ARROW: Study of I-131-1095 Radiotherapy in Combination With Enzalutamide in Patients With Metastatic Castration-resistant Prostate Cancer Who Are Chemotherapy Naive and Have Progressed on Abiraterone

Sponsor

Progenics Pharmaceuticals, Inc. (Industry)

Overall Status

Active, not recruiting

CT.gov ID

NCT03939689

Collaborator

(none)

120

Enrollment

Locations

Arms

60.1

Anticipated Duration (Months)

4.4

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is a multicenter, randomized, controlled, phase 2 clinical trial designed to evaluate the safety and efficacy of I-131-1095 radiotherapy in combination with enzalutamide compared to enzalutamide alone in participants with prostate-specific membrane antigen (PSMA)-avid metastatic castration resistant prostate cancer (mCRPC) who have progressed on abiraterone. Participants must be chemotherapy-naive and must be ineligible or refuse to receive taxane-based chemotherapy at time of study entry. PSMA-avidity will be determined by central imaging review based on assessment of 18F-DCFPyL PET/CT imaging during screening. Eligible participants meeting the PSMA-avidity criteria will be randomized in a 2:1 ratio to receive either I-131-1095 in combination with enzalutamide (80 participants) or enzalutamide alone (40 participants). An interim analysis for efficacy will be performed after a minimum of 48 evaluable participants have PSA data for at least three months following the first dose of randomized treatment.

All participants will be followed for efficacy, safety assessments, survival status, adverse events of special interest, and new anti-cancer therapy for at least one year or to the end of the study (whichever is later) following the first dose of randomized treatment. Safety data will be monitored by an independent Data Monitoring Committee and the sponsor.

Condition or Disease	Intervention/Treatment	Phase
Metastatic Prostate Cancer Castration-resistant Prostate Cancer Prostatic Neoplasm Cancer of the Prostate Progressive mCRPC	Drug: I-131-1095 Drug: Enzalutamide	Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

120 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

The study population includes patients with PSMA-avid mCRPC whose disease has progressed despite abiraterone therapy, and are planned for treatment with enzalutamide.The study population includes patients with PSMA-avid mCRPC whose disease has progressed despite abiraterone therapy, and are planned for treatment with enzalutamide.

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Multicenter, Randomized, Controlled Phase 2 Study: Efficacy and Safety of I-131-1095 Radiotherapy in Combination With Enzalutamide in Metastatic Castration-resistant Prostate Cancer (mCRPC) Patients Who Are 18F-DCFPyL Prostate-specific Membrane Antigen (PSMA)-Avid, Chemotherapy-naive, and Progressed on Abiraterone

Actual Study Start Date :

May 30, 2019

Anticipated Primary Completion Date :

Jun 1, 2023

Anticipated Study Completion Date :

Jun 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Enzalutamide	Drug: Enzalutamide Enzalutamide will be given orally once daily as prescribed by the physician as standard of care. Other Names: Xtandi
Experimental: I-131-1095 in combination with enzalutamide	Drug: I-131-1095 I-131-1095 will be administered intravenously at 100 mCi for the initial therapeutic dose, and up to 3 additional dose(s) at 75 mCi or 100 mCi each, administered at least 8 weeks apart as determined by dosimetry evaluation and occurrence of dose-limiting events. Drug: Enzalutamide Enzalutamide will be given orally once daily as prescribed by the physician as standard of care. Other Names: Xtandi

Arm

Intervention/Treatment

Active Comparator: Enzalutamide

Drug: Enzalutamide

Enzalutamide will be given orally once daily as prescribed by the physician as standard of care.

Other Names:

Xtandi

Experimental: I-131-1095 in combination with enzalutamide

Drug: I-131-1095

I-131-1095 will be administered intravenously at 100 mCi for the initial therapeutic dose, and up to 3 additional dose(s) at 75 mCi or 100 mCi each, administered at least 8 weeks apart as determined by dosimetry evaluation and occurrence of dose-limiting events.

Drug: Enzalutamide

Enzalutamide will be given orally once daily as prescribed by the physician as standard of care.

Other Names:

Xtandi

Outcome Measures

Primary Outcome Measures

PSA Response Rate [Up to 53 weeks]
The proportion of participants with a PSA response according to PCWG3 criteria defined as the first occurrence of a 50 percent or more decline in PSA from baseline, confirmed by a second measurement at least 3 weeks later.

Secondary Outcome Measures

Objective Response Rate (ORR) [Up to 53 weeks]
The proportion of participants who have a partial response (PR) or complete response (CR) based on RECIST 1.1 for soft tissue or PCWG3 for bone (PCWG3-modified RECIST 1.1).
Radiographic Progression Free Survival (rPFS) [Up to 53 weeks]
Time from randomization to the first occurrence of radiographic progression based on RECIST 1.1 for soft tissue or PCWG3-modified RECIST 1.1 for bone, respectively, or unequivocal clinical progression, or death on study from any cause.
Overall Survival (OS) [Up to 5 years]
Overall Survival is defined as time from randomization to death from any cause.
PSA Progression [Up to 53 weeks]
Time from randomization to the date of the first PSA increase from baseline ≥ 25 percent and ≥ 2 ng/ml above nadir confirmed by a second PSA assessment defining progression ≥ 3 weeks later per PCWG3.
Duration Of Response [Up to 53 weeks]
Time from the first date of complete response (CR) or partial response (PR) to the first occurrence of radiographic progression based on PCWG3-modified RECIST 1.1, or unequivocal clinical progression.
Time To Initiation Of Next Treatment For Prostate Cancer [Up to 5 years]
Time from randomization to initiation of any new treatment for prostate cancer.
Incidences Of Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events As Assessed by CTCAE v5.0 (Safety Outcome Measure) [After first administration of study drug to visit week 53]
TEAEs will be summarized by SOC and PT using the frequency and percentage of participants experiencing any adverse event, experiencing each SOC and experiencing each PT within each SOC.
Adverse Events Resulting In Discontinuation Of Study Drug (Safety Outcome Measure) [After first administration of study drug to visit week 53]
A high-level summary of TEAEs will be presented for participants who had at least one TEAE overall, seriousness, and leading to discontinuation of treatment.
Physical Examination Findings (Safety Outcome Measure) [At baseline and weeks 9, 17, 25, and 53]
Percentage of patients with clinically significant abnormal changes on physical examination at weeks 9, 17, 25 and 53 will be presented by treatment group. Clinically significant abnormal physical examination findings will be captured in medical history if prior to study drug treatment.
Changes In Blood Pressure (Safety Outcome Measure) [Baseline to week 53]
Percentage of patients with abnormal clinically significant changes in systolic and diastolic blood pressure will be presented by treatment group and visit.
Changes In Heart Rate (Safety Outcome Measure) [Baseline to week 53]
Percentage of patients with abnormal clinically significant changes in heart rate will be presented by treatment group and visit.
Changes In Temperature (Safety Outcome Measure) [Baseline to week 53]
Percentage of patients with abnormal clinically significant changes in body temperature will be presented by treatment group and visit.
Shift From Baseline In Selected Clinical Chemistry Laboratory Values At Follow-up (Safety Outcome Measure) [Baseline to week 53]
Percentage of patients with clinically significant abnormal values of potassium, sodium, magnesium, calcium (corrected) - per CTCAE5, urea and total protein - per investigator assessment will be presented by treatment group.
Shift From Baseline In Selected Hematology Laboratory Values At Follow-up (Safety Outcome Measure) [Baseline to week 53]
Percentage of patients with clinically significant abnormal changes in hemoglobin, erythrocytes, thrombocytes, leukocytes, absolute neutrophil count, basophils, eosinophils and monocytes will be presented by treatment group.
Changes From Baseline In Overall Electrocardiogram (ECG) Assessment At Follow-up (Safety Outcome Measure) [Baseline and weeks 1, 9, 17, 25, 53 (131-I-1095 + enzalutamide treatment group); Baseline and week 53 (enzalutamide treatment group)]
Percentage of patients with abnormal clinically significant changes on electrocardiogram (ECG) per central reviewer's assessment will be presented by treatment group.
Summary Of Concomitant Medications (Safety Outcome Measure) [Baseline to week 53 (concomitant medications); from week 54 up to 5 years (anti-cancer therapies only)]
Medications will be summarized by ATC4 class and generic term using number of participants and percentages by treatment group and overall.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

Male

Accepts Healthy Volunteers:

Inclusion Criteria:

Male ≥ 18 years of age
Histologically or cytologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation or small cell features at initial diagnosis
Castration-resistant prostate cancer, with serum testosterone ≤ 50 ng/dL at Screening
Radiographic evidence of metastatic disease prior to Randomization or up to 21 days prior to Screening
Disease progression on prior abiraterone therapy as defined by meeting at least one of the following criteria per the investigator:
PSA progression as defined by a minimum of two rising PSA levels at least 1 week apart
Soft tissue disease progression defined by RECIST 1.1
Bone disease progression defined by two or more new lesions on bone scan
Planned to receive treatment with enzalutamide
Subjects who are ineligible or choose not to receive taxane-based chemotherapy based on personal preference or physician opinion. Examples of conditions that could make a patient ineligible or refuse to receive taxane-based chemotherapy, but would allow them to still be eligible to receive I-131-1095 include the following:
Poor performance status
Prior intolerance to cytotoxic agents
History of another malignancy suspected for recurrence or metastases
Other serious medical conditions such as symptomatic peripheral neuropathy CTCAE Grade 2 or higher; or clinically significant cardiovascular disease per the Investigator or treating physician
Subjects receiving bisphosphonate therapy must have been on stable doses for at least 4 weeks prior to Randomization
ECOG performance status 0-2
If sexually active, agree to use a medically acceptable method of birth control or sexual abstinence from the time of dosing through 28 days after the last dose of I-131-1095. Female partners must use hormonal or barrier contraception unless postmenopausal or abstinent.
Estimated life expectancy of at least 6 months as determined by the Investigator.
Able and willing to provide signed informed consent and comply with protocol requirements

Exclusion Criteria:

Received any anti-tumor therapy within 4 weeks of Randomization, with the exception of abiraterone, GnRH therapy and non-radioactive bone-targeted agents
Received prior chemotherapy for castration-resistant prostate cancer
Superscan as evidenced on baseline bone scan
Treatment with Strontium-89, Samarium-153, Rhenium-186, Rhenium-188, Radium-223 within 6 months prior to Randomization
Prior hemi-body irradiation
Prior PSMA-targeted radioligand therapy
Major surgery within 4 weeks of Randomization
Impaired organ function as evidenced by the following laboratory values at Screening:
Absolute neutrophil count < 1500 μL
Platelet count < 100,000/μL
Hemoglobin < 9.5 g/dL
Albumin < 3.0 g/dL (30 g/L)
Total bilirubin > 2 x ULN unless in instances of known or suspected Gilbert's disease
AST or ALT > 2.5 x ULN
Calculated creatinine clearance (CrCL) < 30 mL/min (Cockroft-Gault equation), or currently on renal dialysis.
QT interval corrected for heart rate (QTc) > 470 msec
Previous use of enzalutamide for more than 7 days prior to consent
Planned initiation of alternative therapy for prostate cancer, investigational therapy, or participation in clinical trials during the study
History or risk of seizure (i.e., clinically significant neurological disorder) or any other condition that contraindicates treatment with enzalutamide
Gastrointestinal disorder affecting absorption of oral medications
Known or suspected brain metastasis or active leptomeningeal disease
Active malignancy other than prostate cancer, with the exception of curatively treated non-melanoma skin cancer, carcinoma in situ, or non-muscle invasive bladder/urothelial cancer
Subjects with any medical condition or other circumstances that, in the opinion of the investigator, compromise obtaining reliable data, achieving study objectives, or completing the study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	City of Hope	Duarte	California	United States	91010
2	VA Greater Los Angeles Healthcare System	Los Angeles	California	United States	90073
3	UCLA	Los Angeles	California	United States	90095-7370
4	Hoag Family Cancer Institute	Newport Beach	California	United States	92663
5	VA Palo Alto Healthcare System	Palo Alto	California	United States	94303
6	Medstar Georgetown University Hospital	Washington	District of Columbia	United States	20007
7	The University of Chicago	Chicago	Illinois	United States	60637
8	University of Iowa	Iowa City	Iowa	United States	52242
9	Tulane Medical School	New Orleans	Louisiana	United States	70112
10	University of Maryland	Baltimore	Maryland	United States	21201
11	University of Michigan Comprehensive Cancer Center	Ann Arbor	Michigan	United States	48109
12	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
13	SUNY Upstate Medical University	Syracuse	New York	United States	13210
14	University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104
15	LifeSpan Cancer Institute	Providence	Rhode Island	United States	09206
16	Medical University of South Carolina	Charleston	South Carolina	United States	29425
17	University of Texas MD Anderson Cancer Center	Houston	Texas	United States	77030
18	University of Virginia Cancer Center	Charlottesville	Virginia	United States	22908
19	Virginia Mason Medical Center	Seattle	Washington	United States	98101
20	University of Washington - Seattle Cancer Care Alliance	Seattle	Washington	United States	98109
21	The Ottawa Hospital	Ottawa	Ontario	Canada	K1H 8L6
22	London Health Sciences Centre	Toronto	Ontario	Canada
23	University Health Network - Princess Margaret Cancer Centre	Toronto	Ontario	Canada
24	Centre Hospitalier Del' Universite de Montreal	Montreal	Quebec	Canada
25	Jewish General Hospital	Montreal	Quebec	Canada
26	Centre Hospitalier Universitaire de Quebec	Quebec City	Quebec	Canada
27	Centre Hospitalier Universitaire de Sherbrooke	Sherbrooke	Quebec	Canada