Plerixafor in combination with bevacizumab is a drug combination that may stop cancer cells from growing abnormally. Bevacizumab, also known as Avastin, is FDA approved for use in patients with recurrent glioblastoma and has been studied extensively in other types of solid tumors. Plerixafor, also known as Mozobil, is FDA approved for use in patients with non-Hodgkin's lymphoma and multiple myeloma and has been used in treatment for other cancers. Information from experiments in laboratories suggests that the combination of plerixafor and bevacizumab may help prevent the growth of gliomas. Part 1: The investigators are looking for the highest dose of plerixafor that can be given safely with bevacizumab (with a 21 days on/7 days off regimen of plerixafor). The investigators will also do blood tests to find out how the body uses and breaks down the drug combination. Part 2: The investigators are looking to see if plerixafor can get past the blood-brain barrier and into brain tumors. The investigators will also do blood tests to find out how the body uses and breaks down the drug combination. Part 3: The investigators are looking for for more information re: safety and tolerability of plerixafor in combination with bevacizumab (with a 28 days on/0 days off regimen of plerixafor). The investigators will also do blood tests to find out how the body uses and breaks down the drug combination.
* This study is organized into cycles. Each cycle lasts four weeks (28 days). Cycles occur back to back without a break in between. * Plerixafor is given as subcutaneous injection (under the skin). The injection should be given at approximately the same time each day (If participants would like the option to administer their Plerixfor in the evening rather than in the morning on non-clinic days, this is a possibility, provided certain conditions are met). The research doctor will specify which days participants should take plerixafor. In general, plerixafor will be given once daily during the first three weeks of every cycle (during part 3, patients will receive plerixafor the last week of each cycle, as well). For the first week (5-7 days) of Cycle 1, the injections will be given in the clinic and the nurses will teach the participant and their spouse/friend/family member how to administer the injections. * Bevacizumab (10 mg/kg) will be given as an infusion on Days 1 and 15 of each cycle. * During Part 1 the investigators are looking for the highest dose of the study drug that can be administered safely in combination with bevacizumab so not everyone who participates will receive the same dose of the study drug. The dose given will depend upon on the number of participants who have been enrolled and how well they have tolerated their doses. * During Part 2, before patient begins their post-surgical cycles of treatment, plerixafor will be administered daily for 5-9 days at the MTD established in Part 1 of the study; patient will continue to surgery; and once recovered from surgery, patient will begin post-surgical cycles of treatment (plerixafor and bevacizumab) at the MTD/regimen established in Part 1 of the study. * In addition to taking the study medication, participants will have the following tests and procedures done: physical and neurological exam, assessments of the tumor by MRI or CT scan, routine and research blood tests, routine urine tests, pregnancy test (if applicable), ECG, collection of cerebrospinal fluid (CSF) via spinal tap. * Participants may remain in this research study as long as their tumor is responding or it is determined that receiving further study drugs will not be safe.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
26
Given subcutaneously once a day for 3 weeks followed by 1 week off (standard 3x3 design); MTD determined in Part 1 will be used as dose in Part 2.
Given subcutaneously once daily; MTD determined in Part 1 will be used as dose in Part 3.
Given intravenously on days 1 and 15 (10 mg/kg) of each 28-day cycle
Daily administration for 5-9 days prior to surgery
After receiving 5-9 days of Plerixafor (AMD3100) monotherapy, patients proceed to surgery. After recovering from surgery, patients will proceed to 28-day post-surgical cycles of therapy (Plerixafor at the MTD established in Part 1, 21 days on / 7 days off; bevacizumab 10 mg/kg on days 1 \& 15).
Dana-Farber Cancer Institute
Boston, Massachusetts, United States
Massachusetts General Hospital
Boston, Massachusetts, United States
Determination of Maximum Tolerated Dose (MTD)
To determine the maximum tolerated dose (the highest dose combination that causes DLT in no more than 1 of 6 patients) of plerixafor 3 weeks on, 1 week off in combination with bevacizumab (every two weeks) in this patient population.
Time frame: 9 months
Safety Evaluation (3 weeks on / 1 week off) - Assessment of the proportion of subjects with different grades of toxicities
To evaluate the safety of plerixafor 3 weeks on, 1 week off in combination with bevacizumab (every 2 weeks) in this patient population. Safety variables will be summarized by descriptive statistics for Parts 1 and 2. To assess the probability of toxicity associated with the treatment, the proportion of subjects with different grades of toxicities will be estimated along with 95% confidence intervals. AEs that occur will be reported for each dose level and for each Part of the study.
Time frame: 2 years
Safety and Tolerability (daily plerixafor) - Assessment of the proportion of subjects with different grades of toxicities
To evaluate the safety and tolerability of once daily plerixafor in combination with bevacizumab (every 2 weeks) in this patient population. Safety variables will be summarized by descriptive statistics for Part 3. To assess the probability of toxicity associated with the treatment, the proportion of subjects with different grades of toxicities will be estimated along with 95% confidence intervals. AEs that occur will be reported for each dose level and for each Part of the study.
Time frame: 3 years
Determination of Plasma PK Parameters
To determine the plasma pharmacokinetics of plerixafor in patients receiving bevacizumab (every other week). PK parameters will be calculated from each subject's plerixafor plasma concentration versus time data, and summarized by cohort. The following PK parameters will be determined by non-compartmental analysis: Cmax, Tmax, Clast, Tlast, kel, half-life, AUC0-last, AUCinf, CL, and Vd. Additional parameters may be reported depending on the characteristics of the observed plasma concentration profiles.
Time frame: 2 years
Exploratory Objective #1 - Preliminary data assessment on anti-tumor efficacy
Exploratory Objective #1 - Preliminary data assessment on the anti-tumor efficacy of plerixafor in combination with bevacizumab in this population. Since efficacy is not the primary objective, the efficacy variables will be summarized descriptively by treatment cohort. Efficacy evaluations will occur every 8 weeks and will consist of imaging and clinical assessment. The rates of response (Complete Response and Complete Response + Partial Response) will be estimated for each dose cohort in Part 1, the MTD (expanded) cohort in Part 1, Part 2, and Part 3.
Time frame: 3 years
Exploratory Objective #2 - Investigation of cerebrospinal fluid (CSF) penetration of plerixafor
Plerixafor levels in the cerebrospinal fluid (CSF) will be examined, since despite the potential of plerixafor in inhibiting vasculogenesis and tumor invasion, it is unlikely to be effective unless adequate concentrations can be achieved in the brain.
Time frame: 3 years
Exploratory Objective #3 - Investigation of tumor tissue penetration of plerixafor
Tumor tissue of 10 patients with recurrent HGG who require a reoperation (Part 2) will be examined for plerixafor levels and for evidence of pathway inhibition in vivo, since despite the potential of plerixafor in inhibiting vasculogenesis and tumor invasion, it is unlikely to be effective unless adequate concentrations can be achieved in the brain.
Time frame: 3 years
Exploratory Objective #4 - Investigation of the correlation of treatment response with laboratory correlates including circulating biomarkers
The goal of the analysis of the biological correlate data is providing an increased understanding of the nature of the response to plerixafor (AMD3100) and bevacizumab and whether blood and tissue biomarkers can assist in predicting response and progression. These studies are exploratory. The nature of the analyses and the strength of the conclusions from these laboratory studies depend not only on the amount of data available, but also on the nature of patient response to therapy. The information will be limited by the small number of patients treated at each dose.
Time frame: 3 years
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