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

Sponsor

Arno Therapeutics (Industry)

Overall Status

Unknown status

CT.gov ID

NCT01124539

Collaborator

(none)

Enrollment

Locations

Arm

Duration (Months)

6.4

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Glioblastoma Multiforme GBM Gliosarcoma	Drug: AR-67 (7-t-butyldimethylsiltyl-10-hydroxy-camptothecin)	Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

58 participants

Allocation:

Non-Randomized

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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 Start Date :

Dec 1, 2009

Actual Primary Completion Date :

Sep 1, 2014

Anticipated Study Completion Date :

Feb 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: AR-67	Drug: AR-67 (7-t-butyldimethylsiltyl-10-hydroxy-camptothecin) IV AR-67 administered once daily for 5 days on an every 21-day cycle Other Names: AR67 formerly DB-67 formerly DB67

Arm

Intervention/Treatment

Experimental: AR-67

Drug: AR-67 (7-t-butyldimethylsiltyl-10-hydroxy-camptothecin)

IV AR-67 administered once daily for 5 days on an every 21-day cycle

Other Names:

AR67

formerly DB-67

formerly DB67

Outcome Measures

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. [6 month PFS]
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. [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) [1 year]
the effect of AR-67 on overall PFS [6 Months]
the effect of AR-67 on event-free survival (EFS) [6 Months]
the impact of AR-67 on tumor response in patients with measurable disease [6 Months]
the safety and tolerability of AR-67 [6 Months]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Northwestern University - Robert H Lurie Comprehensive Cancer Center	Chicago	Illinois	United States	60611
2	University of Kentucky - Markey Cancer Center	Lexington	Kentucky	United States	40536
3	North Shore - Long Island Jewish Hospital/Monter Cancer Center	Lake Success	New York	United States	11042
4	Duke University Medical Center - The Preston Robert Tisch Brain Tumor Center	Durham	North Carolina	United States	27710
5	Derrick L Davis Forsyth Regional Cancer Center	Winston-Salem	North Carolina	United States	27103
6	The Ohio State University - James Comprehensive Cancer Center	Columbus	Ohio	United States	43210
7	University of Utah - Huntsman Cancer Center	Salt Lake City	Utah	United States	84112
8	University of Calgary - Tom Baker Cancer Center	Calgary	Alberta	Canada	T2N 4N2
9	University of Alberta - Cross Cancer Institute	Edmonton	Alberta	Canada	T6G 1Z2