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

• Sponsor: Rush University Medical Center (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00467610
• Collaborator: H. Lundbeck A/S (Industry)
• Enrollment: 6
• Location: 1
• Arm: 1
• Duration (Months): 20.1
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief 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)

Condition or Disease	Intervention/Treatment	Phase
Myelodysplastic Syndrome	Drug: Panhematin	Phase 2

Detailed 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 6 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Study Start Date: May 1, 2007
• Actual Primary Completion Date: Dec 1, 2008
• Actual Study Completion Date: Jan 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Panhematin	Drug: Panhematin

Outcome Measures

Primary Outcome Measures

1. Safety and Tolerability of Panhematin®. [participants were followed during therapy with panhematin, and up to six months post completion of therapy, average of 8 months.]

   Number of patients with no adverse events.

2. Response Rate ( CR+PR) at Week 8, Based on the IWG Criteria for Response Assessment ( 2000 Version) [After 8 weeks of therapy with panhematin]

   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)

Secondary Outcome Measures

1. Number of Patients Demonstrating Hematological Improvement to Panhematin® at Week 4. [4 weeks after initiation of treatment with Panhematin]

   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.

2. 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]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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:

4. 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.

5. Patient is not breastfeeding.

6. Patient of childbearing potential must have a negative urine or serum pregnancy test during the screening period.

7. Patient has a diagnosis of low- or intermediate-1 risk MDS, as determined by the International Prognostic Scoring (IPSS) (score of 0-1).

8. 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.

9. Patients must have ≤ 10% blasts in the bone marrow and peripheral blood.

10. Patient must have a platelet counts > 50,000/microliters and absolute neutrophil counts (ANC) >500/microliters.

11. 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.

12. Patient must have an ECOG score of ≤ 2.

13. 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Rush University Medical Center	Chicago	Illinois	United States	60612

Sponsors and Collaborators

• Rush University Medical Center
• H. Lundbeck A/S

Investigators

• Principal Investigator: Jamile Shammo, MD, Rush University Medical Center

Study Documents (Full-Text)

None provided.

More Information

Publications

• Aul C, Germing U, Gattermann N, Minning H. Increasing incidence of myelodysplastic syndromes: real or fictitious? Leuk Res. 1998 Jan;22(1):93-100.
• 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):405-410. doi: 10.1007/BF02994001. Review.
• Catenacci DV, Schiller GJ. Myelodysplasic syndromes: a comprehensive review. Blood Rev. 2005 Nov;19(6):301-19. Review.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• Monette FC, Holden SA. Hemin enhances the in vitro growth of primitive erythroid progenitor cells. Blood. 1982 Aug;60(2):527-30.
• Panhematin® Product Prescribing Information. Abbott Laboratories, August 2000 Edition
• Porter PN, Meints RH, Mesner K. Enhancement of erythroid colony growth in culture by hemin. Exp Hematol. 1979 Jan;7(1):11-6.
• Rund D, Ben-Yehuda D. Therapy-related leukemia and myelodysplasia: evolving concepts of pathogenesis and treatment. Hematology. 2004 Jun;9(3):179-87. Review.
• 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.
• Timonen TT, Kauma H. Therapeutic effect of heme arginate in myelodysplastic syndromes. Eur J Haematol. 1992 Nov;49(5):234-8.
• 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.
• 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.

• Responsible Party: Jamile Shammo, Associate Professor of Medicine and Pathology, Rush University Medical Center
• ClinicalTrials.gov Identifier: NCT00467610
• Other Study ID Numbers: MDS 2005-01; 06011001
• First Posted: Apr 30, 2007
• Last Update Posted: Oct 24, 2014
• Last Verified: Oct 1, 2014

• Keywords provided by Jamile Shammo, Associate Professor of Medicine and Pathology, Rush University Medical Center: myelodysplastic; MDS; Panhematin; Hemin
• Additional relevant MeSH terms: Preleukemia; Myelodysplastic Syndromes; Syndrome

Study Results

Participant Flow

Recruitment Details	Between 5/2007 and 10/2008, 6 patients were enrolled on trial and were treated at Rush university medical center.

Arm/Group Title	Group 1
Arm/Group Description	Panhematin treatment arm
Period Title: Overall Study
STARTED	6
COMPLETED	5
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	Group 1
Arm/Group Description	Panhematin treatment arm
Overall Participants	6
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	1 16.7%
>=65 years	5 83.3%
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	73 (0)
Sex: Female, Male (Count of Participants)
Female	1 16.7%
Male	5 83.3%
Region of Enrollment (participants) [Number]
United States	6 100%

Outcome Measures

1. Primary Outcome

Title	Safety and Tolerability of Panhematin®.
Description	Number of patients with no adverse events.
Time Frame	participants were followed during therapy with panhematin, and up to six months post completion of therapy, average of 8 months.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Group 1
Arm/Group Description	Panhematin treatment arm
Measure Participants	6
Number [participants]	6 100%

2. Secondary Outcome

Title	Number of Patients Demonstrating Hematological Improvement to Panhematin® at Week 4.
Description	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.
Time Frame	4 weeks after initiation of treatment with Panhematin

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Group 1
Arm/Group Description	Panhematin treatment arm
Measure Participants	5
Number [participants]	0 0%

3. Primary Outcome

Title	Response Rate ( CR+PR) at Week 8, Based on the IWG Criteria for Response Assessment ( 2000 Version)
Description	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)
Time Frame	After 8 weeks of therapy with panhematin

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Group 1
Arm/Group Description	Panhematin treatment arm
Measure Participants	5
Number [Participants]	0 0%

4. Secondary Outcome

Title	Hematological Improvement Rate at Week 8 as Defined by the IWG 2000 Criteria for Response Assessment, 2000 Version
Time Frame	At 8 weeks from start of therapy

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Group 1
Arm/Group Description	Panhematin treatment arm
Measure Participants	5
Number [participants]	1 16.7%

Adverse Events

Time Frame	All adverse events occuring from the time of subject signing informed consent through 30 days post completion of study were collected. about 8 months period.
Arm/Group Title	Group 1
Arm/Group Description	Panhematin treatment arm
All Cause Mortality
	Group 1
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Group 1
	Affected / at Risk (%)	# Events
Total	0/06 (0%)
Other (Not Including Serious) Adverse Events
	Group 1
	Affected / at Risk (%)	# Events
Total	0/6 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.