A Phase I/II Trial of Recombinant-Methionyl Human Stem Cell Factor (SCF) in Adult Patients With Sickling Disorders
A Phase I/II Trial of Recombinant-Methionyl Human Stem Cell Factor (SCF) in Adult Patients With Sickling Disorders
Sickle cell anemia is a genetic disorder that results from a single nucleotide substitution
 in codon 6 of the beta-globin gene which, in the homozygous state, produces an abnormal
 hemoglobin that is prone to polymer formation when deoxygenated. The polymerized hemoglobin
 leads to impaired deformability and sickling of red blood cells which subsequently lodge in
 end-arterioles producing the classic and most prominent feature of the disorder, repeated
 vasoocclusive crises. Despite knowledge of the precise genetic defect for decades, only
 recently has there been therapeutic impact based upon this knowledge when a clear benefit
 from treatment with hydroxyurea, a cell cycle-specific agent administered to induce
 production of fetal hemoglobin (HbF) by stimulating gamma-globin synthesis, was reported in
 patients with sickle cell disease (SCD). The reduction in the frequency and severity of
 vasoocclusive crises seen has been attributed to the increase in HbF levels in responsive
 patients. While the majority of patients demonstrate a rise in HbF, not all such patients
 benefit from treatment. Given these results, alternative agents that also stimulate the
 production of HbF warrant investigation in the treatment of SCD. Recombinant-methionyl human
 stem cell factor (SCF) is a hematopoietic growth factor with activity on immature
 hematopoietic progenitor cells. SCF stimulates the production of HbF in vitro and in vivo,
 and this effect is attainable without the myelosuppression associated with hydroxyurea. In
 this phase I/II trial, we will administer SCF in a dose escalating fashion to patients with
 sickling disorders. Parameters to be measured are HbF levels, F cell levels, peripheral blood
 CD34 levels, frequency, duration, and severity of vasoocclusive crises, and toxicity.
Sickle cell anemia is a genetic disorder that results from a single nucleotide substitution
 in codon 6 of the beta-globin gene which, in the homozygous state, produces an abnormal
 hemoglobin that is prone to polymer formation when deoxygenated. The polymerized hemoglobin
 leads to impaired deformability and sickling of red blood cells which subsequently lodge in
 end-arterioles producing the classic and most prominent feature of the disorder, repeated
 vasoocclusive crises. Despite knowledge of the precise genetic defect for decades, only
 recently has there been therapeutic impact based upon this knowledge when a clear benefit
 from treatment with hydroxyurea, a cell cycle-specific agent administered to induce
 production of fetal hemoglobin (HbF) by stimulating gamma-globin synthesis, was reported in
 patients with sickle cell disease (SCD). The reduction in the frequency and severity of
 vasoocclusive crises seen has been attributed to the increase in HbF levels in responsive
 patients. While the majority of patients demonstrate a rise in HbF, not all such patients
 benefit from treatment. Given these results, alternative agents that also stimulate the
 production of HbF warrant investigation in the treatment of SCD. Recombinant-methionyl human
 stem cell factor (SCF) is a hematopoietic growth factor with activity on immature
 hematopoietic progenitor cells. SCF stimulates the production of HbF in vitro and in vivo,
 and this effect is attainable without the myelosuppression associated with hydroxyurea. In
 this phase I/II trial, we will administer SCF in a dose escalating fashion to patients with
 sickling disorders. Parameters to be measured are HbF levels, F cell levels, peripheral blood
 CD34 levels, frequency, duration, and severity of vasoocclusive crises, and toxicity.
INCLUSION CRITERIA:

 Patients with Hb SS, Sbeta-thal, SD, or SO-Arab

 Age greater than or equal to 18 years.

 Patient must have had a previous neurologic event (either symptomatic or found by imaging
 alone).

 More than one painful crises per year for the last 2 years, each requiring hospitalization.

 A previous acute chest syndrome.

 Evidence of renal damage but with a creatinine clearance of greater than 50 percent of
 normal.

 Red cell alloimmunization.

 Bilateral retinopathy.

 Osteonecrosis of multiple bones.

 Unilateral or bilateral leg ulcers.

 Patients who have failed a course of hydroxyurea or who have declined to take hydroxyurea.

 Able to give informed consent.

 No active sickle cell crises or acute chest syndrome.

 No active uncontrolled infection.

 No hydroxyurea, erythropoietin, and/or arginine butyrate therapy in the previous month.

 No patients receiving hypertransfusion therapy.

 No current treatment (or within 2 weeks) with hematopoietic growth factors.

 No allergy to E. coli derived products.

 No history of seasonal or recurrent asthma within the 5 preceding years.

 No asthmatic symptoms (e.g. wheezing) related to a current respiratory tract infection.

 No other significant IgE-mediated hypersensitivities (including but not limited to allergic
 rhinitis, allergic eczema, anaphylactic reactions, congenital or acquired angioedema, and
 urticaria,). An isolated episode of urticaria occurring within the 5 years is not a
 contraindication. Patients with drug allergies manifested solely by rash are not excluded.

 No concurrent use of beta-adrenergic blocking agents.

 No concurrent use of monoamine oxidase inhibitors.

 No significant comorbid conditions including uncontrolled hypertension, congestive heart
 failure(greater NY class II), poorly controlled diabetes mellitus, and significant coronary
 artery disease with recent myocardial infarction or angioplasty (within the previous 6
 months).

 No pregnancy, breast feeding, and unwillingness to use contraception.

 No concurrent use of other investigational products.