Inclusion Criteria:
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 Appendix 4)
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.
Exclusion Criteria:
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 2)
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)
(Appendix 5).
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 sterilized women.
31. Patient has received other investigational drugs within 14 days prior to study
treatment.
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
