Bortezomib and Combination Chemotherapy in Treating Patients With Relapsed or Refractory Acute Lymphoblastic Leukemia

Study Overview
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Brief Summary
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This study evaluates the value of bortezomib in combination with specified chemotherapies for the treatment of patients with relapsed or refractory acute lymphoblastic leukemia. Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Detailed Description
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PRIMARY OBJECTIVE: Determine the response rate of bortezomib in combination with a chemotherapy backbone of doxorubicin (doxorubicin hydrochloride), vincristine (vincristine sulfate), PEG-asparaginase (pegaspargase), and dexamethasone in patients with relapsed/refractory acute lymphoblastic leukemia. SECONDARY OBJECTIVES: Estimate the rate of complete response (CR) and CR with incomplete platelet recovery (CRp) on Day 29 after re-induction. Determine progression-free survival (PFS) at 2 years after re-induction. Determine failure-free survival (FFS) at 1 year after re-induction. Overall survival (OS) at 1 year after re-induction. Assess safety and tolerability of the study drug. Determine whether bortezomib induces reactive oxygen species (ROS) in circulating acute lymphoblastic leukemia (ALL) blast cells. OUTLINE: Patients receive bortezomib subcutaneously (SC) on Days 1, 4, 8, and 11; doxorubicin hydrochloride intravenously (IV) on day 1; pegaspargase IV or intramuscularly (IM) on Days 5 and 22; vincristine sulfate IV on days 1, 8, 15, and 22; dexamethasone orally (PO) daily on Days 1 to 14; cytarabine intrathecally (IT) on Day 1 and methotrexate intrathecally (IT) on Day 15. Patients with central nervous system disease receive intrathecal treatment per investigator's discretion. Participants are followed up every 3 months for up to 2 years after completion of study treatment.

Official Title
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A Phase II Study of Subcutaneous Bortezomib in Combination With Chemotherapy (VXLD) for Relapsed/Refractory Adult Acute Lymphoblastic Leukemia

Conditions
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B-cell Adult Acute Lymphoblastic Leukemia (ALL), Ph-positive Adult Acute Lymphoblastic Leukemia (ALL), Recurrent Adult Acute Lymphoblastic Leukemia (ALL), T-cell Adult Acute Lymphoblastic Leukemia (ALL)

Intervention / Treatment
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* Drug: Bortezomib
* Drug: Doxorubicin hydrochloride (HCl)
* Drug: PEG-Asparaginase
* Drug: Vincristine sulfate
* Drug: Dexamethasone
* Drug: Cytarabine
* Drug: Methotrexate


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA Voluntary written informed consent Female subjects who: Are postmenopausal for at least 1 year before the screening visit, OR Are surgically sterile, OR If they are of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent form through 30 days after the last dose of bortezomib, or agree to completely abstain from heterosexual intercourse Male subjects, even if surgically sterilized (ie, status post vasectomy) who: Agree to practice effective barrier contraception during the entire study treatment period and through a minimum of 30 days after the last dose of study drug, OR Agree to completely abstain from heterosexual intercourse • Relapsed or refractory B or T cell acute lymphoblastic leukemia that has progressed following at least one prior therapy. Ph+ patients are eligible. Relapsed ALL is defined in patients as the reappearance of leukemia cells in the peripheral blood or bone marrow or appearance of extramedullary disease after a complete remission. Refractory ALL is defined in patients as failure to achieve a complete remission after induction therapy. Complete remission is defined by <5% leukemia cells in the bone marrow with recovery of peripheral blood counts. Relapsed disease can be documented by bone marrow biopsy (>5% cells in the bone marrow) or by flow cytometry in the peripheral blood or biopsy of extramedullary disease. Has received at least 1 line of prior systemic therapy that may NOT have included bortezomib (Velcade); patients who have undergone autologous/allogeneic stem cell transplantation are eligible Transplant-eligible patients are eligible Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2 No poorly-controlled intercurrent illness including, but not limited to, ongoing or active infection, poorly controlled diabetes, symptomatic congestive heart failure, or psychiatric illness that in the opinion of the investigator would limit compliance with study requirements Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 2.5 x upper limit of normal (ULN) Total bilirubin ≤ 1.5 x (ULN unless elevation is deemed due to leukemia infiltration) Adequate renal function defined as creatinine clearance of ≥ 30 mL/minute by the Cockcroft-Gault method EXCLUSION CRITERIA > 1.5 x ULN total bilirubin ≥ Grade 2 peripheral neuropathy Myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities; prior to study entry, any electrocardiogram (ECG) abnormality at screening must be documented by the investigator as not medically relevant Hypersensitivity to bortezomib, boron, or mannitol Pregnant or lactating Serious medical or psychiatric illness likely to interfere with participation in this clinical study Diagnosed or treated for another malignancy within 2 years of enrollment, with the exception of complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy Participation in clinical trials with other investigational agents not included in this trial throughout the duration of this trial Radiation therapy within 3 weeks before randomization; enrollment of subjects who require concurrent radiotherapy (which must be localized in its field size) should be deferred until the radiotherapy is completed and 3 weeks have elapsed since the last date of therapy Prior exposure ≥ 350 mg/m² of anthracycline (doxorubicin equivalent) Left ventricular ejection fraction < 40%

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: Bortezomib + Chemotherapy<br>Patients receive bortezomib on Days 1, 4, 8, and 11; doxorubicin hydrochloride on Day 1; PEG-asparaginase on Days 5 and 22; vincristine sulfate on Days 1, 8, 15, and 22; dexamethasone daily on Days 1 to 14; cytarabine on Day 1, and methotrexate on Day 15. | Drug: Bortezomib<br>* Administered subcutaneously (SC) at 1.3 mg/m², on Days 1, 4, 8, and 11.<br>* Other names: MLN341;Drug: Doxorubicin hydrochloride (HCl)<br>* Administered intravenously (IV) over 15 min at 60mg/m², on Day 1.<br>* Other names: VXLD;Drug: PEG-Asparaginase<br>* Administered intravenously (IV) or intramuscularly (IM) 2500 U/m² (maximum 3750 U), on Days 5 and 22.<br>* Other names: PEG-ASP;Drug: Vincristine sulfate<br>* Administered by intravenous (IV) push at 1.5 mg/m² (maximum 2 mg), on Days 1, 8, 15, and 22.<br>* Other names: VCR;Drug: Dexamethasone<br>* Administered orally (PO) at 10 mg/m², daily on Days 1 to 14.<br>* Other names: DXM;Drug: Cytarabine<br>* Administered intrathecally (IT) at 100 mg, on Day 1<br>* Other names: Cytosar-U;Drug: Methotrexate<br>* Administered intrathecally (IT) at 15 mg, on Day 15.<br>* Other names: MTX;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate (RR) | Response Rate (RR) was determined as the sum of complete response (CR) and partial response (PR). Due to overlap, complete response rate without platelet recovery (CRp) is not included in Response Rate (RR). The outcome is reported as the total number without dispersion. CR = No circulating blasts or extramedullary disease; trilineage hematopoiesis; absolute neutrophil count (ANC) > 1,000/microliter; platelets > 100,000/microliter; < 5% blasts in bone marrow. CRp = Meets all criteria for CR except platelet count. PR = Meets all criteria for CR except bone marrow contains 5 to 25% leukemia cells. | Day 29 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Response (CR) | Complete response (CR) was determined the number of participants who achieved CR by Day 29 after induction treatment. The outcome is reported as the total number without dispersion. CR is defined as: CR = No circulating blasts or extramedullary disease; trilineage hematopoiesis; absolute neutrophil count (ANC) > 1,000/microliter; platelets > 100,000/microliter; < 5% blasts in bone marrow. Not CR = All statuses and conditions if less than or not as defined. | Day 29 | 
| Complete Response Without Platelet Recovery (CRp) | Complete response without platelet recovery (CR) was determined as the number of participants who achieved CRp by Day 29 after induction treatment. The outcome is reported as the total number without dispersion. The outcome reflects only those subjects that meet all complete response (CR) criteria except platelet count; participants that meet all criteria including platelet count are not included in this outcome. CR and CRp are defined below. CR =.No circulating blasts or extramedullary disease; trilineage hematopoiesis; absolute neutrophil count (ANC) > 1,000/microliter; platelets > 100,000/microliter; < 5% blasts in bone marrow. CRp = Meets all criteria for CR except platelet count. | Day 29 | 
| Progression-free Survival (PFS) | Progression-free survival (PFS) was assessed as survival without progression at 2 years. The outcome is reported as the number (without dispersion) of the participants alive without progression. Progression = More than 25% increase in circulating and/or bone marrow blasts, or the development of extramedullary disease. | 2 years | 
| Failure-free Survival (FFS) | Failure-free survival (FFS) was assessed as survival without progression or the addition of another systemic therapy, at or within 2 years. The outcome is reported as the number (without dispersion) of the participants alive without progression. Progression is defined below. Progression = More than 25% increase in circulating and/or bone marrow blasts, or the development of extramedullary disease. | 1 year | 
| Overall Survival (OS) | Overall survival (OS) was assessed as participants remaining alive 2 years after induction therapy. The outcome is reported as the number of participants (without dispersion). | 2 years | 
| Related Adverse Events (Grade 3, 4, 5) | Toxicity was assessed as related grade 3, 4, or 5 adverse events (AEs) per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.03. The outcome is reported as the total numbers of events (without dispersion) by CTCAE Body System, and whether the event was a hematologic toxicity or non-hematologic toxicity. | 45 days | 
| Induction of Reactive Oxygen Species (ROS) | Circulating acute lymphoblastic leukemia (ALL) blast cells were to be evaluated for the presence of reactive oxygen species (ROS). | 2 years |