at least one AE, including SAEs.

Secondary Outcome Measures

Name	Time	Method
Composite Response Rate (CRR)	Initiation of study drug through radiographic progression or initiation of new anti-cancer therapy, whichever occurred first, up to 20 months	CRR is a composite endpoint where response is defined as a participant meeting at least one of the following: 1. circulating tumor cells (CTC) change from unfavorable (≥ 5 cells/7.5 mL of blood) to favorable (\<= 4 cells/7.5 mL of blood); 2. ≥ 50% reduction in Prostate-Specific Antigen (PSA) from baseline, with a repeat assessment confirming the results at least 3 weeks later; 3. Per Prostate Cancer Clinical Trials Working Group 3 (PCWG3)-modified Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, a complete response (CR; disappearance of all target and non-target lesions) or partial response (PR; \>=30% decrease in the sum of the longest diameter of target lesions). A repeat tumor assessment must confirm the CR/PR results at least 3 weeks later.
Disease Control Rate (DCR)	Initiation of study drug through radiographic progression or initiation of new anti-cancer therapy, whichever occurred first, up to 20 months	Per Prostate Cancer Clinical Trials Working Group 3 (PCWG3)-modified Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, a complete response (CR) is defined as disappearance of all target and non-target lesions and a partial response (PR) as a \>=30% decrease in the sum of the longest diameter of target lesions. A repeat tumor assessment must confirm the CR/PR results at least 3 weeks later. DCR = CR + PR + stable disease lasting at least 6 months.
Radiographic Progression-free Survival (rPFS)	Initiation of study drug through radiographic progression or initiation of new anti-cancer therapy, whichever occurred first, up to 20 months	Defined as time from initiation of study intervention to the first objective evidence of radiographic progression, or death due to any cause (whichever occurs first). Per Prostate Cancer Clinical Trials Working Group 3 (PCWG3)-modified Response Evaluation Criteria In Solid Tumors Criteria (RECIST) version 1.1, radiographic progression is defined using as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new non-bone lesions, or at least 2 new bone lesions relative to the first post-treatment scan that are confirmed on a subsequent scan.; rPFS and confidence intervals were estimated using the Kaplan-Meier method.
Overall Survival (OS)	From initiation of study drug until death due to any cause, up to 2.5 years	Defined as the time from initiation of study invention until death due to any cause. OS and confidence intervals were estimated using the Kaplan-Meier method.
Overall Survival (OS) at 12 Months	At 12 months	Defined as the overall survival probability at 12 months, calculated using the Kaplan-Meier method.

Trial Locations

Locations (6)

Angeles Clinic; 🇺🇸 Los Angeles, California, United States

University of California San Francisco; 🇺🇸 San Francisco, California, United States

Oregon Health & Science University; 🇺🇸 Portland, Oregon, United States

Mount Sinai; 🇺🇸 New York, New York, United States

Memorial Sloan Kettering Cancer Center; 🇺🇸 New York, New York, United States

The University of Texas MD Anderson Cancer Center; 🇺🇸 Houston, Texas, United States