Study of ES414 in Metastatic Castration-Resistant Prostate Cancer

A Phase 1 Study of ES414 in Patients Wtih Metastatic Castration-Resistant Prostate Cancer

The study will be conducted in 2 Stages. The primary objective of Stage 1 of the study is to identify the maximum tolerated dose (MTD) of ES414 administered intravenously to patients with mCRPC. Secondary objectives are to evaluate the tolerability, pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, cytokine response, and clinical activity of ES414.

The primary objective of Stage 2 of the study is to evaluate the clinical activity of ES414 in patients that have or have not received prior chemotherapy. Secondary objectives are to further characterize the safety profile, PK, PD, and immunogenicity of ES414.

Study Overview

• Status: Completed
• Conditions: Prostate Cancer
• Intervention / Treatment: Biological: ES414

Detailed Description

Stage 1 - Dose Escalation: The dose escalation stage of the study will test weekly doses of 0.2 mcg/kg to 300 mcg/kg over 9 dose levels (cohorts). Cohorts 1 to 3 consist of single patients and Cohorts 4 - 9 will consist of a minimum of 3 patients; an additional 3 patients may be added to the cohort if adverse events possibly related to ES414 or dose-limiting toxicities (DLT) occur. The next dose cohort will only enroll after the patient(s) in the current dose cohort have completed the first cycle of dosing (4 weeks) with no significant adverse events or DLTs. Six patients will be enrolled at the maximum tolerated dose (MTD) and this dose will be used for Stage 2.

Stage 2 - Expansion: The continuous intravenous infusion MTD dose regimen will be further examined in 2 expansion cohorts; the first cohort are patients that have received prior chemotherapy, such as docetaxel for mCRPC, and the second cohort are those that have not received prior chemotherapy for mCRPC. Serum samples will be collected for serial PK assessment for ES414 drug levels and antibody formation. Response will be assessed every 2 months during the first 6 months of treatment and then every 3 months until progression of mCRPC, intolerable side effects, or withdrawal of consent.

• Study Type: Interventional
• Enrollment (Actual): 35
• Phase: Phase 1

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Darlinghurst, New South Wales, Australia, 2010
      • St. Vincent's Hospital Sydney
  • Victoria
    • Clayton, Victoria, Australia, 3168
      • Monash Medical Centre
    • East Melbourne, Victoria, Australia, 3002
      • Peter Maccallum Cancer Centre
• United States
  • California
    • San Francisco, California, United States, 94143
      • University of California
  • New York
    • Buffalo, New York, United States, 14263
      • Roswell Park Cancer Institute
  • Texas
    • Temple, Texas, United States, 76504
      • Central Texas Veterans Health Care System
  • Washington
    • Seattle, Washington, United States, 98109
      • University of Washington/Seattle Cancer Care Alliance

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• Histologically or cytologically confirmed adenocarcinoma of the prostate. No evidence of neuroendocrine differentiation or small cell features.
• Surgically or medically castrated, with testosterone ≤ 50 ng/dL (≤ 1.7 nmol/L).
• Progressive prostate cancer by either serum PSA levels, soft tissue or bone disease as defined by the PCWG2 criteria.
• In Stage 1, patients may or may not have received prior chemotherapy for mCRPC. In Stage 2, patients will be enrolled into two cohorts based on whether or not they have received prior chemotherapy for mCRPC. Any prior chemotherapy must have been completed ≥ 4 weeks prior to administration of ES414. Additionally, in countries where abiraterone or enzalutamide are commercially available, patients in Stage 1 and 2 must have progressed on abiraterone and/or enzalutamide prior to study entry.
• ECOG ≤ 1
• Life expectancy > 6 months per investigator
• Adequate hematologic, renal, and hepatic parameters

Exclusion Criteria:

• Any chemotherapy, sipuleucel-T, or investigational drug in prior 4 weeks, or abiraterone or enzalutamide in prior 2 week
• Any radiation therapy in prior 2 weeks
• Any prior therapy targeted against PSMA
• History of seizures
• History of central nervous system metastasis
• History of nephrotic syndrome
• Spot urine total protein:creatinine ratio >1,000 mg/gm
• Planned palliative procedures for alleviation of bone pain
• Active infection requiring treatment with systemic anti-infectives or major surgery in prior 4 weeks.
• Any prednisone (or equivalent corticosteroids) use within 2 weeks of study entry
• Chronic immunosuppressive therapy
• Known history of HIV, hepatitis B, or hepatitis C infection
• Evidence of severe or uncontrolled systemic diseases
• History of bleeding disorders or thromboembolic events in prior 3 months

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: ES414; Cohorts 1-3 of the dose escalation stage of the study (Stage 1) will test weekly doses of 0.2 mcg/kg to 2 mcg/kg. Cohorts 4-9 of the dose escalation stage of the study (Stage 1) will test continuous infusion at flat doses of 25 mcg to 300 mcg per day delivered continuously over 24 hours. The maximum tolerated dose from Stage 1 of the study will be further examined in Stage 2. Patients in cohorts 1-3 will receive ES414 weekly via intravenous (IV) infusion during the first three 28-day cycles and then on Day 1 and 15 of each subsequent cycle until disease progression, intolerable toxicity occurs, or the patient withdraws consent. Patients in cohorts 4-9 will receive ES414 as a continuous IV infusion for 6 months until disease progression, intolerable toxicity occurs, or the patient withdraws consent.

Biological: ES414; ES414 is a novel humanized bispecific antibody which is designed to treat mCRPC by redirecting T-cell cytotoxicity against prostate cancer cells expressing prostate-specific membrane antigen (PSMA).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Tolerated Dose of ES414	Identify the maximum tolerated dose in dose-escalation stage (Stage 1) by assessment of dose-limiting toxicities	during first 28 days of treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety Profile of ES414	The safety profile of ES414 will be assessed by monitoring incidence and severity of adverse events	Patients will be followed for the duration of treatment, an expected average of 6 months, and for 28 days following last treatment
Maximum Serum Drug Concentration (Cmax)	Blood samples will be obtained from all patients for determination of the maximum serum concentration of ES414.	Pre- and post-infusion at least weekly during first 28-day cycle, and on Days 1 and 15 of subsequent cycles for an expected duration of 6 months, and for up to 8 weeks following last treatment
Area under the concentration versus time curve (AUC)	Blood samples will be obtained from all patients for determination of the AUC of ES414.	Pre- and post-infusion at least weekly during first 28-day cycle, and on Days 1 and 15 of subsequent cycles for an expected duration of 6 months, and for up to 8 weeks following last treatment
Elimination half-life (T1/2)	Blood samples will be obtained from all patients for determination of the T1/2 of ES414.	Pre- and post-infusion at least weekly during first 28-day cycle, and on Days 1 and 15 of subsequent cycles for an expected duration of 6 months, and for up to 8 weeks following last treatment
Immune-Related Response Criteria (irRC)	Investigator measurements of target lesions	Baseline and 6 months
Response Evaluation Criteria in Solid Tumors (RECIST 1.1)	Investigator measurements of target lesions	Baseline and 6 months
Pharmacodynamics of ES414	Blood samples will be collected from all patients and evaluated by flow cytometry for changes in lymphocytes	Patients will be followed for the duration of treatment, an expected average of 6 months, and for 28 days following last treatment
PSA Response	Blood samples will be collected from all patients and tested for PSA	Baseline and 6 months
Circulating Tumor Cells	Blood samples will be collected from all patients and evaluated for the number of circulating tumor cells	Patients will be followed for the duration of treatment, an expected average of 6 months, and for 28 days following last treatment
Immunogenicity of ES414	Blood samples will be collected from all patients and tested for antibody formation to ES414.	Patients will be followed for the duration of treatment, an expected average of 6 months, and for 8 weeks following last treatment

Collaborators and Investigators

• Sponsor: Aptevo Therapeutics
• Investigators: Study Director: Scott C Stromatt, MD, Aptevo Therapeutics

Study record dates

Study Major Dates

• Study Start: January 1, 2015
• Primary Completion (Actual): December 1, 2018
• Study Completion (Actual): February 18, 2019

Study Registration Dates

• First Submitted: September 26, 2014
• First Submitted That Met QC Criteria: October 7, 2014
• First Posted (Estimate): October 13, 2014

Study Record Updates

• Last Update Posted (Actual): August 28, 2019
• Last Update Submitted That Met QC Criteria: August 22, 2019
• Last Verified: August 1, 2019

More Information

Terms related to this study

• Keywords: metastatic castration-resistant prostate cancer; CRPC
• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Genital Neoplasms, Male; Prostatic Diseases; Prostatic Neoplasms
• Other Study ID Numbers: 401 (Other Identifier: AGORA HCL)