A Phase 1/1b Study of MEDI3726 in Adults Subjects With Metastatic Castration Resistant Prostate Cancer (MEDI3726)

A Phase 1/1b Multicenter, Open-label, Dose-escalation and Dose-expansion Study to Evaluate the Safety, Pharmacokinetics, Immunogenicity, and Antitumor Activity of MEDI3726 in Subjects With Metastatic Castration Resistant Prostate Cancer Who Have Received Prior Treatment With Abiraterone or Enzalutamide.

The purpose of this study is to assess the safety and tolerability, describe the dose-limiting toxicities (DLTs), and determine the maximum tolerated dose (MTD) or maximum administered dose (MAD [in the absence of establishing the MTD]) for single agent MEDI3726 in subjects with mCRPC who have received prior treatment with abiraterone or enzalutamide, with or without a prior taxane-based chemotherapy in the mCRPC setting.

Study Overview

• Status: Completed
• Conditions: Metastatic Castration Resistant Prostate Cancer
• Intervention / Treatment: Biological: MEDI3726 Post-Chemo; Biological: MEDI3726 Pre-Chemo; Biological: MEDI3726 & Enzalutamide Combo

• Study Type: Interventional
• Enrollment (Actual): 33
• Phase: Phase 1

Contacts and Locations

Study Locations

• Switzerland
  • Chur, Switzerland, 7000
    • Research Site
• United Kingdom
  • London, United Kingdom, SM2 5PT
    • Research Site
• United States
  • Connecticut
    • New Haven, Connecticut, United States, 06519
      • Research Site
  • Florida
    • Sarasota, Florida, United States, 34232
      • Research Site
  • Virginia
    • Norfolk, Virginia, United States, 23502
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 98 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• Age ≥ 18 years at the time of screening.
• Histologically confirmed diagnosis of metastatic castration-resistant prostate adenocarcinoma (mCRPC).

• Documented PD in subjects with mCRPC as assessed by the Investigator and defined by at least one of the following according to the PCWG3 criteria:

  1. Radiographic progression.
  2. PSA progression.
• Prior exposure to abiraterone or enzalutamide of at least 12 weeks in the mCRPC setting.

NOTE: Subjects who have received both abiraterone and enzalutamide in the mCRPC setting are eligible.

• In dose escalation: Prior taxane-based chemotherapy in the mCRPC setting is:

  1. Required for Arm A.
  2. Excluded for Arm B.

  3. Optional for Arm C.

     Exclusion Criteria:

• Subjects with neuroendocrine, neuroendocrine differentiation and/or small cell prostate cancer.

• The subject has received any conventional or investigational anti-cancer treatment within 21 days before the first dose of investigational product, with the following modifications:

  1. At least 14 days before the first dose of investigational product since completion of treatment with abiraterone or enzalutamide
  2. At least 14 days before the first dose of investigational product since completion of prior taxane-based chemotherapy
  3. At least 28 days before the first dose of investigational product since completion of treatment with Radium-223.
  4. At least 42 days before the first dose of investigational product since completion of prior bicalutamide and nilutamide treatment.

NOTE: An LHRH agonist or antagonist required for ongoing testosterone suppression will be permitted if Inclusion Criterion is satisfied.

• Prior exposure to PSMA-directed therapies.

• Subjects with previous radiotherapy for the treatment of unresectable, locally advanced or metastatic prostate cancer are excluded if:

  1. More than 25% of marrow-bearing bone has been irradiated.
  2. The last fraction of radiotherapy has been administered within approximately 2 weeks prior to the first dose of investigational product.
• Brain metastases that are untreated, symptomatic, or require therapy to control symptoms; or any radiation, surgery, or other therapy to control symptoms from brain metastases within 2 months prior to the first dose of investigational product.
• Subjects with known history of peripheral vasculopathies including, but not limited to, macro and microangiopathies secondary to diabetes, peripheral arteriopathy of any cause, intermittent claudication, repeated and/or non-healing ulcers of any cause.

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

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm A; MEDI3726 Post-Chemo	Biological: MEDI3726 Post-Chemo; Single agent MEDI3726 after abiraterone or enzalutatmide, with a prior taxane-based chemotherapy in the mCRPC setting
Experimental: Arm B; MEDI3726 Pre-Chemo	Biological: MEDI3726 Pre-Chemo; Single agent MEDI3726 after abiraterone or enzalutatmide, without a prior taxane-based chemotherapy in the mCRPC setting
Experimental: Arm C; MEDI3726 & Enzalutamide Combo	Biological: MEDI3726 & Enzalutamide Combo; MEDI3726 in combination with Enzalutatmide after prior treatment with abiraterone, with or without a prior taxane-based chemotherapy in the mCRPC setting

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Occurrence of adverse events (AEs)	Safety Endpoint	From time of informed consent through 90 days after last dose of MEDI3726
Occurrence of serious adverse events (SAEs)	Safety Endpoint	From time of informed consent through 90 days after last dose of MEDI3726
Occurrence of dose-limiting toxicities (DLTs)	Safety Endpoint	From time of first dose through 21 days after first dose of MEDI3726
Number of patients with changes in laboratory parameters from baseline	Safety Endpoint	From time of informed consent through 90 days after last dose of MEDI3726
Number of patients with changes in vital signs from baseline	Safety Endpoint	From time of informed consent through 21 days after last dose of MEDI3726
Number of patients with changes in electrocardiogram (ECG) results from baseline	Safety Endpoint	From time of informed consent through 21 days after last dose of MEDI3726

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Response Evaluation Criteria in Solid Tumors (RECIST) response	Response according to RECIST version 1.1	From time of informed consent through 90 days after last dose of MEDI3726
PSA50 response	Reduction in PSA level of 50% (PSA50) or more compared with baseline	From time of fist dose through at least 12 weeks after first dose of MEDI3726
Circulating Tumor Cell (CTC) response	Conversion in the CTC count defined as a reduction from ≥ 5 cells/7.5 mL blood to < 5 cells/7.5 mL blood with a confirmatory assessment at least 4 weeks later	From time of informed consent through 90 days after last dose of MEDI3726
Safety and tolerability of MEDI3726 in combination with Enzalutamide	Measured by occurrence of AEs, SAEs, DLTs and number of patients with changes in laboratory parameters, vital signs, and ECG results from baseline	From time of informed consent through 90 days after last dose of MEDI3726 with enzalutamide
MEDI3726 plasma concentrations for pharmacokinetics (PK)		From time of informed consent through 90 days after last dose of MEDI3726
MEDI3726 maximum observed concentration for PK		From time of informed consent through 90 days after last dose of MEDI3726
MEDI3726 area under the concentration-time curve for PK		From time of informed consent through 90 days after last dose of MEDI3726
MEDI3726 clearance for PK		From time of informed consent through 90 days after last dose of MEDI3726
MEDI3726 terminal half-life for PK		From time of informed consent through 90 days after last dose of MEDI3726
Number and percentage of subjects who develop anti-drug antibodies (ADAs)	To determine the immunogenicity of MEDI3726	From time of informed consent through 90 days after last dose of MEDI3726

Collaborators and Investigators

• Sponsor: MedImmune LLC

Publications and helpful links

General Publications

• Cho S, Zammarchi F, Williams DG, Havenith CEG, Monks NR, Tyrer P, D'Hooge F, Fleming R, Vashisht K, Dimasi N, Bertelli F, Corbett S, Adams L, Reinert HW, Dissanayake S, Britten CE, King W, Dacosta K, Tammali R, Schifferli K, Strout P, Korade M 3rd, Masson Hinrichs MJ, Chivers S, Corey E, Liu H, Kim S, Bander NH, Howard PW, Hartley JA, Coats S, Tice DA, Herbst R, van Berkel PH. Antitumor Activity of MEDI3726 (ADCT-401), a Pyrrolobenzodiazepine Antibody-Drug Conjugate Targeting PSMA, in Preclinical Models of Prostate Cancer. Mol Cancer Ther. 2018 Oct;17(10):2176-2186. doi: 10.1158/1535-7163.MCT-17-0982. Epub 2018 Jul 31.

Study record dates

Study Major Dates

• Study Start (Actual): January 6, 2017
• Primary Completion (Actual): September 30, 2019
• Study Completion (Actual): September 30, 2019

Study Registration Dates

• First Submitted: December 1, 2016
• First Submitted That Met QC Criteria: December 9, 2016
• First Posted (Estimate): December 14, 2016

Study Record Updates

• Last Update Posted (Actual): January 18, 2020
• Last Update Submitted That Met QC Criteria: January 14, 2020
• Last Verified: January 1, 2020

More Information

Terms related to this study

• Keywords: metastatic, prostate cancer
• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Genital Neoplasms, Male; Prostatic Diseases; Prostatic Neoplasms
• Other Study ID Numbers: D9320C00001

Drug and device information, study documents

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