Prostate Cancer Biomarker Enrichment and Treatment Selection

• ClinicalTrials.gov Identifier: NCT03385655
• Recruitment Status: Recruiting
• First Posted: December 28, 2017
• Last Update Posted: January 5, 2023
• Sponsor: Canadian Cancer Trials Group
• Collaborators: Canadian Cancer Clinical Trials Network; BC Cancer Foundation
• Information provided by (Responsible Party): Canadian Cancer Trials Group

Study Description

Brief Summary:

The purpose of the pre-study screening is to test for DNA abnormalities or biomarkers.

Condition or disease	Intervention/treatment	Phase
Prostate Cancer	Drug: Adavosertib; Drug: Savolitinib; Drug: Darolutamide; Drug: CFI-400945; Drug: Ipatasertib; Drug: Durvalumab and Tremelimumab; Drug: Carboplatin	Phase 2

Detailed Description:

This testing will be done on a samples of blood to see whether or not patients are eligible to take part in one of the sub-studies. Each study will be looking at what effects a new drug or drugs has on prostate cancer and will also be looking at the side effects of treatment. The purpose of the main studies is to see if the biomarkers that were identified screening samples can help predict which patients are most likely to be helped by that drug or drugs and to see how the cancer cells respond to treatment.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 600 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Prostate Cancer Biomarker Enrichment and Treatment Selection (PC-BETS) Study
• Actual Study Start Date: December 12, 2017
• Estimated Primary Completion Date: July 31, 2023
• Estimated Study Completion Date: July 31, 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: WEE-1 inhibitor - ARM CLOSED	Drug: Adavosertib; 250mg, may dose escalate to 300mg if no drug-related GI tox in cycle 1
Experimental: cMET inhibitor	Drug: Savolitinib; 600mg once daily, orally.
Experimental: novel non-steroidal androgen receptor (AR) antagonist	Drug: Darolutamide; 600mg twice daily, orally.
Experimental: CFI400945 PLK4 inhibitor - ARM CLOSED	Drug: CFI-400945; Dose level assigned at enrollment, starting at 32mg/day on Days 1-7 and 15-21 or 15-28 depending on toxicity experienced.
Experimental: Ipatasertib AKT inhibitor	Drug: Ipatasertib; 400mg daily 3 weeks on, 1 week off
Experimental: Durvalumab and Tremelimumab immunotherapy	Drug: Durvalumab and Tremelimumab; Durvalumab 1500mg day 1 every 4 weeks; Tremelimumab 225mg day 1 cycle 1
Experimental: Carboplatin platinum based chemotherapy	Drug: Carboplatin; AUC 5 IV 60min Day 1 q 21 days

Outcome Measures

Primary Outcome Measures :

1. Clinical benefit rate defined as proportion of patients who had PSA decline ≥ 50%, complete or partial objective response, or Stable disease for ≥ 12 weeks. [ Time Frame: 2 years ]

Secondary Outcome Measures :

1. Measure effect of each study drug on PSA decline [ Time Frame: 2 years ]
2. Measure objective response as determined by RECIST 1.1 criteria [ Time Frame: 2 years ]
3. Number and severity of adverse events [ Time Frame: 2 years ]
4. Measure effect of each study drug on time to PSA progression [ Time Frame: 2 years ]
5. To summarize progression-free survival [ Time Frame: 2 years ]
6. To summarize overall survival [ Time Frame: 2 years ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: Male
• Gender Based Eligibility: Yes
• Gender Eligibility Description: Male
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

The following will be required prior to REGISTRATION:

• Patients must have histologically confirmed adenocarcinoma of the prostate without pathologic or clinical evidence (e.g. PSA < 2.0 μg/L with liver metastases) of small cell neuroendocrine differentiation.
• Patients must consent prior to blood collection for screening correlative testing by a central reference laboratory. The screening blood sample cannot be sent for analysis prior to screening registration.
• All patients must have consented to the release of a tumour block from their primary or metastatic tumour. The centre/pathologist must have agreed to the submission of the specimen(s). Contact CCTG if no archival tissue is available.
• Patients must have evidence of castrate resistance with either biochemical or radiological disease progression in the setting of surgical or medical castration:

PSA Progression:

• Minimum of two rising PSA values from a baseline measurement with an interval of ≥ 1 week between each measurement
• PSA must be ≥ 2.0 µg/L (ng/mL)

Objective progression:

• RECIST 1.1, or
• PCWG3 Criteria for bone progression

Surgical/Medical Castration:

• Prior bilateral orchiectomy, or
• LHRH agonist/antagonist and testosterone < 50 ng/dL or < 1.7 nmol/L. LHRH agonist/antagonist therapy must be maintained for the duration of study therapy and if previously discontinued, must be restarted and castrate level of testosterone present.
• Patients must be ≥18 years of age.
• ECOG performance status 0 or 1 (Appendix I) and have a life expectancy of ≥ 6 months.
• Patients must have radiologically documented disease (measurable or non-measurable as defined by RECIST 1.1. Patients with elevated PSA only are not eligible.
• Neutrophils ≥ 1.5 x 10^9/L
• Platelets ≥ 100 x 10^9/L
• Hemoglobin ≥ 90 g/L; contact CCTG if hemoglobin is between 80-89 g/L, patient is not decompensated, is asymptomatic and transfusion is not indicated.
• Serum potassium within normal limits
• Bilirubin ≤ 1.5 ULN; if confirmed Gilbert's then bilirubin ≤ 3.0 x ULN
• ALT ≤ 2.5 x ULN; if patient has liver metastases ≤ 5.0 x ULN
• Serum creatinine ≤ 1.5 x ULN or Creatinine clearance ≥ 45 mL/min; measured directly by 24-hour urine sampling OR as calculated by Cockcroft and Gault equation: Males: GFR = 1.23 x (140-age) x weight in kg/serum creatinine in μmol/L
• Patient consent for screening and subsequent enrollment (as applicable) must be appropriately obtained in accordance with applicable local and regulatory requirements. Each patient must sign a consent form prior to screening and subsequent enrollment (as applicable) in the trial to document their willingness to participate.

Additional Criteria to be met prior to SUB-STUDY ENROLLMENT:

• Patients must have recovered from any treatment-related toxicities prior to enrollment (unless ≤ grade 1, irreversible, or considered by investigator as not clinically significant).
• Prior major surgery is permitted provided that a minimum of 14 days have elapsed between any major surgery and enrollment (7 days for minor surgery e.g. port insertion), and that wound healing has occurred.
• Prior external beam radiation or radium-223 is permitted provided a minimum of 28 days (4 weeks) have elapsed between the last dose and enrollment. Consult CCTG if patients have received other therapeutic radioisotopes. Exceptions may be made for low-dose non-myelosuppressive radiotherapy after consultation with CCTG. Concurrent radiation is not permitted. If radiation is required for example for pain control, it must be completed prior to enrollment. Prior strontium-89 at any time is not permitted.
• Previous Hormone Therapy: Patients must have received prior hormonal treatment with at least one of: abiraterone acetate, enzalutamide, apalutamide (ARN-509), darolutamide (ODM-201), TAK-700 and TOK-001 or other next-generation AR-pathway inhibitor (if agent is not listed, must be discussed and approved with CCTG prior to registration). Consult substudies for additional criteria
• Prior cytotoxic therapy: Patients may have received cytotoxic therapy in the castrate sensitive setting as well as up to 1 regimen of cytotoxic therapy in the CRPC setting
• Patients must have an adequate washout prior to enrollment as follows:

• Longest of one of the following:

  • Standard cycle length of standard therapies;
  • Two weeks;
  • The longer of 30 days or 5 half-lives for investigational agents;
• Patients must have discontinued anti-androgens for at least 4 weeks prior to substudy entry/enrollment (at least 6 weeks for bicalutamide).
• LHRH agonist therapy must continue unless surgically castrated. Note: after discussion, CCTG selected patients may be screened prior to adequate washout.
• Patient must have progressed (biochemically or radiologically, as defined in 4.1.4) during or after their last systemic therapy
• Patients must be accessible for treatment and follow up. Patients registered enrolled on this trial must be treated and followed at the participating centre. This implies there must be reasonable geographical limits (for example: 1 ½ hour's driving distance) placed on patients being considered for this trial.
• Investigators must assure themselves the patients enrolled on this trial will be available for complete documentation of the treatment, adverse events, response assessment and follow-up.
• Patients must agree to return to their primary care facility for any adverse events, which may occur through the course of the trial.
• In accordance with CCTG policy, protocol treatment is to begin within 2 working days of patient enrollment.
• Men of childbearing potential must have agreed to use a highly effective contraceptive method during study drug treatment for 6 months after stopping treatment and should not father a child or donate sperm during this period.
• In addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation, or vasectomy / vasectomized partner. However, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he is responsible for beginning contraceptive measures.

Exclusion Criteria:

• Patients with a history of other malignancies, except: adequately treated non-melanoma skin cancer, or other solid tumours curatively treated with no evidence of disease for ≥ 2 years.
• Patients with central nervous system (CNS) involvement unless at least 4 weeks from prior therapy completion (including radiation and/or surgery) AND clinically stable and not receiving steroids and/or enzyme-inducing anti-epileptic medications for brain metastases. Patients with epilepsy not due to CNS metastases are eligible as long as no contraindication or concern with drug interactions.

• Patients with serious illnesses or medical conditions which could cause unacceptable safety risks or would not permit the patient to be managed according to the protocol. This includes but is not limited to:

  • active infection requiring systemic therapy;
  • active or known human immunodeficiency virus (HIV) with detectable viral load;

  • uncontrolled or recent clinically significant cardiac disease, including:

    • angina pectoris, symptomatic pericarditis, coronary artery bypass grafting, coronary angioplasty, or stenting, or myocardial infarction in the previous 12 months;
    • history of documented congestive heart failure (New York Heart Association functional classification III-IV) or cardiomyopathy;
    • history of any cardiac arrhythmias, e.g. ventricular, supraventricular, nodal arrhythmias, or conduction abnormality in the previous 12 months;
    • patients with uncontrolled hypertension.
  • Patients with significant liver diseases including viral/other hepatitis, current alcohol abuse or cirrhosis.
• Patients 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. Crohn's disease, ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, active bowel inflammation (e.g. diverticulitis) or small bowel resection), unless agreed with CCTG (exceptions may be given if parenteral substudy is available/appropriate.

• Patients who require continued or concurrent treatment with:

  • Systemic corticosteroids at a dose equivalent to prednisone > 10 mg daily. Topical applications (e.g. rash), inhaled sprays (e.g. obstructive airways diseases), eye drops or local injections (e.g. intra-articular) are allowed.
  • Bisphosphonates / denosumab for reasons other than hypercalcemia, osteoporosis or prevention of skeletal-related events.
  • Other anti-cancer or investigational agents (except LHRH)
• History of hypersensitivity to any of the study drugs or any excipient.
• Patients with a history of non-compliance to medical regimens.
• Patients who have received growth factors within 28 days prior to initiation of dosing of study drug or who are likely to require treatment with growth factors throughout the duration of the trial.

Contacts and Locations

Contacts

Contact: Lesley Seymour; 613-533-6430; lseymour@ctg.queensu.ca

Locations

Canada, Alberta

Cross Cancer Institute; Recruiting

Edmonton, Alberta, Canada, T6G 1Z2

Contact: Michael Kolinsky 780 432-8762

Canada, British Columbia

BCCA - Vancouver Cancer Centre; Recruiting

Vancouver, British Columbia, Canada, V5Z 4E6

Contact: Kim Chi 604 877-6000 ext 2746

Canada, Nova Scotia

QEII Health Sciences Centre; Recruiting

Halifax, Nova Scotia, Canada, B3H 1V7

Contact: Robyn J. Macfarlane 902 473-6106

Canada, Ontario

Juravinski Cancer Centre at Hamilton Health Sciences; Recruiting

Hamilton, Ontario, Canada, L8V 5C2

Contact: Som Mukherjee 905 387-9495 ext 64605

London Regional Cancer Program; Recruiting

London, Ontario, Canada, N6A 5W9

Contact: Eric W. Winquist 519 685-8261

Ottawa Hospital Research Institute; Recruiting

Ottawa, Ontario, Canada, K1H 8L6

Contact: Michael Ong 613 737-7700 ext 75051

University Health Network; Recruiting

Toronto, Ontario, Canada, M5G 2M9

Contact: Di (Maria) Jiang 647 993-0448

Canada, Quebec

CHUM-Centre Hospitalier de l'Universite de Montreal; Recruiting

Montreal, Quebec, Canada, H2X 3E4

Contact: Fred Saad 514 890-8000 ext 27466

The Jewish General Hospital; Recruiting

Montreal, Quebec, Canada, H3T 1E2

Contact: Cristiano Ferrario 514 398-8307

Canada, Saskatchewan

Allan Blair Cancer Centre; Recruiting

Regina, Saskatchewan, Canada, S4T 7T1

Contact: Muhammad Salim 306 766-2691

Saskatoon Cancer Centre; Recruiting

Saskatoon, Saskatchewan, Canada, S7N 4H4

Contact: Nayyer Iqbal 306 655-2710

Sponsors and Collaborators

Canadian Cancer Trials Group

Canadian Cancer Clinical Trials Network

BC Cancer Foundation

Investigators

• Study Chair: Michael Kolinsky; Cross Cancer Institute, Edmonton, AB Canada
• Study Chair: Som Mukherjee; Juravinski Cancer Centre at Hamilton Health Sciences Centre, ON Canada
• Study Chair: Michael Ong; Ottawa Hospital Research Institute, Ottawa, ON Canada
• Study Chair: Kim Chi; BCCA - Vancouver Cancer Centre
• Study Chair: Aaron Hansen; University Health Network, Toronto, ON, Canada
• Study Chair: Sebastien Hotte; Juravinski Cancer Centre at Hamilton Health Sciences, Hamilton, ON Canada
• Study Chair: Zineb Hamilou; CHUM-Centre Hospitalier de l'Universite de Montreal

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Maia MC, Salgia M, Pal SK. Harnessing cell-free DNA: plasma circulating tumour DNA for liquid biopsy in genitourinary cancers. Nat Rev Urol. 2020 May;17(5):271-291. doi: 10.1038/s41585-020-0297-9. Epub 2020 Mar 17.

• Responsible Party: Canadian Cancer Trials Group
• ClinicalTrials.gov Identifier: NCT03385655
• Other Study ID Numbers: I234
• First Posted: December 28, 2017
• Last Update Posted: January 5, 2023
• Last Verified: January 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Prostatic Neoplasms; Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Prostatic Diseases; Carboplatin; Durvalumab; Tremelimumab; Adavosertib; Antineoplastic Agents; Antineoplastic Agents, Immunological; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action