Clofarabine, Idarubicin, Cytarabine, Vincristine Sulfate, and Dexamethasone in Treating Patients With Newly Diagnosed or Relapsed Mixed Phenotype Acute Leukemia

Study Overview
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Brief Summary
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This phase II trial studies how well clofarabine, idarubicin, cytarabine, vincristine sulfate, and dexamethasone work in treating patients with mixed phenotype acute leukemia that is newly diagnosed or has returned after a period of improvement (relapsed). Drugs used in chemotherapy, such as clofarabine, idarubicin, cytarabine, vincristine sulfate, and dexamethasone, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading.

Detailed Description
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PRIMARY OBJECTIVE: I. To evaluate the response rate of the chemotherapy regimen in patients with mixed phenotype acute leukemia. SECONDARY OBJECTIVE: I. To evaluate the durability of response, the overall and event-free survival rates, and the safety profile of the regimen. OUTLINE: INDUCTION THERAPY: Patients receive clofarabine intravenously (IV) over 60 minutes on days 1-4 or 1-3; idarubicin IV over 30-60 minutes on days 1-3 or 1-2; cytarabine IV over 2 hours on days 1-4; vincristine sulfate IV over 15-30 minutes on days 1, 8, and 15; and dexamethasone IV over 10-30 minutes on days 1-4 and 15-18. Patients with a certain type of leukemia may receive rituximab IV over 4-6 hours on days 1 and 8 or sorafenib tosylate orally (PO) twice daily (BID) on days 1-14. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. CONSOLIDATION THERAPY: Patients receive clofarabine IV over 60 minutes on days 1-3 or 1-2; idarubicin IV over 30-60 minutes on days 1-2; cytarabine IV over 2 hours on days 1-3 or 1-2; vincristine sulfate IV over 15-30 minutes on days 1, 8, and 15; and dexamethasone IV over 10-30 minutes on days 1-4 and 15-18. Patients with a certain type of leukemia may receive rituximab IV over 4-6 hours on days 1 and 8 of cycles 1-3 or sorafenib tosylate PO BID on days 1-28 of cycle 1-6 and beyond. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days and then every 6 months thereafter.

Official Title
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A Phase 2 Study of Clofarabine, Idarubicin, Cytarabine, Vincristine, and Corticosteroids for Patients With Newly Diagnosed or Relapsed Mixed Phenotype Acute Leukemia

Conditions
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Acute Bilineal Leukemia, Acute Biphenotypic Leukemia, Acute Leukemia of Ambiguous Lineage, Acute Undifferentiated Leukemia, Mixed Phenotype Acute Leukemia, Mixed Phenotype Acute Leukemia, B/Myeloid, Not Otherwise Specified, Mixed Phenotype Acute Leukemia, T/Myeloid, Not Otherwise Specified, Recurrent Mixed Phenotype Acute Leukemia

Intervention / Treatment
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* Drug: Clofarabine
* Drug: Cytarabine
* Drug: Dexamethasone
* Drug: Idarubicin
* Biological: Rituximab
* Drug: Sorafenib
* Drug: Sorafenib Tosylate
* Drug: Vincristine
* Drug: Vincristine Sulfate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Sign an informed consent document Newly diagnosed or relapsed mixed phenotype acute leukemia (MPAL), which for this protocol, will be defined as follows: bone marrow result interpreted by the reading pathologist (or tissue biopsy for cases of extramedullary disease) as: biphenotypic leukemia, bilineal leukemia, undifferentiated leukemia, mixed lineage leukemia, leukemia of ambiguous lineage, T/myeloid leukemia, B/myeloid leukemia, or other diagnosis indicating the presence of multiple lineages within the cell population Eastern Cooperative Oncology Group (ECOG) performance status of =< 3 at study entry Adequate organ function as outlined below (unless due to leukemia) Serum creatinine =< 3 mg/dL Total bilirubin =< 2.5 mg/dL Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) and/or aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) =< 3 x upper limit of normal (ULN) or =< 5 x ULN if related to disease Women of childbearing potential must have a negative serum or urine pregnancy test within 7 days; women of childbearing potential and men must agree to use contraception at study entry and for the duration of active study treatment Cardiac ejection fraction >= 40% (by either cardiac echocardiogram [echo] or multi gated acquisition [MUGA] scan); documentation of recent (=< 6 months from screening) outside reports is acceptable If newly diagnosed, prior therapy with hydrea and/or steroid and the use of a single or a two day dose of cytarabine (up to 3 g/m^2), for emergency use up to 24 hours prior to start of study therapy is allowed Exclusion Criteria: Breast feeding females Patients with active, uncontrolled infections Patients with active secondary malignancy will not be eligible unless approved by the principal investigator

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (combination chemotherapy)<br>See Detailed Description. | Drug: Clofarabine<br>* Given IV<br>* Other names: Clolar;Drug: Cytarabine<br>* Given IV<br>* Other names: WR-28453;Drug: Dexamethasone<br>* Given IV<br>* Other names: ZoDex;Drug: Idarubicin<br>* Given IV<br>* Other names: 4-DMDR;Biological: Rituximab<br>* Given IV<br>* Other names: Truxima;Drug: Sorafenib<br>* Given PO<br>* Other names: Bay-439006;Drug: Sorafenib Tosylate<br>* Given PO<br>* Other names: sorafenib;Drug: Vincristine<br>* Given IV<br>* Other names: Vincrystine;Drug: Vincristine Sulfate<br>* Given IV<br>* Other names: Vincristine, sulfate;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response (complete response or overall response rate) | The two groups of patients (newly diagnosed or relapsed/refractory) will be evaluated separately. The posterior response rate and their 95% credible intervals will be estimated. | Up to 2 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 4-week mortality rate (Newly diagnosed patients) | For discrete or categorical data, descriptive statistics will include tabulations of frequencies. For continuous data, summary statistics including n, mean, standard deviation, median, minimum and maximum will be computed. | At 4 weeks | 
| Incidence of toxicity (Newly diagnosed patients) | Will be defined as any grade 3 or greater clinically significant non-hematological toxicity related to treatment. Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0. For discrete or categorical data, descriptive statistics will include tabulations of frequencies. | Up to 4 weeks after completion of study treatment | 
| 4-week mortality rate (Relapsed patients) |  | At 4 weeks | 
| Incidence of toxicity (Relapsed patients) | Will be defined as any grade 3 or greater clinically significant non hematological toxicity related to treatment. Graded according to NCI CTCAE version 4.0. | Up to 4 weeks after completion of study treatment |