Decitabine for High-Risk Sickle Cell Disease
Decitabine for High-Risk Sickle Cell Disease
Background:

 -  In sickle cell disease (SCD), the proteins in the red blood cells that carry oxygen do
 not behave normally. In parts of the body where there are low levels of oxygen or where
 oxygen is used more, the sickle hemoglobin proteins may change shape and stick together.
 This causes the red cells to clump, which reduces blood flow. This leads to even lower
 oxygen levels and causes damage and/or pain.

 -  One way to stop the red blood cells from sticking together is to increase the levels of
 fetal (baby or good ) hemoglobin. The good hemoglobin then takes the place of the sickle
 hemoglobin.

 -  Hydroxyurea is the only approved drug for SCD. But hydroxyurea works in only about
 two-thirds of people with SCD. Even in those cases it sometimes stops working over time.

 -  Researchers are interested in testing decitabine. The drug may help to increase fetal
 hemoglobin levels. But it has not yet been approved to treat SCD.

 Objectives:

 - To test the safety and effectiveness of decitabine in increasing fetal hemoglobin levels
 and improving the symptoms of sickle cell disease.

 Eligibility:

 - People at least 18 years of age who have sickle cell disease that has not improved after at
 least 6 months of hydroxyurea therapy. Those who cannot take hydroxyurea because of side
 effects may also participate.

 Design:

 -  Participants will be screened with a physical exam and medical history. They will also
 have blood and urine tests, a lung function test, and other tests as required.

 -  Participants will receive decitabine injections up to twice a week for 1 year. Depending
 on the response to treatments, the dose will remain the same or be reduced to once a
 week.

 -  Participants will be monitored with frequent blood tests and other studies as directed
 by the study doctors.

 -  After the study is completed, participants will go back to their usual sickle cell care.
 If decitabine has improved a participant's SCD, treatment may be continued under regular
 health coverage insurance if this can be arranged.
Overview: Elevated fetal hemoglobin (HbF), whether pharmacologically induced or congenital,
 has a favorable impact on the morbidity and mortality of SCD. The agent currently used to
 elevate HbF, hydroxyurea (HU), has limited efficacy. There are mechanistic reasons to believe
 that the DNA methyltransferase inhibitor 5-aza-2 -deoxycytidine (decitabine) can more
 potently increase HbF. This has been demonstrated in vivo in animals and small phase 1/2
 studies of decitabine in SCD subjects. Decitabine at low, non-cytotoxic doses was very well
 tolerated and very efficacious at increasing HbF and total hemoglobin (Hb) in subjects who
 did not respond to, or were intolerant of, HU. In addition to HbF levels, major improvements
 were noted in a range of surrogate clinical endpoints measuring red blood cell (RBC)
 adhesion, endothelial damage, and coagulation pathway activity. Also, substantial clinical
 improvement was seen in severely ill patients treated off-label. The primary objective herein
 is to provide evidence and guidance for a phase III study by demonstrating the dose and
 schedule of decitabine that when given over a 12 month period, produces sustained elevations
 in HbF without significant toxicity. Secondary objectives examine patient reported outcome
 measurements (PROMIS), crisis frequency, and laboratory indices that measure different
 domains of sickle cell pathophysiology and DNA methylation. These secondary and scientific
 measurements will be correlated with each other and examined over time to understand
 mechanisms of disease and the mechanism of action of the study drug.

 Intervention: Decitabine starting dose of 0.2 mg/kg (range, 0.05-0.3 mg/kg) 1-2x/wk x 48
 weeks

 Hypotheses:

 In SCD subjects at risk of early death, non-cytotoxic DNMT1 depletion using a metronomic
 (frequent but intermittent) regimen of the nucleoside analogue decitabine directly
 antagonizes a mechanism of gamma-globin repression, and produces sustained, clinically
 significant HbF elevations.

 Primary Objective: To measure, in high-risk SCD subjects, the effect of chronic metronomic
 subcutaneous (SQ) decitabine administration on HbF levels. These aims are achieved through
 the conduct of an extended, open-label, phase 2 study in subjects who remain at high risk of
 early mortality and morbidity despite HU therapy.

 Secondary Objectives: To measure, in high-risk SCD subjects, the effect of chronic metronomic
 SQ decitabine administration on clinical and laboratory indices of safety, patient reported
 outcome measures (PROMIS), frequency of crises, SCD pathophysiologic activity (hemolysis,
 coagulation, platelet activation and inflammation), and molecular effects of study drug.

 Criteria for Evaluation:

 Primary Endpoint: the percentage change in HbF level from baseline to the average percent
 over the final 3 months of the study period (48 weeks).

 Secondary Endpoints: clinical and laboratory assessment of safety, patient reported outcomes
 (PROMIS), frequency of crises, quantity of F cells and F cell subsets, measurements of
 hemolysis, coagulation, platelet activation, inflammation, endothelial damage, pulmonary
 arterial pressure, DNMT levels, global and beta-globin locus specific DNA methylation.

 Study Design: This is an extended, single arm, open-label, phase II clinical trial.

 Study Population: Adults with symptomatic SCD who are at high risk of early mortality despite
 greater than or equal to 6 months of HU therapy. Specifically, they still have: HbF <5
 percent, OR 3 or more pain episodes per year requiring parenteral narcotics, OR 1 or more
 acute chest syndrome episodes, OR hemoglobin <9 g/dL and absolute reticulocyte count (ARC)
 less than or equal to 250,000/mm(3). Subjects who meet the above criteria for high risk but
 are unwilling or unable to tolerate HU are also eligible.

 Clinical and Laboratory Evaluations:

 Pre-treatment and every 2 weeks: CBC, chem 20 including LDH, and retic count

 Pre-treatment and every 4 weeks: interim medical history & physical exam, HbF%, and pregnancy
 test

 Pre-treatment and every 12 weeks: urinanalysis, percent F-cells & percent F-reticulocytes,
 biomarkers, scientific correlative studies of DNA methylation

 Pre-treatment, 24 and 48 weeks: PROMIS, PFT, 6 minute walk, endo-PAT

 Pre-treatment and 48 weeks: erythropoietin level

 Follow-ups every 3-4 months between 52-54 weeks and 93-96 weeks: interim medical history &
 physical exam, CBC, reticulocyte count, HbF percent, chem 20 (including LDH), and pregnancy
 test

 Sample Size: 40 subjects

 Data Analyses: The effect of decitabine on HbF levels over time will be explored using a
 general linear mixed model from which the average percent change from baseline to the average
 HbF level on the final 3 months of treatment will be estimated along with a 95 percent
 confidence interval. AE and other safety measurements will be summarized by age group, dose,
 and dose frequency at the time of AE onset. No interim analyses will be performed in this
 study.

 Human Subjects: There is a risk of neutropenia, thrombocytosis, and teratogenicity. Patients
 must take precautions to use contraception and avoid pregnancy during treatment.
-  INCLUSION CRITERIA:

 Subjects who meet all of the following criteria are eligible for enrollment into the study:

 1. Age 18 years or older.

 2. Written, informed consent provided by the subject before study entry.

 3. Confirmed SCD (SS, S-beta (0)-thalassemia, or SC on hemoglobin electrophoresis),

 4. Symptomatic SCD while on 6 months of HU OR symptomatic SCD and intolerant of HU
 (unable or unwilling to tolerate HU due to hematological or other toxicities).
 Symptomatic SCD is defined as having one of following:

 -  HbF <5 percent, OR

 -  3 or more pain episodes per year requiring parenteral narcotics, OR

 -  1 or more acute chest syndrome episodes, OR

 -  Hemoglobin <9 degree g/dL and ARC less than or equal to 250,000/mm(3),

 5. Subject is in his/her steady state and not amidst any acute complication due to SCD.

 6. Willing to use 2 forms of contraception. Some acceptable combinations include male
 partner using condoms and female partner using oral contraceptives, male partner using
 condoms and female partner who had bilateral oophorectomy, male partner who had a
 vasectomy and female partner using injectable contraceptives (e.g. Depo Provera).

 EXCLUSION CRITERIA:

 Since the protocol targets an at risk population, and the tolerability and potential
 benefits of this approach have been suggested in off-label treatment of seriously ill SCD
 patients, the exclusion criteria are not overly stringent and are primarily directed at
 avoiding teratogenic risks.

 Subjects who meet any of the following criteria are disqualified from enrollment in the
 study:

 1. Inability to give informed consent.

 2. Experienced severe sepsis or septic shock within the previous 12 weeks.

 3. Last HU or erythropoietin dose obtained within the previous 4 weeks. Renal replacement
 doses of erythropoietin is allowed as decitabine would not be expected to exert a red
 cell and/or HbF response when there is no endogenous erythropoietin production.

 4. Participant is on chronic transfusion therapy (e.g., for history of TIA or stroke) and
 medically contraindicated to discontinue transfusions.

 5. Currently pregnant or breast-feeding.

 6. Sexually active female of childbearing potential (all females except those who are
 menopausal [appropriate age and no period for more than 12 months] or have had a
 hysterectomy and/or bilateral oophorectomy) who is unwilling to use at least 2
 acceptable methods of contraception as determined by the investigators. The use of a
 condom by a male partner would be considered one acceptable method of contraception.

 7. Sexually active male whose partner is of child-bearing potential and who is unwilling
 to use at least 2 acceptable methods of contraception as determined by the
 investigators during treatment and for 8 weeks after the last dose of decitabine.

 8. Moribund or any concurrent disease (e.g., hepatic, renal, cardiac, metabolic) of such
 severity that death within 24 weeks is likely.

 9. Other experimental or investigational drug therapy in the past 28 days.

 10. Inability to bring ANC above 2 x 10(9) cells/L or platelet count less than 1,000 x
 10(9) cells/L.

 For female participants: Not having heterosexual sexual contact starting 4 weeks before
 beginning to take decitabine and continuing until 4 weeks after the last dose of decitabine
 OR using TWO methods of birth control. One birth control method must be highly effective,
 such as an Intrauterine Device (IUD), birth control pills, Depo-Provera
 (medroxyprogesterone acetate) injections, or tying of the fallopian tubes. The other
 additional effective method of birth control can be use of a diaphragm or a condom by the
 male partner. Birth control should begin at the screening visit and continue until 4 weeks
 after the last dose of decitabine. These steps must be taken even if the patient has a
 history of infertility, unless the patient has had a hysterectomy or has not had periods
 for at least 24 months.

 For male participants: during decitabine treatment and 8 weeks after last dose of drug, a
 condom must be used when engaging in any sexual contact with a woman of child-bearing age,
 even in patients who have had a successful vasectomy.