Clofarabine, Cyclophosphamide and Etoposide for Minimal Residual Disease Positive Acute Leukemia

Study Overview
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Brief Summary
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Study Design: This is a two-stage Phase II trial investigating the efficacy of Clofarabine, Cyclophosphamide and Etoposide in acute leukemia patients with detectable minimal residual disease (MRD) prior to allo-HCT. The primary objective is to determine the impact of the study treatment in eliminating the presence of minimal residual disease without causing a significant delay of allo-HCT due to treatment related toxicity. The intent of this study is to allow patients to proceed to transplant (independent of this study) within 42 days of Day 1 of Clofarabine based therapy.

Detailed Description
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Patients will be stratified at the time of enrollment based on diagnosis (ALL versus AML). Based on this two-stage optimal design, a maximum of 49 patients with ALL and a maximum of 49 patients with AML will be needed. For each disease cohort, 21 patients will be enrolled in stage 1. If at the end of stage 1, the criteria is met for activating stage 2 (based on success of clearing MRD, proceeding to transplant within 42 days and without excessive toxicity) for one or both groups, stage 2 will be activated with an additional 28 patients enrolled.

Official Title
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A Phase II Trial Investigating Clofarabine, Cyclophosphamide and Etoposide for Minimal Residual Disease Positive Acute Leukemia

Conditions
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Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia

Intervention / Treatment
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* Drug: Clofarabine
* Drug: Etoposide
* Drug: Cyclophosphamide
* Biological: allogeneic hematopoietic cell transplantation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML) with <5% blasts in the bone marrow (M1) by morphology and that meets one of the following criteria: Flow cytometric evidence of MRD (≥ 0.1% leukemic blasts for ALL or <5% leukemic blasts for AML detected in the bone marrow) OR Molecular/cytogenetic evidence of disease (FISH or PCR methodology) performed within 7 days AND with the intent of going on to an allogeneic hematopoietic cell transplantation (allo-HCT) independent of this study Age 0 to 60 years Karnofsky Performance Status ≥ 50% for patients 16 years and older and Lansky Play Score ≥ 50 for patients under 16 years of age Patients must have a life expectancy ≥ 8 weeks as determined by the enrolling investigator Have acceptable organ function as defined within 7 days of study registration: Renal: creatinine clearance ≥70mL/min/1.73m2 or serum creatinine based on age/gender Hepatic: aspartate aminotransferase (ALT) < 5 x upper limit of normal (ULN) and total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age Cardiac: left ventricular ejection fraction ≥ 40% by echocardiogram (ECHO/MUGA) Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study. At least 14 days must have elapsed from prior chemotherapy; at least 7 days must have elapsed since receiving biological therapy. Hematopoietic growth factors: At least 7 days since the completion of therapy with a growth factor and at least 14 days since pegfilgrastim (Neulasta®) administration. Sexually active females of child bearing potential must agree to use adequate contraception (diaphragm, birth control pills, injections, intrauterine device [IUD], surgical sterilization, subcutaneous implants, or abstinence, etc.) for the duration of treatment and for 2 months after the last dose of chemotherapy. Sexually active men must agree to use barrier contraceptive for the duration of treatment and for 2 months after the last dose of chemotherapy. Voluntary written consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care Exclusion Criteria: Acute Promyelocytic Leukemia (APL) Active central nervous system (CNS) leukemia or known chloromatous disease Receiving or plans to receive concomitant chemotherapy, radiation therapy; immunotherapy or other anti-cancer therapy other than is specified in the protocol 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. The agents used in this study are known to be teratogenic to a fetus and there is no information on the excretion of agents into breast milk. All females of childbearing potential must have a blood test or urine study within 2 weeks prior to registration to rule out pregnancy. Known allergy to any of the agents or their ingredients used in this study

Ages Eligible for Study
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Maximum Age: 60 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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ALL patients receiving transplant<br>Patients intent on receiving an allogeneic hematopoietic cell transplantation (allo-HCT) with the diagnosis of acute lymphoblastic leukemia (ALL) along with Clofarabine, Etoposide and Cyclophosphamide. | Drug: Clofarabine<br>* Days 1-5: Clofarabine 30 mg/m^2 for 0-30 years of age or 20 mg/m^2 for > 30 years of age intravenously (IV) over 2 hours<br>* Other names: Clolar;Drug: Etoposide<br>* Days 1-5: Etoposide 100mg/m^2 IV over 2 hours<br>* Other names: VP-16;Drug: Cyclophosphamide<br>* Days 1-5: Cyclophosphamide 300 mg/m^2 as a 30-60 minute infusion<br>* Other names: Cytoxan;Biological: allogeneic hematopoietic cell transplantation<br>* Between Days 28 and 42: infused independent of this study<br>* Other names: allo-HCT;|
| Experimental: AML patients receiving transplant<br>Patients intent on receiving an allogeneic hematopoietic cell transplantation (allo-HCT) with the diagnosis of acute myeloid leukemia (AML) along with Clofarabine, Etoposide and Cyclophosphamide. | Drug: Clofarabine<br>* Days 1-5: Clofarabine 30 mg/m^2 for 0-30 years of age or 20 mg/m^2 for > 30 years of age intravenously (IV) over 2 hours<br>* Other names: Clolar;Drug: Etoposide<br>* Days 1-5: Etoposide 100mg/m^2 IV over 2 hours<br>* Other names: VP-16;Drug: Cyclophosphamide<br>* Days 1-5: Cyclophosphamide 300 mg/m^2 as a 30-60 minute infusion<br>* Other names: Cytoxan;Biological: allogeneic hematopoietic cell transplantation<br>* Between Days 28 and 42: infused independent of this study<br>* Other names: allo-HCT;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients Unable to Proceed to Transplantation | The primary endpoint of this study will be to determine the impact of Clofarabine, Cyclophosphamide and Etoposide on the conversion to an minimal residual disease (MRD) negative state at day 30 (<0.01% leukemic blasts by flow cytometry) or day 42 if day 30 marrow is un-evaluable due to hypocellularity per RECIST criteria as well as the ability of patients to reach allo-HCT without significant delay due to study treatment related toxicity. Unable to proceed to transplant by Day 42 will be considered unacceptable. | Between Day 30 and Day 42 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of Pre-Transplant Chemotherapy-Induced Aplasia | defined as greater than 42 days after infusion of chemotherapy | After Day 42 | 
| Rate of Infectious Complications |  | Day 1 Through Day 30 | 
| Treatment-Related Mortality After Transplant | In the field of transplantation, toxicity is high and all deaths without previous relapse or progression are usually considered as related to transplantation. | Day 100 | 
| Disease-Free Survival After Transplant | The length of time after treatment ends that a patient survives without any signs or symptoms of that cancer or any other type of cancer. In a clinical trial, measuring the disease-free survival is one way to see how well a new treatment works. | 1 Year | 
| Rate of Leukemic Relapse After Transplant | The return of disease after its apparent recovery/cessation. | Day 100 |