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Study of AR-67 in Adult Patients With Recurrence of Glioblastoma Multiforme (GBM) or Gliosarcoma

Primary Purpose

Glioblastoma Multiforme, GBM, Gliosarcoma

Status
Unknown status
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
AR-67 (7-t-butyldimethylsiltyl-10-hydroxy-camptothecin)
Sponsored by
Arno Therapeutics
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Glioblastoma Multiforme focused on measuring Adult Patients, Recurrence of Glioblastoma Multiforme, Recurrence of GBM, Gliosarcoma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Male or female age 18 years or older.
  2. Patient, or legal representative, able to provide study-specific informed consent after risks and benefits of treatment have been explained prior to screening.
  3. Confined histopathology of World Health Organization (WHO) Grade IV GBM or Gliosarcoma at primary diagnosis or recurrence by local pathology review.
  4. Unequivocal radiographic evidence of recurrence of tumor by MRI within 14 days prior to enrollment.
  5. Patients who have progressed, had surgery, and have no measurable disease are eligible as long as they have adequately recovered from the surgery.
  6. Received prior radiotherapy and temozolomide treatment.
  7. Received last chemotherapy or biologic therapy treatment ≥14 days before first dose of study drug (≥42 days if nitrosourea or ≥90 days if bevacizumab for the non-bevacizumab failure cohort or therapeutic antibody was administered) or, for daily type regimens, ≥7 days or 5 half-lives of the drugs' pharmacokinetics/dynamics or biologic activities, whichever is longer, before the first dose of study drug. For subjects that have received prior chemotherapy, all toxicities need to have resolved ≤ Grade 1 prior to the administration of study drug. For the patients in the bevacizumab failure cohort, failure must have occurred within the prior 90 days of receiving the last bevacizumab dose.
  8. Completed radiotherapy ≥90 days before study starts.
  9. Completed the administration of any investigational agent ≥14 days or 5 half-lives of the drugs' PK/dynamics or biologic activities, whichever is longer, before study starts.
  10. Karnofsky performance status of ≥60%.
  11. Recovered to Grade 1 or less from the toxic effects of any earlier intervention.
  12. Patients receiving EIADs must be switched to non-EIADs at least 14 days prior to study start.
  13. Adequate renal, liver, and bone marrow function according to the following criteria:

    • Absolute neutrophil count ≥1500/mcL
    • Platelets ≥150,000/mcL
    • Total bilirubin within upper limit of normal (ULN)
    • Aspartate aminotransferase (AST) ≤ 2.5 X institutional ULN
    • Creatinine within normal limits or creatinine clearance ≥ 50 mL/min for patients with creatinine levels above normal limits.
  14. Demonstrated, in the opinion of the investigator, the ability to follow directions necessary to participate in the clinical trial.
  15. Women of childbearing potential must agree to use acceptable contraceptive methods as follows:

    • An intrauterine device with a documented failure rate of less than 1% per year.
    • Vasectomized partner who is sterile prior to the female patient's entry and is the sole sexual partner for that female.
    • Complete abstinence from sexual intercourse for 14 days before exposure to investigational product, through the dosing period, and for at least 21 days after the last dose of investigational product.
    • Double-barrier contraception (condom with spermicidal jelly, foam suppository, or film; diaphragm with spermicide, or male condom and diaphragm with spermicide).

    Note: These methods are to be used consistently and in accordance with both the product label and the instructions of the treating physician. Oral contraceptives are not reliable due to potential drug-drug interactions and should be used with caution if the patient insists on their use as a contraceptive.

  16. A life expectancy of greater than 2 months.

Exclusion Criteria:

  1. Patients on therapeutic Coumadin; however, patients on therapeutic Coumadin that can switch to low molecular weight heparin (LMWH) at least 7 days prior to first dosing will be eligible for study participation.
  2. Female patients who are pregnant or breastfeeding.
  3. Prior malignancy other than curatively treated basal cell or cervical carcinoma in situ or adequately treated Stage I or II cancer from which the patient is currently in complete remission and from which the patient has been disease-free for three years.
  4. Uncontrolled concurrent illness including active infection requiring intravenous antibiotics, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
  5. Known HIV infection.
  6. Any other condition that would compromise treatment and/or evaluation with reasonable safety.
  7. Completed intracranial surgery ≤ 14 days before the study starts.
  8. Received an anti-epilpetic drug, which is a CYP3A4 inducer from ≤ 14 days prior to screening until study end. See Appendix 1 for the list of enzyme inducing anti-epileptic drugs.

    Inducers of CYP3A4 may also alter the metabolism of AR-67. The following list of CYP3A4 inducers are prohibited from 14 days prior to screening through discontinuation from the study:

    • HIV: efavirenz, nevirapine
    • Antibiotics: rifampin (rifampicin), rifabutin, rifapentine
    • Antiretrovirals: efavirenz, nevirapine
    • Miscellaneous: St. John's Wort, modafinil
    • Anti-Epileptic Drugs: phenytoin, phenobarbital, primidone, carbamazapine, oxcarbazapine and topiramate
  9. Co-administration of AR-67 and medications that are substrates for the CYP450 enzymes and have the potential to cause serious and/or life-threatening AE's is prohibited. These medications include (but are not limited to):

    • Anticoagulants: therapeutic coumadin
    • Oral hypoglycemics: glilpizide, glyburide, tolbutamide, glimepiride, nateglinice
    • Erectile dysfunction agents: sildenafil, tadalafil, vardenafil
    • Ergot derivatives: dihydroergotamine, ergonovine, ergotamine, methylergonovine
    • Neuroleptics: pimozide
    • Antiarrhythmics: bepridil, flecainide, lidocaine, meziletine, amiodarone, quinidine, propafenone
    • Immune modulators: cyclosporine, tacrolimus, sirolimus
    • Miscellaneous: theophylline, quetiapine, risperidone, tacrine, clozapine, atomoxetine
  10. The following list of CYP3A4 inhibitors are prohibited from 14 days prior to screening through discontinuation from the study:

    • Antibiotics: clarithromycin, erythromycin, troleandomycin
    • HIV: antiretrovirals (delaviridine), protease inhibitors (ritonavir, indinavir, saquinavir, nelfinavir, amprenavir, lopinavir)
    • Antifungals: itraconazole, ketoconazole, voriconazole, fluconazole (>150 mg daily)
    • Antidepressants: nefazodone, fluvoxamine
    • Calcium channel blockers: verapamil, diltiazem
    • Gastrointestinal: cimetidine, aprepitant
    • Miscellaneous: grapefruit or its juice
  11. Progressive disease with any topoisomerase I inhibitors.
  12. History of anaphylactic injection reaction of > Grade 3 to any product used to formulate AR-67.

Sites / Locations

  • Northwestern University - Robert H Lurie Comprehensive Cancer Center
  • University of Kentucky - Markey Cancer Center
  • North Shore - Long Island Jewish Hospital/Monter Cancer Center
  • Duke University Medical Center - The Preston Robert Tisch Brain Tumor Center
  • Derrick L Davis Forsyth Regional Cancer Center
  • The Ohio State University - James Comprehensive Cancer Center
  • University of Utah - Huntsman Cancer Center
  • University of Calgary - Tom Baker Cancer Center
  • University of Alberta - Cross Cancer Institute

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

AR-67

Arm Description

Outcomes

Primary Outcome Measures

Determine the 6-month Progression free survival (PFS) AR-67 is administered in adults with confirmed recurrence of GBM who have not recently (> 90 days) recurred after treatment bevacizumab.
Thirty-two (32) patients will be accrued to the non-bevacizumab failure cohort.
The primary objective in the rapid bevacizumab failure group (< 90 days) is to determine the 2-month PFS.
26 subjects will be enrolled in the second cohort (Rapid Avastin Progressors).

Secondary Outcome Measures

the effect of AR-67 on overall survival (OS)
the effect of AR-67 on overall PFS
the effect of AR-67 on event-free survival (EFS)
the impact of AR-67 on tumor response in patients with measurable disease
the safety and tolerability of AR-67

Full Information

First Posted
May 12, 2010
Last Updated
December 8, 2014
Sponsor
Arno Therapeutics
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1. Study Identification

Unique Protocol Identification Number
NCT01124539
Brief Title
Study of AR-67 in Adult Patients With Recurrence of Glioblastoma Multiforme (GBM) or Gliosarcoma
Official Title
A Phase 2 Study of AR-67 (7-t-butyldimethylsiltyl-10-hydroxy-camptothecin) in Adult Patients With Recurrence of Glioblastoma Multiforme (GBM) or Gliosarcoma
Study Type
Interventional

2. Study Status

Record Verification Date
January 2014
Overall Recruitment Status
Unknown status
Study Start Date
December 2009 (undefined)
Primary Completion Date
September 2014 (Actual)
Study Completion Date
February 2015 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Arno Therapeutics

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
The primary objective of this study is to determine the 6-month Progression free survival (PFS) when intravenous (IV) AR-67 is administered in adults with confirmed recurrence of GBM who have not recently (> 90 days) recurred after treatment bevacizumab (including patients who've received temazolamide, but no bevacizumab). The primary objective in the rapid bevacizumab failure group (< 90 days) is to determine the 2-month PFS.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Glioblastoma Multiforme, GBM, Gliosarcoma
Keywords
Adult Patients, Recurrence of Glioblastoma Multiforme, Recurrence of GBM, Gliosarcoma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
58 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
AR-67
Arm Type
Experimental
Intervention Type
Drug
Intervention Name(s)
AR-67 (7-t-butyldimethylsiltyl-10-hydroxy-camptothecin)
Other Intervention Name(s)
AR67, formerly DB-67, formerly DB67
Intervention Description
IV AR-67 administered once daily for 5 days on an every 21-day cycle
Primary Outcome Measure Information:
Title
Determine the 6-month Progression free survival (PFS) AR-67 is administered in adults with confirmed recurrence of GBM who have not recently (> 90 days) recurred after treatment bevacizumab.
Description
Thirty-two (32) patients will be accrued to the non-bevacizumab failure cohort.
Time Frame
6 month PFS
Title
The primary objective in the rapid bevacizumab failure group (< 90 days) is to determine the 2-month PFS.
Description
26 subjects will be enrolled in the second cohort (Rapid Avastin Progressors).
Time Frame
2 month PFS
Secondary Outcome Measure Information:
Title
the effect of AR-67 on overall survival (OS)
Time Frame
1 year
Title
the effect of AR-67 on overall PFS
Time Frame
6 Months
Title
the effect of AR-67 on event-free survival (EFS)
Time Frame
6 Months
Title
the impact of AR-67 on tumor response in patients with measurable disease
Time Frame
6 Months
Title
the safety and tolerability of AR-67
Time Frame
6 Months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Male or female age 18 years or older. Patient, or legal representative, able to provide study-specific informed consent after risks and benefits of treatment have been explained prior to screening. Confined histopathology of World Health Organization (WHO) Grade IV GBM or Gliosarcoma at primary diagnosis or recurrence by local pathology review. Unequivocal radiographic evidence of recurrence of tumor by MRI within 14 days prior to enrollment. Patients who have progressed, had surgery, and have no measurable disease are eligible as long as they have adequately recovered from the surgery. Received prior radiotherapy and temozolomide treatment. Received last chemotherapy or biologic therapy treatment ≥14 days before first dose of study drug (≥42 days if nitrosourea or ≥90 days if bevacizumab for the non-bevacizumab failure cohort or therapeutic antibody was administered) or, for daily type regimens, ≥7 days or 5 half-lives of the drugs' pharmacokinetics/dynamics or biologic activities, whichever is longer, before the first dose of study drug. For subjects that have received prior chemotherapy, all toxicities need to have resolved ≤ Grade 1 prior to the administration of study drug. For the patients in the bevacizumab failure cohort, failure must have occurred within the prior 90 days of receiving the last bevacizumab dose. Completed radiotherapy ≥90 days before study starts. Completed the administration of any investigational agent ≥14 days or 5 half-lives of the drugs' PK/dynamics or biologic activities, whichever is longer, before study starts. Karnofsky performance status of ≥60%. Recovered to Grade 1 or less from the toxic effects of any earlier intervention. Patients receiving EIADs must be switched to non-EIADs at least 14 days prior to study start. Adequate renal, liver, and bone marrow function according to the following criteria: Absolute neutrophil count ≥1500/mcL Platelets ≥150,000/mcL Total bilirubin within upper limit of normal (ULN) Aspartate aminotransferase (AST) ≤ 2.5 X institutional ULN Creatinine within normal limits or creatinine clearance ≥ 50 mL/min for patients with creatinine levels above normal limits. Demonstrated, in the opinion of the investigator, the ability to follow directions necessary to participate in the clinical trial. Women of childbearing potential must agree to use acceptable contraceptive methods as follows: An intrauterine device with a documented failure rate of less than 1% per year. Vasectomized partner who is sterile prior to the female patient's entry and is the sole sexual partner for that female. Complete abstinence from sexual intercourse for 14 days before exposure to investigational product, through the dosing period, and for at least 21 days after the last dose of investigational product. Double-barrier contraception (condom with spermicidal jelly, foam suppository, or film; diaphragm with spermicide, or male condom and diaphragm with spermicide). Note: These methods are to be used consistently and in accordance with both the product label and the instructions of the treating physician. Oral contraceptives are not reliable due to potential drug-drug interactions and should be used with caution if the patient insists on their use as a contraceptive. A life expectancy of greater than 2 months. Exclusion Criteria: Patients on therapeutic Coumadin; however, patients on therapeutic Coumadin that can switch to low molecular weight heparin (LMWH) at least 7 days prior to first dosing will be eligible for study participation. Female patients who are pregnant or breastfeeding. Prior malignancy other than curatively treated basal cell or cervical carcinoma in situ or adequately treated Stage I or II cancer from which the patient is currently in complete remission and from which the patient has been disease-free for three years. Uncontrolled concurrent illness including active infection requiring intravenous antibiotics, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. Known HIV infection. Any other condition that would compromise treatment and/or evaluation with reasonable safety. Completed intracranial surgery ≤ 14 days before the study starts. Received an anti-epilpetic drug, which is a CYP3A4 inducer from ≤ 14 days prior to screening until study end. See Appendix 1 for the list of enzyme inducing anti-epileptic drugs. Inducers of CYP3A4 may also alter the metabolism of AR-67. The following list of CYP3A4 inducers are prohibited from 14 days prior to screening through discontinuation from the study: HIV: efavirenz, nevirapine Antibiotics: rifampin (rifampicin), rifabutin, rifapentine Antiretrovirals: efavirenz, nevirapine Miscellaneous: St. John's Wort, modafinil Anti-Epileptic Drugs: phenytoin, phenobarbital, primidone, carbamazapine, oxcarbazapine and topiramate Co-administration of AR-67 and medications that are substrates for the CYP450 enzymes and have the potential to cause serious and/or life-threatening AE's is prohibited. These medications include (but are not limited to): Anticoagulants: therapeutic coumadin Oral hypoglycemics: glilpizide, glyburide, tolbutamide, glimepiride, nateglinice Erectile dysfunction agents: sildenafil, tadalafil, vardenafil Ergot derivatives: dihydroergotamine, ergonovine, ergotamine, methylergonovine Neuroleptics: pimozide Antiarrhythmics: bepridil, flecainide, lidocaine, meziletine, amiodarone, quinidine, propafenone Immune modulators: cyclosporine, tacrolimus, sirolimus Miscellaneous: theophylline, quetiapine, risperidone, tacrine, clozapine, atomoxetine The following list of CYP3A4 inhibitors are prohibited from 14 days prior to screening through discontinuation from the study: Antibiotics: clarithromycin, erythromycin, troleandomycin HIV: antiretrovirals (delaviridine), protease inhibitors (ritonavir, indinavir, saquinavir, nelfinavir, amprenavir, lopinavir) Antifungals: itraconazole, ketoconazole, voriconazole, fluconazole (>150 mg daily) Antidepressants: nefazodone, fluvoxamine Calcium channel blockers: verapamil, diltiazem Gastrointestinal: cimetidine, aprepitant Miscellaneous: grapefruit or its juice Progressive disease with any topoisomerase I inhibitors. History of anaphylactic injection reaction of > Grade 3 to any product used to formulate AR-67.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
James J Vredneburgh, MD
Organizational Affiliation
Duke University Medical Center - The Preston Robert Tisch Brain Tumor Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Northwestern University - Robert H Lurie Comprehensive Cancer Center
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60611
Country
United States
Facility Name
University of Kentucky - Markey Cancer Center
City
Lexington
State/Province
Kentucky
ZIP/Postal Code
40536
Country
United States
Facility Name
North Shore - Long Island Jewish Hospital/Monter Cancer Center
City
Lake Success
State/Province
New York
ZIP/Postal Code
11042
Country
United States
Facility Name
Duke University Medical Center - The Preston Robert Tisch Brain Tumor Center
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27710
Country
United States
Facility Name
Derrick L Davis Forsyth Regional Cancer Center
City
Winston-Salem
State/Province
North Carolina
ZIP/Postal Code
27103
Country
United States
Facility Name
The Ohio State University - James Comprehensive Cancer Center
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43210
Country
United States
Facility Name
University of Utah - Huntsman Cancer Center
City
Salt Lake City
State/Province
Utah
ZIP/Postal Code
84112
Country
United States
Facility Name
University of Calgary - Tom Baker Cancer Center
City
Calgary
State/Province
Alberta
ZIP/Postal Code
T2N 4N2
Country
Canada
Facility Name
University of Alberta - Cross Cancer Institute
City
Edmonton
State/Province
Alberta
ZIP/Postal Code
T6G 1Z2
Country
Canada

12. IPD Sharing Statement

Learn more about this trial

Study of AR-67 in Adult Patients With Recurrence of Glioblastoma Multiforme (GBM) or Gliosarcoma

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