Using danazol to treat blood cell deficiencies in patients with cirrhosis

A Phase II Single Center Single Arm Pilot Study Administering Danazol for Treatment of Cytopenias in Patients With Cirrhosis

This study is testing if the medication danazol can help improve blood cell counts in people with cirrhosis who have low levels of red or white blood cells.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 10 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: University of Southern California (Academic / other)
• Drugs / interventions: methotrexate, cyclophosphamide, prednisone
• Locations: 1 site (Los Angeles, California)
• Trial ID: NCT04873102 on ClinicalTrials.gov

What this trial studies

This phase II pilot study aims to evaluate the safety and effectiveness of danazol in treating cytopenias, such as anemia and thrombocytopenia, in patients with compensated Child-Pugh Class A/B cirrhosis. Participants will receive a daily dose of 600 mg of danazol for 24 months. The study will include a total of 10 patients, focusing on those with or without telomere mutations. The research addresses the significant morbidity associated with abnormal hematologic indices in cirrhotic patients, which can complicate treatment and increase mortality risk.

Who should consider this trial

Good fit: Ideal candidates are adults aged 18 and older with compensated Child-Pugh Class A/B cirrhosis and specific cytopenias.

Not a fit: Patients with chronic hepatitis B or those with decompensated cirrhosis may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could improve blood cell counts and reduce complications associated with cirrhosis-related cytopenias.

How similar studies have performed: While there is limited data on the use of danazol for this specific indication, similar approaches targeting cytopenias in cirrhosis have shown promise in other studies.

Eligibility criteria

Inclusion Criteria:

* Age 18 years or older and able to provide informed consent
* ECOG 0-2
* Compensated Child-Pugh class A of any etiology with the exception of chronic hepatitis B with one or more of the following cytopenias

  1. Leukopenia defined as white blood cell count \<2000/mm3 or absolute neutrophil count \<1000/mm3 along with thrombocytopenia \<150,000/mm3 measured on two separate occasions at least 3 months apart within 6 months of enrollment
  2. Thrombocytopenia defined as platelet count \<50,000/mm3 along with white blood cell count \<4000/mm3 measured on two separate occasions at least 3 months apart within 6 months of enrollment
* Compensated Child-Pugh class B cirrhosis of any etiology with the exception of chronic hepatitis B with one or more of the following cytopenias:

  1\. Leukopenia defined as white blood cell count ≤ 3500/mm3 measured on two separate occasions at least 3 months apart within 6 months of enrollment 3. Thrombocytopenia defined as platelet count ≤ 100,000/mm3 measured on two separate occasions at least 3 months apart within 6 months of enrollment
* Enrolled patients must have one or more of the following:

  * Presence of a genetic variant (defined as a known mutation, variant likely to be pathogenic or variant of undetermined significance with likely deleterious effect on transcription or translation) in at least one of the following genes: TERT, TERC, RTEL1, DKC, NOP10, NHP2, TINF2, WRAP53
  * Shortened telomere length in peripheral blood mononuclear cells (defined as age-adjusted telomere length at or below the 5th percentile)
  * Of note, patient's found to have telomere mutations know to confer a gain of function will be excluded
* For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of \< 1% per year during the treatment period

  * A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state (\>= 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus)
  * Examples of contraceptive methods with a failure rate of \< 1% per year include bilateral tubal ligation, male sterilization, proper use of hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices
  * The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient; periodic abstinence (e.g., calendar, ovulation, symptothermal, or post ovulation methods) and withdrawal are not acceptable methods of contraception
* Women of childbearing potential (WOCBP) must have a negative serum test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin \[HCG\]) within 72 hours prior to the start of treatment

Exclusion Criteria:

* Cirrhosis secondary to chronic hepatitis B or any history of hepatitis B
* Patients with telomere related mutations know to confer gain of function will be excluded
* Patients known to be infected with HIV
* History of any hormone sensitive malignancy, including breast cancer, prostate cancer, hepatocellular carcinoma or liver adenoma as well as any patient considered high risk for developing malignancy (i.e. history of familial cancers including a first degree relative)
* Patients who are actively receiving anti-cancer therapy
* Liver decompensation event within the last 6 months (i.e. variceal bleed, ascites requiring paracentesis, hepatic encephalopathy)
* Active thrombosis or history of unprovoked thromboembolic disease, including cardiovascular events. If a patient has received and completed adequate anticoagulation for a provoked thrombosis, they can be included in the study.
* Pregnant or planning to become pregnant
* Females patients who are breast feeding
* Any contraindication to danazol use
* Uncontrolled co-morbid condition which would make the administration of danazol unsafe, including decompensated heart failure or known EF less than 40%, unstable angina pectoris, uncontrolled cardiac arrhythmia, decompensated liver failure, renal failure defined as creatinine greater than \>1.6 or psychiatric illness that would limit compliance with study requirements
* Alanine aminotransferase and/or aspartate aminotransferase \>3x upper limit of normal
* Alkaline phosphatase \>2.5 x upper limit of normal
* Total bilirubin or direct bilirubin \>2.5 x upper limit of normal
* Patients with known alcohol or drug abuse within the last year
* Concomitant use of hormone stimulants or hormone blocking agents.
* Concomitant use of other bone marrow stimulating agents that may affect white blood cell and platelet counts (i.e. G-CSF, romiplostim, eltrombopag, corticosteroids). Short term use of growth factors per standard of care in preparation for procedure or for other medical indications is acceptable. Patients taking corticosteroids above 5 mg of prednisone or the equivalent who are on a stable dose for at least 8 weeks prior to enrollment can be included.
* Concomitant treatment with systemic immunosuppressive medications (including but not limited to cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor \[anti-TNF\] agents)

Where this trial is running

Los Angeles, California

• Keck Hosital of USC — Los Angeles, California, United States (Recruiting)

Study contacts

• Principal investigator: Casey O'Connell, MD — Keck Hospital of USC
• Study coordinator: Ibrahim Syed, MBBS

Conditions Cirrhosis, Liver; Cytopenia