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Safety and Efficacy Trial of Danazol in Patients With Fanconi Anemia or Dyskeratosis Congenita

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01001598
Recruitment Status : Terminated (Study was terminated due to under enrollment)
First Posted : October 26, 2009
Results First Posted : February 19, 2019
Last Update Posted : February 19, 2019
Sponsor:
Information provided by (Responsible Party):
Colin Sieff, Boston Children’s Hospital

Tracking Information
First Submitted Date  ICMJE October 22, 2009
First Posted Date  ICMJE October 26, 2009
Results First Submitted Date  ICMJE December 20, 2018
Results First Posted Date  ICMJE February 19, 2019
Last Update Posted Date February 19, 2019
Study Start Date  ICMJE November 2009
Actual Primary Completion Date May 2014   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 31, 2019)
Number of Participants With Toxicity Associated With Danazol Therapy: Virilization, and/or New or Progressive Evidence of Either Hepatic or Renal Toxicity at a Grade II Level Using National Cancer Institute Common Toxicity Criteria (NCI-CTC). [ Time Frame: 48 weeks (24 weeks treatment and 24 weeks extension phase) ]
All toxicities were collected and adjudicated to definitely-related, possibly-related, or unrelated to the treatment.
Original Primary Outcome Measures  ICMJE
 (submitted: October 23, 2009)
Toxicity associated with danazol therapy: virilization, and/or new or progressive evidence of either hepatic or renal toxicity at a Grade II level using National Cancer Institute Common Toxicity Criteria (NCI-CTC). [ Time Frame: 24 weeks ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 31, 2019)
  • The Optimal Dose and Number of Participants With Hematologic Response Rate in Fanconi Anemia (FA) and Dyskeratosis Congenita (DC) Patients Receiving Danazol Therapy [ Time Frame: 12, 18 and 24 weeks ]
    The optimal dose could not be calculated because the number of participants needed to do this were not enrolled. Hematologic response rate (HR) was calculated for each participant at Week 12, 18, and 24. HR was defined by hemoglobin (Hg), platelets or neutrophil response. Please find the evaluation criteria used below: Hemoglobin response: Hgb≥8 g/dL if baseline Hgb≤7 g/dL, or Hgb rise ≥1 g/dL from baseline if baseline Hgb>7 g/dL. No RBC transfusion during the 8 weeks prior to response evaluation. Platelet response: Platelet count ≥30,000/ μL if baseline platelet count ≤20,000/ μL, or platelet count rise >10,000/ μL from baseline if baseline platelet count >20,000/ μL. No platelet transfusion during the 4 weeks prior to response evaluation. ANC response: ANC count ≥1,000/ μL if baseline ANC count ≤500/ μL, or ANC count rise >500/ μL from baseline if baseline ANC count >500/ μL.
  • The Gene Expression Profile of Progenitor Cells in Response to Danazol, Both to Predict Responsiveness and to Screen for Small Molecules That Show a Profile Similar to That of Responsive Patients [ Time Frame: Baseline and 24 weeks ]
    The gene expression profiles were planned to be run on bone marrow samples collected from patients at baseline and 24 weeks but bone marrow was never collected at 24 weeks.
Original Secondary Outcome Measures  ICMJE
 (submitted: October 23, 2009)
  • The optimal dose and hematologic response rate in Fanconi anemia (FA) and Dyskeratosis congenita (DC) patients receiving danazol therapy [ Time Frame: 24 weeks ]
  • The Gene Expression Profile of Progenitor Cells in Response to Danazol, Both to Predict Responsiveness and to Screen for Small Molecules That Show a Profile Similar to That of Responsive Patients [ Time Frame: 24 weeks ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Safety and Efficacy Trial of Danazol in Patients With Fanconi Anemia or Dyskeratosis Congenita
Official Title  ICMJE Phase I/II Dose Escalation Trial of Danazol in Patients With Fanconi Anemia or Dyskeratosis Congenita
Brief Summary

Fanconi anemia (FA) and Dyskeratosis congenita (DC) are inherited bone marrow failure syndromes. The current androgen treatments (e.g., oxymetholone) used to treat FA and DC can cause unwanted masculinizing side effects, indicating a need for a different medication. Danazol is a less potent androgen,and may therefore have fewer masculinizing side effects. Danazol is currently approved by the Food and Drug Administration (FDA) for the treatment of other diseases, but it has never been studied in patients with FA and DC.

The main purpose of this study is to see if danazol is a safe treatment for FA and DC. Specifically,we would like to determine:

  • the best dose of danazol;
  • how fast hemoglobin (a protein that carries oxygen in the blood) levels rise in FA and DC patients receiving danazol therapy; and
  • the genetic pattern (known as expression profile) of certain cells in response to danazol, which can predict how well people respond to the medication.

Subjects who enroll in the study will be treated with danazol for up to 24 weeks (about 6 months), and will have up to 11 study visits, including followup visits at 38 weeks (9 months) and 52 weeks (one year).

Detailed Description

Eligible patients with either Fanconi anemia (FA) or Dyskeratosis congenita (DC) will initially receive danazol at a dose of 5 mg/kg/d orally, rounded to the nearest 100 mg. For the first 8 weeks, the patient will be evaluated at weeks 2, 5, and 8 for hematologic response (HR). If the patient shows a hematological response (either a hemoglobin or platelet value no longer meeting blood cell count criteria for protocol inclusion in the absence of recent transfusions)within the first 12 weeks on the initial dose, the study drug will be continued at this dose for the next 6 weeks. If the patient fails to show any hematologic response within the first 12 weeks, the dose will be escalated to 10 mg/kg/day for the next 6 weeks, and an additional monitoring visit will be required at week 14. If at week 18, the patient fails to show any hematological response on the increased dose, the dose will be increased to 15 mg/kg/day for another 6 weeks (not to exceed 800 mg/day), and an additional monitoring visit will be required at week 20. At 24 weeks, if there is no response to this dose the patient will be taken off study drug and classified as a treatment failure, and will be monitored at weeks 38 and week 52). After week 24, if the patient continues to show a response, however, the study drug may be continued at the discretion of their primary care physician, with monitoring at weeks 38 and 52.

Should the patient lose the hematologic response on 5 or 10 mg/kg/day dosing at any point within the first 18 weeks of treatment, the dose will be escalated to 10 or 15 mg/kg/day (not to exceed 800 mg/day), respectively. The patient will continue to be evaluated at the next visit. If after week 24 no hematologic improvement is seen, the patient is then taken off study drug and monitored at weeks 38 and 52.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Fanconi Anemia
  • Dyskeratosis Congenita
Intervention  ICMJE Drug: danazol
Dosage is done according to weight; capsules are 50, 100, 200 mg
Other Name: Danocrine, Danol, Danatrol
Study Arms  ICMJE danazol
Subjects with either Fanconi anemia or Dyskeratosis congenita
Intervention: Drug: danazol
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: September 12, 2014)
5
Original Estimated Enrollment  ICMJE
 (submitted: October 23, 2009)
20
Actual Study Completion Date  ICMJE May 2014
Actual Primary Completion Date May 2014   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Patients must be diagnosed with FA that is documented by a positive test for increased chromosomal breakage with mitomycin C or diepoxybutane. DC patients must have clinical features consistent with the diagnosis, abnormally short lymphocyte telomeres < 1st centile by flow-FISH evaluation, or mutation in one of the known DC genes (DKC1, TERT, TERC, TINF2, NOP10, NHP2).
  2. At least the following peripheral blood cytopenias: (without transfusion) Absolute neutrophil count < 500/uL or Platelet count < 30,000/uL or Hemoglobin < 8.0 gm/dl
  3. Negative pregnancy test by hCG testing, if of child-bearing potential.
  4. Agreement to use a medically approved form of birth control, if of child-bearing potential.
  5. Signed informed consent by the patient or legally authorized representative.
  6. Patients must be either 3 years of age or > 14 kg.

Exclusion Criteria:

  1. Malignancy
  2. Concurrent enrollment in any other study using an investigational drug.
  3. Concurrent use of anticoagulants.
  4. Use of androgen therapy within last three months.
  5. Patients with liver disease as defined by SGOT, SGPT or bilirubin greater than the upper limit of normal.
  6. Patients with renal disease as defined by serum creatinine greater than the upper limit of normal for age.
  7. Patients less than either 3 years of age or 14 kg.
  8. Patients who have HLA matched sibling donors.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 3 Years and older   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01001598
Other Study ID Numbers  ICMJE 09-03-0131
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Colin Sieff, Boston Children’s Hospital
Study Sponsor  ICMJE Boston Children’s Hospital
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Colin A Sieff, MB.BCh Boston Children’s Hospital
PRS Account Boston Children’s Hospital
Verification Date January 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP