ARRx in Combination With Enzalutamide in Metastatic Castration Resistant Prostate Cancer

Study Overview
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Brief Summary
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The purpose of this study is to test the effectiveness (how well the drug works), safety, and tolerability of the investigational drug combination of ARRx (also known as AZD5312) plus enzalutamide in patients with metastatic castration resistant prostate cancer.

Detailed Description
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This is a single dose-finding one-arm phase Ib/II trial to determine the maximum tolerated dose (MTD) from among three dose levels of ARRx in combination with a fixed dose of enzalutamide and to obtain a preliminary estimate of efficacy at this MTD, as measured by PSA response rate. Success for the trial is defined as finding a dose level that is likely to be both tolerable and effective.

Official Title
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ARRO-CITO: (UMCC 2017.055) Phase Ib/II Single-Arm Multi-Center Study of IONIS-AR-2.5Rx, a Next Generation Androgen Receptor Antisense Oligonucleotide, in Combination With Enzalutamide in Metastatic Castration Resistant Prostate Cancer

Conditions
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Prostate Cancer

Intervention / Treatment
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* Drug: ARRx
* Drug: Enzalutamide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ability to understand and voluntarily agree to participate by providing written informed consent for the trial. Histologically confirmed prostate adenocarcinoma cancer, either pure or mixed. Small cell/neuroendocrine differentiation is not allowed. Castrate levels of serum testosterone (≤ 50 ng/dL). Patients must continue androgen deprivation therapy with an LHRH analogue or antagonist if they have not undergone bilateral orchiectomy. Patients must have metastatic disease; either non-measurable disease OR measurable disease per RECIST 1.1. Progressive disease despite ongoing treatment with Androgen Deprivation Therapy (ADT). Patients treated with first generation anti-androgen as most recent systemic therapy (e.g. bicalutamide, nilutamide) must have at least 4 weeks elapsed from treatment discontinuation to start of protocol therapy with evidence of disease progression (per protocol) following discontinuation of prior anti-androgen. Minimum PSA at entry of 1 ng/mL is required. ECOG Performance Status 0, 1 or 2. Be ≥18 years of age on the day of signing informed consent. Demonstrate adequate organ function. Subjects must agree to use an adequate method of contraception as outlined in the protocol starting with the time of informed consent through 120 days after the last dose trial therapy. Exclusion Criteria: Prior chemotherapy and/or enzalutamide for metastatic castration-resistant prostate cancer. Chemotherapy administered in the castration-sensitive setting is allowed provided last dose of chemotherapy was greater than 6 months prior to study entry. Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigation device within 4 weeks prior to enrollment. Has not recovered (i.e., AE ≤Grade 1 or at baseline) from AEs due to a previously administered agent. Subjects with ≤Grade 2 neuropathy or ≤Grade 2 alopecia are an exception to this criterion and are allowed if relevant toxicity is stabilized. If subjects received major surgery they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting trial therapy. Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. At the time of signing informed consent is a known regular user (including recreational use) of any illicit drug(s) or had a recent history (within the last year) of drug or alcohol abuse. Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies). Has known active hepatitis B (e.g., HBsAg reactive) or hepatitis C (e.g., HCV RNA [qualitative] is detected). Has received a live virus vaccine within 30 days of planned start of trial therapy. Has known active CNS metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they have stable brain metastases (stability is normally defined as a period of 1 to 3 months in which there is no evidence of new or enlarging CNS metastases). Has symptomatic ascites or pleural effusion; a subject who is clinically stable following treatment for these conditions is eligible. Has had a prior allogeneic stem cell or bone marrow transplant. Has known contraindication to aspirin (81 mg).

Ages Eligible for Study
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Minimum Age: 18 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ARRx + Enzalutamide<br>Phase 1b: All registered subjects will be treated with ARRx (ASO) in combination with enzalutamide. ARRx will be given intravenously on Days 1, 4, 8, 11, 15 on cycle 1, then on days 1, 8, 15 in subsequent 21-day cycles. Enzalutamide will be taken daily in 21 day cycles starting Day 1 of cycle 1. Treatment will continue until clinical or radiologic progression or unacceptable toxicity. Phase 2: Subjects will be treated with ARRx (ASO) at the maximum tolerated (MTD), in combination with enzalutamide until clinical or radiologic progression or unacceptable toxicity. (Schedule of administration as in phase 1b.) | Drug: ARRx<br>* Given intravenously (IV)<br>* Other names: AZD5312;Drug: Enzalutamide<br>* Given by mouth (PO)<br>* Other names: Xtandi;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of subjects with dose-limiting toxicity (DLT) during the first cycle of ARRx (in combination with enzalutamide) | DLTs will be counted based on the number of subjects with DLT at a given dose level. No single subject can trigger more than one DLT event. DLT is defined as any Grade 3 or higher toxicity as defined by CTCAE v5.0. Toxicity that is clearly and directly related to the primary disease or to another etiology is excluded from this definition. | Up to day 21 of treatment | 
| Best PSA response | Using the Prostate Cancer Clinical Trials Working Group 3 (PCWG3) criteria. From the start of the treatment until disease progression/recurrence. | Up to  3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to radiographic progression-free survival (rPFS) | Using PCWG3-modified RECIST 1.1 (Response Evaluation Criteria in Solid Tumors). | Up to  5 years | 
| Percentage of patients with a reduction in PSA of at least 30% from baseline | Using PCWG3 criteria | Up to  3 years | 
| Time to PSA progression | Using PCWG3 criteria | Up to  5 years | 
| PSA progression-free survival (PFS) | PSA PFS is defined as the duration of time from start of treatment to time of PSA progression. PSA progression is defined by PCWG3 criteria. | Up to  5 years | 
| Duration of therapy (DOT) | Defined by the time interval from the start of treatment to the day of permanent discontinuation of treatment (including death). | Up to  3 years | 
| Duration of PSA Response (DOR) | From the time measurement criteria are met for PSA response until the first date that recurrent or progressive disease is objectively documented. | Up to  5 years | 
| Progression-free survival | From start of treatment to time of progression, whether PSA progression by PCWG3 criteria and/or RECIST 1.1 criteria as applicable. | Up to  5 years | 
| Overall survival | Defined as the time from the start of treatment until death from any cause. Patients alive or lost to follow-up at the time of analysis will be censored at their last date of follow-up. | Up to  5 years | 
| Intrapatient dose delays | Median number of dose delays per patient while on treatment (with minimum and maximum as measures of variability of the statistic) | Up to  3 years | 
| Intrapatient dose reductions | Median number of dose reductions per patient while on treatment (with minimum and maximum as measures of variability of the statistic) | Up to  3 years |