Study of HPN424 in Patients With Advanced Prostate Cancer

A Phase 1/2a Open-label, Multicenter, Dose Escalation and Dose Expansion Study of the Safety, Tolerability, and Pharmacokinetics of HPN424 in Patients With Advanced Prostate Cancer Refractory to Androgen Therapy

An open-label, Phase 1/2a, study of HPN424 as monotherapy to assess the safety, tolerability and PK in patients with advanced prostate cancer refractory to androgen therapy

Study Overview

• Status: Terminated
• Conditions: Advanced Prostate Cancer
• Intervention / Treatment: Biological: HPN424 Fixed IV 1.3 to 150 ng/kg; Biological: HPN424 Prime Step IV 36 ng/kg Target; Biological: HPN424 1 Prime Step IV 225-300 ng/kg Target; Biological: HPN424 2 Prime Step IV 300 ng/kg Target; Biological: HPN424 2 Prime Step IV 450 ng/kg Target; Biological: HPN424 Fixed SC

• Study Type: Interventional
• Enrollment (Actual): 104
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • Surrey
    • Sutton, Surrey, United Kingdom, SM2 5PT
      • The Royal Marsden Hospital
• United States
  • California
    • Los Angeles, California, United States, 90033
      • USC Norris Comprehensive Cancer Center
    • San Francisco, California, United States, 94143
      • University of California San Francisco
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Hospital
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
    • Chicago, Illinois, United States, 60637
      • University of Chicago
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Karmanos Cancer Institute
  • New York
    • New York, New York, United States, 10032
      • New York Presbyterian Hospital-Columbia University Medical Center.
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health & Science University Knight Cancer Institute
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19111-2497
      • Fox Chase Cancer Center
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Sarah Cannon Research Institute
  • Texas
    • Dallas, Texas, United States, 75390
      • UT Southwestern Medical Center
    • Dallas, Texas, United States, 75230
      • Mary Crowley Cancer Research
  • Wisconsin
    • Madison, Wisconsin, United States, 53972
      • University of Wisconsin Carbone Cancer Center

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Male patients ≥18 years of age at the time of signing informed consent
2. Histologically or cytologically confirmed adenocarcinoma of the prostate

3. Progressive metastatic castrate-resistant prostate cancer (mCRPC):

   1. Serum testosterone levels less than 50 ng/dL (or ≤0.50 ng/mL or 1.73 nmol/L) within 28 days prior to start of study drug
   2. Radiographic evidence of metastatic disease
   3. Disease progression on the prior systemic regimen, per Prostate Cancer Clinical Trials Working Group 3 (PCWG3) criteria:

   i. A sequence of at least 2 rising PSA values measured at a minimum of 1 week apart with a 2 ng/mL minimum starting value, or ii. Appearance of two or more new lesions on bone scans, or iii. Progressive visceral disease, or iv. Progressive nodal disease; previously normal (<1.0 cm) lymph nodes must have grown by ≥5 mm in the short axis from baseline or nadir and be ≥1.0 cm in the short axis to be considered to have progressed

4. Must have received at least 2 prior systemic therapies approved for mCRPC
5. Ongoing androgen depletion therapy with a gonadotropin releasing hormone analog or inhibitor, or orchiectomy (surgical or medical castration)
6. For patients previously treated with first generation anti-androgens, discontinuation must have occurred ≥4 weeks (for flutamide or nilutamide) or ≥6 weeks (for bicalutamide) prior to start of study drug, with no evidence of an anti-androgen withdrawal response (i.e., no decline in serum PSA)
7. For patients previously treated with a second-generation anti-androgen (e.g., enzalutamide or equivalent) or with abiraterone acetate, discontinuation must have occurred 2 weeks or 5 half-lives prior to start of study drug
8. For patients previously treated with systemic chemotherapy, targeted therapy, immunotherapy, or treatment with an investigational anticancer agent, discontinuation must have occurred ≥2 weeks, or at least 4 half-lives (up to 4 weeks), whichever is longer, prior to start of study drug
9. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

10. Adequate bone marrow function, including:

    1. Absolute neutrophil count (ANC) ≥1500/mm3 or ≥1.5 x 109/L
    2. Platelets ≥100,000/mm3 or ≥100 x 109/L
    3. Hemoglobin ≥9 g/dL (no transfusions allowed within 1 week prior to screening)

11. Adequate renal function, including:

    a. Estimated creatinine clearance ≥50 mL/min as calculated using the method standard for the institution

12. Adequate liver function, including:

    1. Total serum bilirubin ≤1.5 x upper limit of normal (ULN) unless the patient has documented Gilbert syndrome in which case the maximum total serum bilirubin should be 5 mg/dL
    2. Aspartate and Alanine transaminase (AST and ALT) ≤2.5 x ULN
13. Resolved acute effects of any prior therapy to baseline severity or CTCAE Grade ≤1 except for adverse events (AEs) not constituting a safety risk per the Investigator
14. If of reproductive potential, willing to use 1 effective method of contraception (as defined in this protocol) during the treatment period, if partner is a female of childbearing potential
15. Willing to complete all scheduled visits and assessments at the institution administering therapy
16. Able to read, understand and provide written informed consent

Exclusion Criteria:

1. Previously treated or current brain metastases
2. Untreated spinal cord compression. Participants must be neurologically stable off steroids for at least 4 weeks prior to first dose of study drug
3. Ongoing treatment with anti-tumor necrosis factor (TNF) alpha therapies, systemic corticosteroids (prednisone dose >10 mg per day or equivalent), or other immune suppressive drugs
4. History of or known or suspected autoimmune disease (exception(s): patients with vitiligo, resolved childhood atopic dermatitis, hypothyroidism, or hyperthyroidism that is clinically euthyroid at Screening are allowed)
5. History of clinically significant cardiovascular disease such as symptomatic congestive heart failure (CHF), uncontrolled hypertension defined as sustained BP >150 mmHg systolic, or >100 mmHg diastolic despite optimal antihypertensive treatment (BP must be controlled at screening), unstable angina pectoris, clinically significant cardiac arrhythmias, history of stroke (including TIA, or other ischemic event) within 6 months before first dose of study drug, myocardial infarction within 6 months before first dose of study drug, history of thromboembolic event within 3 months before first dose of study drug
6. Known active or chronic hepatitis B or hepatitis C as demonstrated by hepatitis B surface antigen (HBsAg) positivity and/or anti-hepatitis C virus (HCV) positivity, respectively, or known history of human immunodeficiency virus (HIV) seropositive status
7. Clinically active liver disease, including liver cirrhosis of Child-Pugh class B or C
8. Second primary malignancy that has not been in remission for greater than 3 years. Exceptions that do not require a 3-year remission: non-melanoma skin cancer, resected melanoma in situ, or non-muscle invasive urothelial carcinoma
9. In the judgment of the Investigator, patient has a clinically significant concurrent illness or psychological, familial, sociological, geographical, or other concomitant condition that would not permit adequate follow-up and compliance with the study protocol
10. Any serious underlying medical or psychiatric condition (e.g., alcohol or drug abuse), dementia or altered mental status or any issue that would impair the ability of the patient to understand informed consent or that in the opinion of the Investigator would contraindicate the patient's participation in the study or confound the results of the study
11. Known hypersensitivity, allergies, or intolerance to immunoglobulins, or to any excipient contained in HPN424 (see Investigator's Brochure)
12. Is a participant or plans to participate in another interventional clinical study, while taking part in this protocol. Participation in an observational study is acceptable

Study Plan

How is the study designed?

Design Details

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

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Fixed IV; HPN424 administered once weekly via IV infusion in doses ranging from 1.3 to 150 ng/kg	Biological: HPN424 Fixed IV 1.3 to 150 ng/kg; Fixed dose IV cohorts at doses from 1.3 to 150 ng/kg
Experimental: 1 Prime Step IV 36 ng/kg Target; Step-dosing IV cohort who received a single Prime Dose followed by the Target Dose (12/36 ng/kg)	Biological: HPN424 Prime Step IV 36 ng/kg Target; Step-dosing IV cohort at a single Prime Dose followed by the Target Dose (12/36 ng/kg)
Experimental: 1 Prime Step IV 225-300 ng/kg Target; Step-dosing IV cohorts who received a single Prime Dose followed by the Target Dose (100/300 ng/kg and 75/225 ng/kg]	Biological: HPN424 1 Prime Step IV 225-300 ng/kg Target; Step-dosing IV cohorts who received a single Prime Dose followed by the Target Dose (100/300 ng/kg and 75/225 ng/kg)
Experimental: 2 Prime Step IV 300 ng/kg Target; Step-dosing IV cohorts who received 2 Prime Doses followed by the Target Dose (50/150/300 ng/kg with prior chemotherapy and 50/150/300 ng/kg no prior chemotherapy)	Biological: HPN424 2 Prime Step IV 300 ng/kg Target; Step-dosing IV cohorts who received 2 Prime Doses followed by the Target Dose (50/150/300 ng/kg with prior chemotherapy and 50/150/300 ng/kg no prior chemotherapy)
Experimental: 2 Prime Step IV 450 ng/kg Target; Step-dosing IV cohorts who received 2 Prime Doses followed by the Target Dose (100/300/450 ng/kg and 50/150/450 ng/kg)	Biological: HPN424 2 Prime Step IV 450 ng/kg Target; Step-dosing IV cohorts who received 2 Prime Doses followed by the Target Dose (100/300/450 ng/kg and 50/150/450 ng/kg)
Experimental: Fixed SC; Fixed subcutaneous dose (120 ng/kg)	Biological: HPN424 Fixed SC; Fixed subcutaneous dose 120 ng/kg

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number and Severity of Dose Limiting Toxicities (DLTs) Following Treatment With Escalating Doses of HPN424	Assess safety and tolerability at increasing dose levels of HPN424 in successive cohorts of patients with metastatic castrate resistant prostate cancer (mCRPC) to estimate the maximum tolerated dose (MTD). The study was terminated early, therefore the primary goal of the final data analysis was to look at dosing schedule rather than individual dose levels. The results displayed are shown broken out by dosing schedules and no analysis of specific dose levels was performed. This analysis is as outlined in the final Statistical Analysis Plan.	21 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part 1 and 2: Adverse events (NCI CTCAE version 5.0)	Evaluate the overall safety profile of HPN424 administered by IV infusion or SC injection, as measured by adverse events.	up to 4 years
Part 1: Progression-free survival (PFS) using PCWG3 criteria	Evaluate preliminary clinical anti-tumor activity by measuring PFS.	up to 4 years
Part 1: Duration of response (DOR) using PCWG3 criteria	Evaluate preliminary clinical anti-tumor activity by measuring DOR.	up to 4 years
Part 1: Overall survival (OS)	Evaluate preliminary clinical anti-tumor activity by measuring OS.	up to 4 years
Part 1: Prostate Specific Antigen (PSA) levels	Evaluate preliminary clinical anti-tumor activity by measuring PSA levels in blood.	up to 4 years
Part 1 and 2: Pharmacokinetics of HPN424	Characterize single dose and multiple dose PK of HPN424 following IV administration by measuring levels of HPN424 in blood serum.	up to 4 years
Part 1 and 2: Incidence of anti-drug antibodies (ADA) against HPN424	Evaluate the immunogenicity of HPN424 by assessing anti-drug antibodies in blood serum.	up to 4 years
Part 1 and 2: Effects of HPN424 on circulating lymphocytes and systemic soluble immune factors	Characterize the impact of HPN424 on activation of circulating lymphocytes and on systemic soluble immune factors by immunophenotyping of lymphocytes in whole blood and measuring cytokines in serum.	up to 4 years

Collaborators and Investigators

• Sponsor: Harpoon Therapeutics

Study record dates

Study Major Dates

• Study Start (Actual): July 24, 2018
• Primary Completion (Actual): February 27, 2023
• Study Completion (Actual): February 27, 2023

Study Registration Dates

• First Submitted: June 22, 2018
• First Submitted That Met QC Criteria: June 22, 2018
• First Posted (Actual): July 5, 2018

Study Record Updates

• Last Update Posted (Actual): February 14, 2024
• Last Update Submitted That Met QC Criteria: January 18, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Prostate Cancer; Metastatic Castration Resistant Prostate Cancer; Harpoon; TriTAC
• 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
• Other Study ID Numbers: HPN424-1001

Drug and device information, study documents

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