The primary objectives of this study are to determine the maximal tolerated dose (MTD) of
PAC-1 in combination with temozolomide in patients with high grade glioma: glioblastoma
multiforme (GBM) or anaplastic astrocytoma after progression following standard first line
therapy (Component 2), by evaluation of toxicity and tolerability.
PAC-1 in combination with temozolomide (Component 2): after the MTD is established for single
agent PAC-1 in Component 1, a modified-Fibonacci dose-escalation 3+3 design starts in
Component 2, at a PAC-1 dose one level lower than the MTD of PAC-1 established in the single
agent PAC-1 component (i.e., Component 1) and 150 mg/m2 dose of temozolomide given for the 5
days starting at day 8 of cycle 1 in cohorts of 3-6 patients. The combination cohort that
reaches MTD will expanded to at least 9 patients, similar to the PAC-1 alone cohort at MTD.
For all dose cohorts, pharmacokinetics of PAC-1 will be assessed following doses administered
on days 1 and 11 of the first cycle. Temozolomide pharmacokinetics will be performed on Day
11 of the first cycle.
1. Male or female ≥ 18 years of age
2. Diagnosis of advanced solid tumor or hematologic malignancy (limited to lymphoma) that
has failed or become intolerant to standard therapy (Component 1 - single agent PAC-1)
Note: Gliomas are excluded from Component 1 (see exclusion #19)
3. Diagnosis of high grade glioma: glioblastoma multiforme (GBM) or anaplastic
astrocytoma after progression following treatment with standard first line therapy
(Component 2 - PAC-1 in combination with temozolomide).
4. Has measurable disease, defined as at least 1 tumor that fulfills the criteria for a
target lesion according to RECIST 1.1 (Component 1).
5. For patients in study Component 2 measurable disease RANO criteria will be used.
6. Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 (see
7. Has adequate hepatic function defined as total bilirubin < 1.5 mg/dL, serum albumin >
3.0 gm/dL, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 1.5 ×
upper limit of normal (ULN) or < 3 x ULN for subjects with known hepatic metastases
8. Has adequate renal function defined as serum creatinine < 1.5 × ULN
9. Has adequate bone marrow function defined as a hemoglobin ≥ 10 g/dL, absolute
neutrophil count (ANC) ≥ 1.5 × 109/L, and platelet count ≥ 100 × 109/L
10. Patients taking antiepileptic drugs (AED) must be on stable doses of AED for at least
two weeks prior to registration and have no episode of seizures for at least 14 days
prior to registration. Because some AEDs enhance or inhibit enzymes that may affect
PAC-1 metabolism, those AEDs will not be permitted in this study. The AEDs that are
and are not permissible are in Appendix 6.
11. Patient must be able to take oral medication and to maintain a fast as required for 2
hours before and 1 hour after capsule(s) administration
12. Must be willing and able to comply with study visits and procedures
13. Has read, understood and signed the informed consent form (ICF) approved by the
Institutional Review Board/Independent Ethics Committee (IRB/IEC)
14. Women of childbearing potential (WOCP) must not be pregnant (confirmed by a negative
pregnancy test, with a serum B-HCG with a sensitivity of 50 mL U/L within 7 days of
study treatment) or breast-feeding. In addition, a medically acceptable method of
birth control must be used such as an oral, implantable, injectable, or transdermal
hormonal contraceptive, an intrauterine device (IUD), use of a double barrier method
(condoms, sponge, diaphragm, or vaginal ring with spermicidal jellies or cream), or
total abstinence during the study participation and for one month after last dose of
study drug(s). Women who are postmenopausal for at least 1 year or surgically sterile
(bilateral tubal ligation, bilateral oophorectomy, or hysterectomy) are not considered
to be WOCP.
15. Men who are not surgically or medically sterile must agree to use an acceptable method
of contraception. Male patients with female sexual partners who are pregnant, possibly
pregnant, or who could become pregnant during the study must agree to use condoms at
least one month after the last dose of study drug. Total abstinence for the same study
period is an acceptable alternative.
16. Prior systemic treatments for metastatic disease are permitted but may not be ongoing,
including targeted therapies, biologic response modifiers, chemotherapy, hormonal
therapy, or investigational therapy (see Exclusion #20).
17. Willingness to donate blood for biomarker studies related to the type of therapies
used in this trial and the tumor types being treated
18. Had surgery within 4 weeks prior to study treatment except for minor procedures
(hepatic biliary stent placement is allowed)
19. For Component 1 (PAC-1 alone), gliomas are excluded, as well as any history of brain
metastases, seizures or underlying brain injury (e.g., traumatic brain injury, or
hemorrhagic or ischemic stroke)
20. Patients may not have received cytotoxic chemotherapy, targeted therapies, biologic
response modifiers, chemotherapy, and hormonal therapy within the last 3 weeks, or
nitrosureas within the last 6 weeks prior to study treatment.
21. Has a known hypersensitivity to temozolomide (this criterion applies only in Component
22. Has a history of blood clots, pulmonary embolism, or deep vein thrombosis unless
controlled by anticoagulant treatment (patient must be on stable dose for 2 weeks)
23. Has a history of an arterial thromboembolic event within the prior six months
including cerebrovascular accident, transient ischemic attack, myocardial infarction,
or unstable angina.
24. Has uncontrolled human immunodeficiency virus (HIV) (defined as HIV RNA >500 copies/ml
and CD4+ count<200/mm3 on antiretroviral therapy) infection or hepatitis B (defined as
ALT > 1 x ULN, and HBV DNA >2000 IU/ml) or hepatitis C (defined as ALT > 1 x ULN,
persistent viremia on antiviral therapy) infections.
25. Has any clinically significant infection, i.e., any acute viral, bacterial, or fungal
infection that requires specific treatment (anti-infective treatment has to be
completed ≥ 7 days prior to study entry)
26. Has any other severe, uncontrolled medical condition, including uncontrolled diabetes
mellitus (defined as a Hemoglobin A1C≥ 9% in patients with a prior history of
diabetes, 28 days prior to study ) or clinical signs of unstable congestive heart
failure (Stage III-IV of the New York Heart Association Functional Classification)
27. Radiation therapy to more than 25% of the bone marrow. Whole pelvic radiation is
considered to be over 25%.
28. Prior allogeneic bone marrow or organ transplantation.
29. > Grade 1 peripheral neuropathy within 14 days before enrollment.
30. Pregnant or breastfeeding - temozolomide is Pregnancy Category D - can cause fetal
harm. Confirmation that the subject is not pregnant must be established by a negative
serum beta-human chorionic gonadotropin (beta-hCG) pregnancy test result obtained
during screening. Pregnancy testing is not required for post-menopausal or surgically
31. Patient has received other investigational drugs within 14 days prior to study
32. Other severe acute or chronic medical or psychiatric conditions or laboratory
abnormality that may increase the risk associated with study participation or
investigational product administration or may interfere with the interpretation of
study results and, in the judgment of the investigator, would make the patient
inappropriate for enrollment in this study.
33. Abnormalities on 12-lead electrocardiogram (ECG) considered by the investigator to be
clinically significant (such as acute ischemia, left bundle branch block, ventricular
arrhythmias) or baseline prolongation of the rate-corrected QT interval (e.g.,
repeated demonstration of QTc interval > 480 milliseconds).
34. Presence of any non-healing wound, fracture, or ulcer within 28 days prior to the
first dose of study drug.
35. Has any condition that, in the opinion of the investigator, might jeopardize the
safety of the patient or interfere with protocol compliance
36. Has any mental or medical condition that prevents the patient from giving informed
consent or participating in the trial