Clinical trial NCT03939689: 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
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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Metastatic Prostate Cancer
Castration-resistant Prostate Cancer
Prostatic Neoplasm
Cancer of the Prostate
Progressive mCRPC
Keywords: bone metastases
18F-DCFPyL
PSMA PET
PSMA-avidity
biomarker
radioligand therapy
adjunct radiation therapy
dosimetry
SPECT/CT
docetaxel
Lead sponsor: Progenics Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
First posted: 2019-05-07
Enrollment: 120
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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.
Primary purpose: TREATMENT

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.


Eligibility criteria: Inclusion Criteria:

1. Male ≥ 18 years of age
2. Histologically or cytologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation or small cell features at initial diagnosis
3. Castration-resistant prostate cancer, with serum testosterone ≤ 50 ng/dL at Screening
4. Radiographic evidence of metastatic disease prior to Randomization or up to 21 days prior to Screening
5. Disease progression on prior abiraterone therapy as defined by meeting at least one of the following criteria per the investigator:

   1. PSA progression as defined by a minimum of two rising PSA levels at least 1 week apart
   2. Soft tissue disease progression defined by RECIST 1.1
   3. Bone disease progression defined by two or more new lesions on bone scan
6. Planned to receive treatment with enzalutamide
7. 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:

   1. Poor performance status
   2. Prior intolerance to cytotoxic agents
   3. History of another malignancy suspected for recurrence or metastases
   4. 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
8. Subjects receiving bisphosphonate therapy must have been on stable doses for at least 4 weeks prior to Randomization
9. ECOG performance status 0-2
10. 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.
11. Estimated life expectancy of at least 6 months as determined by the Investigator.
12. Able and willing to provide signed informed consent and comply with protocol requirements

Exclusion Criteria:

1. Received any anti-tumor therapy within 4 weeks of Randomization, with the exception of abiraterone, GnRH therapy and non-radioactive bone-targeted agents
2. Received prior chemotherapy for castration-resistant prostate cancer
3. Superscan as evidenced on baseline bone scan
4. Treatment with Strontium-89, Samarium-153, Rhenium-186, Rhenium-188, Radium-223 within 6 months prior to Randomization
5. Prior hemi-body irradiation
6. Prior PSMA-targeted radioligand therapy
7. Major surgery within 4 weeks of Randomization
8. Impaired organ function as evidenced by the following laboratory values at Screening:

   1. Absolute neutrophil count \< 1500 μL
   2. Platelet count \< 100,000/μL
   3. Hemoglobin \< 9.5 g/dL
   4. Albumin \< 3.0 g/dL (30 g/L)
   5. Total bilirubin \> 2 x ULN unless in instances of known or suspected Gilbert's disease
   6. AST or ALT \> 2.5 x ULN
   7. Calculated creatinine clearance (CrCL) \< 30 mL/min (Cockroft-Gault equation), or currently on renal dialysis.
9. QT interval corrected for heart rate (QTc) \> 470 msec
10. Previous use of enzalutamide for more than 7 days prior to consent
11. Planned initiation of alternative therapy for prostate cancer, investigational therapy, or participation in clinical trials during the study
12. History or risk of seizure (i.e., clinically significant neurological disorder) or any other condition that contraindicates treatment with enzalutamide
13. Gastrointestinal disorder affecting absorption of oral medications
14. Known or suspected brain metastasis or active leptomeningeal disease
15. 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
16. 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.

Primary outcomes:
measure: PSA Response Rate
timeFrame: Up to 53 weeks
Secondary outcomes:
measure: Objective Response Rate (ORR)
timeFrame: Up to 53 weeks
measure: Radiographic Progression Free Survival (rPFS)
timeFrame: Up to 53 weeks
measure: Overall Survival (OS)
timeFrame: Up to 5 years
measure: PSA Progression
timeFrame: Up to 53 weeks
measure: Duration Of Response
timeFrame: Up to 53 weeks
measure: Time To Initiation Of Next Treatment For Prostate Cancer
timeFrame: Up to 5 years
measure: Incidences Of Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events As Assessed by CTCAE v5.0 (Safety Outcome Measure)
timeFrame: After first administration of study drug to visit week 53
measure: Adverse Events Resulting In Discontinuation Of Study Drug (Safety Outcome Measure)
timeFrame: After first administration of study drug to visit week 53
measure: Physical Examination Findings (Safety Outcome Measure)
timeFrame: At baseline and weeks 9, 17, 25, and 53
measure: Changes In Blood Pressure (Safety Outcome Measure)
timeFrame: Baseline to week 53
measure: Changes In Heart Rate (Safety Outcome Measure)
timeFrame: Baseline to week 53
measure: Changes In Temperature (Safety Outcome Measure)
timeFrame: Baseline to week 53
measure: Shift From Baseline In Selected Clinical Chemistry Laboratory Values At Follow-up (Safety Outcome Measure)
timeFrame: Baseline to week 53
measure: Shift From Baseline In Selected Hematology Laboratory Values At Follow-up (Safety Outcome Measure)
timeFrame: Baseline to week 53
measure: Changes From Baseline In Overall Electrocardiogram (ECG) Assessment At Follow-up (Safety Outcome Measure)
timeFrame: Baseline and weeks 1, 9, 17, 25, 53 (131-I-1095 + enzalutamide treatment group); Baseline and week 53 (enzalutamide treatment group)
measure: Summary Of Concomitant Medications (Safety Outcome Measure)
timeFrame: Baseline to week 53 (concomitant medications); from week 54 up to 5 years (anti-cancer therapies only)
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope
state: California
city: Los Angeles
country: United States
facility: VA Greater Los Angeles Healthcare System
state: California
city: Los Angeles
country: United States
facility: UCLA
state: California
city: Newport Beach
country: United States
facility: Hoag Family Cancer Institute
state: California
city: Palo Alto
country: United States
facility: VA Palo Alto Healthcare System
state: California
city: Washington
country: United States
facility: Medstar Georgetown University Hospital
state: District of Columbia
city: Chicago
country: United States
facility: The University of Chicago
state: Illinois
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
city: New Orleans
country: United States
facility: Tulane Medical School
state: Louisiana
city: Baltimore
country: United States
facility: University of Maryland
state: Maryland
city: Ann Arbor
country: United States
facility: University of Michigan Comprehensive Cancer Center
state: Michigan
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Syracuse
country: United States
facility: SUNY Upstate Medical University
state: New York
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Providence
country: United States
facility: LifeSpan Cancer Institute
state: Rhode Island
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Houston
country: United States
facility: University of Texas MD Anderson Cancer Center
state: Texas
city: Charlottesville
country: United States
facility: University of Virginia Cancer Center
state: Virginia
city: Seattle
country: United States
facility: Virginia Mason Medical Center
state: Washington
city: Seattle
country: United States
facility: University of Washington - Seattle Cancer Care Alliance
state: Washington
city: Ottawa
country: Canada
facility: The Ottawa Hospital
state: Ontario
city: Toronto
country: Canada
facility: London Health Sciences Centre
state: Ontario
city: Toronto
country: Canada
facility: University Health Network - Princess Margaret Cancer Centre
state: Ontario
city: Montreal
country: Canada
facility: Centre Hospitalier Del' Universite de Montreal
state: Quebec
city: Montreal
country: Canada
facility: Jewish General Hospital
state: Quebec
city: Quebec City
country: Canada
facility: Centre Hospitalier Universitaire de Quebec
state: Quebec
city: Sherbrooke
country: Canada
facility: Centre Hospitalier Universitaire de Sherbrooke
state: Quebec
Study officials:
affiliation: Progenics Pharmaceuticals, Inc.
name: Jean-Claude Provost, MD
role: STUDY_DIRECTOR
References:
citation: Afshar-Oromieh A, Haberkorn U, Zechmann C, Armor T, Mier W, Spohn F, Debus N, Holland-Letz T, Babich J, Kratochwil C. Repeated PSMA-targeting radioligand therapy of metastatic prostate cancer with 131I-MIP-1095. Eur J Nucl Med Mol Imaging. 2017 Jun;44(6):950-959. doi: 10.1007/s00259-017-3665-9. Epub 2017 Mar 9.
citation: Zechmann CM, Afshar-Oromieh A, Armor T, Stubbs JB, Mier W, Hadaschik B, Joyal J, Kopka K, Debus J, Babich JW, Haberkorn U. Radiation dosimetry and first therapy results with a (124)I/ (131)I-labeled small molecule (MIP-1095) targeting PSMA for prostate cancer therapy. Eur J Nucl Med Mol Imaging. 2014 Jul;41(7):1280-92. doi: 10.1007/s00259-014-2713-y. Epub 2014 Feb 28.