Comeback From Long coursE Androgen Deprivation Therapy (ADT) With RElugolix and Darolutamide (CLEARED)

NCT06463457 | Active Not Recruiting Phase 2 DMC FDA Drug

• 1 other identifier: 24-217
• Study Type: interventional
• Target: 33
• Locations: 1 country
• Sites: 3

Brief Summary

This research study is being done to determine the rate of testosterone recovery after completing two years of treatment with the combination of relugolix and darolutamide as well as to assess the safety of the drugs when administered in combination. The names of the drugs in this study are:

• Relugolix (a type of gonadotropin-releasing hormone receptor antagonist)
• Darolutamide (a type of androgen receptor antagonist)

Conditions

Advanced Prostate Cancer; Prostate Cancer; Hormone Sensitive Prostate Cancer

Keywords

Hormone-Sensitive Prostate Cancer; Prostate Cancer; Advanced Prostate Cancer

Outcome Measures

Primary Outcomes (2)

• 18-month Rate of Testosterone Recovery

  Rate of testosterone recovery (TR) defined as the proportion of participants achieving testosterone ≥ lower limit of normal by 18 months after completion of study treatment. Participants who withdrew from trial therapy (due to early progression, toxicity, patient/physician decision or death) before completing 2 years of treatment will be excluded from the analysis. Participants who require resumption of androgen deprivation, withdraw, are lost to follow-up, or die before 18 months of post-treatment follow up has been completed without having achieved testosterone recovery ≥ lower limit of normal beforehand will be included in the analysis and will be considered to be non-recovered.

  42 months (18 months after completion of 2 years of treatment)

• Grade 3-5 Treatment-related Toxicity Rate

  All grade 3-5 adverse events (AE) with treatment attribution of possibly, probably or definitely related to study treatment based on Common Terminology Criteria for Adverse Events (CTCAE) version 5 are counted. Rate is the proportion of treated participants experiencing at least one of these adverse events as defined during the time of observation.

  24 months. AE collected on day 1 of each cycle (up to 26 cycles in total, each cycle is 28 days)

Secondary Outcomes (3)

• Geometric Mean Ratio of Single-dose Cmax (highest concentration of drug) and Steady-state Ctrough (the concentration of drug in the blood immediately before the next dose is administered)

  29 days. Pharmacokinetic (PK) collection prior to the first dose of both drugs and then after 2 hours, 4 hours and 8 hours (Cohort 1) or after 24 hours, 7 days, and 28 days (Cohort 2) of uninterrupted dosing during cycle 1 (each cycle is 28 days).

• Rate of Treatment Discontinuation

  24 months. Treatment planned on day 1 of each cycle (up to 26 cycles in total, each cycle is 28 days)

• Mean Functional Assessment of Cancer Therapy - Prostate (FACT-P) Score

  42 months. Collected at Cycle 1 day 1 (each cycle is 28 days), end of treatment (24 months), and end of study at 18 months after completion of treatment (42 months)

Study Arms (2)

Cohort 1 Short Pharmacokinetics (PK)

EXPERIMENTAL

Enrolled participants will complete study procedures as follows: * Cycle 1: * Day 1 of 28 Day Cycle: Predetermined dose of Relugolix 1x daily. First dose will be administered in-clinic. * Day 1 of 28 Day Cycle: Predetermined dose of Darolutamide 2x daily. First dose will be administered in-clinic. * Cycle 2 through End of Treatment: * Predetermined dose of Relugolix 1x daily. * Predetermined dose of Darolutamide 2x daily. * End of Treatment visit. * Follow Up: every 3 months for 18 months.

Drug: Darolutamide; Drug: Relugolix

Cohort 2 Long Pharmacokinetics (PK)

EXPERIMENTAL

Enrolled participants will complete study procedures as follows: * Cycle 1: * Days 1, 2, 8 of 28 Day Cycle: Predetermined dose of Relugolix 1x daily. First dose will be administered in-clinic. * Days 1, 2, 8 of 28 Day Cycle: Predetermined dose of Darolutamide 2x daily. First dose will be administered in-clinic. * Cycle 2: * Day 1 of 28 Day Cycle: Predetermined dose of Relugolix 1x daily. First dose will be administered in-clinic. * Day 1 of 28 Day Cycle: Predetermined dose of Darolutamide 2x daily. First dose will be administered in-clinic. * Cycle 3 through End of Treatment: * Predetermined dose of Relugolix 1x daily. * Predetermined dose of Darolutamide 2x daily. * End of Treatment visit. * Follow Up: every 3 months for 18 months.

Drug: Darolutamide; Drug: Relugolix

Interventions

Darolutamide DRUG

Androgen receptor antagonist, tablet taken orally per protocol.

Also known as: ODM-201, Bay 1841788, C19H19CIN6O2

Cohort 1 Short Pharmacokinetics (PK); Cohort 2 Long Pharmacokinetics (PK)

Relugolix DRUG

Gonadotropin-releasing hormone (GnRH) receptor antagonist, tablet taken orally per protocol.

Also known as: Orgovyx, RVT-601, TAK-385, 1-[4-[1-[(2,6-difluorophenyl)methyl]-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-2,4-dioxothieno[2,3-d]pyrimidin-6-yl]phenyl]-3-methoxyurea, C29H27F2N7O5S

Cohort 1 Short Pharmacokinetics (PK); Cohort 2 Long Pharmacokinetics (PK)

Eligibility Criteria

• Age: 18 Years+
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Participants must have histologically or cytologically confirmed prostate cancer.
• Hormone-sensitive prostate cancer (with detectable prostate-specific antigen \[PSA\] \> 0.02 ng/ml, testosterone ≥ lower limit of normal \[LLN\] per institutional assay) planned for two years of intensified androgen deprivation therapy per investigator discretion. This includes the following indications:
• Treatment-naïve high risk lymph node-negative (N0) disease planned for primary radiation therapy
• Treatment-naïve clinically pelvic lymph node positive (cN+) disease planned for primary radiation therapy
• Pathologically pelvic lymph node positive (pN+) disease after prostatectomy planned for salvage radiation therapy
• Regional nodal recurrence after prior local therapy (often in the context of radiation to lymph nodes)
• Synchronous or metachronous low volume metastatic hormone sensitive prostate cancer (mHSPC) by Chemohormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease (CHAARTED) criteria planned for treatment interruption after 2 years (often in the context of radiation to sites of disease).
• N.B: While CHAARTED criteria were established based on conventional imaging, patients who had PSMA PET imaging that would meet criteria for high volume disease (visceral metastases or ≥ 4 definitive bone metastases with at least one outside the axial skeleton) are excluded from this study.
• Prior hormonal therapy is permitted in the context of neoadjuvant/concurrent/adjuvant treatment with prior local therapy or biochemical recurrence by conventional imaging (for patients enrolling for recurrent rather than treatment-naïve disease), but patients must have had testosterone recovery to ≥ LLN at time of enrollment to this trial.
• Age ≥18 years. Children under 18 are excluded from this study as prostate cancer is a disease of adults.
• Eastern Cooperative Oncology Group (ECOG) performance status ≤1 (Karnofsky ≥70%).
• Participants must meet the following organ and marrow function as defined below:
• leukocytes ≥2500/mcL
• absolute neutrophil count ≥1000/mcL
• platelets ≥100,000/mcL

You may not qualify if:

• Participants who received prior systemic therapy for the disease state (high risk localized, lymph node positive, or low volume mHSPC) for which they are enrolling on this trial. Prior hormonal therapy is permitted for patients with recurrent disease after prior therapy.
• Participants who previously experienced any rise in PSA with castrate level testosterone (\< 50 ng/dl).
• Participants who are receiving any other investigational agents for this condition.
• Participants with brain metastases, leptomeningeal disease, or metastases involving other visceral organs since these patients would be considered to have "high volume" metastatic disease by CHAARTED criteria.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to relugolix or darolutamide.
• Participants with predicted significant drug-drug interaction with darolutamide and/or relugolix are ineligible or must be monitored carefully as detailed below:
• Participants receiving combined P-glycoprotein (P-gp) and strong CYP3A inducers (e.g. apalutamide, carbamazepine, fosphenytoin, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort) or combined P-gp and moderate CYP3A4 inducers (e.g. efavirenz, rifabutin) are ineligible.
• Participants receiving combined P-gp and strong CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, posaconazole, clarithromycin, cobicistat, cyclosporine, tacrolimus, nelfinavir, ritonavir, lopinavir, saquinivir, tipranavir) are ineligible to enroll.
• Participants receiving Breast cancer resistance protein (BCRP) substrates (e.g. glyburide, cimetidine, nitrofurantoin, dipyridamole, sulfasalazine, and rosuvastatin) are not excluded but participants should be monitored more frequently for adverse reactions to the BCRP substrate drug, and dose reduction of the BCRP substrate drug should be considered.
• Participants receiving P-gp inhibitors are not excluded but participants must be able to dose the P-gp inhibitor at least 6 hours after relugolix dose during the conduct of the study. Participants unable to dose the P-gp inhibitor at least 6 hours after relugolix dose, or requiring twice daily or more frequent dosing of a P-gp inhibitor are ineligible.
• Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference. As part of the enrollment/informed consent procedures, the participant will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the participant is considering a new over-the-counter medicine or herbal product.
• Participants with uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia.
• Participants with psychiatric illness/social situations that would limit compliance with study requirements.
• Pregnant and nursing women are excluded from this study because they do not develop prostate cancer.
• Concurrent active malignancy. Patients with non-melanomatous skin cancer, superficial bladder cancer, cancer not needing active systemic therapy for at least 2 years and would not affect imaging assessments for prostate cancer, cancer for which the treating investigator deems the subject to be in remission, or any prior malignancy that was treated with curative intent (no evidence of disease for at least 3 years) are also permitted to enroll.

Sponsors & Collaborators

• Atish Choudhury, MD: lead
• Bayer: collaborator
• Pfizer: collaborator
• National Comprehensive Cancer Network: collaborator
• Sumitomo Pharma America, Inc.: collaborator

Study Sites (3)

Beth Israel Deaconess Medical Center

Boston, Massachusetts, 02215, United States

Location

Brigham and Women's Hospital

Boston, Massachusetts, 02215, United States

Location

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

MeSH Terms

Conditions

Prostatic Neoplasms

Interventions

darolutamide; relugolix

Condition Hierarchy (Ancestors)

Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Genital Diseases, Male; Genital Diseases; Urogenital Diseases; Prostatic Diseases; Male Urogenital Diseases

Study Officials

• Atish Choudhury, MD, PhD

  Dana-Farber Cancer Institute

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Sponsor Investigator

Study Record Dates

• First Submitted: June 11, 2024
• First Posted: June 17, 2024
• Study Start: December 13, 2024
• Primary Completion (Estimated): November 30, 2028
• Study Completion (Estimated): November 30, 2028
• Last Updated: March 9, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: Data can be shared no earlier than 1 year following the date of publication
• Access Criteria: Contact the Belfer Office for Dana-Farber Innovations (BODFI) at innovation@dfci.harvard.edu

Locations

US (3)