Prostate Cancer
Conditions
Brief summary
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
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. The study was originally registered as a phase 1/ phase 2 study; however, the study was cancelled by the sponsor before opening the phase 2 portion. Outcome measures were updated to include those relevant to the Phase 1 portion as the study was terminated before enrolling into phase 2
Interventions
DRUGARRx
Given intravenously (IV)
DRUGEnzalutamide
Given by mouth (PO)
Sponsors
National Cancer Institute (NCI)
University of Michigan Rogel Cancer Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects With Dose-limiting Toxicity (DLT) During the First Cycle of ARRx (in Combination With Enzalutamide) | Up to day 21 of treatment | 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. |
| Best PSA Response | 3.5 years | Number of subjects with at least 50% decline in PSA from Baseline |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients With a Reduction in PSA of at Least 30% From Baseline | 3.5 years | Using PCWG3 criteria. Number of patient with a reduction in PSA of at least 30% from baseline |
| Overall Survival at One Year | 1 year | One year KM estimate. Patients alive or lost to follow-up at the time of analysis will be censored at their last date of follow-up. |
| Intrapatient Dose Delays | 3.5 years | Number of participants that experienced dose delays while on study treatment |
| Intrapatient Dose Reductions | 3.5 years | Number of participants that experienced dose reductions while on study treatment |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Dose Level 1 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.
ARRx: Given intravenously (IV) Enzalutamide: Given by mouth (PO) Dose Level 1: 600 mg IONIS
Dose Level 2: 750 mg IONIS
Dose Level 3: 900 mg IONIS | 1 |
| Dose Level 2 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.
ARRx: Given intravenously (IV) Enzalutamide: Given by mouth (PO) Dose Level 1: 600 mg IONIS Dose Level 2: 750 mg IONIS Dose Level 3: 900 mg IONIS | 5 |
| Dose Level 3 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.
ARRx: Given intravenously (IV) Enzalutamide: Given by mouth (PO) Dose Level 1: 600 mg IONIS Dose Level 2: 750 mg IONIS Dose Level 3: 900 mg IONIS | 3 |
| Total | 9 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 2 |
| Overall Study | Death | 0 | 1 | 0 |
| Overall Study | Sponsor Termination | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 1 |
Baseline characteristics
| Characteristic | Dose Level 1 | Dose Level 2 | Dose Level 3 | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 4 Participants | 2 Participants | 6 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 0 Participants | 5 Participants | 3 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 4 Participants | 2 Participants | 6 Participants |
| Region of Enrollment United States | — | 5 participants | 3 participants | 8 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 0 Participants | 5 Participants | 3 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 0 | 1 / 5 | 0 / 3 |
| other Total, other adverse events | 0 / 0 | 5 / 5 | 3 / 3 |
| serious Total, serious adverse events | 0 / 1 | 2 / 5 | 1 / 3 |
Outcome results
Primary
Best PSA Response
Number of subjects with at least 50% decline in PSA from Baseline
Time frame: 3.5 years
Population: Only a single participant was included in the Dose Level 1 arm and data are not reported publicly to protect participant confidentiality
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Level 2 | Best PSA Response | 4 Participants |
| Level 3 | Best PSA Response | 3 Participants |
Primary
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.
Time frame: Up to day 21 of treatment
Population: Only a single participant was included in the Dose Level 1 arm and data are not reported publicly to protect participant confidentiality
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Level 2 | Number of Subjects With Dose-limiting Toxicity (DLT) During the First Cycle of ARRx (in Combination With Enzalutamide) | 0 Participants |
| Level 3 | Number of Subjects With Dose-limiting Toxicity (DLT) During the First Cycle of ARRx (in Combination With Enzalutamide) | 0 Participants |
Secondary
Intrapatient Dose Delays
Number of participants that experienced dose delays while on study treatment
Time frame: 3.5 years
Population: Only a single participant was included in the Dose Level 1 arm and data are not reported publicly to protect participant confidentiality
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Level 2 | Intrapatient Dose Delays | 3 Participants |
| Level 3 | Intrapatient Dose Delays | 3 Participants |
Secondary
Intrapatient Dose Reductions
Number of participants that experienced dose reductions while on study treatment
Time frame: 3.5 years
Population: Only a single participant was included in the Dose Level 1 arm and data are not reported publicly to protect participant confidentiality
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Level 2 | Intrapatient Dose Reductions | 1 Participants |
| Level 3 | Intrapatient Dose Reductions | 1 Participants |
Secondary
Overall Survival at One Year
One year KM estimate. Patients alive or lost to follow-up at the time of analysis will be censored at their last date of follow-up.
Time frame: 1 year
Population: Only a single participant was included in the Dose Level 1 arm and data are not reported publicly to protect participant confidentiality
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Level 2 | Overall Survival at One Year | 67 percentage of participants |
| Level 3 | Overall Survival at One Year | 100 percentage of participants |
Secondary
Percentage of Patients With a Reduction in PSA of at Least 30% From Baseline
Using PCWG3 criteria. Number of patient with a reduction in PSA of at least 30% from baseline
Time frame: 3.5 years
Population: Only a single participant was included in the Dose Level 1 arm and data are not reported publicly to protect participant confidentiality
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Level 2 | Percentage of Patients With a Reduction in PSA of at Least 30% From Baseline | 4 Participants |
| Level 3 | Percentage of Patients With a Reduction in PSA of at Least 30% From Baseline | 3 Participants |