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.
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.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Stanford University
Palo Alto, California, United States
Johns Hopkins University/Sidney Kimmel Cancer Center
Baltimore, Maryland, United States
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.
Time frame: Up to day 1 of cycle 2
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.
Time frame: 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.
Time frame: 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.
Time frame: Up to 1 year
Progression Free Survival (PFS)
PFS will be defined as the time from treatment initiation until disease progression.
Time frame: 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.
Time frame: 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.
Time frame: Up to 30 days from the first dose of treatment
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