Back to resultsSafety and Pharmacokinetics Study of SyB L-1101 in Patients With Recurrent/Relapsed or Refractory Myelodysplastic Syndrome (MDS)
Primary Purpose
Myelodysplastic Syndrome
Status
Completed
Phase
Phase 1
Locations
Japan
Study Type
Interventional
Intervention
SyB L-1101
Sponsored by
About this trial
This is an interventional treatment trial for Myelodysplastic Syndrome
Eligibility Criteria
Inclusion Criteria:
- Patients must satisfy the following conditions listed below.
Patients who have been histologically documented or cytologically confirmed with myelodysplastic syndrome (MDS), and who have been found to meet any of the following criteria on the basis of the World Health Organization (WHO) classification or French-American-British (FAB) classification.
- Refractory Anemia (RA) (< 5% myeloblasts, < 15% ringed sideroblasts)
- RA with Ring Sideroblasts (RARS) (< 5% myeloblasts, >= 15% ringed sideroblasts)
- RA with Excess of Blasts (RAEB)-1 (5% to 9% myeloblasts)
- RAEB-2 (10% to 19% myeloblasts)
- RAEB in transformation (RAEB-t) (20% to 29% myeloblasts or < 25,000/mm^3 peripheral leukocytes)
- Chronic myelomonocytic leukemia (CMML) (10% to 19% myeloblasts in marrow, >= 1,000/mm^3 peripheral monocytes, < 13,000/mm^3 leukocytes) However, RA patients must have score of Int-2 or higher in International prognostic scoring system (IPSS).
Patients with a low value in at least one blood cell lineage (having at least one of the following cytopenias).
- Neutrophils : < 1,800/mm^3
- Platelets : < 100,000/mm^3
- Hemoglobin : < 10 g/dL
Patients with a previous history of chemotherapy (including lenalidomide) for the target disease who meet any of the following criteria.
- Patients who have not achieved complete remission, partial remission, or hematologic improvement*
- Patients with recurrence/relapse after complete remission, partial remission, or hematologic improvement*
- Patients with intolerability that has led to discontinuation of treatment because of the development of liver dysfunction, kidney dysfunction, etc., after the start of treatment. * Proximate therapeutic efficacy judged under International Working Group (IWG) 2006 criteria
- Patients who have not been treated for four weeks or longer after the end of the previous therapy and who are judged to have no residual effects (antitumor effects) from the previous therapy.
- Patients who can be expected to survive at least three months or longer.
- Patients at least 20 years old (when informed consent is obtained).
- Patients who have score of 0 to 2 in Eastern Cooperative Oncology Group (ECOG) Performance Status (P.S.).
Patients with adequate function in major organs (heart, lungs, liver, kidneys, etc.).
- Aspartate aminotransferase (AST) (Glutamic oxaloacetic transaminase, GOT) : no greater than 3.0 times the upper boundary of the reference range at each institution
- Alanine aminotransferase (ALT) (Glutamic pyruvic transaminase, GPT): no greater than 3.0 times the upper boundary of the reference range at each institution
- Total bilirubin: no more than 1.5 times the upper boundary of the reference range at each institution
- Serum creatinine: no more than 1.5 times the upper boundary of the reference range at each institution
- ECG: no abnormal findings requiring treatment
- Echocardiography: no abnormal findings requiring treatment
- Patients who personally signed an informed consent document for participation in this study.
Exclusion Criteria:
- Patients who satisfy any of the following conditions will not be enrolled in the study.
- Patients with anemia caused by factors other than MDS (hemolytic anemia, gastrointestinal (GI) bleeding, etc.).
- Patients who have undergone treatment for an active malignant tumor within the past year (except basal cell or squamous cell skin cancer or carcinoma in situ of the cervix or breast).
- Patients who have been administered a cytokine preparation such as granulocyte-colony stimulating factor (G-CSF), erythropoietin, etc. within 14 days of tests for enrollment of the study.
- Patients with obvious infectious diseases (including viral infections).
- Patients with serious complications (liver failure, renal failure, etc.).
- Patients with a complicating or previous history of serious heart disease (myocardial infarction, ischemic heart disease, etc.) within the past two years before enrollment, and with cardiac arrhythmia requiring treatment.
- Patients with a serious gastrointestinal condition (severe or significant nausea/vomiting, diarrhea, etc.).
- Patients who are positive for the Hepatitis B surface (HBs) antigen or HIV antibodies.
- Patients with serious bleeding tendencies (disseminated intravascular coagulation (DIC), internal hemorrhage, etc.).
- Ascites requiring active medical management including paracentesis, or hyponatremia (defined as serum sodium value of <130 mEq/L).
- Patients who have been administered a drug in a clinical trial or an unapproved drug within three months before enrollment.
- Patients with an addiction to a legal or illegal drug, or with alcohol dependency.
- Patients who are pregnant or may become pregnant.
Patients who have not consented to the following contraceptive measures.
Patients will avoid sexual intercourse with sexual partners or should use the following contraceptive methods in these time periods: for male patients during the administration period of the trial and for six months after the end of administration; female patients during the administration period of the trial, and until a second menstrual period is confirmed after the end of administration (or in the case of female patients with no menstrual period, for two months after the end of administration).
•Male patients
The patient will always use a condom. For effective contraception, it is recommended that the female partner also use the contraceptive methods for female patients.
•Female patients
Female patients who may become pregnant should use one or more types of the following contraceptive methods. In addition, the male partner will always use a condom.
- Oral contraceptive (birth control pills)
- Intrauterine device (IUD)
- Tubal ligation
- Other patients judged to be unsuitable by an investigator or sub-investigator.
Sites / Locations
- Research Site
- Research Site
- Research Site
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
SyB L-1101
Arm Description
In Cohort 1, SyB L-1101 1200 mg/day group, Participants were administered 1200 mg/day of SyB L-1101 intravenously for 3 consecutive days, followed by 11-day observation period. In Cohort 2, SyB L-1101 1800 mg/day group, Participants were administered 1800 mg/day of SyB L-1101 intravenously for 3 consecutive days, followed by 11-day observation period. For both Cohorts, the treatment period of 14 days constitutes 1 cycle, and the treatment was allowed for up to 8 cycles.
Outcomes
Primary Outcome Measures
Number of Participants Who Experienced Dose-limiting Toxicities (DLTs)
A DLT was defined as adverse events for which a causal relationship with the investigational drug could not be ruled out and which met the following criteria that occurred by the final observation in Cycle 2. DLTs were also to be assessed in the Efficacy and Safety Assessment Committee.
Criteria:
Grade 3 or higher non-hematologic toxicity. However, nausea, vomiting, diarrhea, pyrexia, stomatitis, and esophagitis/dysphagia are excluded (Grade 3 nausea, vomiting, diarrhea, and pyrexia that cannot be controlled with antiemetic, antidiarrheal, or antifebrile agents are regarded as DLTs)
Grade 3 or higher stomatitis, esophagitis, and dysphagia that persist for >= 4 days
Secondary Outcome Measures
Hematologic Remission Effect (IWG 2006 Criteria, Responses Must be Sustained at Least 4 Weeks)
Definition
Complete remission (CR) Bone marrow: <= 5% myeloblasts; normal maturation of all cell lines Peripheral blood: Hemoglobin (Hgb) >= 11 g/dL, Platelets >= 100×10^9/L, Neutrophils >= 1.0×10^9/L, Blasts 0%
Partial remission (PR) Same as CR criteria except bone marrow blasts decreased by >= 50% over pretreatment but still > 5%
Marrow CR Bone marrow: <= 5% myeloblasts and decrease by >= 50% over pretreatment Peripheral blood: will be noted in addition to marrow CR
Stable disease Failure to achieve at least PR, but no evidence of progression for > 8 wks
Disease progression
Patients with:
Less than 5% blasts: >= 50% increase in blasts to > 5% blasts 5%-10% blasts: >= 50% increase to > 10% blasts 10%-20% blasts: >= 50% increase to > 20% blasts 20%-30% blasts: >= 50% increase to > 30% blasts
Any of the following:
At least 50% decrement from maximum remission/response in granulocytes or platelets Reduction in Hgb by >= 2 g/dL Transfusion dependence
Hematologic Improvement Effect (IWG 2006 Criteria, Responses Must be Sustained at Least 8 Weeks)
Definition
Hematologic Improvement Erythrocyte (HI-E):
Hgb increase by >= 1.5 g/dL Relevant reduction of units of red blood cell (RBC) transfusions by an absolute number of at least 4 RBC transfusions/8 week compared with the pretreatment transfusion number in the previous 8 week. Only RBC transfusions given for a Hgb of <= 9.0 g/dL pretreatment will count in the RBC transfusion response evaluation
Hematologic Improvement Platelet (HI-P):
Absolute increase of >= 30×10^9/L for patients starting with > 20×10^9/L platelets Increase from < 20×10^9/L to > 20×10^9/L and by at least 100%
Hematologic Improvement Neutrophil (HI-N):
At least 100% increase and an absolute increase > 0.5×10^9/L
Progressive disease / Relapse:
At least 1 of the following:
At least 50% decrement from maximum response levels in granulocytes or platelets Reduction in Hgb by >= 1.5 g/dL Transfusion dependence
Full Information
NCT ID
NCT01700335
First Posted
August 7, 2012
Last Updated
November 14, 2022
Sponsor
SymBio Pharmaceuticals
1. Study Identification
Unique Protocol Identification Number
NCT01700335
Brief Title
Safety and Pharmacokinetics Study of SyB L-1101 in Patients With Recurrent/Relapsed or Refractory Myelodysplastic Syndrome (MDS)
Official Title
Phase I Clinical Trial of SyB L-1101 in Patients With Myelodysplastic Syndrome
Study Type
Interventional
2. Study Status
Record Verification Date
October 2022
Overall Recruitment Status
Completed
Study Start Date
June 2012 (undefined)
Primary Completion Date
February 2015 (Actual)
Study Completion Date
February 2015 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
SymBio Pharmaceuticals
4. Oversight
5. Study Description
Brief Summary
The purpose of this study is to investigate tolerability when SyB L-1101 is administered intravenously in patients with recurrent/relapsed or refractory myelodysplastic syndrome, to determine the dose-limiting toxicity and maximum tolerated dose, and to estimate the recommended dose for phase II studies. Pharmacokinetics and antitumor effects will also be investigated.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Myelodysplastic Syndrome
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
9 (Actual)
8. Arms, Groups, and Interventions
Arm Title
SyB L-1101
Arm Type
Experimental
Arm Description
In Cohort 1, SyB L-1101 1200 mg/day group, Participants were administered 1200 mg/day of SyB L-1101 intravenously for 3 consecutive days, followed by 11-day observation period.
In Cohort 2, SyB L-1101 1800 mg/day group, Participants were administered 1800 mg/day of SyB L-1101 intravenously for 3 consecutive days, followed by 11-day observation period.
For both Cohorts, the treatment period of 14 days constitutes 1 cycle, and the treatment was allowed for up to 8 cycles.
Intervention Type
Drug
Intervention Name(s)
SyB L-1101
Intervention Description
SyB L-1101（rigosertib sodium） will be administered to two cohorts at either 1200 mg/day or 1800 mg/day.
The dose will be administered intravenously for 72 continuous hours (3 days), followed by 11-day observation period. The treatment period of 14 days (3 days of administration + 11 days of observation) constitutes 1 cycle.
The study will involve treatment through the second cycle, but treatment can be continued for 3 or more cycles if conditions for continued administration are satisfied.
Primary Outcome Measure Information:
Title
Number of Participants Who Experienced Dose-limiting Toxicities (DLTs)
Description
A DLT was defined as adverse events for which a causal relationship with the investigational drug could not be ruled out and which met the following criteria that occurred by the final observation in Cycle 2. DLTs were also to be assessed in the Efficacy and Safety Assessment Committee.
Criteria:
Grade 3 or higher non-hematologic toxicity. However, nausea, vomiting, diarrhea, pyrexia, stomatitis, and esophagitis/dysphagia are excluded (Grade 3 nausea, vomiting, diarrhea, and pyrexia that cannot be controlled with antiemetic, antidiarrheal, or antifebrile agents are regarded as DLTs)
Grade 3 or higher stomatitis, esophagitis, and dysphagia that persist for >= 4 days
Time Frame
Up to 60 weeks
Secondary Outcome Measure Information:
Title
Hematologic Remission Effect (IWG 2006 Criteria, Responses Must be Sustained at Least 4 Weeks)
Description
Definition
Complete remission (CR) Bone marrow: <= 5% myeloblasts; normal maturation of all cell lines Peripheral blood: Hemoglobin (Hgb) >= 11 g/dL, Platelets >= 100×10^9/L, Neutrophils >= 1.0×10^9/L, Blasts 0%
Partial remission (PR) Same as CR criteria except bone marrow blasts decreased by >= 50% over pretreatment but still > 5%
Marrow CR Bone marrow: <= 5% myeloblasts and decrease by >= 50% over pretreatment Peripheral blood: will be noted in addition to marrow CR
Stable disease Failure to achieve at least PR, but no evidence of progression for > 8 wks
Disease progression
Patients with:
Less than 5% blasts: >= 50% increase in blasts to > 5% blasts 5%-10% blasts: >= 50% increase to > 10% blasts 10%-20% blasts: >= 50% increase to > 20% blasts 20%-30% blasts: >= 50% increase to > 30% blasts
Any of the following:
At least 50% decrement from maximum remission/response in granulocytes or platelets Reduction in Hgb by >= 2 g/dL Transfusion dependence
Time Frame
Up to 60 weeks
Title
Hematologic Improvement Effect (IWG 2006 Criteria, Responses Must be Sustained at Least 8 Weeks)
Description
Definition
Hematologic Improvement Erythrocyte (HI-E):
Hgb increase by >= 1.5 g/dL Relevant reduction of units of red blood cell (RBC) transfusions by an absolute number of at least 4 RBC transfusions/8 week compared with the pretreatment transfusion number in the previous 8 week. Only RBC transfusions given for a Hgb of <= 9.0 g/dL pretreatment will count in the RBC transfusion response evaluation
Hematologic Improvement Platelet (HI-P):
Absolute increase of >= 30×10^9/L for patients starting with > 20×10^9/L platelets Increase from < 20×10^9/L to > 20×10^9/L and by at least 100%
Hematologic Improvement Neutrophil (HI-N):
At least 100% increase and an absolute increase > 0.5×10^9/L
Progressive disease / Relapse:
At least 1 of the following:
At least 50% decrement from maximum response levels in granulocytes or platelets Reduction in Hgb by >= 1.5 g/dL Transfusion dependence
Time Frame
Up to 60 weeks
Other Pre-specified Outcome Measures:
Title
Maximum Tolerated Dose (MTD)
Description
MTD was investigated with an index of DLT
Time Frame
Up to 16 weeks
10. Eligibility
Sex
All
Minimum Age & Unit of Time
20 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
- Patients must satisfy the following conditions listed below.
Patients who have been histologically documented or cytologically confirmed with myelodysplastic syndrome (MDS), and who have been found to meet any of the following criteria on the basis of the World Health Organization (WHO) classification or French-American-British (FAB) classification.
Refractory Anemia (RA) (< 5% myeloblasts, < 15% ringed sideroblasts)
RA with Ring Sideroblasts (RARS) (< 5% myeloblasts, >= 15% ringed sideroblasts)
RA with Excess of Blasts (RAEB)-1 (5% to 9% myeloblasts)
RAEB-2 (10% to 19% myeloblasts)
RAEB in transformation (RAEB-t) (20% to 29% myeloblasts or < 25,000/mm^3 peripheral leukocytes)
Chronic myelomonocytic leukemia (CMML) (10% to 19% myeloblasts in marrow, >= 1,000/mm^3 peripheral monocytes, < 13,000/mm^3 leukocytes) However, RA patients must have score of Int-2 or higher in International prognostic scoring system (IPSS).
Patients with a low value in at least one blood cell lineage (having at least one of the following cytopenias).
Neutrophils : < 1,800/mm^3
Platelets : < 100,000/mm^3
Hemoglobin : < 10 g/dL
Patients with a previous history of chemotherapy (including lenalidomide) for the target disease who meet any of the following criteria.
Patients who have not achieved complete remission, partial remission, or hematologic improvement*
Patients with recurrence/relapse after complete remission, partial remission, or hematologic improvement*
Patients with intolerability that has led to discontinuation of treatment because of the development of liver dysfunction, kidney dysfunction, etc., after the start of treatment. * Proximate therapeutic efficacy judged under International Working Group (IWG) 2006 criteria
Patients who have not been treated for four weeks or longer after the end of the previous therapy and who are judged to have no residual effects (antitumor effects) from the previous therapy.
Patients who can be expected to survive at least three months or longer.
Patients at least 20 years old (when informed consent is obtained).
Patients who have score of 0 to 2 in Eastern Cooperative Oncology Group (ECOG) Performance Status (P.S.).
Patients with adequate function in major organs (heart, lungs, liver, kidneys, etc.).
Aspartate aminotransferase (AST) (Glutamic oxaloacetic transaminase, GOT) : no greater than 3.0 times the upper boundary of the reference range at each institution
Alanine aminotransferase (ALT) (Glutamic pyruvic transaminase, GPT): no greater than 3.0 times the upper boundary of the reference range at each institution
Total bilirubin: no more than 1.5 times the upper boundary of the reference range at each institution
Serum creatinine: no more than 1.5 times the upper boundary of the reference range at each institution
ECG: no abnormal findings requiring treatment
Echocardiography: no abnormal findings requiring treatment
Patients who personally signed an informed consent document for participation in this study.
Exclusion Criteria:
- Patients who satisfy any of the following conditions will not be enrolled in the study.
Patients with anemia caused by factors other than MDS (hemolytic anemia, gastrointestinal (GI) bleeding, etc.).
Patients who have undergone treatment for an active malignant tumor within the past year (except basal cell or squamous cell skin cancer or carcinoma in situ of the cervix or breast).
Patients who have been administered a cytokine preparation such as granulocyte-colony stimulating factor (G-CSF), erythropoietin, etc. within 14 days of tests for enrollment of the study.
Patients with obvious infectious diseases (including viral infections).
Patients with serious complications (liver failure, renal failure, etc.).
Patients with a complicating or previous history of serious heart disease (myocardial infarction, ischemic heart disease, etc.) within the past two years before enrollment, and with cardiac arrhythmia requiring treatment.
Patients with a serious gastrointestinal condition (severe or significant nausea/vomiting, diarrhea, etc.).
Patients who are positive for the Hepatitis B surface (HBs) antigen or HIV antibodies.
Patients with serious bleeding tendencies (disseminated intravascular coagulation (DIC), internal hemorrhage, etc.).
Ascites requiring active medical management including paracentesis, or hyponatremia (defined as serum sodium value of <130 mEq/L).
Patients who have been administered a drug in a clinical trial or an unapproved drug within three months before enrollment.
Patients with an addiction to a legal or illegal drug, or with alcohol dependency.
Patients who are pregnant or may become pregnant.
Patients who have not consented to the following contraceptive measures.
Patients will avoid sexual intercourse with sexual partners or should use the following contraceptive methods in these time periods: for male patients during the administration period of the trial and for six months after the end of administration; female patients during the administration period of the trial, and until a second menstrual period is confirmed after the end of administration (or in the case of female patients with no menstrual period, for two months after the end of administration).
•Male patients
The patient will always use a condom. For effective contraception, it is recommended that the female partner also use the contraceptive methods for female patients.
•Female patients
Female patients who may become pregnant should use one or more types of the following contraceptive methods. In addition, the male partner will always use a condom.
Oral contraceptive (birth control pills)
Intrauterine device (IUD)
Tubal ligation
Other patients judged to be unsuitable by an investigator or sub-investigator.
Facility Information:
Facility Name
Research Site
City
Nagoya
State/Province
Aichi
Country
Japan
Facility Name
Research Site
City
Fukuoka
Country
Japan
Facility Name
Research Site
City
Tokyo
Country
Japan
12. IPD Sharing Statement
Learn more about this trial
Safety and Pharmacokinetics Study of SyB L-1101 in Patients With Recurrent/Relapsed or Refractory Myelodysplastic Syndrome (MDS)
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