Testing the Anti-cancer Drug Darolutamide in Patients With Testosterone-Driven Salivary Gland Cancers

A Phase 2 Study of Darolutamide in Combination With Leuprolide Acetate in Hormone-Therapy Naive Recurrent and/or Metastatic Androgen Receptor (AR) Positive Salivary Gland Cancer

This phase II trial tests how well darolutamide and leuprolide acetate work in treating patients with androgen receptor positive salivary cancer that has spread from where it first started (primary site) to other places in the body (metastatic), cannot be removed by surgery (unresectable) or that has come back after a period of responding to prior therapy (recurrent). Darolutamide is in a class of medications called androgen receptor inhibitors. It works by blocking the effects of androgen (a male reproductive hormone) to stop the growth and spread of cancer cells. Leuprolide acetate is in a class of medications called gonadotropin-releasing hormone (GnRH) agonists. It works by decreasing the amount of certain hormones in the body. Giving darolutamide in combination with leuprolide acetate may help to stop the growth of tumor cells that need androgens to grow or shrink them.

Study Overview

• Status: Active, not recruiting
• Conditions: Recurrent Salivary Gland Carcinoma; Metastatic Salivary Gland Carcinoma; Unresectable Salivary Gland Carcinoma; Locally Advanced Salivary Gland Carcinoma
• Intervention / Treatment: Procedure: Biospecimen Collection; Procedure: Magnetic Resonance Imaging; Procedure: Computed Tomography; Drug: Leuprolide Acetate; Drug: Darolutamide; Procedure: Biopsy Procedure

Detailed Description

PRIMARY OBJECTIVE:

I. To evaluate the best overall response rate (BOR) of recurrent/metastatic androgen receptor positive (AR+) salivary gland cancer (SGC) patients within one year of darolutamide and androgen deprivation therapy (ADT).

SECONDARY OBJECTIVES:

I. To evaluate progression-free survival (PFS). II. To evaluate overall survival (OS). III. To evaluate toxicity by Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0.

EXPLORATORY OBJECTIVES:

I. To evaluate molecular, genomic and transcriptomic biomarkers in serial research biopsies obtained before and on darolutamide and ADT.

II. To evaluate the differences in BOR, PFS, OS with darolutamide and ADT treatment among patients who did and did not receive prior systemic therapy for AR+ SGC.

OUTLINE:

Patients receive darolutamide orally (PO) twice daily (BID) on days 1-28 of each cycle and leuprolide acetate intramuscularly (IM) every 4 or 12 weeks. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo biopsy, collection of blood samples, and computed tomography (CT)/magnetic resonance imaging (MRI) throughout the trial.

After completion of study treatment, patients are followed every 3-6 months for 2 years after treatment discontinuation or until death, whichever occurs first.

• Study Type: Interventional
• Enrollment (Estimated): 21
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Irvine, California, United States, 92612
      • UCI Health - Chao Family Comprehensive Cancer Center and Ambulatory Care
    • Los Angeles, California, United States, 90033
      • USC / Norris Comprehensive Cancer Center
    • Los Angeles, California, United States, 90033
      • Los Angeles General Medical Center
    • Orange, California, United States, 92868
      • UC Irvine Health/Chao Family Comprehensive Cancer Center
    • Sacramento, California, United States, 95817
      • University of California Davis Comprehensive Cancer Center
  • Colorado
    • Aurora, Colorado, United States, 80045
      • UCHealth University of Colorado Hospital
  • Georgia
    • Atlanta, Georgia, United States, 30308
      • Emory University Hospital Midtown
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago Comprehensive Cancer Center
    • New Lenox, Illinois, United States, 60451
      • UC Comprehensive Cancer Center at Silver Cross
    • Orland Park, Illinois, United States, 60462
      • University of Chicago Medicine-Orland Park
  • Indiana
    • Crown Point, Indiana, United States, 46307
      • UChicago Medicine Northwest Indiana
  • New Jersey
    • Basking Ridge, New Jersey, United States, 07920
      • Memorial Sloan Kettering Basking Ridge
    • Middletown, New Jersey, United States, 07748
      • Memorial Sloan Kettering Monmouth
    • Montvale, New Jersey, United States, 07645
      • Memorial Sloan Kettering Bergen
  • New York
    • Commack, New York, United States, 11725
      • Memorial Sloan Kettering Commack
    • Harrison, New York, United States, 10604
      • Memorial Sloan Kettering Westchester
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center
    • New York, New York, United States, 10016
      • Laura and Isaac Perlmutter Cancer Center at NYU Langone
    • Uniondale, New York, United States, 11553
      • Memorial Sloan Kettering Nassau
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • UNC Lineberger Comprehensive Cancer Center
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • University of Oklahoma Health Sciences Center
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15232
      • University of Pittsburgh Cancer Institute (UPCI)
  • Texas
    • Houston, Texas, United States, 77030
      • M D Anderson Cancer Center
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • Huntsman Cancer Institute/University of Utah
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia Cancer Center
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin Carbone Cancer Center - University Hospital
    • Madison, Wisconsin, United States, 53718
      • University of Wisconsin Carbone Cancer Center - Eastpark Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients must have histologically or cytologically confirmed salivary gland cancer that is recurrent/metastatic or unresectable/locally advanced, with AR expression detected by immunohistochemistry (IHC) on a Clinical Laboratory Improvement Act (CLIA)-approved assay. Androgen receptor testing by immunohistochemistry (IHC) can be performed locally in a CLIA (Clinical Laboratory Improvement Amendments) certified lab
• Patients must have measurable disease
• Patients must have not had prior AR-targeted therapy, except for AR-targeted therapy administered in the neoadjuvant and/or adjuvant setting and with disease recurrence more than 6 months since treatment completion
• Age >= 18 years. Because no dosing or adverse event data are currently available on the use of darolutamide in combination with leuprolide acetate in patients < 18 years of age, children are excluded from this study
• Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
• Absolute neutrophil count >= 1,000/mcL
• Platelets >= 100,000/mcL
• Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (exception: patients with elevated bilirubin due to Gilbert's disease would be eligible for the trial)
• Aspartate aminotransferase (AST) (serum (glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase ([SGPT]) =< 3 x institutional ULN
• Creatinine =< 1.5 x institutional ULN
• Glomerular filtration rate (GFR) >= 30 mL/min/1.73 m^2 (by Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI])
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
• Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
• Patients with treated brain metastases are eligible
• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
• Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better
• The effects of darolutamide on the developing human fetus are unknown. For this reason and because androgen receptor inhibitor agents as well as other therapeutic agents used in this trial are known to be teratogenic (leuprolide-acetate), women of child-bearing potential and men must agree to use adequate contraception (non-hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men and women treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 7 days after completion of darolutamide administration or after the depot interval for the leuprolide-acetate dose used has been completed, whichever is longer
• Ability to understand and the willingness to sign a written informed consent document

• Patients must have tumors that are safely accessible for biopsy.

  • Note: Two research biopsies are mandated in this trial. If the biopsy is deemed to be unsafe after attempting the first biopsy, the patient will remain eligible for the trial and subsequent tumor biopsies will not be required

Exclusion Criteria:

• Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1) with the exception of alopecia and peripheral neuropathy
• Patients with a vascular or ischemic event within 6 months of study registration
• Patients who are receiving any other investigational agents
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to darolutamide or leuprolide acetate
• Patients on combined P-gp and strong or moderate CYP3A inducers or BCRP substrates are excluded. 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 patient 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 patient is considering a new over-the-counter medicine or herbal product
• Patients with uncontrolled intercurrent illness
• Pregnant women are excluded from this study because darolutamide is an androgen receptor inhibitor agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with darolutamide and leuprolide-acetate, breastfeeding should be discontinued if the mother is treated with darolutamide and leuprolide-acetate. These potential risks may also apply to other agents used in this study.
• Patients with moderate hepatic impairment (Child-Pugh Class B or C)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment (darolutamide, leuprolide acetate); Patients receive darolutamide PO BID on days 1-28 of each cycle and leuprolide acetate IM every 4 or 12 weeks. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo biopsy, collection of blood samples, and CT/MRI throughout the trial.

Procedure: Biospecimen Collection; Undergo collection of blood; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection; Sample Collection; Procedure: Magnetic Resonance Imaging; Undergo MRI; Other Names: MRI; Magnetic Resonance; Magnetic Resonance Imaging Scan; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; MR; MR Imaging; MRI Scan; NMR Imaging; NMRI; Nuclear Magnetic Resonance Imaging; Magnetic Resonance Imaging (MRI); sMRI; Magnetic resonance imaging (procedure); MRIs; Structural MRI; Procedure: Computed Tomography; Undergo CT; Other Names: CT; CAT; CAT Scan; Computed Axial Tomography; Computerized Axial Tomography; Computerized Tomography; CT Scan; tomography; Computerized axial tomography (procedure); Computerized Tomography (CT) scan; Diagnostic CAT Scan; Diagnostic CAT Scan Service Type; Drug: Leuprolide Acetate; Given IM; Other Names: Enantone; LEUP; Lupron; Lupron Depot; Leuprorelin Acetate; A-43818; Abbott 43818; Abbott-43818; Carcinil; Depo-Eligard; Eligard; Enanton; Enantone-Gyn; Ginecrin; Leuplin; Lucrin; Lucrin Depot; Lupron Depot-3 Month; Lupron Depot-4 Month; Lupron Depot-Ped; Lutrate; Procren; Procrin; Prostap; TAP-144; Trenantone; Uno-Enantone; Viadur; Luprodex Depot; A 43818; A43818; Fensolvi; TAP 144; TAP144; Drug: Darolutamide; Given PO; Other Names: ODM-201; Nubeqa; Antiandrogen ODM-201; BAY 1841788; BAY-1841788; BAY1841788; ODM 201; ODM201; Procedure: Biopsy Procedure; Undergo biopsy; Other Names: Bx; BIOPSY_TYPE; Biopsy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Best overall response (BOR)	The trial will be considered positive if 8 or more complete response/partial response are observed in stage 1 and stage 2 combined.	Within 1 year of initiating treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of adverse events (AEs)	Will be listed individually per patient according to Common Terminology Criteria for Adverse Events version 5.0, and the number of patients experiencing each AE will be summarized.	Up to 2 years
Progression-free survival (PFS)	Will be estimated using Kaplan-Meier methodology. Patients without an event (progression, death) will be censored at the time of last follow-up or last day known to be alive.	From day 1 of treatment until progression or death, assessed up to 2 years
Overall survival (OS)	Will be estimated using Kaplan-Meier methodology. Patients without an event (progression, death) will be censored at the time of last follow-up or last day known to be alive.	From day 1 of treatment until progression or death, assessed up to 2 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Molecular, genomic, and transcriptomic biomarkers	Will be summarized by descriptive statistics, including mean, median and standard deviation for continuous biomarker data and frequency (%) for categorical data. Differences in a biomarker at baseline, on treatment, and change between those two time points amongst responders and non-responders will be compared using Fisher's exact tests for categorical biomarker data and Wilcoxon Rank-Sum tests for continuous biomarker data. In addition, a Cox proportional hazards model will be used to explore the prognostic relationship for these biomarkers measured at baseline and PFS and OS.	Up to 2 years
Differences in BOR, PFS, OS in patients who did and did not receive prior systemic therapy for androgen receptor positive salivary gland cancer	The BOR, PFS, and OS with darolutamide plus androgen deprivation therapy in patients with and without prior systemic therapies for recurrent/metastatic/unresectable disease will be compared using Fisher's exact for binary outcome and log-rank test for time-to-events outcomes.	Up to 2 years

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Alan L Ho, JHU Sidney Kimmel Comprehensive Cancer Center LAO

Study record dates

Study Major Dates

• Study Start (Actual): July 20, 2023
• Primary Completion (Estimated): April 11, 2027
• Study Completion (Estimated): April 11, 2027

Study Registration Dates

• First Submitted: December 30, 2022
• First Submitted That Met QC Criteria: December 30, 2022
• First Posted (Actual): January 3, 2023

Study Record Updates

• Last Update Posted (Actual): May 13, 2026
• Last Update Submitted That Met QC Criteria: May 12, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mouth Diseases; Stomatognathic Diseases; Neoplasms by Site; Neoplasms; Head and Neck Neoplasms; Salivary Gland Diseases; Mouth Neoplasms; Salivary Gland Neoplasms; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Pituitary Hormone-Releasing Hormones; Hypothalamic Hormones; Peptide Hormones; Neuropeptides; Peptides; Amino Acids, Peptides, and Proteins; Oligopeptides; Nerve Tissue Proteins; Proteins; Investigative Techniques; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Surgical Procedures, Operative; Cytological Techniques; Cytodiagnosis; Diagnostic Techniques, Surgical; Chemistry Techniques, Analytical; Spectrum Analysis; Gonadotropin-Releasing Hormone; Leuprolide; luprolide acetate gel depot; darolutamide; Biopsy; Specimen Handling; Magnetic Resonance Spectroscopy
• Other Study ID Numbers: NCI-2022-10701 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); UM1CA186691 (U.S. NIH Grant/Contract); 10553 (Other Identifier: CTEP)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No