Myelodysplastic Syndrome (MDS)
Conditions
Brief summary
This is a Phase II, single-arm, open-label, multinational, multicenter study of rATG in patients with low or intermediate-1 risk MDS who have either failed 1 prior treatment with growth factor(s), hypomethylating agents (5-azacitidine or decitabine), or the antiangiogenic agents lenalidomide or thalidomide, or who have never been treated for MDS (i.e., treatment-naïve patients).
Interventions
BIOLOGICALThymoglobulin®, Rabbit Anti-thymocyte Globulin (rATG)
All patients were to be treated with rATG 3.75 mg/kg/day administered by intravenous (IV) infusion over ≥6 hours for 5 consecutive days (cumulative dose: 18.75 mg/kg)
Sponsors
Genzyme, a Sanofi Company
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Patient provided signed written informed consent. * Patient had pathologically confirmed low or intermediate-1 risk MDS at the time of MDS diagnosis and at the time of screening. * Patient had received no more than 1 prior treatment for MDS. * Patient exhibited at least 1 hematologic cytopenia (anemia, neutropenia, or thrombocytopenia) over a period of ≥1 week. * Patient had documentation of any prior transfusion requirements. * Patient had an Eastern Cooperative Oncology Group (ECOG) performance score of 0, 1, or 2. * Patient was ≥18 and ≤70 years of age at time of signing the informed consent document (ICD). * Patient was able to adhere to study visit schedule and all other protocol requirements. * Patient was willing to practice a medically approved method of birth control during participation in the study (at least 12 months after the last infusion of rATG) (fertile male and female patients).
Exclusion criteria
* Patient was pregnant or lactating. * Patient has had prior treatment with any ATG. * Patient has received any immunomodulatory or immunosuppressing agents (excluding steroids) \<12 weeks prior to the first infusion of rATG. * Patient has had a prior hematopoietic stem cell transplantation and/or other organ transplant. * Patient has had a prior allergic reaction to rabbit proteins or excipients. * Patient had any of the following subtypes of MDS: refractory anemia with ringed sideroblasts (RARS); chronic myelomonocytic leukemia (CMML) if white blood counts \>13x10\^9/L; or other MDS/myeloproliferative diseases (MPD). * Patient had MDS associated with a 5q chromosomal deletion unless the patient received prior lenalidomide treatment \<4 weeks prior to the first infusion of rATG. * Patient had MDS presumed secondary to exposure to chemicals or treatment with radiotherapy or chemotherapy. * Patient received any investigational agents within 4 weeks prior to the first infusion of rATG. * Patient has any of the following abnormalities: serum creatinine \>1.5 x upper limit of normal (ULN); aspartate transaminase (AST) and alanine transaminase (ALT) \>2.5 x ULN; or serum total bilirubin \>1.5 x ULN, except for unconjugated hyperbilirubinemia related to the patient's MDS. * Patient received any treatment with non-steroidal anti-inflammatory drugs (NSAIDs) within 14 days prior to the start of treatment. * Patient was known to be human immunodeficiency virus (HIV) positive. * Patient had any prior diagnosis of malignancy other than MDS, unless the patient had been disease-free for at least 5 years following the completion of curative intent therapy. * Patient had any serious medical condition (other than MDS) that would limit survival to \<2 years. * Patient had active acute or chronic infection, including cytomegaloviremia (CMV) infection or deep tissue infection. * Patient had any other serious medical condition, uncontrolled illness (including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia), social condition, or psychiatric illness that would prevent the patient from signing the informed consent document (ICD), or would place the patient at unacceptable risk if he/she participated in the study, or that would limit compliance with study requirements.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Achieved Hematologic Improvement (HI) | 12 months | This is a measure of HI in the erythroid, platelet, and neutrophil lineages. Note that HI was observed in the erythroid lineage only, which is defined as a participant who had a \>=1.5 g/dL increase in hemoglobin from baseline (pretreatment value must have been \<11 g/dL) and who had a relevant reduction of units of red blood cell (RBC) transfusions by an absolute number of \>=4 RBC transfusions over 8 weeks as compared with the pretreatment transfusion number in the previous 8 weeks. These criteria were taken from the 2006 International Working Group criteria. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Achieved Disease Remission | 36 months | Disease remission is defined as a participant whose best response to therapy was a complete remission or partial remission. A complete remission is defined as: bone marrow \<=5% myeloblasts with normal maturation of all cell lines; persistent dysplasia noted; and peripheral blood hemoglobin \>=11 g/dL, platelets \>=100 x 10\^9/L, neutrophils \>=1.0 x 10\^9/L, and blasts 0%. Partial remission is defined as: all complete remission criteria if abnormal before treatment, except bone marrow blasts decreased by \>=50% over pretreatment, but still \>5%; and cellularity and morphology not relevant. |
| Duration of Disease Remission | 36 months | This is a measure of the duration of overall disease remission only for those participants who achieved an overall remission. Duration of overall remission is defined as the time from first documentation of overall remission to the date of first documentation of disease relapse or death due to any cause, whichever occurs first. |
| Number of Participants Who Achieved Transfusion Independence | 36 months | This is a measure of transfusion independence, which is defined as a participant with no transfusions for a period of 8 consecutive calendar weeks after first dose. Transfusion independence was to be calculated only for those participants who had documented transfusions during the 8 weeks prior to enrollment. |
| Number of Participants With Duration of Transfusion Independence | 36 months | This is a measure of the duration of transfusion independence only for those participants who achieved transfusion independence. Duration of transfusion independence is defined as the longest period of time during which a participant requires no transfusions. |
| Number of Participants With a Relapse Following HI | 36 months | This is a measure of relapse following HI, which is defined as a participant who experiences at least one of the following: \>=50% decrease from maximum response levels in granulocytes or platelets; \>=1.5 g/dL reduction in hemoglobin; or transfusion dependence. |
| Number of Participants With Duration of HI | 36 months | This is a measure of the duration of HI for those participants who achieved HI. Duration of HI is defined as the time from confirmation of HI response to the date of first documentation of HI relapse or death due to any cause, whichever occurs first. |
| Number of Participants With Progression-free Survival | 36 months | This is a measure of a progression-free survival which is defined as the time from the participant's first dose to the date of disease progression, lost to follow-up or death due to any cause, whichever occurs first. |
| Number of Participants With Transformation to Acute Myeloid Leukemia | 36 months | This is a measure of transformation to acute myeloid leukemia only for participants who have bone marrow assessments. Transformation to acute myeloid leukemia is defined as the earliest date a participant experiences bone marrow blasts of \>=20% after the start of treatment. |
| Number of Participants With a Cytogenetic Response | 36 months | This is a measure of cytogenic response for participants whose best response to therapy is a either a complete or partial cytogenetic response. A complete cytogenetic response is defined as the disappearance of the chromosomal abnormality without appearance of new ones. A partial cytogenetic response is defined as at least 50% reduction of the chromosomal abnormality. |
| Number of Participants With a Marrow Remission | 36 months | This is a measure of bone marrow complete remission for participants who experience a remission. Bone marrow complete remission is defined as a bone marrow assessment of \<=5% myeloblasts and decrease by \>=50% over pretreatment. |
| Number of Participants With a Relapse Following Overall Remission | 36 months | This is a measure of relapse following an overall remission only for participants who experienced either a complete or partial remission. Relapse following an overall remission is defined as a participant who meets any of the following criteria: a return to pretreatment bone marrow blast percentage; decrease of \>=50% from maximum remission levels in neutrophils or platelets; reduction in hemoglobin concentration by \>=1.5 g/dL from maximum remission levels; or transfusion dependence. |
Countries
France, Germany, Netherlands, United Kingdom
Participant flow
Recruitment details
Enrollment period: 05 November 2007 through 06 May 2009. Study participants were enrolled at 7 study centers in Europe.
Pre-assignment details
Because the study was terminated early due to slow enrollment, only 16 participants were enrolled in the study. Of these, 14 participants went on to receive treatment with Thymoglobulin.
Participants by arm
| Arm | Count |
|---|---|
| Thymoglobulin Thymoglobulin 3.75 mg/kg/day for 5 consecutive days | 14 |
| Total | 14 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Did Not Receive Thymoglobulin Treatment | 2 |
| Overall Study | Need for Prohibited Treatment | 3 |
| Overall Study | Physician Decision | 1 |
| Overall Study | Study Prematurely Discontinued | 7 |
Baseline characteristics
| Characteristic | Thymoglobulin |
|---|---|
| Age, Continuous | 55.4 years STANDARD_DEVIATION 7.67 |
| Age, Customized <60 years | 10 participants |
| Age, Customized >=60 years | 4 participants |
| Race/Ethnicity, Customized Black | 1 participants |
| Race/Ethnicity, Customized Not Reported | 2 participants |
| Race/Ethnicity, Customized White | 11 participants |
| Sex: Female, Male Female | 7 Participants |
| Sex: Female, Male Male | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 14 / 14 |
| serious Total, serious adverse events | 7 / 14 |
Outcome results
Primary
Number of Participants Who Achieved Hematologic Improvement (HI)
This is a measure of HI in the erythroid, platelet, and neutrophil lineages. Note that HI was observed in the erythroid lineage only, which is defined as a participant who had a \>=1.5 g/dL increase in hemoglobin from baseline (pretreatment value must have been \<11 g/dL) and who had a relevant reduction of units of red blood cell (RBC) transfusions by an absolute number of \>=4 RBC transfusions over 8 weeks as compared with the pretreatment transfusion number in the previous 8 weeks. These criteria were taken from the 2006 International Working Group criteria.
Time frame: 12 months
Population: Number of participants analyzed includes those who received treatment with Thymoglobulin and completed follow-up efficacy assessments. However, no formal efficacy analysis was conducted due to the small sample size and early study termination.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Thymoglobulin | Number of Participants Who Achieved Hematologic Improvement (HI) | 3 participants |
Secondary
Duration of Disease Remission
This is a measure of the duration of overall disease remission only for those participants who achieved an overall remission. Duration of overall remission is defined as the time from first documentation of overall remission to the date of first documentation of disease relapse or death due to any cause, whichever occurs first.
Time frame: 36 months
Population: This secondary outcome measure was not formally analyzed or assessed due to the small sample size and early study termination (i.e., no study participants reached the 36-month time point).
Secondary
Number of Participants Who Achieved Disease Remission
Disease remission is defined as a participant whose best response to therapy was a complete remission or partial remission. A complete remission is defined as: bone marrow \<=5% myeloblasts with normal maturation of all cell lines; persistent dysplasia noted; and peripheral blood hemoglobin \>=11 g/dL, platelets \>=100 x 10\^9/L, neutrophils \>=1.0 x 10\^9/L, and blasts 0%. Partial remission is defined as: all complete remission criteria if abnormal before treatment, except bone marrow blasts decreased by \>=50% over pretreatment, but still \>5%; and cellularity and morphology not relevant.
Time frame: 36 months
Population: This secondary outcome measure was not formally analyzed or assessed due to the small sample size and early study termination (i.e., no study participants reached the 36-month time point).
Secondary
Number of Participants Who Achieved Transfusion Independence
This is a measure of transfusion independence, which is defined as a participant with no transfusions for a period of 8 consecutive calendar weeks after first dose. Transfusion independence was to be calculated only for those participants who had documented transfusions during the 8 weeks prior to enrollment.
Time frame: 36 months
Population: This secondary outcome measure was not formally analyzed or assessed due to the small sample size and early study termination (i.e., no study participants reached the 36-month time point).
Secondary
Number of Participants With a Cytogenetic Response
This is a measure of cytogenic response for participants whose best response to therapy is a either a complete or partial cytogenetic response. A complete cytogenetic response is defined as the disappearance of the chromosomal abnormality without appearance of new ones. A partial cytogenetic response is defined as at least 50% reduction of the chromosomal abnormality.
Time frame: 36 months
Population: This secondary outcome measure was not formally analyzed or assessed due to the small sample size and early study termination (i.e., no study participants reached the 36-month time point).
Secondary
Number of Participants With a Marrow Remission
This is a measure of bone marrow complete remission for participants who experience a remission. Bone marrow complete remission is defined as a bone marrow assessment of \<=5% myeloblasts and decrease by \>=50% over pretreatment.
Time frame: 36 months
Population: This secondary outcome measure was not formally analyzed or assessed due to the small sample size and early study termination (i.e., no study participants reached the 36-month time point).
Secondary
Number of Participants With a Relapse Following HI
This is a measure of relapse following HI, which is defined as a participant who experiences at least one of the following: \>=50% decrease from maximum response levels in granulocytes or platelets; \>=1.5 g/dL reduction in hemoglobin; or transfusion dependence.
Time frame: 36 months
Population: This secondary outcome measure was not formally analyzed or assessed due to the small sample size and early study termination (i.e., no study participants reached the 36-month time point).
Secondary
Number of Participants With a Relapse Following Overall Remission
This is a measure of relapse following an overall remission only for participants who experienced either a complete or partial remission. Relapse following an overall remission is defined as a participant who meets any of the following criteria: a return to pretreatment bone marrow blast percentage; decrease of \>=50% from maximum remission levels in neutrophils or platelets; reduction in hemoglobin concentration by \>=1.5 g/dL from maximum remission levels; or transfusion dependence.
Time frame: 36 months
Population: Secondary outcome measure was not formally analyzed or assessed due to early study termination and small sample size (i.e., no study participants reached the 36-month time point)
Secondary
Number of Participants With Duration of HI
This is a measure of the duration of HI for those participants who achieved HI. Duration of HI is defined as the time from confirmation of HI response to the date of first documentation of HI relapse or death due to any cause, whichever occurs first.
Time frame: 36 months
Population: This secondary outcome measure was not formally analyzed or assessed due to the small sample size and early study termination (i.e., no study participants reached the 36-month time point).
Secondary
Number of Participants With Duration of Transfusion Independence
This is a measure of the duration of transfusion independence only for those participants who achieved transfusion independence. Duration of transfusion independence is defined as the longest period of time during which a participant requires no transfusions.
Time frame: 36 months
Population: This secondary outcome measure was not formally analyzed or assessed due to the small sample size and early study termination (i.e., no study participants reached the 36-month time point).
Secondary
Number of Participants With Progression-free Survival
This is a measure of a progression-free survival which is defined as the time from the participant's first dose to the date of disease progression, lost to follow-up or death due to any cause, whichever occurs first.
Time frame: 36 months
Population: This secondary outcome measure was not formally analyzed or assessed due to the small sample size and early study termination (i.e., no study participants reached the 36-month time point).
Secondary
Number of Participants With Transformation to Acute Myeloid Leukemia
This is a measure of transformation to acute myeloid leukemia only for participants who have bone marrow assessments. Transformation to acute myeloid leukemia is defined as the earliest date a participant experiences bone marrow blasts of \>=20% after the start of treatment.
Time frame: 36 months
Population: This secondary outcome measure was not formally analyzed or assessed due to the small sample size and early study termination (i.e., no study participants reached the 36-month time point).