Leukemia, Myelodysplastic Syndromes, Myelodysplastic/Myeloproliferative Neoplasms
Conditions
Keywords
refractory anemia with excess blasts, refractory anemia with ringed sideroblasts, refractory cytopenia with multilineage dysplasia, chronic myelomonocytic leukemia, de novo myelodysplastic syndromes, secondary myelodysplastic syndromes, myelodysplastic/myeloproliferative neoplasm, unclassifiable, refractory anemia, previously treated myelodysplastic syndromes
Brief summary
RATIONALE: Vatalanib may be effective in preventing the development of leukemia in patients who have myelodysplastic syndromes. PURPOSE: This phase II trial is studying vatalanib to see how well it works in treating patients with primary or secondary myelodysplastic syndromes.
Detailed description
OBJECTIVES: Primary * Determine the response rate, in terms of hematologic improvement and complete and partial remission, in patients with primary or secondary (therapy-related) myelodysplastic syndromes treated with vatalanib. * Determine the time to transformation to acute myeloid leukemia (at least 20% blasts) or death in patients treated with this drug. Secondary * Determine the safety of this drug in these patients. * Determine the duration of response in patients treated with this drug. * Determine the cytogenetic response rate in patients treated with this drug. * Determine the overall and progression-free survival of patients treated with this drug. * Determine the incidence of infections requiring antibiotics or hospitalization or bleeding requiring red blood cell transfusions in patients treated with this drug. OUTLINE: This is a multicenter study. Patients are stratified\* according to risk group (low grade \[refractory anemia with or without ringed sideroblasts, refractory anemia with excess blasts-1, refractory cytopenia with multilineage dysplasia with or without ringed sideroblasts, myelodysplastic syndromes-unclassified, or chronic myelomonocytic leukemia-1\] vs high grade \[refractory anemia with excess blasts-2 or chronic myelomonocytic leukemia-2\]). NOTE: \*Stratification according to risk (low vs high) does not occur after 11/30/06. Patients receive oral vatalanib once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients with a complete response (CR) receive 6 additional courses after documentation of a CR. Patients are followed periodically for up to 5 years from study entry. PROJECTED ACCRUAL: Approximately 144 patients will be accrued for this study within 2.5 years.
Interventions
DRUGvatalanib
Pts registered before 1/15/05 1250 mg/day PO After 1/15/05: Start w/ 750 mg/day PO; escalate q 4 wks in absence of Grade 2 or \> tox (1st increase=1000mg/day; 2nd increase 1250 mg/day)
Sponsors
National Cancer Institute (NCI)
Alliance for Clinical Trials in Oncology
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
DISEASE CHARACTERISTICS: * Diagnosis of primary or secondary (therapy-related) myelodysplastic syndromes\* (MDS), including the following cellular types: * Refractory anemia (RA)\*\* * RA with excess blasts (RAEB)-1 * RA with ringed sideroblasts\*\* * Refractory cytopenia with multilineage dysplasia * Refractory cytopenia with multilineage dysplasia with ringed sideroblasts\* * MDS-unclassified\*\* * MDS associated with isolated del (5q)\*\* * Chronic myelomonocytic leukemia (CMML)-1 NOTE: \*High-risk MDS (i.e., RAEB-2 or CMML-2) is closed to accrual as of 11/30/06 NOTE: \*\*Accompanied with at least 1 of the following laboratory values: hemoglobin less than 10 g/dL, platelet count less than 50,000/mm3, or absolute neutrophil count less than 1,000/mm3 * No prior leukemia (i.e., 20% or greater blasts) * No prior primary or metastatic brain tumor or carcinomatous meningitis PATIENT CHARACTERISTICS: Age * 18 and over Performance status * WHO 0-2 Life expectancy * Not specified Hematopoietic * See Disease Characteristics Hepatic * Bilirubin no greater than 1.5 times upper limit of normal (ULN) * AST no greater than 2.5 times ULN * APTT no greater than 1.5 times ULN * INR no greater than 1.5 Renal * Creatinine no greater than 1.5 times ULN * Urine protein negative by urinalysis * Protein 1+ by dipstick allowed provided total urine protein no greater than 500 mg AND creatinine clearance at least 50 mL/min by 24-hour urine collection Cardiovascular * No significant cardiac or vascular events within the past 6 months, including any of the following: * Acute myocardial infarction * Unstable angina * Uncontrolled hypertension * Severe peripheral vascular disease (e.g., ischemic pain at rest or nonhealing ulcers or wounds) * New York Heart Association class II-IV congestive heart failure * Cardiac arrhythmia * Disseminated intravascular coagulation or other coagulopathies * Deep vein or arterial thrombosis * No history of congenital long QTc syndrome or elongated QTc (\> 450 msec for males or 470 for females) Pulmonary * No pulmonary embolism within the past 6 months Other * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective barrier contraception during and for at least 3 months after study participation * No need for full anticoagulation within the past 6 months * No significant hemorrhage (e.g., visceral, gastrointestinal, genitourinary, or gynecological) requiring red blood cell transfusion within the past month * No known cerebral aneurysms, other cerebrovascular malformations, or CNS bleeding * No unhealed fractures, wounds, or ulcers PRIOR CONCURRENT THERAPY: Biologic therapy * More than 12 months since prior autologous stem cell or allogeneic transplantation * More than 6 months since prior antiangiogenic agents * More than 1 month since prior interferon for MDS * More than 1 month since prior hematopoietic growth factors for MDS * More than 1 month since prior epoetin alfa (EPO) for MDS * More than 1 month since prior thalidomide for MDS * More than 1 month since prior immunotherapy for MDS * No concurrent prophylactic growth factors or cytokines (e.g., filgrastim \[G-CSF\], sargramostim \[GM-CSF\], EPO or EPO-derivatives, or interleukin-11) Chemotherapy * No prior low-dose antimetabolites for MDS (e.g., hydroxyurea, azacitidine, or low-dose cytarabine) * More than 12 months since prior chemotherapy for another disease\* NOTE: \*Not MDS or leukemia Endocrine therapy * More than 1 month since prior corticosteroids for MDS * More than 1 month since prior androgens for MDS Radiotherapy * More than 12 months since prior radiotherapy for another disease\* NOTE: \*Not MDS or leukemia Surgery * More than 1 month since prior surgery, including needle biopsy of visceral organs and recovered * Bone marrow biopsy allowed * More than 2 weeks since prior placement of a subcutaneous or tunneled venous access device (e.g., PortaCath or Hickman's catheter) and adequately healed Other * No prior cytotoxic therapy for MDS * More than 1 month since prior administration of any of the following medications for MDS: * Danazol * Retinoids * Amifostine * Investigational agents * No concurrent administration of any of the following medications: * Warfarin * Heparin * Derivatives of heparin * Other anticoagulants * No concurrent grapefruit or grapefruit juice
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Response | Duration of study (up to 5 years) | Response was measured by International Standardized Response Criteria for MDS * Complete Response: Bone marrow showing \< 5% myeloblasts with normal maturation of all cell lines; Hgb \> 11 g/dL (untransfused), ANC ≥1.5 K/L, PLT ≥ 100 K/L, No blasts, no dysplasia * Partial remission: All of the CR criteria (if abnormal at baseline), except BM evaluation. Blasts decreased by ≥ 50% over baseline. Cellularity and morphology are not relevant. Hematologic improvement: * Erythroid (HI-E): For participants with baseline HGB \< 11g/dL, Major: \> 2g/dL increase, transfusion independence. Minor: 1-2g/dL increase, ≥ 50% decrease in transfusion requirements * Platelet (HI-P): For participants with baseline PLT \< 100 K/L: Major: absolute increase of \> 30 K/L, transfusion independence. Minor: ≥ 50% increase (net increase of \>10 K/L) * Neutrophil (HI-N): For participants with baseline ANC \< 1.5 K/L, Major: \> 100% increase (net increase \> 0.5 K/L). Minor: \> 100% increase (absolute increase \< 0.5 K/L) |
| Time to Transformation to AML | Duration of study (up to 5 years) | Time to transformation to AML is defined as the time from registration to the transformation of MDS to AML or death of any cause. Participants not meeting these criteria were censored at the date of last follow-up. This outcome was estimated using the Kaplan Meier method. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response | 5 yrs | Duration of response (DOR) was defined as the time from response (complete remission, partial remission or hematologic improvement) to progression or death of any cause. Responding and alive patients were censored at the date of last follow-up. The median DOR with 95% CI was estimated using the Kaplan Meier method. Response was measured by International Standardized Response Criteria for MDS (described in above outcome measure). |
| Overall Survival | Duration of study (up to 5 years) | Overall survival (OS) as the interval from the on-study date until death. OS was estimated using the Kaplan Meier method. |
| Progression-free Survival | Duration of study (up to 5 years) | Progression free survival (PFS) was defined as the time from registration to progression or death of any cause. Progression free and alive patients were censored at the date of last clinical assessment. The median PFS with 95% CI was estimated using the Kaplan Meier method. Progression is defined as * For patients with \<5% bone marrow blasts: ≥50% increase in blasts to \>5% blasts * For patients with 5-10% bone marrow blasts: ≥50% increase to \>10% blasts * For patients with 10-19% bone marrow blasts: increase to ≥20% blasts * One or more of the following: 50% or greater decrement from maximum remission/response levels in ANC \< 1.5 K/L or PLT\< 100 K/L, or reduction in HGB by at least 2 g/dL or becoming transfusion dependent Progression after HI: Includes one or more of the following * Decrement of 50% or greater from maximum response levels in ANC \< 1.5 K/L or PLT \< 100 K/L * Reduction in HGB concentration by at least 2 g/dL * Becoming transfusion dependent |
Countries
United States
Participant flow
Recruitment details
A total of 155 participants were enrolled between December 2003 and April 2008.
Pre-assignment details
Of the 155 participants recruited, 2 participants cancelled prior to starting treatment; 7 were determined to have AML at registration and 4 had diagnosis other than MDS. Thus 142 participants were evaluable for response and 153 for adverse events.
Participants by arm
| Arm | Count |
|---|---|
| Vatalanib Adult patients with MDS receive treatment with vatalanib.
vatalanib: Pts registered before 1/15/05 1250 mg/day PO
After 1/15/05: Start w/ 750 mg/day PO; escalate q 4 wks in absence of Grade 2 or \> tox (1st increase=1000mg/day; 2nd increase 1250 mg/day) | 142 |
| Total | 142 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 44 |
| Overall Study | Death | 3 |
| Overall Study | Patient/Investigator Decision | 4 |
| Overall Study | Withdrawal by Subject | 46 |
Baseline characteristics
| Characteristic | Vatalanib |
|---|---|
| Age, Continuous | 71 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants |
| Race (NIH/OMB) More than one race | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 133 Participants |
| Region of Enrollment United States | 142 participants |
| Sex: Female, Male Female | 52 Participants |
| Sex: Female, Male Male | 90 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 134 / 153 |
| serious Total, serious adverse events | 51 / 153 |
Outcome results
Primary
Number of Participants With Response
Response was measured by International Standardized Response Criteria for MDS * Complete Response: Bone marrow showing \< 5% myeloblasts with normal maturation of all cell lines; Hgb \> 11 g/dL (untransfused), ANC ≥1.5 K/L, PLT ≥ 100 K/L, No blasts, no dysplasia * Partial remission: All of the CR criteria (if abnormal at baseline), except BM evaluation. Blasts decreased by ≥ 50% over baseline. Cellularity and morphology are not relevant. Hematologic improvement: * Erythroid (HI-E): For participants with baseline HGB \< 11g/dL, Major: \> 2g/dL increase, transfusion independence. Minor: 1-2g/dL increase, ≥ 50% decrease in transfusion requirements * Platelet (HI-P): For participants with baseline PLT \< 100 K/L: Major: absolute increase of \> 30 K/L, transfusion independence. Minor: ≥ 50% increase (net increase of \>10 K/L) * Neutrophil (HI-N): For participants with baseline ANC \< 1.5 K/L, Major: \> 100% increase (net increase \> 0.5 K/L). Minor: \> 100% increase (absolute increase \< 0.5 K/L)
Time frame: Duration of study (up to 5 years)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Vatalanib | Number of Participants With Response | Complete Remission | 0 participants |
| Vatalanib | Number of Participants With Response | Partial Remission | 0 participants |
| Vatalanib | Number of Participants With Response | HI-E Major | 3 participants |
| Vatalanib | Number of Participants With Response | HI-E Minor | 1 participants |
| Vatalanib | Number of Participants With Response | HI-P Major | 2 participants |
| Vatalanib | Number of Participants With Response | HI-P Minor | 1 participants |
| Vatalanib | Number of Participants With Response | HI-N Major | 0 participants |
| Vatalanib | Number of Participants With Response | HI-N Minor | 0 participants |
Primary
Time to Transformation to AML
Time to transformation to AML is defined as the time from registration to the transformation of MDS to AML or death of any cause. Participants not meeting these criteria were censored at the date of last follow-up. This outcome was estimated using the Kaplan Meier method.
Time frame: Duration of study (up to 5 years)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Vatalanib | Time to Transformation to AML | 17.2 months |
Secondary
Duration of Response
Duration of response (DOR) was defined as the time from response (complete remission, partial remission or hematologic improvement) to progression or death of any cause. Responding and alive patients were censored at the date of last follow-up. The median DOR with 95% CI was estimated using the Kaplan Meier method. Response was measured by International Standardized Response Criteria for MDS (described in above outcome measure).
Time frame: 5 yrs
Population: Per the description, only patients who achieved a response were evaluable for this outcome.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Vatalanib | Duration of Response | 6 months |
Secondary
Overall Survival
Overall survival (OS) as the interval from the on-study date until death. OS was estimated using the Kaplan Meier method.
Time frame: Duration of study (up to 5 years)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Vatalanib | Overall Survival | 18.9 months |
Secondary
Progression-free Survival
Progression free survival (PFS) was defined as the time from registration to progression or death of any cause. Progression free and alive patients were censored at the date of last clinical assessment. The median PFS with 95% CI was estimated using the Kaplan Meier method. Progression is defined as * For patients with \<5% bone marrow blasts: ≥50% increase in blasts to \>5% blasts * For patients with 5-10% bone marrow blasts: ≥50% increase to \>10% blasts * For patients with 10-19% bone marrow blasts: increase to ≥20% blasts * One or more of the following: 50% or greater decrement from maximum remission/response levels in ANC \< 1.5 K/L or PLT\< 100 K/L, or reduction in HGB by at least 2 g/dL or becoming transfusion dependent Progression after HI: Includes one or more of the following * Decrement of 50% or greater from maximum response levels in ANC \< 1.5 K/L or PLT \< 100 K/L * Reduction in HGB concentration by at least 2 g/dL * Becoming transfusion dependent
Time frame: Duration of study (up to 5 years)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Vatalanib | Progression-free Survival | 10.2 months |