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

Study Overview
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Brief Summary
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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.

Official Title
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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.

Conditions
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Metastatic Castration Resistant Prostate Cancer

Intervention / Treatment
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* Biological: MEDI3726 Post-Chemo
* Biological: MEDI3726 Pre-Chemo
* Biological: MEDI3726 & Enzalutamide Combo


Participation Criteria
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Eligibility Criteria
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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: Radiographic progression. 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: Required for Arm A. Excluded for Arm B. 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: At least 14 days before the first dose of investigational product since completion of treatment with abiraterone or enzalutamide At least 14 days before the first dose of investigational product since completion of prior taxane-based chemotherapy At least 28 days before the first dose of investigational product since completion of treatment with Radium-223. 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: More than 25% of marrow-bearing bone has been irradiated. 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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metastatic, prostate cancer