Testing the Addition of Itraconazole or Ritonavir to Relugolix for Maintaining Testosterone Suppression in Patients with Prostate Cancer

Status: administratively complete

This phase Ib clinical trial evaluates the safety and effectiveness of adding itraconazole or ritonavir to relugolix for maintaining testosterone suppression in patients with prostate cancer. Prostate cancer cells usually need hormones to grow. One of these hormones is testosterone. The usual approach for treating prostate cancer after it progresses involves taking medications to decrease or block the development of hormones (including testosterone) so that prostate cancer cells can’t continue to grow. Relugolix is a medication approved by the Food and Drug Administration (FDA) to help decrease testosterone. While relugolix can be effective, it can also be expensive. Itraconazole is an enzyme inhibitor used to treat fungal infections. Ritonavir is an enzyme inhibitor commonly used to treat patients with HIV. Though itraconazole and ritonavir have been approved by the FDA to treat other conditions, adding them to treatment with relugolix for prostate cancer is experimental. Adding itraconazole or ritonavir to relugolix may help decrease testosterone levels and maintain testosterone suppression while requiring fewer doses of relugolix.

Inclusion Criteria

Patients must have histologically or cytologically confirmed prostate cancer with plans to start medical castration therapy
Age >= 18 years. Because no dosing or adverse event data are currently available on the use of relugolix in combination with itraconazole or ritonavir in patients < 18 years of age, children are excluded from this study
Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
Testosterone > 200 ng/dl
QTc within normal limits
Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) < 3x upper limit of normal
Ability to take oral medication and be willing to adhere to the medication regimen
Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria

Need for combination systemic therapy for prostate cancer including docetaxel and/or second-generation androgen receptor pathway targeted agents (i.e. abiraterone, enzalutamide, apalutamide, darolutamide, etc)
Concurrent therapy with strong interacting drugs with CYP3A4 and P-gp due to concerning possible drug-drug interactions with itraconazole, ritonavir and relugolix. Potential drug-drug interactions will also be reviewed by co-investigator Dr. Ratain prior to enrollment
History of allergic reactions attributed to compounds of similar chemical or biologic composition to relugolix, itraconazole or ritonavir
Patients receiving treatment with another investigational drug or other intervention within 3 expected half-lives of the agent
Serious or uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, unstable angina pectoris, or psychiatric illness/social situations that would limit compliance with study requirements
New York Heart Association class III of IV congestive heart failure
Known gastrointestinal malabsorption
Active psychiatric illness/social situations that would limit compliance with protocol requirements

PRIMARY OBJECTIVE:

I. To determine whether the addition of itraconazole and ritonavir to relugolix sustains testosterone suppression.

SECONDARY OBJECTIVES:

I. To evaluate whether itraconazole or ritonavir significantly decreases relugolix clearance in patients with prostate cancer as assessed by relugolix serum levels on days 8 and 15.

II. To evaluate the efficacy of itraconazole or ritonavir combined with relugolix in patients with prostate cancer as assessed by a reduction in prostate-specific antigen (PSA) levels of patients after study treatment.

III. To evaluate the safety of itraconazole or ritonavir combined with longer interval relugolix dosing regimens in patients with prostate cancer as assessed by the rate of reported adverse events according to Common Terminology Criteria for Adverse Events (CTCAE) version (V)5.

OUTLINE: Patients are assigned to 1 of 5 cohorts.

COHORT I: Patients receive relugolix orally (PO) once daily (QD) on days 1-7. Patients also undergo collection of blood samples at screening, and on days 1, 8, 15, and 29.

COHORT IIA: Patients receive relugolix PO QD on days 1-7 and itraconazole PO QD on days 1-14. Patients also undergo collection of blood samples at screening, and on days 1, 8, 15, and 29.

COHORT IIB: Patients receive relugolix PO QD on days 1-7 and ritonavir PO twice daily (BID) on days 1-14. Patients also undergo collection of blood samples at screening, and on days 1, 8, 15, and 29.

COHORT IIIA: Patients receive relugolix PO QD on days 1-4 and itraconazole PO QD on days 1-14. Patients also undergo collection of blood samples at screening, and on days 1, 8, 15, and 29.

COHORT IIIB: Patients receive relugolix PO QD on days 1-4 and ritonavir PO BID on days 1-14. Patients also undergo collection of blood samples at screening, and on days 1, 8, 15, and 29.

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Testing the Addition of Itraconazole or Ritonavir to Relugolix for Maintaining Testosterone Suppression in Patients with Prostate Cancer

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