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

Myelodysplastic Syndrome Clinical Trial

Official title:

A Phase 2, Open-Label, Multiple-Dose Study Investigating the Efficacy and Safety of Panhematin in Patients With Low or Intermediate-1 Risk Myelodysplastic Syndrome

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00467610
• Other study ID #: MDS 2005-01
• Secondary ID: 06011001
• Status: Terminated
• Phase: Phase 2
• First received: April 26, 2007
• Last updated: October 23, 2014
• Start date: May 2007
• Est. completion date: January 2009

Study information

• Verified date: October 2014
• Source: Rush University Medical Center
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

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)

Description:

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 6
• Est. completion date: January 2009
• Est. primary completion date: December 2008
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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.

Study Design

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Myelodysplastic Syndrome
• Myelodysplastic Syndromes
• Preleukemia

Intervention

Drug:
• Panhematin

Locations

Country	Name	City	State
United States	Rush University Medical Center	Chicago	Illinois

Sponsors (2)

Lead Sponsor	Collaborator
Rush University Medical Center	H. Lundbeck A/S

Country where clinical trial is conducted

United States, 

References & Publications (17)

Aul C, Germing U, Gattermann N, Minning H. Increasing incidence of myelodysplastic syndromes: real or fictitious? Leuk Res. 1998 Jan;22(1):93-100. — View Citation

Aul C, Giagounidis A, Germing U. Epidemiological features of myelodysplastic syndromes: results from regional cancer surveys and hospital-based statistics. Int J Hematol. 2001 Jun;73(4):405-10. Review. — View Citation

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

Cheson BD, Bennett JM, Kantarjian H, Pinto A, Schiffer CA, Nimer SD, Löwenberg B, Beran M, de Witte TM, Stone RM, Mittelman M, Sanz GF, Wijermans PW, Gore S, Greenberg PL; World Health Organization(WHO) international working group. Report of an international working group to standardize response criteria for myelodysplastic syndromes. Blood. 2000 Dec 1;96(12):3671-4. — View Citation

Dhar GJ, Bossenmaier I, Cardinal R, Petryka ZJ, Watson CJ. Transitory renal failure following rapid administration of a relatively large amount of hematin in a patient with acute intermittent porphyria in clinical remission. Acta Med Scand. 1978;203(5):437-43. — View Citation

Fibach E, Kollia P, Schechter AN, Noguchi CT, Rodgers GP. Hemin-induced acceleration of hemoglobin production in immature cultured erythroid cells: preferential enhancement of fetal hemoglobin. Blood. 1995 May 15;85(10):2967-74. — View Citation

Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G, Sanz M, Vallespi T, Hamblin T, Oscier D, Ohyashiki K, Toyama K, Aul C, Mufti G, Bennett J. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood. 1997 Mar 15;89(6):2079-88. Erratum in: Blood 1998 Feb 1;91(3):1100. — View Citation

Mauritzson N, Albin M, Rylander L, Billström R, Ahlgren T, Mikoczy Z, Björk J, Strömberg U, Nilsson PG, Mitelman F, Hagmar L, Johansson B. Pooled analysis of clinical and cytogenetic features in treatment-related and de novo adult acute myeloid leukemia and myelodysplastic syndromes based on a consecutive series of 761 patients analyzed 1976-1993 and on 5098 unselected cases reported in the literature 1974-2001. Leukemia. 2002 Dec;16(12):2366-78. — View Citation

McHale CM, Winter PC, Lappin TR. Erythroid gene expression is differentially regulated by erythropoietin, haemin and delta-aminolaevulinic acid in UT-7 cells. Br J Haematol. 1999 Mar;104(4):829-37. — View Citation

Monette FC, Holden SA. Hemin enhances the in vitro growth of primitive erythroid progenitor cells. Blood. 1982 Aug;60(2):527-30. — View Citation

Porter PN, Meints RH, Mesner K. Enhancement of erythroid colony growth in culture by hemin. Exp Hematol. 1979 Jan;7(1):11-6. — View Citation

Rund D, Ben-Yehuda D. Therapy-related leukemia and myelodysplasia: evolving concepts of pathogenesis and treatment. Hematology. 2004 Jun;9(3):179-87. Review. — View Citation

Thompson JE, Luger SM. The role of hematopoietic stem cell transplantation in myelodysplastic syndrome. Oncology (Williston Park). 2005 Apr;19(4):533-42; discussion 542-4, 547-8. Review. — View Citation

Timonen TT, Kauma H. Therapeutic effect of heme arginate in myelodysplastic syndromes. Eur J Haematol. 1992 Nov;49(5):234-8. — View Citation

Vidaza® Product Prescribing Information. Pharmion Corporation, 5-18-04 Edition

Volin L, Ruutu T, Knuutila S, Tenhunen R. Heme arginate treatment for myelodysplastic syndromes. Leuk Res. 1988;12(5):423-31. — View Citation

Williamson PJ, Kruger AR, Reynolds PJ, Hamblin TJ, Oscier DG. Establishing the incidence of myelodysplastic syndrome. Br J Haematol. 1994 Aug;87(4):743-5. — View Citation

* Note: There are 17 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Safety and Tolerability of Panhematin®.	Number of patients with no adverse events.	participants were followed during therapy with panhematin, and up to six months post completion of therapy, average of 8 months.	Yes
Primary	Response Rate ( CR+PR) at Week 8, Based on the IWG Criteria for Response Assessment ( 2000 Version)	Complete response(CR): <5% blasts in the bone marrow,with normal maturation of all cell lines, Hemoglobin >11 g/dL, neutrophils>1500/mm3 platelets>100,000/mm3.; Partial response (PR): >50% decrease in blasts, or less advanced IPSS than pretreatment value, same hematological parameters as in CR.; Stable disease (SD): No evidence of disease progression in bone marrow, stable peripheral blood counts failure: Increase in bone marrow blast percentage, progression to more advanced IPSS than pretreatment and worsening of cytopenias.; (Cheson, 2000)	After 8 weeks of therapy with panhematin	No
Secondary	Number of Patients Demonstrating Hematological Improvement to Panhematin® at Week 4.	Hematological improvement (HI); Major: HI-Erythroid:>2 g/dL rise in hemoglobin, or transfusion independence HI-Neutrophil: Absolute increase of >500/mm3, or >100% increase HI-Platelet: Absolute increase of >30,000, or transfusion independence; Minor: HI-Erythroid:1 to 2 g/dL increase in hemoglobin or 50% decrease in transfusion dependence.; HI-P: For patients with pretreatment platelet count < 100,000/mm3, = 50% increase with a net increase > 10,000/mm3 but < 30,000/mm3.; HI-N: For patients with pretreatment ANC < 1500/mm3, = 100% increase, but < 500/mm3 increase.	4 weeks after initiation of treatment with Panhematin	No
Secondary	Hematological Improvement Rate at Week 8 as Defined by the IWG 2000 Criteria for Response Assessment, 2000 Version		At 8 weeks from start of therapy	No