Plerixafor (AMD3100) and Bevacizumab for Recurrent High-Grade Glioma

Plerixafor (AMD3100) and Bevacizumab for Recurrent High-Grade Glioma
This study is currently recruiting participants.
Verified July 2012 by Dana-Farber Cancer Institute

First Received on April 6, 2011.  
Last Updated on July 31, 2012  
History of Changes
Sponsor: Patrick Y. Wen, MD
Collaborators: Dana-Farber Cancer Institute
Brigham and Women’s Hospital
Massachusetts General Hospital
Genzyme
Information provided by (Responsible Party): Patrick Y. Wen, MD, Dana-Farber Cancer Institute
ClinicalTrials.gov Identifier: NCT01339039
  Purpose

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.

Condition Intervention Phase
High Grade Glioma: Glioblastoma (GBM)
High Grade Glioma: Gliosarcoma
Anaplastic Astrocytoma (AA)
Anaplastic Oligodendroglioma (AO)
Mixed Anaplastic Oligoastrocytoma (AOA)
Drug: Plerixafor
Drug: Bevacizumab
Procedure: Surgery
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I Study of Plerixafor (AMD3100) and Bevacizumab for Recurrent High-Grade Glioma

Resource links provided by NLM:

Further study details as provided by Dana-Farber Cancer Institute:

Primary Outcome Measures:

  • Determination of Maximum Tolerated Dose (MTD) [ Time Frame: 9 months ] [ Designated as safety issue: Yes ]
    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.

Secondary Outcome Measures:

  • Safety Evaluation (3 weeks on / 1 week off) – Assessment of the proportion of subjects with different grades of toxicities [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
    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.

  • Safety and Tolerability (daily plerixafor) – Assessment of the proportion of subjects with different grades of toxicities [ Time Frame: 3 years ] [ Designated as safety issue: Yes ]
    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.

  • Determination of Plasma PK Parameters [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    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.

  • Exploratory Objective #1 – Preliminary data assessment on anti-tumor efficacy [ Time Frame: 3 years ] [ Designated as safety issue: No ]
    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.

  • Exploratory Objective #2 – Investigation of cerebrospinal fluid (CSF) penetration of plerixafor [ Time Frame: 3 years ] [ Designated as safety issue: No ]
    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.

  • Exploratory Objective #3 – Investigation of tumor tissue penetration of plerixafor [ Time Frame: 3 years ] [ Designated as safety issue: No ]
    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.

  • Exploratory Objective #4 – Investigation of the correlation of treatment response with laboratory correlates including circulating biomarkers [ Time Frame: 3 years ] [ Designated as safety issue: No ]
    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.

Estimated Enrollment: 46
Study Start Date: December 2011
Estimated Study Completion Date: April 2015
Estimated Primary Completion Date: April 2013 (Final data collection date for primary outcome measure)

Arms

Assigned Interventions
Experimental: Part 1

Maximum Tolerated Dose Determination of Plerixafor (3 weeks on, 1 week off) and Bevacizumab (every 2 weeks)
Drug: Plerixafor

Given subcutaneously once a day for 3 weeks followed by 1 week off (standard 3×3 design); MTD determined in Part 1 will be used as dose in Part 2.
Other Names:
  • AMD3100
  • Mozobil

Drug: Bevacizumab

Given intravenously on days 1 and 15 (10 mg/kg) of each 28-day cycle
Other Name: Avastin
Experimental: Part 2

Surgical Arm: Safety evaluation of Plerixafor (3 weeks on, 1 week off) and Bevacizumab (every 2 weeks)
Drug: Plerixafor

Given subcutaneously once a day for 3 weeks followed by 1 week off (standard 3×3 design); MTD determined in Part 1 will be used as dose in Part 2.
Other Names:
  • AMD3100
  • Mozobil

Drug: Bevacizumab

Given intravenously on days 1 and 15 (10 mg/kg) of each 28-day cycle
Other Name: Avastin

Drug: Plerixafor

Daily administration for 5-9 days prior to surgery
Other Names:
  • AMD3100
  • Mozobil

Procedure: 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).
Experimental: Part 3

Safety and tolerability of Plerixafor (daily) and Bevacizumab (every 2 weeks)
Drug: Plerixafor

Given subcutaneously once daily; MTD determined in Part 1 will be used as dose in Part 3.
Other Names:
  • AMD3100
  • Mozobil

Drug: Bevacizumab

Given intravenously on days 1 and 15 (10 mg/kg) of each 28-day cycle
Other Name: Avastin

Detailed Description:

  • 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. 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 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.
  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Histologic diagnosis of glioblastoma (GBM), gliosarcoma, anaplastic astrocytoma (AA), anaplastic oligodendroglioma (AO), or anaplastic mixed oligoastrocytoma (AOA). Patients are eligible if the original histology was lower-grade glioma.
  • Patients must have supratentorial disease without infratentorial involvement.
  • Unequivocal progression by MRI or CT
  • Patients with recurrence who undergo resection and are left without measurable or evaluable disease are eligible.
  • Patients must have recurrent disease and may have had any number of prior relapses (including no prior relapses). Relapse is defined as progression following initial therapy.
  • 18 years of age or older
  • Life expectancy of greater than 8 weeks
  • Karnofsky performance status of 60 or greater
  • Normal organ and marrow function as outlined in the protocol
  • Protocol treatment must begin within 5 consecutive days after registration
  • Patients enrolled in Part 2 must be willing to undergo surgical resection and have pre-treatment archival tumor tissue available for molecular analysis
  • Women of child-bearing potential must have a negative serum or urine pregnancy test within 72 hours before the start of the investigational product. In addition, women of child-bearing potential and men must agree to use adequate contraception prior to study entry and for the duration of the study participation.
  • Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

  • Patients who have had prior chemotherapy within the past 4 weeks (6 weeks for nitrosoureas or mitomycin C) or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier. Patients who received non-cytotoxic drug therapy must be off treatment for at least 2 weeks.
  • Patients who have received any form of cranial radiation within 3 months of study entry.
  • Major surgical procedure (including craniotomy) or significant traumatic injury less than 28 days or those who receive minor surgical procedures (e.g. core biopsy or fine needle aspiration) within 7 days.
  • Patients may not be receiving any other investigational agents within the past 28 days.
  • Patients who have had prior therapy with CXCR4 inhibitors or anti-VEGF targeted agents. Prior therapy with thalidomide and lenalidomide is allowed.
  • Patients who have received prior treatment with implanted radiotherapy or chemotherapy sources such as wafers of polifeprosan 20 with carmustine.
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to plerixafor or bevacizumab.
  • For the first 20 patients to register, no anti-coagulation is allowed; for all subsequent patients screened, patients requiring therapeutic anticoagulation with warfarin at baseline are excluded (however, therapeutic or prophylactic therapy with a low-molecular weight heparin is acceptable).
  • Patients must not have a known coagulopathy that increases risk of bleeding or a history of clinically significant hemorrhages in the past.
  • Patients whose MRI scan demonstrates intratumoral hemorrhage or peritumoral hemorrhage are not eligible for treatment if deemed significant by the treating physician.
  • Patients with gastrointestinal bleeding or any other hemorrhage/bleeding event CTCAE Grade > 3 within 30 days prior to study entry.
  • Uncontrolled intercurrent illness including but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
  • Patients with greater than 1+ proteinuria on a urine dipstick or equivalent routine laboratory analysis will require further testing with a urine protein to creatinine ratio.
  • History of non-healing wounds or ulcers, or bone refractures within 3 months of fracture
  • HIV-positive patients on combination antiretroviral therapy
  • Participants with a history of a different malignancy are ineligible except for the following circumstances: Individuals with a history of other malignancies are eligible if they have been disease-free for at least 3 years AND are deemed by the investigator to be at low risk for recurrence of that malignancy. Individuals with the following cancers are eligible if diagnosed and treated within the past 3 years: cervical cancer in situ, and basal cell or squamous cell carcinoma of the skin.
  • Pregnant and breastfeeding women
  • Men or women of childbearing potential who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for up to 1 month after the last dose of study drug.
  Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01339039

Contacts
Contact: Patrick Y. Wen, MD 617-632-2166 pwen@partners.org
Contact: Lisa M Doherty, APRN, OCN 617-632-5925 Lisa_Doherty@dfci.harvard.edu

Locations
United States, Massachusetts
Dana-Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02115
Contact: Lisa M Doherty, APRN, OCN     617-632-5925     Lisa_Doherty@dfci.harvard.edu    
Contact: Christine J Sceppa McCluskey     617-632-5394     christine_sceppa@dfci.harvard.edu    
Principal Investigator: Patrick Y. Wen, MD            
Massachusetts General Hospital Not yet recruiting
Boston, Massachusetts, United States, 02214
Contact: Elizabeth Gerstner, MD     617-724-8770     egerstner@partners.org    
Contact: Susan E Hahn, RN     617-726-9579     shahn16@partners.org    
Principal Investigator: Tracy Batchelor, MD            
Sponsors and Collaborators
Patrick Y. Wen, MD
Dana-Farber Cancer Institute
Brigham and Women’s Hospital
Massachusetts General Hospital
Genzyme
Investigators
Principal Investigator: Patrick Y. Wen, MD Dana-Farber Cancer Institute
  More Information

No publications provided

Responsible Party: Patrick Y. Wen, MD, Disease Center Leader, Center For Neuro-Oncology, Dana-Farber Cancer Institute
ClinicalTrials.gov Identifier: NCT01339039    
History of Changes
Other Study ID Numbers: 10-329
Study First Received: April 6, 2011
Last Updated: July 31, 2012
Health Authority: United States: Food and Drug Administration

Keywords provided by Dana-Farber Cancer Institute:

AMD3100
plerixafor
Mozobil
bevacizumab

Additional relevant MeSH terms:

Astrocytoma
Glioblastoma
Glioma
Oligodendroglioma
Gliosarcoma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
JM 3100
Bevacizumab
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors
Antineoplastic Agents

ClinicalTrials.gov processed this record on August 21, 2012

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