Volasertib and Vincristine Sulfate Liposome in Treating Patients With Relapsed or Refractory Acute Lymphoblastic Leukemia

Study Overview
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Brief Summary
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The main purpose of this investigational research study is to determine how safe and tolerable the study drug volasertib is in combination with liposomal vincristine (Marqibo; an FDA-approved drug) in patients with relapsed/refractory acute lymphoblastic leukemia. While VSLI demonstrated an overall response rate of 35% in Acute Lymphoblastic Leukemia (ALL) patients that had failed to respond to or relapsed after chemotherapy, combining it with other agents may increase clinical benefit. Volasertib inhibits proteins involved in the cell cycle that are increased in ALL. When volasertib inhibits these proteins ALL cells die. In the laboratory, volasertib has been shown to increase activity of vincristine against ALL cells. Therefore, we think the combination of volasertib and VSLI will be more effective against your leukemia than either drug used alone. This study will try to find out what effects, good and/or bad, this drug combination has on the patient and their cancer, and to find a dose that may be used in future studies.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose (MTD) of the combination of volasertib and vincristine sulfate liposomal injection (VSLI) in relapsed/refractory (RR) acute lymphoblastic leukemia (ALL). SECONDARY OBJECTIVES: I. To determine the toxicity profile of volasertib and VSLI, rate of complete remission (with or without complete hematologic recovery; complete response [CR]/CR with incomplete hematologic recovery [CRi]), duration of remission (DOR), rate of minimal residual disease (MRD)-negativity, progression free survival (PFS), overall survival (OS), 30-day mortality rate. TERTIARY OBJECTIVES: I. To determine if volasertib and polo-like kinase (plk)-inhibition down-regulates the mammalian target of rapamycin (mTOR) pathway. II. Whether plk and mTOR inhibition correlates with clinical response to treatment. III. to determine if volasertib acts synergistically to potentiate the bioavailability and distribution of VSLI. OUTLINE: This is a dose-escalation study of volasertib. Patients receive volasertib intravenously (IV) over 1 hour on day 1 and vincristine sulfate liposome IV over 1 hour on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression, development of an inter-current illness that prevents further administration of treatment, unacceptable toxicity, patient decides to withdraw or treating investigator determines that the patient should be taken off treatment for any reason. After completion of study, patients are followed up every 28 days for up to 1 year.

Official Title
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A Phase I Clinical Trial Evaluating the Combination of Volasertib (BI-6727) With Vincristine Sulfate Liposomal Injections (VSLI) in Adult Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia

Conditions
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Recurrent Adult Acute Lymphoblastic Leukemia, Refractory Adult Acute Lymphoblastic Leukemia

Intervention / Treatment
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* Other: Laboratory Biomarker Analysis
* Other: Pharmacological Study
* Drug: Vincristine Sulfate Liposome
* Drug: Volasertib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have histologically confirmed diagnosis of Philadelphia-negative ALL by bone marrow biopsy or aspirate Patients must have >= 5% blasts in the bone marrow Patients must have refractory disease, disease relapse or progression after at least two prior systemic chemotherapy or immunotherapy regimens Note: Exceptions may be made if a patient is deemed unfit for first-line salvage therapy by the treating physician; such cases should be clearly documented Patients with a history of CNS (central nervous system) leukemia are eligible if they are not symptomatic from current CNS involvement; if there is CNS involvement that is known prior to enrollment or identified subsequently, it will be treated accordingly with intrathecal chemotherapy per the treating physician Patients must exhibit an Eastern Cooperative Oncology Group (ECOG) performance status of =< 2 Patients must have adequate organ function within 14 days prior to registration, as defined below: Total bilirubin =< 2 x institutional upper limit of normal (ULN) Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/aspartate aminotransferase (ALT) (serum glutamic pyruvic transaminase [SPGT]) =< 3 x ULN Creatinine =< 2 X ULN Females of child-bearing potential (FOCBP) and males must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 6 months following completion of therapy; should a female patient become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately NOTE: A FOCBP is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria: Has not undergone a hysterectomy or bilateral oophorectomy Has had menses at any time in the preceding 12 consecutive months (and therefore has not been naturally postmenopausal for > 12 months) FOCBP must have a negative pregnancy test within 14 days prior to registration on study Patients must have the ability to understand and the willingness to sign a written informed consent prior to registration on study Exclusion Criteria: Patients who have had chemotherapy, immunotherapy, or radiotherapy within 2 weeks prior to entering the study or those who have not recovered from adverse events (=< grade 1 or patient's baseline) due to agents administered more than 2 weeks earlier are not eligible Patients may not be receiving any other investigational agents within 7 days of registration Patients may not be receiving any medications that are known to prolong QT interval unless reviewed and approved by the principal investigator (PI) Patients who have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to volasertib or VSLI are not eligible Subject may not have had hematopoietic stem cell transplant (HSCT) meeting any of the following: Is within 2 months of transplant from cycle 1 day 1 (C1D1) Has clinically significant graft-versus-host disease requiring treatment Has >= grade 2 persistent non-hematological toxicity related to the transplant Donor lymphocyte infusion (DLI) is not permitted < 30 days prior to study registration Patients with >= grade 2 sensory or motor neuropathy are not eligible Fridericia's corrected QT (QTcF) prolongation > 470 ms or QT prolongation deemed clinically relevant by the investigator (e.g., congenital long QT syndrome); the QTcF will be calculated as the mean of the 3 electrocardiograms (ECGs) taken at screening NOTE: The formula used to calculate QTcF can be physician's choice, but it must be used consistently throughout the study Patients who have an uncontrolled intercurrent illness including, but not limited to any of the following, are not eligible: Ongoing or active infection requiring systemic treatment Symptomatic congestive heart failure (>= class 3) Unstable angina pectoris Cardiac arrhythmia Psychiatric illness/social situations that would, in the investigator's opinion, limit compliance with study requirements Known human immunodeficiency virus (HIV) infection Known John Cunningham virus (JC) virus infection and/or progressive multifocal leukoencephalopathy (PML) Known clinically active hepatitis A, B, or C infections NOTE: Patients with chronic hepatitis C virus (HCV) or hepatitis B virus (HBV) infection may enroll if other laboratory criteria are met; those with HBV surface antigen positivity may enroll only if maintained on appropriate suppressive antiviral therapy for the duration of enrollment in the trial Second malignancy that requires active treatment Any other illness or condition that the treating investigator feels would interfere with study compliance or would compromise the patient's safety or study endpoints Female patients who are pregnant or nursing are not eligible

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 (volasertib, vincristine sulfate liposome)<br>Patients receive volasertib IV over 1 hour on day 1 and vincristine sulfate liposome IV over 1 hour on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression, development of an inter-current illness that prevents further administration of treatment, unacceptable toxicity, patient decides to withdraw or treating investigator determines that the patient should be taken off treatment for any reason. | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Pharmacological Study<br>* Correlative studies<br>Drug: Vincristine Sulfate Liposome<br>* Given IV<br>* Other names: Marqibo;Drug: Volasertib<br>* Given IV<br>* Other names: Polo-like Kinase 1 Inhibitor BI 6727;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) | Determine the MTD of volasertib and VSLI in RR ALL, the MTD will be defined as the highest dose level at which ≤ 1 Dose-Limiting Toxicity (DLT) occurs in 6 patients and will be assessed by the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. | Up to day 1 of cycle 2 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of complete remission (CR/Cri) | Evaluate the rate of complete remission (with or without complete hematologic recovery; CR/CRi). Rates will be based on the number and percentage of patients that achieve a CR/CRi. Response will be assessed by bone marrow biopsy and blood counts. | After every 2 even number cycles during treatment then every 28 days up to 1 year during follow-up | 
| Duration of Remission (DOR) | DOR will be defined from the time, measured in months, of CR or CRi until disease progression. | Up to 1 year from end of treatment | 
| Minimal Residual Disease (MRD-negativity) rate | The rate of MRD-negativity will be assessed in bone marrow mononuclear cells by multi-color flow cytometry analysis. | Up to 1 year | 
| Progression Free Survival (PFS) | PFS will be defined as the time from treatment initiation until disease progression. | Up to 1 year from end of treatment | 
| Overall Survival (OS) | OS is defined as the time from treatment initiation until death from any cause. | Up to 1 year from end of treatment | 
| 30-day mortality rate | Evaluated as the number of patients deceased within the first 30 days from the first dose of treatment. | Up to 30 days from the first dose of treatment |