Testing the Anti-Cancer Drug Darolutamide in Patients With Testosterone-driven Salivary Gland Cancers
Study Details
Study Description
Brief Summary
This phase II trial tests how well darolutamide and leuprolide acetate works in treating androgen receptor positive salivary cancer that has spread from where it started to other places in the body (metastatic), that cannot be removed by surgery (unresectable) or that has come back (after a period of improvement) (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 injection is in a class of medications called gonadotropin-releasing hormone 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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Detailed Description
PRIMARY OBJECTIVE:
- To evaluate the best overall response rate (BOR) of recurrent/metastatic androgen receptor positive (AR+) salivary gland cancer (SGC) patients with darolutamide and androgen deprivation therapy (ADT).
SECONDARY OBJECTIVES:
- 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:
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To evaluate molecular, genomic and transcriptomic biomarkers in serial research biopsies obtained before and on darolutamide and ADT.
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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: This is a dose-escalation study of darolutamide.
Patients receive darolutamide orally (PO) and leuprolide acetate intramuscularly (IM) on study. Patients also undergo a tumor biopsy at baseline and on study, and collection of blood throughout the study.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Treatment (darolutamide, leuprolide acetate) Patients receive darolutamide PO and leuprolide acetate IM on study. Patients also undergo a tumor biopsy at baseline and on study, and collection of blood throughout the study. |
Procedure: Biopsy
Undergo biopsy
Other Names:
Procedure: Biospecimen Collection
Undergo collection of blood
Other Names:
Drug: Darolutamide
Given PO
Other Names:
Drug: Leuprolide Acetate
Given IM
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Best overall response (BOR) [Up to 2 years]
A two-stage minmax design will be utilized. The trial will be considered positive if 8 or more complete response/partial response are observed in stage 1 and stage 2 combined.
Secondary Outcome Measures
- Progression-free survival (PFS) [From day 1 of treatment until progression or death, assessed up to 2 years]
Will be estimated using Kaplan-Meier methodology.
- Overall survival (OS) [From day 1 of treatment until progression or death, assessed up to 2 years]
Will be estimated using Kaplan-Meier methodology.
- Incidence of adverse events (AEs) [Up to 2 years]
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.
Other Outcome Measures
- Molecular, genomic, and transcriptomic biomarkers [Up to 2 years]
Analyses of 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 biomarkers 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.
- Differences in BOR, PFS, OS who did and did not receive prior systemic therapy for androgen receptor positive salivary gland cancer [Up to 2 years]
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.
Eligibility Criteria
Criteria
Inclusion Criteria:
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A two-step registration process is being utilized. Androgen receptor testing by immunohistochemistry (IHC) can be performed locally in a CLIA (Clinical Laboratory Improvement Amendments) certified lab. Patients must have histologically or cytologically confirmed salivary gland cancer that is recurrent/metastatic or unresectable/locally advanced, with AR expression detected by IHC on a CLIA-approved assay.
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Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >= 20 mm (>= 2 cm) by chest x-ray or as >= 10 mm (>= 1 cm) with computed tomography (CT) scan, magnetic resonance imaging (MRI) or calipers by clinical exam
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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
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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
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Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
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Absolute neutrophil count >= 1,000/mcL
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Platelets >= 100,000/mcL
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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)
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Aspartate aminotransferase (AST) (serum (glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase ([SGPT]) =< 3 x institutional ULN
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Creatinine =< 1.5 x institutional ULN
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Glomerular filtration rate (GFR) >= 30 mL/min/1.73 m^2 (by Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI])
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Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
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For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
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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
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Patients with treated brain metastases are eligible
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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
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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
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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, women of child-bearing potential and men must agree to use adequate contraception (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 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
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Ability to understand and the willingness to sign a written informed consent document
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Patients must have tumors accessible for research biopsy
Exclusion Criteria:
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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
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Patients with a vascular or ischemic event within 6 months of study registration
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Patients who are receiving any other investigational agents
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History of allergic reactions attributed to compounds of similar chemical or biologic composition to darolutamide or leuprolide acetate
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Patients on combined P-gp and strong or moderate CYP3A inducers or BCRP substrates are excluded
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Patients with uncontrolled intercurrent illness
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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, breastfeeding should be discontinued if the mother is treated with darolutamide. These potential risks may also apply to other agents used in this study
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Patients with moderate hepatic impairment (Child-Pugh Class B or C)
Contacts and Locations
Locations
No locations specified.Sponsors and Collaborators
- National Cancer Institute (NCI)
Investigators
- Principal Investigator: Alan L Ho, JHU Sidney Kimmel Comprehensive Cancer Center LAO
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- NCI-2022-10701
- NCI-2022-10701
- 10553
- 10553
- UM1CA186691