A Phase 2 Study of AR-67 (7-t-butyldimethylsiltyl-10-hydroxy-camptothecin) in Adult Patients With Recurrence of Glioblastoma Multiforme (GBM) or Gliosarcoma
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
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
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
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
- 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
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.
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
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
5. Known HIV infection.
6. Any other condition that would compromise treatment and/or evaluation with reasonable
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
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,
- Immune modulators: cyclosporine, tacrolimus, sirolimus
- Miscellaneous: theophylline, quetiapine, risperidone, tacrine, clozapine,
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
- 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