Myelodysplastic Syndrome
Conditions
Keywords
myelodysplastic, MDS, Panhematin, Hemin
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)
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.
Interventions
DRUGPanhematin
Sponsors
H. Lundbeck A/S
Rush University Medical Center
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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: 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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 | — |
Countries
United States
Participant flow
Recruitment details
Between 5/2007 and 10/2008, 6 patients were enrolled on trial and were treated at Rush university medical center.
Participants by arm
| Arm | Count |
|---|---|
| Group 1 Panhematin treatment arm | 6 |
| Total | 6 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Group 1 |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 5 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants |
| Age, Continuous | 73 years FULL_RANGE 0 |
| Region of Enrollment United States | 6 participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 0 / 6 |
| serious Total, serious adverse events | 0 / 6 |
Outcome results
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)
Time frame: After 8 weeks of therapy with panhematin
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1 | Response Rate ( CR+PR) at Week 8, Based on the IWG Criteria for Response Assessment ( 2000 Version) | 0 Participants |
Primary
Safety and Tolerability of Panhematin®.
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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1 | Safety and Tolerability of Panhematin®. | 6 participants |
Secondary
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
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1 | Hematological Improvement Rate at Week 8 as Defined by the IWG 2000 Criteria for Response Assessment, 2000 Version | 1 participants |
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.
Time frame: 4 weeks after initiation of treatment with Panhematin
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1 | Number of Patients Demonstrating Hematological Improvement to Panhematin® at Week 4. | 0 participants |