Leukemia, Myelodysplastic Syndromes
Conditions
Keywords
de novo myelodysplastic syndromes, secondary myelodysplastic syndromes, chronic myelomonocytic leukemia, refractory anemia with excess blasts in transformation, refractory anemia with excess blasts, refractory anemia with ringed sideroblasts, refractory anemia, refractory cytopenia with multilineage dysplasia
Brief summary
RATIONALE: Drugs used in chemotherapy, such as azacitidine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as lintuzumab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Giving chemotherapy together with monoclonal antibodies may be a better way to block cancer growth. PURPOSE: This phase II trial is studying the side effects and how well giving azacitidine together with lintuzumab works in treating patients with previously untreated myelodysplastic syndromes.
Detailed description
OBJECTIVES: Primary * To determine the complete response rate of the combination of lintuzumab and azacitidine in patients with myelodysplastic syndromes. Secondary * To define the specific toxicities of this regimen. * To determine the overall response rate. * To determine the relationship between pretreatment expression of Syk and clinical response. * To determine whether the investigational agents modulate Syk expression and to correlate drug-induced changes in Syk with response to treatment. * To provide preliminary data on the biological activity of azacitidine as a demethylating agent (changes in target gene methylation and gene expression, DNMT1 protein expression, global methylation). * To perform exploratory studies of azacitidine-triphosphate with global DNA methylation. * To explore the biologic role of microRNA in determining clinical response to this regimen and achievement of the other pharmacodynamic endpoints. OUTLINE: Patients receive azacitidine IV or subcutaneously once daily on days 1-7 and lintuzumab IV on days 2, 7, 15, and 22 (days 2 and 15 of course 1 only). Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity. Treatment modifications may apply according to response. Blood and bone marrow samples are collected periodically for pharmacodynamic studies. After completion of study treatment, patients are followed up for 5 years.
Interventions
BIOLOGICALlintuzumab
Cycle 1 600mg as an IV infusion (flat dose for all), given on days 2, 7, 15, and 22. Subsequent Cycles (cycles to be repeated every 28 days) 600mg as an IV infusion, given every other week, twice during each cycle, including one dose given during AZA therapy. Doses should be given at least 12 days apart. By convention, dosing on days 7 and 22 of each cycle will be encouraged, but due to expected issues of patient convenience (time, travel, etc.), the study requirements are every other week, twice during each cycle, with one dose during AZA treatment.
DRUG5-azacytidine
75mg/m2 IV/SC daily on days 1-7.
Sponsors
Seagen Inc.
Alison Walker
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Eligibility Criteria: * Age \>18 with untreated MDS by FAB or WHO criteria (note: FAB criteria for MDS includes \<29% blasts; FAB criteria includes CMML). * Patients with therapy related disease (t-MDS). * If the patient has co-morbid medical illness, life expectancy attributed to this must be greater than 6 months. * Eastern Cooperative Oncology Group (ECOG) performance status \<2. * Must have adequate organ function as defined below: * total bilirubin \<2.0mg/dL * AST(SGOT)/ALT(SGPT) \<2.5 X institutional upper limit of normal * creatinine \<2.0mg/dL * NYHA CHF(congestive heart failure)Class II or better * Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence). * Ability to understand and willingness to sign the written informed consent document. * CD33 expression is required on at least 25% of left shifted dysplastic myeloid cells, including blasts. This testing will be done on bone marrow aspirate, but for patients whose CD33 expression in this cellular compartment cannot be ascertained, peripheral blood will be allowed to determine this.
Exclusion criteria
* Patients who have had chemotherapy or radiotherapy within 6 months (for other cancers) prior to entering the study. * Patients receiving any other investigational agents or patients that have received other investigational agents within 1 month of enrollment. * Patients with active central nervous system disease or with granulocytic sarcoma as sole site of disease. * Patients with history of allergic reactions attributed to compounds of similar chemical or biologic composition to AZA or lintuzumab that are not easily managed are excluded. Patients with hypersensitivity to mannitol are excluded. * Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, serious cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. As infection is a common feature of MDS, patients with active infection are permitted to enroll provided that the infection is under control. Myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. * Psychiatric conditions that prevent compliance with protocol or consent. * Pregnant women or women who are breastfeeding are excluded from this study. * HIV-positive patients on combination antiretroviral therapy are ineligible. * Patients with serious medical or psychiatric illness likely to interfere with participation in this clinical study. * Patients with serious medical or psychiatric illness likely to interfere with participation in this clinical study. * Patients with baseline fibrinogen \<100mg/dL, or those with clinically significant disseminated intravascular coagulation, are excluded. * Patients who require ongoing therapeutic anticoagulation with warfarin, lovenox, or similar agent are excluded. This does not apply to patients on low dose prophylaxis therapy. * Patients who require ongoing clopidogrel therapy are excluded. In cases where clopidogrel use at screening is subsequently discontinued due to ongoing or future risk of drug and treatment related cytopenias, such patients will be eligible. * Patients with platelet \<10,000/uL who are refractory to platelet transfusion are not eligible (must bump to at least \>10,000/uL after transfusion) * Patients who have previously received lenalidomide or thalidomide are excluded.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Complete Response Rate | up to 5 years | Response to therapy was determined based on percentage of blasts in bone marrow, hematopoiesis, and requirement for supportive care (i.e., transfusions or cytokine growth factors). The modified International Working Group response criteria was used, based on Cheson, et al. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Toxicities of the Combination | up to 5 years | All patients who received study drug were closely monitored for adverse events (AEs). All AEs that occured during study period were reported and the investigator determined the severity and relationship to study drug (unrelated, unlikely, possibly, probably, or definitely related). The NCI's CTCAE(Common Toxicity Criteria for Adverse Effects)v3.0 was used for grading AEs. |
| Determine the Relationship Between Pretreatment Expression of Syk and Clinical Response; to Determine Whether the Investigational Agents Modulate Syk Expression and Correlate Drug-induced Changes in Syk With Response to Treatment | up to 5 years | — |
| Overall Response Rate | up to 5 years | Response to therapy was determined based on percentage of blasts in bone marrow, hematopoiesis, and requirement for supportive care (i.e., transfusions or cytokine growth factors). The modified International Working Group response criteria was used, based on Cheson, et al. |
| Perform Exploratory Studies of AZA-triphosphate With Global DNA Methylation | up to 5 years | — |
| Explore the Biologic Role of microRNAs in Determining Clinical Response to the AZA Plus Lintuzumab Combination and Achievement of the Other Pharmacodynamic Endpoints | Up to 5 years | — |
| Provide Preliminary Data on the Biological Activity of AZA as a Demethylating Agent (Changes in Target Gene Methylation and Gene Expression, DNMT1[Deoxyribonucleic Acid Methyltransferase 1 DNA Methyltransferase 1]Protein Expression, Global Methylation) | up to 5 years | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 75 mg/m2 5-azacytidine (Vidaza, AZA) and 600 mg Lintuzumab 5-azacytidine (Vidaza, AZA) 75mg/m2 IV/SC daily on days 1-7 cycle 1 and all subsequent cycles. Lintuzumab 600mg as an IV infusion (flat dose for all), given on days 2, 7, 15, and 22 for cycle 1 and 600mg as an IV infusion, given every other week, twice during each cycle, including one dose given during AZA therapy for all other subsequent cycles. | 7 |
| Total | 7 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Early termination of study by sponsor | 7 |
Baseline characteristics
| Characteristic | 75 mg/m2 5-azacytidine (Vidaza, AZA) and 600 mg Lintuzumab |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 5 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants |
| Region of Enrollment United States | 7 participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 7 / 7 |
| serious Total, serious adverse events | 7 / 7 |
Outcome results
Primary
Complete Response Rate
Response to therapy was determined based on percentage of blasts in bone marrow, hematopoiesis, and requirement for supportive care (i.e., transfusions or cytokine growth factors). The modified International Working Group response criteria was used, based on Cheson, et al.
Time frame: up to 5 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 5-azacytidine and Lintuzumab | Complete Response Rate | 14 percentage of participants |
Secondary
Determine the Relationship Between Pretreatment Expression of Syk and Clinical Response; to Determine Whether the Investigational Agents Modulate Syk Expression and Correlate Drug-induced Changes in Syk With Response to Treatment
Time frame: up to 5 years
Population: No participants were analyzed due to withdrawal of the investigational agent by the company.
Secondary
Explore the Biologic Role of microRNAs in Determining Clinical Response to the AZA Plus Lintuzumab Combination and Achievement of the Other Pharmacodynamic Endpoints
Time frame: Up to 5 years
Population: No participants were analyzed due to withdrawal of the investigational agent by the company.
Secondary
Overall Response Rate
Response to therapy was determined based on percentage of blasts in bone marrow, hematopoiesis, and requirement for supportive care (i.e., transfusions or cytokine growth factors). The modified International Working Group response criteria was used, based on Cheson, et al.
Time frame: up to 5 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 5-azacytidine and Lintuzumab | Overall Response Rate | 14 percentage of participants |
Secondary
Perform Exploratory Studies of AZA-triphosphate With Global DNA Methylation
Time frame: up to 5 years
Population: No participants were analyzed due to withdrawal of the investigational agent by the company.
Secondary
Provide Preliminary Data on the Biological Activity of AZA as a Demethylating Agent (Changes in Target Gene Methylation and Gene Expression, DNMT1[Deoxyribonucleic Acid Methyltransferase 1 DNA Methyltransferase 1]Protein Expression, Global Methylation)
Time frame: up to 5 years
Population: No participants were analyzed due to withdrawal of the investigational agent by the company.
Secondary
Toxicities of the Combination
All patients who received study drug were closely monitored for adverse events (AEs). All AEs that occured during study period were reported and the investigator determined the severity and relationship to study drug (unrelated, unlikely, possibly, probably, or definitely related). The NCI's CTCAE(Common Toxicity Criteria for Adverse Effects)v3.0 was used for grading AEs.
Time frame: up to 5 years
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 5-azacytidine and Lintuzumab | Toxicities of the Combination | Thrombosis/embolism (vascular access-related) | 14 percentage of participants |
| 5-azacytidine and Lintuzumab | Toxicities of the Combination | Platelets | 100 percentage of participants |
| 5-azacytidine and Lintuzumab | Toxicities of the Combination | Neutrophils/granulocytes (ANC/AGC) | 100 percentage of participants |
| 5-azacytidine and Lintuzumab | Toxicities of the Combination | Lymphopenia | 57 percentage of participants |
| 5-azacytidine and Lintuzumab | Toxicities of the Combination | Leukocytes (total WBC) | 100 percentage of participants |
| 5-azacytidine and Lintuzumab | Toxicities of the Combination | Infection with unknown ANC - Upper airway NOS | 14 percentage of participants |
| 5-azacytidine and Lintuzumab | Toxicities of the Combination | Infection with normal ANC or Grade 1 or 2 neutroph | 14 percentage of participants |
| 5-azacytidine and Lintuzumab | Toxicities of the Combination | Infection with unknown ANC - Bladder (urinary) | 14 percentage of participants |
| 5-azacytidine and Lintuzumab | Toxicities of the Combination | Infection | 28 percentage of participants |
| 5-azacytidine and Lintuzumab | Toxicities of the Combination | Infection Grade 3 or 4 neutrophils-blood | 28 percentage of participants |
| 5-azacytidine and Lintuzumab | Toxicities of the Combination | Hemorrhage, GI (lower GI NOS/Rectum) | 14 percentage of participants |
| 5-azacytidine and Lintuzumab | Toxicities of the Combination | Hemorrhage/Bleeding - Other | 14 percentage of participants |
| 5-azacytidine and Lintuzumab | Toxicities of the Combination | Hemoglobin | 100 percentage of participants |
| 5-azacytidine and Lintuzumab | Toxicities of the Combination | Fever (in the absence of neutropenia) | 28 percentage of participants |
| 5-azacytidine and Lintuzumab | Toxicities of the Combination | Febrile neutropenia (fever of unknown origin) | 14 percentage of participants |