Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities, Adult Acute Myeloid Leukemia With Del(5q), Adult Acute Myeloid Leukemia With Inv(16)(p13;q22), Adult Acute Myeloid Leukemia With t(16;16)(p13;q22), Adult Acute Myeloid Leukemia With t(8;21)(q22;q22), Myelodysplastic Syndrome With Isolated Del(5q), Previously Treated Myelodysplastic Syndromes, Recurrent Adult Acute Myeloid Leukemia
Conditions
Brief summary
This phase I/II trial studied the side effects and best dose of clofarabine when given together with cytarabine and to see how well they work in treating older patients with acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes (MDS) that have relapsed or not responded to treatment.
Detailed description
PRIMARY OBJECTIVES: I. To estimate the maximum tolerated dose (MTD) of oral clofarabine when given with LDAC (cytarabine) in patients age \>= 60 with previously treated AML or high risk MDS. SECONDARY OBJECTIVES: I. To determine the response rate, disease-free survival (DFS), and overall survival (OS) after therapy with oral clofarabine and LDAC for previously treated AML or high-risk MDS. OUTLINE: This is a phase I, dose-escalation study of clofarabine followed by a phase II study. Patients receive clofarabine orally (PO) once daily (QD) on days 1-5 and low-dose cytarabine subcutaneously (SC) twice daily (BID) on days 1-10 or SC QD on days 1-14. Treatment repeats every 21-28 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months for 2 years and then annually for 3 years.
Interventions
DRUGclofarabine
Given PO
DRUGcytarabine
Given SC
Sponsors
National Cancer Institute (NCI)
Fred Hutchinson Cancer Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
60 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Diagnosis of 1st relapse or refractory AML; or patients with high risk MDS (10-19% blasts) who have received previous therapy 1st remission must have been \< 1 year * Must not have received previous ara-C (cytarabine) or clofarabine * Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2 * Not candidates for standard 7 + 3 regimen (Ara-C and an anthracycline), high dose Ara-C, or hematopoietic stem-cell transplantation * Serum creatinine =\< 1.0 mg/dL; if serum creatinine \> 1.0 mg/dL, then the estimated glomerular filtration rate (GFR) must be \> 50 L/min/1.73 m\^2 as calculated by the Modification of Diet in Renal Disease equation * Serum bilirubin =\< 1.5 x upper limit of normal (ULN) * Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =\< 2.5 x ULN * Alkaline phosphatase =\< 2.5 x ULN * Capable of understanding the investigational nature, potential risks and benefits of the study, and able to provide valid informed consent * Female patients of childbearing potential must have a negative serum pregnancy test within 2 weeks prior to enrollment * Male and female patients should use an effective contraceptive method during the study and for a minimum of 6 months after study treatment
Exclusion criteria
* Current concomitant chemotherapy, radiation therapy, or immunotherapy other than as specified in the protocol * Patients with acute promyelocytic leukemia (APL) * Use of investigational agents within 30 days or any anticancer therapy within 2 weeks before study entry with the exception of hydroxyurea; the patient must have recovered from all acute toxicities from any previous therapy * Have any other severe concurrent disease, or have a history of serious organ dysfunction or disease involving the heart, kidney, liver, or other organ system that may place the patient at undue risk to undergo treatment * Patients with a systemic fungal, bacterial, viral, or other infection not controlled (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment) * Pregnant or lactating patients * Any significant concurrent disease, illness, or psychiatric disorder that would compromise patient safety or compliance, interfere with consent, study participation, follow up, or interpretation of study results * Have had a diagnosis of another malignancy, unless the patient has been disease free for at least 3 years following the completion of curative intent therapy including the following: * Patients with treated non-melanoma skin cancer, in situ carcinoma, or cervical intraepithelial neoplasia, regardless of the disease-free duration, are eligible for this study if definitive treatment for the condition has been completed. * Patients with organ-confined prostate cancer with no evidence of recurrent or progressive disease based on prostate-specific antigen (PSA) values are also eligible for this study if hormonal therapy has been initiated, or a radical prostatectomy or definitive radiotherapy has been performed * Have currently active gastrointestinal disease, or prior surgery that may affect the ability of the patient to absorb oral clofarabine
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Dose Limiting Toxicity | Outcomes by day 30 | Dose limiting toxicity (DLT) consists of grade 3-4 non-hematologic toxicity at least possibly related to study drug. Exceptions include neutropenic fever; drug-related fever; alopecia; anorexia; inadequately treated nausea, vomiting and/or diarrhea; and grade 3/4 increase in ALT, AST, or bilirubin recovering to \< grade 2 by 7 days. Prolonged grade 2 myelosuppression lasting longer than 49 days in patients who don't proceed to additional cytotoxic therapy is considered a DLT. The MTD or recommended phase II dose is the highest dose level at which no more than 1 patient out of 6 experiences DLT. |
| Maximum Tolerated Dose | up to 5 years | We identified 20 mg/d for 5 d as the maximum tolerated dose (MTD) of oral clofarabine. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Treatment Response | Up to 5 years | CR = no evidence of leukemia with complete blood count recovery (ANC \>1,000 and PLTS \>100k) CRi = no evidence of leukemia but with incomplete blood count recovery |
| Disease Free Survival | Up to 5 years | Median disease-free survival |
| Overall Survival | Up to 5 years | Median overall survival |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Treatment (Chemotherapy) Patients receive clofarabine PO QD on days 1-5 and low-dose cytarabine SC BID on days 1-10 or SC QD on days 1-14. Treatment repeats every 21-28 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.
clofarabine: Given PO
cytarabine: Given SC | 35 |
| Total | 35 |
Baseline characteristics
| Characteristic | Treatment (Chemotherapy) |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 32 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants |
| Age, Continuous | 72 years |
| Region of Enrollment United States | 35 Participants |
| Sex: Female, Male Female | 11 Participants |
| Sex: Female, Male Male | 24 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 5 / 35 |
| other Total, other adverse events | 0 / 35 |
| serious Total, serious adverse events | 24 / 35 |
Outcome results
Primary
Maximum Tolerated Dose
We identified 20 mg/d for 5 d as the maximum tolerated dose (MTD) of oral clofarabine.
Time frame: up to 5 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Level 1 | Maximum Tolerated Dose | 20 mg/day |
Primary
Number of Patients With Dose Limiting Toxicity
Dose limiting toxicity (DLT) consists of grade 3-4 non-hematologic toxicity at least possibly related to study drug. Exceptions include neutropenic fever; drug-related fever; alopecia; anorexia; inadequately treated nausea, vomiting and/or diarrhea; and grade 3/4 increase in ALT, AST, or bilirubin recovering to \< grade 2 by 7 days. Prolonged grade 2 myelosuppression lasting longer than 49 days in patients who don't proceed to additional cytotoxic therapy is considered a DLT. The MTD or recommended phase II dose is the highest dose level at which no more than 1 patient out of 6 experiences DLT.
Time frame: Outcomes by day 30
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose Level 1 | Number of Patients With Dose Limiting Toxicity | 0 Participants |
| Dose Level 2 | Number of Patients With Dose Limiting Toxicity | 4 Participants |
| Dose Level 3 | Number of Patients With Dose Limiting Toxicity | 2 Participants |
| Dose Level 4 | Number of Patients With Dose Limiting Toxicity | 2 Participants |
p-value: 0.03Chi-squared
Secondary
Disease Free Survival
Median disease-free survival
Time frame: Up to 5 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Level 1 | Disease Free Survival | 7.4 median months |
Secondary
Overall Survival
Median overall survival
Time frame: Up to 5 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Level 1 | Overall Survival | 6.8 median months |
Secondary
Treatment Response
CR = no evidence of leukemia with complete blood count recovery (ANC \>1,000 and PLTS \>100k) CRi = no evidence of leukemia but with incomplete blood count recovery
Time frame: Up to 5 years
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dose Level 1 | Treatment Response | CR | 1 Participants |
| Dose Level 1 | Treatment Response | No CR | 3 Participants |
| Dose Level 1 | Treatment Response | CRi | 0 Participants |
| Dose Level 2 | Treatment Response | CR | 10 Participants |
| Dose Level 2 | Treatment Response | No CR | 15 Participants |
| Dose Level 2 | Treatment Response | CRi | 1 Participants |
| Dose Level 3 | Treatment Response | CRi | 0 Participants |
| Dose Level 3 | Treatment Response | CR | 1 Participants |
| Dose Level 3 | Treatment Response | No CR | 1 Participants |
| Dose Level 4 | Treatment Response | CR | 0 Participants |
| Dose Level 4 | Treatment Response | No CR | 3 Participants |
| Dose Level 4 | Treatment Response | CRi | 0 Participants |