Phase 2, Open-Label, Multi-Dose Study of Panhematin in Patients With MDS

• Response rate (i.e., the number and percentage of patients demonstrating a complete response, partial response, or overall response) to Panhematin® at Week 8 (as defined by the International Working Group (IWG). [ Time Frame: 6 months ] [ Designated as safety issue: No ]
• Safety and Tolerability of Panhematin®. [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]

• Response rate (i.e., the number and percentage of patients demonstrating a complete response, partial response, or overall response) to Panhematin® at Week 8 (as defined by the International Working Group (IWG).
• Safety and Tolerability of Panhematin®.

• The number and percent of patients demonstrating a complete response, partial response, or overall response to Panhematin® at Week 4. [ Time Frame: 3 months ] [ Designated as safety issue: No ]
• Mean number of days/treatment required for complete response to Panhematin®. [ Time Frame: 12 months ] [ Designated as safety issue: No ]
• Assessment of transfusion independence. [ Time Frame: 12 months ] [ Designated as safety issue: No ]
• Hematological improvement rate ( i.e., the number and percentage of patients demonstrating a major and complete responses in each of the 3 cell lines, and combination of cell lines at Weeks 4 and 8 (as defined by the International Working Group (IWG). [ Time Frame: 12 months ] [ Designated as safety issue: No ]
• Mean change in ferritin concentrations from Baseline (Day 1) to Weeks 4 and 8, and end of study [ Time Frame: 12 months ] [ Designated as safety issue: No ]

• The number and percent of patients demonstrating a complete response, partial response, or overall response to Panhematin® at Week 4.
• Mean number of days/treatment required for complete response to Panhematin®.
• Assessment of transfusion independence.
• Hematological improvement rate ( i.e., the number and percentage of patients demonstrating a major and complete responses in each of the 3 cell lines, and combination of cell lines at Weeks 4 and 8 (as defined by the International Working Group (IWG).
• Mean change in ferritin concentrations from Baseline (Day 1) to Weeks 4 and 8, and end of study

This is a Phase II, open-label clinical trial examining the role of Panhematin® in patients with MDS. The objective of this study is to evaluate the safety and efficacy of Panhematin® (hematin for injection) in the treatment of adult patients (≥ 18 years of age) with low-risk MDS.

The study will be conducted on an outpatient basis and will consist of the following:

• A Screening Period (within 28 days of the Day 1)
• Screening bone marrow aspiration and biopsy up to 60 days prior to receiving study medication
• An 8-week Treatment Period (Days 1 through 4 of Week 1, and weekly visits during Weeks 2 through 8); partial and complete responders in any of the three cell lines may continue treatment for an additional 4 weeks
• A 6-month Post treatment Follow-up Period (monthly clinic visits during Weeks 12 40)

The myelodysplastic syndromes (MDS), a diverse group of hematopoietic stem cell (HSC) disorders, are characterized by ineffective hematopoiesis that manifest clinically as anemia, neutropenia, and/or thrombocytopenia. MDS is most frequently observed in the elderly population (median age between 60 and 70 years) and has a male predominance. The incidence of MDS varies from 2.1 to 12.6 cases per 100,000 people per year, with an estimated prevalence of up to 55,000 patients in the United States [Catenacci, 2005; Williamson, 1994; Aul, 1998; Aul, 2001]. Patients with MDS most frequently present with symptoms of fatigue, pallor, exertional dyspnea, infection, bleeding or bruising [Catenacci, 2005].

MDS can be divided into 2 major subtypes: indolent (or early) MDS, in which pro-apoptotic forces predominate, and aggressive (or advanced) MDS, in which pro-proliferative factors are more common.

The only curative therapy for MDS is allogeneic transplantation [Catenacci, 2005; Thompson, 2005]. Curative treatments are restricted to younger, healthier individuals with histocompatible-matched donors or those able to undergo intensive chemotherapeutic regimens [Catenacci, 2005]. Recently, the FDA approved 3 agents for the treatment of this disease, Vidaza, Dacogen, and revlimid. The latter is approved for a subset of patients with MDS with del 5q abnormality, the former two are more applicable to higher risk disease. Rhu-EPO is currently available to patients with low risk MDS however, if they fail, their options are limited to the agents mentioned above, all of which have significant myelotoxic effects. Effective and less myelosuppressive treatments for low-risk MDS are needed.

We are proposing a novel approach for the treatment of patients with low-risk MDS using heme supplementation with Panhematin® (hemin for injection). Panhematin® is an iron-containing metalloporphyrin, indicated for the amelioration of recurrent attacks of acute intermittent porphyria; it acts to limit the hepatic and/or marrow synthesis of porphyrin, presumably, as a result of the inhibition of aminolevulinic acid synthetase (the enzyme which limits the rate of porphyrin/heme biosynthetic pathway) [Panhematin® Product Prescribing Information].

There are pre-clinical and clinical data to suggest that heme supplementation with Panhematin® (hematin for injection) has potential as a treatment option for patients with MDS. Preliminary data indicate hemin administration has the potential to stimulate progenitor cell growth, stimulate globin synthesis, and elevate overall hemoglobin levels. Panhematin® has been proven to be well tolerated when used therapeutically in patients with acute intermittent porphyria, and it is anticipated to be well tolerated in this patient population. For this study, selected patients will have low or intermediate 1 risk disease by IPSS, and the standard of care for MDS (supportive therapies) will be administered as needed. Measurement of serum porphyrin levels and Hgb F will be done at baseline and at week 8.

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• Catenacci DV, Schiller GJ. Myelodysplasic syndromes: a comprehensive review. Blood Rev. 2005 Nov;19(6):301-19. Review.
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Inclusion Criteria:

A patient will be eligible for study participation if all of the following criteria are met:

1. The patient must sign and date the IRB/IEC approved Informed Consent Form/HIPAA Authorization prior to study participation.
2. Patient is at least 18 years of age.

3. If female:

   1. Patient, either male or female, is either not of childbearing potential, defined as postmenopausal for at least 1 year or surgically sterile (bilateral tubal ligation, bilateral oophorectomy or hysterectomy), or if of childbearing potential, must comply with an effective method of birth control acceptable to the Investigator during the study (oral contraceptives, Depo-Provera, intra-uterine device), for at least 1 month prior to enrollment and for 1 month following the completion of the study.
   2. Patient is not breastfeeding.
   3. Patient of childbearing potential must have a negative urine or serum pregnancy test during the screening period.
4. Patient has a diagnosis of low- or intermediate-1 risk MDS, as determined by the International Prognostic Scoring (IPSS) (score of 0-1).
5. Patient must be transfusion dependent (i.e., received ≥ 2 units over an 8-week period prior to registration) or have a hemoglobin value ≤ 10 g/dL on the screening laboratories.
6. Patients must have ≤ 10% blasts in the bone marrow and peripheral blood.
7. Patient must have a platelet counts > 50,000/microliters and absolute neutrophil counts (ANC) >500/microliters.
8. Patient must have adequate hepatic and renal functions, defined as serum bilirubin, serum glutamic-oxaloacetic transaminase (SGOT), and serum glutamate pyruvate transaminase (SGPT) ≤ 2 times the upper limit of normal (ULN), and creatinine ≤ 1.5 times the ULN.
9. Patient must have an ECOG score of ≤ 2.
10. The patient has a negative human immunodeficiency virus antibody (HIV) test result.

Exclusion Criteria:

A patient will be ineligible for study participation if any of the following criteria are met:

1. The patient has a history of an allergic reaction or significant sensitivity to Panhematin®.
2. The patient has taken or used any investigational drug or device in the 30 days prior to screening.
3. The patient has chronic myelomonocytic leukemia (CMML).
4. The patient has a history of deep vein thrombosis or known hypercoagulable state.
5. The patient has a history of a pre-existing medical condition that, in the opinion of the investigator, will interfere with the participation in the study.
6. The patient has poor peripheral venous access, if central venous access is not available.
7. The patient has an uncontrolled active infection.
8. The patient has positive test results for hepatitis B surface antigen, and hepatitis C virus antibody.
9. The patient has any other condition or prior therapy that, in the opinion of the Investigator, would make the patient unsuitable for the study.