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

A Multicenter, Open-Label, Exploratory Platform Study to Evaluate Biomarkers and Immunotherapy Combinations for the Treatment of Patients With Metastatic Castration-resistant Prostate Cancer

Status

Completed

Phases

Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03835533

Acronym

PORTER

Enrollment

Registered

2019-02-08

Start date

2019-06-21

Completion date

2022-10-03

Last updated

2024-04-12

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Metastatic Castration-resistant Prostate Cancer

Keywords

Metastatic Castration-resistant Prostate Cancer, Immunotherapy, Platform study, NKTR-214, Nivolumab, CDX-301, Poly-ICLC, INO-5151

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.

Interventions

DRUGNKTR-214 (Cohort A)

NKTR-214 will be administered intravenously every 3 weeks for up to 2 years

DRUGNivolumab (Cohort A, B and C)

Nivolumab will be administered intravenously every 3 weeks for up to 2 years to cohort A, every 4 weeks for up to 2 years for cohort B and C.

RADIATIONStereotactic body radiation therapy (SBRT) (Cohort B)

Radiation therapy will be administered at 30 - 50 Gy in 1 - 5 doses, starting on Day 1 or 2 of Cycle 1

DRUGCDX-301 (Cohort B and C)

CDX-301 will be subcutaneously once a day for 5 days for cohort B. CDX-301 will be subcutaneously once a day for 10 days of immune-priming lead-in for cohort C.

DRUGPoly-ICLC (Cohort B)

Poly-ICLC will be administered intramuscularly twice weekly for 3 weeks starting on Day 1 of Cycle 1

DRUGINO-5151 (Cohort C)

INO-5151 will be administered intramuscularly on Day 8 of the Immune-priming Lead-in, and on day 1 of Cycle 1, 2 and 3, then every 12 weeks thereafter

DEVICECellectra 2000

Electroporation device

Study design

Allocation

NON_RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

MALE

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

Key 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.

Design outcomes

Primary

Measure	Time frame	Description
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

Measure	Time frame	Description
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.
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.
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.

Countries

United States

Participant flow

Participants by arm

Arm	Count
Cohort A: NKTR-214 + Nivolumab NKTR-214 (Cohort A): NKTR-214 will be administered intravenously every 3 weeks for up to 2 years Nivolumab (Cohort A, B and C): Nivolumab will be administered intravenously every 3 weeks for up to 2 years to cohort A, every 4 weeks for up to 2 years for cohort B and C.	14
Cohort B: SBRT + CDX-301 + Poly-ICLC + Nivolumab Nivolumab (Cohort A, B and C): Nivolumab will be administered intravenously every 3 weeks for up to 2 years to cohort A, every 4 weeks for up to 2 years for cohort B and C. Stereotactic body radiation therapy (SBRT) (Cohort B): Radiation therapy will be administered at 30 - 50 Gy in 1 - 5 doses, starting on Day 1 or 2 of Cycle 1 CDX-301 (Cohort B and C): CDX-301 will be subcutaneously once a day for 5 days for cohort B. CDX-301 will be subcutaneously once a day for 10 days of immune-priming lead-in for cohort C. Poly-ICLC (Cohort B): Poly-ICLC will be administered intramuscularly twice weekly for 3 weeks starting on Day 1 of Cycle 1	15
Cohort C: CDX-301 + INO-5151 + Nivolumab Nivolumab (Cohort A, B and C): Nivolumab will be administered intravenously every 3 weeks for up to 2 years to cohort A, every 4 weeks for up to 2 years for cohort B and C. CDX-301 (Cohort B and C): CDX-301 will be subcutaneously once a day for 5 days for cohort B. CDX-301 will be subcutaneously once a day for 10 days of immune-priming lead-in for cohort C. INO-5151 (Cohort C): INO-5151 will be administered intramuscularly on Day 8 of the Immune-priming Lead-in, and on day 1 of Cycle 1, 2 and 3, then every 12 weeks thereafter Cellectra 2000: Electroporation device	14
Total	43

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002
Overall Study	Death	5	10	9
Overall Study	Lost to Follow-up	1	0	0
Overall Study	Withdrawal by Subject	2	2	2

Baseline characteristics

Characteristic	Cohort A: NKTR-214 + Nivolumab	Cohort B: SBRT + CDX-301 + Poly-ICLC + Nivolumab	Cohort C: CDX-301 + INO-5151 + Nivolumab	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	5 Participants	9 Participants	10 Participants	24 Participants
Age, Categorical Between 18 and 65 years	9 Participants	6 Participants	4 Participants	19 Participants
Age, Continuous	63.9 years STANDARD_DEVIATION 6.9	69.7 years STANDARD_DEVIATION 10.3	71.4 years STANDARD_DEVIATION 9.3	68.4 years STANDARD_DEVIATION 9.3
Cancer Stage at Initial Diagnosis Stage 1	2 Participants	1 Participants	0 Participants	3 Participants
Cancer Stage at Initial Diagnosis Stage 2	2 Participants	2 Participants	1 Participants	5 Participants
Cancer Stage at Initial Diagnosis Stage 3	2 Participants	2 Participants	4 Participants	8 Participants
Cancer Stage at Initial Diagnosis Stage 4	8 Participants	8 Participants	8 Participants	24 Participants
Cancer Stage at Initial Diagnosis Unknown	0 Participants	2 Participants	1 Participants	3 Participants
Circulating Tumor Cells (CTC) value (cells/7.5 mL of blood) at Baseline	4.5 cells/7.5 mL of blood	13.0 cells/7.5 mL of blood	5.5 cells/7.5 mL of blood	5.0 cells/7.5 mL of blood
ECOG Performance Score at Screening 0	8 Participants	8 Participants	10 Participants	26 Participants
ECOG Performance Score at Screening 1	5 Participants	7 Participants	4 Participants	16 Participants
ECOG Performance Score at Screening Missing	1 Participants	0 Participants	0 Participants	1 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants	5 Participants	2 Participants	7 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	14 Participants	10 Participants	12 Participants	36 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants	0 Participants
Prostate-Specific Antigen (PSA) (ng/mL) at Baseline	25.3 ng/mL	37.1 ng/mL	43.0 ng/mL	32.7 ng/mL
Race/Ethnicity, Customized Race Asian	2 Participants	0 Participants	0 Participants	2 Participants
Race/Ethnicity, Customized Race Black or African American	0 Participants	3 Participants	2 Participants	5 Participants
Race/Ethnicity, Customized Race Other	0 Participants	4 Participants	1 Participants	5 Participants
Race/Ethnicity, Customized Race White	12 Participants	8 Participants	11 Participants	31 Participants
Region of Enrollment United States	14 Participants	15 Participants	14 Participants	43 Participants
Sex: Female, Male Female	0 Participants	0 Participants	0 Participants	0 Participants
Sex: Female, Male Male	14 Participants	15 Participants	14 Participants	43 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	5 / 14	10 / 15	9 / 14
other Total, other adverse events	13 / 14	15 / 15	13 / 14
serious Total, serious adverse events	7 / 14	4 / 15	5 / 14

Outcome results

Primary

Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE)

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.

Time frame: 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.