Dyskeratosis Congenita, Fanconi Anemia
Conditions
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.
Interventions
DRUGdanazol
Dosage is done according to weight; capsules are 50, 100, 200 mg
Sponsors
Boston Children's Hospital
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
3 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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). | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Optimal Dose and Number of Participants With Hematologic Response Rate in Fanconi Anemia (FA) and Dyskeratosis Congenita (DC) Patients Receiving Danazol Therapy | 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 | 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. |
Countries
United States
Participant flow
Recruitment details
Patients recruited from clinic and by letter to Pediatric Hematologists in USA
Pre-assignment details
1. Patients with documented Fanconi anemia (FA) or dyskeratosis congenita (DC) 2. Peripheral blood cytopenias (without transfusion, and at least one result obtained in the past two months that meet criteria): ANC \< 500/uL or platelets \< 30,000/uL or Hb \< 8.0 gm/dl 3. . Not pregnant 4. Not on birth control 5. Consent 6. 3 yrs/ \> 14 kg.
Participants by arm
| Arm | Count |
|---|---|
| Danazol Subjects with either Fanconi anemia or Dyskeratosis congenita
danazol: Dosage is done according to weight; capsules are 50, 100, 200 mg | 5 |
| Total | 5 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
| Overall Study | Hematopoietic Stem Cell Transplant | 1 |
Baseline characteristics
| Characteristic | Danazol |
|---|---|
| Age, Categorical <=18 years | 5 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 4 Participants |
| Region of Enrollment United States | 5 participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 2 / 5 |
| serious Total, serious adverse events | 1 / 5 |
Outcome results
Primary
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).
All toxicities were collected and adjudicated to definitely-related, possibly-related, or unrelated to the treatment.
Time frame: 48 weeks (24 weeks treatment and 24 weeks extension phase)
Population: 4 patients with Fanconi anemia and 1 with dyskeratosis congenita
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Danazol | 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). | Virilization - definitely related | 2 Participants |
| Danazol | 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). | Hepatic - possibly related | 1 Participants |
Secondary
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
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.
Time frame: Baseline and 24 weeks
Population: Baseline samples were too noisy to determine gene expression.
Secondary
The Optimal Dose and Number of Participants With Hematologic Response Rate in Fanconi Anemia (FA) and Dyskeratosis Congenita (DC) Patients Receiving Danazol Therapy
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.
Time frame: 12, 18 and 24 weeks
Population: 2 participants withdrew before HR could be assessed.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Danazol | The Optimal Dose and Number of Participants With Hematologic Response Rate in Fanconi Anemia (FA) and Dyskeratosis Congenita (DC) Patients Receiving Danazol Therapy | HR by hemoglobin at 12 weeks | 3 Participants |
| Danazol | The Optimal Dose and Number of Participants With Hematologic Response Rate in Fanconi Anemia (FA) and Dyskeratosis Congenita (DC) Patients Receiving Danazol Therapy | HR by hemoglobin at 18 weeks | 3 Participants |
| Danazol | The Optimal Dose and Number of Participants With Hematologic Response Rate in Fanconi Anemia (FA) and Dyskeratosis Congenita (DC) Patients Receiving Danazol Therapy | HR by hemoglobin at 24 weeks | 3 Participants |
| Danazol | The Optimal Dose and Number of Participants With Hematologic Response Rate in Fanconi Anemia (FA) and Dyskeratosis Congenita (DC) Patients Receiving Danazol Therapy | HR by platelets at 12 weeks | 0 Participants |
| Danazol | The Optimal Dose and Number of Participants With Hematologic Response Rate in Fanconi Anemia (FA) and Dyskeratosis Congenita (DC) Patients Receiving Danazol Therapy | HR by platelets at 18 weeks | 0 Participants |
| Danazol | The Optimal Dose and Number of Participants With Hematologic Response Rate in Fanconi Anemia (FA) and Dyskeratosis Congenita (DC) Patients Receiving Danazol Therapy | HR by platelets at 24 weeks | 2 Participants |
| Danazol | The Optimal Dose and Number of Participants With Hematologic Response Rate in Fanconi Anemia (FA) and Dyskeratosis Congenita (DC) Patients Receiving Danazol Therapy | HR by neutrophils at 12 weeks | 0 Participants |
| Danazol | The Optimal Dose and Number of Participants With Hematologic Response Rate in Fanconi Anemia (FA) and Dyskeratosis Congenita (DC) Patients Receiving Danazol Therapy | HR by neutrophils at 18 weeks | 0 Participants |
| Danazol | The Optimal Dose and Number of Participants With Hematologic Response Rate in Fanconi Anemia (FA) and Dyskeratosis Congenita (DC) Patients Receiving Danazol Therapy | HR by neutrophils at 24 weeks | 2 Participants |