Filgrastim, Cladribine, Cytarabine, and Mitoxantrone Hydrochloride in Treating Patients With Newly Diagnosed or Relapsed/Refractory Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndromes

Study Overview
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Brief Summary
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This phase I/II trial studies the side effects and best dose of mitoxantrone hydrochloride when given together with filgrastim, cladribine, and cytarabine and to see how well they work in treating patients with acute myeloid leukemia or high-risk myelodysplastic syndromes that is newly diagnosed, has returned, or does not respond to treatment. Drugs used in chemotherapy, such as filgrastim, cladribine, cytarabine, and mitoxantrone hydrochloride, 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 OBJECTIVES: I. Estimate the maximum tolerated dose (MTD) of dose-intensified mitoxantrone hydrochloride (mitoxantrone) as part of the filgrastim (G-CSF), cladribine, cytarabine, mitoxantrone hydrochloride (G-CLAM) regimen separately for adults with newly diagnosed acute myeloid leukemia (AML) and those with relapsed/refractory AML receiving first or greater salvage therapy. SECONDARY OBJECTIVES: I. To determine, within the limits of a phase 1/2 study, disease response and duration of remission separately for patients with newly diagnosed and relapsed/refractory AML. II. To describe, within the limits of a phase 1/2 study, the toxicity profile of the study regimen separately for patients with newly diagnosed and relapsed/refractory AML. OUTLINE: This is a phase I, dose-escalation study of mitoxantrone hydrochloride followed by phase II study. INDUCTION CHEMOTHERAPY (G-CLAM): Patients receive G-CLAM chemotherapy comprising filgrastim subcutaneously (SC) daily on days 0-5, mitoxantrone hydrochloride intravenously (IV) over 60 minutes on days 1-3, cladribine IV over 2 hours daily on days 1-5, and cytarabine IV over 2 hours daily on days 1-5. Patients achieving complete remission with incomplete peripheral blood count recovery (CRi), partial remission, or persistent disease may receive a second course of induction chemotherapy. Patients achieving complete remission (CR) or CR with incomplete platelet count recovery (CRp) may continue on to Consolidation Chemotherapy. CONSOLIDATION CHEMOTHERAPY (G-CLA): Beginning within 6 weeks of achieving CR/CRp/CRi, patients receive G-CLA comprising filgrastim SC on days 0-5, cladribine IV over 2 hours daily on days 1-5, and cytarabine IV over 2 hours daily on days 1-5. Treatment continues for up to 4 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up periodically for up to 5 years.

Official Title
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A Phase 1/2 Trial of G-CSF, Cladribine, Cytarabine, and Dose-Escalated Mitoxantrone (G-CLAM) in Adults With Newly Diagnosed or Relapsed/Refractory Acute Myeloid Leukemia (AML) or High-Risk Myelodysplastic Syndromes (MDS)

Conditions
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Acute Biphenotypic Leukemia, de Novo Myelodysplastic Syndrome, Previously Treated Myelodysplastic Syndrome, Recurrent Adult Acute Myeloid Leukemia, Untreated Adult Acute Myeloid Leukemia, Secondary Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: Cladribine
* Drug: Cytarabine
* Biological: Filgrastim
* Other: Laboratory Biomarker Analysis
* Drug: Mitoxantrone Hydrochloride


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: For patients with newly diagnosed disease: diagnosis of high-risk myelodysplastic syndrome (MDS) (>= 10% blasts) or AML other than acute promyelocytic leukemia (APL) with t(15;17)(q22;q12) or variants according to the 2008 World Health Organization (WHO) classification; for patients with relapsed/refractory disease: prior diagnosis of high-risk MDS or non-APL AML, with relapsed/refractory disease according to standard criteria requiring first or subsequent salvage therapy; patients with biphenotypic AML are eligible Outside diagnostic material is acceptable as long as peripheral blood and/or bone marrow slides are reviewed at the study institution; flow cytometric analysis of peripheral blood and/or bone marrow should be performed according to institutional practice guidelines For patients with relapsed/refractory disease: patients with prior autologous or allogeneic hematopoietic cell transplantation (HCT) for MDS/AML are eligible if relapse occurs provided symptoms of graft-versus host disease are well controlled with stable use of immunosuppressive agents Treatment-related mortality (TRM) score =< 6.9 as calculated with simplified model The use of hydroxyurea prior to study registration is allowed; patients with symptoms/signs of hyperleukocytosis or white blood cell (WBC) > 100,000/uL can be treated with leukapheresis or may receive up to 2 doses of cytarabine (up to 500 mg/m^2/dose) prior to enrollment For patients with relapsed/refractory disease: patients may have previously received chemotherapy with a mitoxantrone- or cladribine-based regimen for MDS or AML; if that patient has received G-CLAM before and has been sensitive to this regimen, eligibility will be determined on a case-by-case basis by the study principal investigator (PI) Should be off any active systemic therapy for AML with the exception of hydroxyurea for at least 14 days prior to study registration unless patient has rapidly progressive disease, and all grade 2-4 non-hematologic toxicities should have resolved Bilirubin =< 2.5 x institutional upper limit of normal (IULN) unless elevation is thought to be due to hepatic infiltration by AML, Gilbert's syndrome, or hemolysis (assessed within 14 days prior to study day 0) Serum creatinine =< 2.0 mg/dL (assessed within 14 days prior to study day 0) Left ventricular ejection fraction >= 45%, assessed within 3 months prior to study day 0, e.g. by multi gated acquisition scan (MUGA) scan or echocardiography, or other appropriate diagnostic modality and no clinical evidence of congestive heart failure; if the patient had anthracycline-based therapy since the most recent cardiac assessment, cardiac evaluation should be repeated if there is clinical or radiographic suspicion of cardiac dysfunction, or if the previous cardiac assessment was abnormal Women of childbearing potential and men must agree to use adequate contraception Provide written informed consent Exclusion Criteria: Myeloid blast crisis of chronic myeloid leukemia (CML), unless patient is not considered candidate for tyrosine kinase inhibitor treatment Concomitant illness associated with a likely survival of < 1 year Active systemic fungal, bacterial, viral, or other infection, unless disease is under treatment with anti-microbials and/or controlled or stable (e.g. if specific, effective therapy is not available/feasible or desired [e.g. chronic viral hepatitis, human immunodeficiency virus (HIV)]); patient needs to be clinically stable as defined as being afebrile and hemodynamically stable for 24 hours; patients with fever thought to be likely secondary to leukemia are eligible Known hypersensitivity to any study drug Pregnancy or lactation Treatment with any other investigational agent

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 (filgrastim, mitoxantrone, cladribine, cytarabine)<br>INDUCTION CHEMOTHERAPY (G-CLAM): Patients receive G-CLAM chemotherapy comprising filgrastim SC daily on days 0-5, mitoxantrone hydrochloride IV over 60 minutes on days 1-3, cladribine IV over 2 hours daily on days 1-5, and cytarabine IV over 2 hours daily on days 1-5. Patients achieving CRi, partial remission, or persistent disease may receive a second course of induction chemotherapy. Patients achieving CR or CRp may continue on to Consolidation Chemotherapy. CONSOLIDATION CHEMOTHERAPY (G-CLA): Beginning within 6 weeks of achieving CR/CRp/CRi, patients receive G-CLA comprising filgrastim SC on days 0-5, cladribine IV over 2 hours daily on days 1-5, and cytarabine IV over 2 hours daily on days 1-5. Treatment continues for up to 4 courses in the absence of disease progression or unacceptable toxicity. | Drug: Cladribine<br>* Given IV<br>* Other names: RWJ-26251;Drug: Cytarabine<br>* Given IV<br>* Other names: WR-28453;Biological: Filgrastim<br>* Given SC<br>* Other names: Zarxio;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Mitoxantrone Hydrochloride<br>* Given IV<br>* Other names: Pralifan;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Dose Limiting Toxicities of Mitoxantrone (Phase I, Dose Level 4) | Defined as the highest dose studied in which the incidence of dose-limiting toxicity is < 33%, graded according to NCI Common Terminology Criteria for Adverse Events version 4.0 | Up to day 45 after start of induction chemotherapy | 
| Minimal Residual Disease Negative Complete Remission Rate in Patients With Newly Diagnosed Disease (Phase II) | Remission Rate defined as Recist Category of Complete Resposne (CR) Disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size(<10 mm short axis). | Up to day 45 after start of second course of induction chemotherapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (Phase II) | Number of subjects that have survived | From date of randomization until the date of death from any cause, assessed up to 12 months | 
| Remission Rate (Complete Remission and Complete Remission With Incomplete Platelet Count Recovery) of This Regimen in Patients With Relapsed/Refractory Disease (Phase II) |  | Up to 5 years |