Genomic Biomarker-Selected Umbrella Neoadjuvant Study for High Risk Localized Prostate Cancer (GUNS)
The objective of this study is to see if providing an appropriate therapy based on the genomic testing of prostate tumour tissue will result in an improved clinical response.
Each participant will be treated with 8 weeks of a luteinizing hormone-releasing hormone agonist (LHRHa) plus apalutamide (APA) while genome sequence characterization is being done. Participants with biopsy specimens deemed unevaluable for genomic testing will remain on LHRHa plus APA for an additional 16 weeks.
Participants with evaluable tissue will be assigned to one of the open-label sub-studies on the basis of genomic profiling results. Within each group, they will be randomized to a specific treatment arm either LHRHa plus APA alone or adding abiraterone acetate and prednisone, docetaxel or niraparib.
The study will evaluate the response rate and outcomes after radical prostatectomy in each arm of the trial.
Study Overview
Status
Conditions
Detailed Description
This is a multi-centre adaptive multi-arm phase II study. Participants are treated with an induction period of at least 8 weeks of LHRH agonist/antagonist (LHRHa) plus apalutamide (APA) while genome sequence characterization is being done.
Genomic sequencing analysis will be performed centrally by Tempus, a CLIA (Clinical Laboratory Improvement Amendments)-certified laboratory. For the DNA gene profiling, formalin-fixed paraffin-embedded (FFPE) prostate cancer and surrounding healthy tissue from diagnostic biopsies will be used for genetic analysis. Copy number profiling will be performed using array Comparative Genomic Hybridisation (aCGH). Targeted sequencing using MiSeq (Illumina) and Ion Proton (Life Technologies) platforms will be performed to identify mutations in a panel of 648 genes.
Based on previous studies, we conservatively expect up to 25% of unevaluable needle biopsy specimens with inadequate/insufficient tumor tissue for genome sequencing. The patients with unevaluable tissue will continue on the master protocol (LHRHa + APA) for an additional 16 weeks followed by radical prostatectomy.
The genomically evaluable patients will be assigned to a specific sub-protocol according to the results of the genomic profile and randomized to a treatment arm within the sub-protocol for 16 weeks, with additional inclusion and exclusion criteria specified in dedicated sub-protocols. Radical prostatectomy will follow sub-protocol treatment.
Sub-protocol 1 - AR axis: No targetable actionable aberration; presence of TMPRSS2-ERG fusion, CHD1 loss or SPOP mutations: (~50% expected prevalence in study population) randomized to:
- LHRHa + APA for 16 weeks or
- LHRHa + APA + AAP (Abiraterone Acetate + Prednisone) for 16 weeks
Sub-protocol 2 - Loss of tumour suppressor genes - PTEN, TP53 or TB loss (~40%, bad prognosis) randomized to:
- LHRHa + AAP for 16 weeks or
- LHRHa + AAP + docetaxel for 6 cycles
Sub-protocol 3 - DNA damage response alterations (e.g. BRCA1/2, ATM, FANCONI, CDK12) in 6-8% assigned to:
- LHRHa + AAP + PARP (Poly [ADP-ribose] polymerase) inhibitors (niraparib) for 16 weeks
Sub-protocol 4 - Hypermutation, microsatellite instability (MSI), Lynch syndrome or CDK12 in less than 5% assigned to:
LHRHa + APA plus PD-L1 inhibitor (atezolizumab) for 16 weeks
- This arm is closed to enrollment
Sub-Protocol 5 - cancers primed for lineage plasticity: Loss of function DNA alteration in TP53 or RB1 and/or evidence of stem cell or neuroendocrine (NE) features (~20%) assigned to:
a. LHRHa + AAP + tazemetostat for 16 weeks
***This arm is closed to enrollment
Sub-protocol 6 - favorable genomic alterations as defined in SP-1, or PTENdef/AKTgain alterations (20%), will be assigned to SP-6a and SP-6b respectively, and receive
a. LHRHa + AAP + capivasertib (CAPIVA) for 16 weeks
Study Type
Enrollment (Estimated)
Phase
- Phase 2
Contacts and Locations
Study Contact
- Name: Martin E Gleave, MD
- Phone Number: 604-875-5006
- Email: m.gleave@ubc.ca
Study Contact Backup
- Name: Doron Berlin
- Email: Doron.Berlin@uhn.ca
Study Locations
-
-
British Columbia
-
Vancouver, British Columbia, Canada, V5Z 1M9
- Recruiting
- Vancouver Prostate Centre
-
Contact:
- Jonathan Ma
- Phone Number: 16048755675
- Email: jma@prostatecentre.com
-
Principal Investigator:
- Martin E Gleave, MD
-
-
Ontario
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London, Ontario, Canada, N6A 5W9
- Recruiting
- London Health Sciences Centre
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Principal Investigator:
- Brant Inman, MD
-
Contact:
- Yoonbee Kim
- Phone Number: 56916 519-685-8500
- Email: yoonbee.kim@lhsc.on.ca
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Ottawa, Ontario, Canada, K1H 8L6
- Recruiting
- Ottawa Hospital Research Institute (OHRI)
-
Principal Investigator:
- Rodney Breau, MD
-
Contact:
- Pascale Juneau
- Phone Number: 71064 613-737-8899
- Email: pjuneau@ohri.ca
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Toronto, Ontario, Canada, M5G 2C4
- Recruiting
- University Health Network
-
Principal Investigator:
- Neil Fleshner, M.D.
-
Contact:
- Jenny Su
- Phone Number: 3141 416-946-4501
- Email: Jenny.su@uhn.ca
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-
-
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California
-
Sacramento, California, United States, 95817
- Recruiting
- University of California Davis
-
Principal Investigator:
- Mamta Parikh, MD
-
Principal Investigator:
- Marc Dall'Era, MD
-
Contact:
- Mark Cokee
- Phone Number: 916-734-8603
- Email: Mcokee@health.ucdavis.edu
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Massachusetts
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Boston, Massachusetts, United States, 02115
- Recruiting
- Dana-Farber Cancer Institute / Beth Israel Deaconess Medical Center
-
Principal Investigator:
- Himisha Beltran, MD
-
Contact:
- Daniella Furtado
- Phone Number: 617-525-8782
- Email: Daniella_Furtado@dfci.harvard.edu
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Michigan
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Ann Arbor, Michigan, United States, 48109-5946
- Recruiting
- University of Michigan Health
-
Principal Investigator:
- Todd Morgan, MD
-
Contact:
- Main Line
- Phone Number: 800-962-3555
- Email: canceranswerline@umich.edu
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Texas
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Houston, Texas, United States, 77030
- Recruiting
- U.T. MD Anderson Cancer Center
-
Contact:
- askMDAnderson
- Phone Number: 877-632-6789
- Email: askmdanderson@mdanderson.org
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Principal Investigator:
- Brian Chapin, M.D.
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Washington
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Seattle, Washington, United States, 98109
- Recruiting
- Fred Hutchinson Cancer Center
-
Principal Investigator:
- Michael Schweizer, MD
-
Contact:
- Michael Schweizer, M.D.
- Phone Number: 206-606-6252
- Email: schweize@uw.edu
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
Inclusion Criteria:
i. Males ≥ 18 years of age. ii. Histologically confirmed adenocarcinoma of the prostate without pathologic evidence of small cell differentiation at the time of initial diagnosis. Screening biopsy must be performed within 4 months of the screening visit.
iii. High-risk localized prostate cancer as defined by at least one of the following:
- Any combination of Gleason Score 4+3=7 and Gleason Score 8 (4+4 or 5+3) in ≥6 systematic cores (with ≥1 core Gleason Score 8 [4+4 or 5+3] included);
- Any combination of Gleason Score 4+3 and Gleason Score 8 (4+4 or 5+3) in ≥3 systematic cores and PSA ≥20 ng/mL (with at least 1 core Gleason Score 8 [4+4 or 5+3] included);
- Gleason Score ≥9 in at least 1 systematic or targeted core;
- At least 2 systematic or targeted cores with Gleason Score ≥8, each with at least 80% involvement"; or
Gleason Score 4+3=7 in at least 6 systematic or targeted cores and PSA ≥20 ng/mL iv. Participants must provide consent blood collection and evaluation of diagnostic prostate tissue for genetic testing at registration and prior to assignment by a central reference laboratory.
v. No prior systemic or localized treatment for prostate cancer (exception: up to 12 weeks of luteinizing hormone-releasing hormone agonist or antagonist (LHRHa) and bicalutamide is allowable prior to registration).
vi. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 (Appendix II) and a life expectancy of ≥ 3 years in the opinion of the treating oncologist.
vii. Laboratory Requirements: Participants must have adequate end-organ function and all laboratory tests must be performed within 8 weeks prior to registration into master protocol (Table 1).
viii. Patient consent must be appropriately obtained in accordance with applicable local and regulatory requirements. Each patient must sign a consent form prior to registration in the trial to document their willingness to participate.
ix. Archival tissue must be available for genetic analysis.
Exclusion Criteria:
Participants will be excluded if ANY of the following criteria are met:
i. Received more than 12 weeks of LHRHa prior to registration. ii. Stage T4 prostate cancer by clinical examination or radiologic evaluation. iii. Hypogonadism or severe androgen deficiency as determined by the treating physician, or screening serum testosterone less than 50 ng/dL (1.7 nmol/L) iv. Participants with serious illnesses or medical conditions which could cause unacceptable safety risks or would not permit the participant to be managed according to the protocol. This includes but is not limited to:
- Active infection or chronic liver disease requiring systemic therapy;
- Active or known human immunodeficiency virus (HIV) with detectable viral load;
- Participants with uncontrolled hypertension or diabetes.
Uncontrolled or recent clinically significant cardiac disease, including history of any of the following within 12 months prior to screening:
- Severe or unstable angina, symptomatic pericarditis, symptomatic congestive heart failure, arterial or venous thromboembolic events (e.g., pulmonary embolism, cerebrovascular accident including transient ischemic attacks), clinically significant ventricular arrhythmias or New York Heart Association Class II to IV heart disease, coronary artery bypass grafting, coronary angioplasty, stenting, or myocardial infarction; uncomplicated deep vein thrombosis is not considered exclusionary).
History of any cardiac arrhythmias that preclude prostatectomy or treatment with study drugs, e.g. ventricular, supraventricular, nodal arrhythmias, or conduction abnormality.
v. Participants who are unable to swallow oral medication and/or have impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the study drugs (e.g. ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection).
vi. Participants with a history of hypersensitivity to any of the study drugs or any excipient.
vii. Participants with a history of non-compliance to medical regimens. viii. Severe concurrent disease, infection, or co-morbidity that, in the judgment of the Investigator, would make the participant inappropriate for registration or prostatectomy.
ix. Prior androgen deprivation, chemotherapy, surgery, or radiation for prostate cancer.
x. Receiving concurrent androgens, estrogens, or progestational agents, or received any of these agents within the 6 months prior to registration.
xi. M1 by conventional imaging (CT, bone scan) or PSMA-PET. Participants with oligometastatic (<3) metastases by PSMA imaging only who are deemed candidates for radical prostatectomy are eligible.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
|---|---|
|
Active Comparator: Group 1a
LHRHa plus apalutamide.
|
4 tablets by mouth once a day for 24 weeks
|
|
Active Comparator: Group 1b
LHRHa plus apalutamide plus abiraterone acetate plus prednisone.
|
4 tablets by mouth once a day for 24 weeks
4 tablets by mouth on an empty stomach once a day for 16 weeks
1 tablet by mouth once daily while taking abiraterone acetate
|
|
Active Comparator: Group 2a
LHRHa plus abiraterone acetate plus prednisone.
|
4 tablets by mouth on an empty stomach once a day for 16 weeks
1 tablet by mouth once daily while taking abiraterone acetate
|
|
Active Comparator: Group 2b
LHRHa plus abiraterone acetate plus prednisone plus docetaxel.
|
4 tablets by mouth on an empty stomach once a day for 16 weeks
1 tablet by mouth once daily while taking abiraterone acetate
Infusion every 3 weeks for 6 cycles (each cycle has 3 weeks)
|
|
Active Comparator: Group 3
LHRHa plus abiraterone acetate plus prednisone plus niraparib
|
4 tablets by mouth on an empty stomach once a day for 16 weeks
1 tablet by mouth once daily while taking abiraterone acetate
3 capsules by mouth once daily for 16 weeks
|
|
Active Comparator: Group 4
LHRHa plus apalutamide plus atezolizumab
|
4 tablets by mouth once a day for 24 weeks
1200mg infusion every 3 weeks for 6 cycles
|
|
Active Comparator: Group 5
LHRHa plus abiraterone acetate plus prednisone plus tazemetostat
|
4 tablets by mouth on an empty stomach once a day for 16 weeks
1 tablet by mouth once daily while taking abiraterone acetate
200 mg 4 tablets by mouth twice daily with or without food for 16 weeks
|
|
Active Comparator: Group 6
LHRHa plus abiraterone acetate plus prednisone plus Capivasertib
|
4 tablets by mouth on an empty stomach once a day for 16 weeks
1 tablet by mouth once daily while taking abiraterone acetate
200 mg 2 tablets by mouth twice a day with or without food on an intermittent dosing schedule (days 1-4, then 3 days off) each week for 16 weeks
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
|---|---|---|
|
Complete Pathologic Response (pCR)
Time Frame: 6 years
|
Pathological Minimal Residual Disease (pMRD): pathological minimal residual disease (pMRD) is defined as residual tumour 5mm or less.
|
6 years
|
|
Pathological Minimal Residual Disease (pMRD)
Time Frame: 6 years
|
Pathological minimal residual disease is defined as residual tumour 5 mm or less.
|
6 years
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
|---|---|---|
|
Pain level assessment
Time Frame: 6 years
|
The Brief Pain Inventory-Short Form (BPI-SF) is a 9-item, self administered questionnaire which evaluates the severity of a participant's level of pain and impact on daily functioning.
This questionnaire will be administered at screening, prior to receiving master protocol therapy (0 weeks), the end of receiving therapy (8 weeks), as well as the End of Treatment (EoT) visit.
|
6 years
|
|
Generic Quality of Life (QoL)
Time Frame: 6 years
|
The EQ-5D-5L is a widely used instrument developed in Europe to evaluate the generic quality of life.
The EQ-5D-5L has two components: the EQ-5D descriptive system and the EQ visual analogue scale.
This questionnaire will be administered at screening, prior to receiving master protocol therapy (0 weeks), the end of receiving therapy (8 weeks) as well as at the EoT visit.
|
6 years
|
|
Quality of Life-Prostate Cancer Patients
Time Frame: 6 years
|
This will be measured using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire.
The FACT-P is a multidimensional, self-report QoL instrument specifically designed for use with patients who have prostate cancer.
This questionnaire will be administered at screening, prior to receiving master protocol therapy (0 weeks), the end of receiving therapy (8 weeks) as well as at the EoT visit.
|
6 years
|
Collaborators and Investigators
Sponsor
Investigators
- Study Chair: Martin E Gleave, MD, University of British Columbia
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Urogenital Diseases
- Genital Diseases
- Genital Neoplasms, Male
- Urogenital Neoplasms
- Neoplasms by Site
- Neoplasms
- Genital Diseases, Male
- Prostatic Diseases
- Male Urogenital Diseases
- Prostatic Neoplasms
- Organic Chemicals
- Hydrocarbons
- Cycloparaffins
- Hydrocarbons, Alicyclic
- Hydrocarbons, Cyclic
- Terpenes
- Polycyclic Compounds
- Taxoids
- Cyclodecanes
- Diterpenes
- Pregnadienes
- Pregnanes
- Steroids
- Fused-Ring Compounds
- Pregnadienediols
- Androstenes
- Androstanes
- Docetaxel
- Abiraterone Acetate
- Prednisone
- capivasertib
- niraparib
- atezolizumab
- apalutamide
- tazemetostat
Other Study ID Numbers
- H20-03434
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
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