Clinical Trial Finder

Inclusion Criteria:

• - The subject is at least 18 years of age.

• - The subject has the ability to understand the purposes and risks of the study and to have signed a written informed consent form approved by the investigator's IRB/Ethics Committee.

• - The subject has histologically confirmed glioblastoma.

• - The subject has progression following standard combined modality treatment with radiation and temozolomide chemotherapy.

• - The subject has an ECOG (Eastern Cooperative Oncology Group) performance status ≤ 2.

• - The subject has a life expectancy of at least 3 months.

• - The subject has acceptable liver function: - Bilirubin ≤ 1.5 times upper limit of normal.

• - AST (aspartate aminotransferase) (SGOT) and ALT (alanine transaminase 0 (SGPT) ≤ 3.0 times upper limit of normal (ULN) - The subject has acceptable renal function: - Serum creatinine ≤ULN.

• - The subject has acceptable hematologic status (without hematologic support): - ANC (absolute neutrophil count) ≥1500 cells/uL.

• - Platelet count ≥100,000/uL.

• - Hemoglobin ≥9.0 g/dL.

• - All women of childbearing potential (not surgically sterilized or at least 1 year post-menopausal) must have a negative serum pregnancy test.

Additionally, male and female subjects must agree to use effective means of contraception (surgical sterilization or the use or barrier contraception with either a condom or diaphragm in conjunction with spermicidal gel or an IUD) with their partner from entry into the study through 6 months after the last dose.

Exclusion Criteria:

• - The subject is receiving warfarin (or other coumarin derivatives) and is unable to switch to low molecular weight heparin (LMWH) before the first dose of study drug.

• - The subject has evidence of acute intracranial or intratumoral hemorrhage either by MRI or computerized tomography (CT) scan.

Subjects with resolving hemorrhage changes, punctate hemorrhage, or hemosiderin are eligible.

• - The subject is unable to undergo MRI scan (eg, has pacemaker).

• - The subject has received enzyme-inducing anti-epileptic agents within 14 days of study drug (eg, carbamazepine, phenytoin, phenobarbital, primidone).

• - The subject has not recovered to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0 Grade ≤ 1 from AEs (except alopecia, anemia and lymphopenia) due to surgery, antineoplastic agents, investigational drugs, or other medications that were administered prior to study drug.

• - The subject has evidence of wound dehiscence.

• - The subject is pregnant or breast-feeding.

• - The subject has a history of cardiac disease, including arrhythmia, conduction abnormality, congenital prolonged QT syndrome, myocardial infarction, unstable angina pectoris or congestive heart failure.

• - A prolonged QTc rhythm noted during initial ECG >480 ms.

• - The subject has serious intercurrent illness, such as: - Hypertension (two or more blood pressure [BP] readings performed at screening of > 150 mmHg systolic or > 100 mmHg diastolic) despite optimal treatment.

• - Non-healing wound, ulcer, or bone fracture.

• - Untreated hypothyroidism.

• - Unhealed rectal or peri-rectal abscess.

• - Uncontrolled active infection.

• - Stroke, or transient ischemic attack within 6 months.

• - The subject has received any of the following prior anticancer therapy: - Non-standard radiation therapy such as brachytherapy, systemic radioisotope therapy (RIT), or intra-operative radiotherapy (IORT).

Note: stereotactic radiosurgery (SRS) is allowed.

• - Non-bevacizumab systemic therapy (including investigational agents and small- molecule kinase inhibitors) or non-cytotoxic hormonal therapy (eg, tamoxifen) within 7 days or 5 half-lives, whichever is shorter, prior to first dose of study drug.

• - Biologic agents (antibodies, immune modulators, vaccines, cytokines) within 21 days prior to first dose of study drug.

• - Nitrosoureas or mitomycin C within 42 days, or metronomic/protracted low-dose chemotherapy within 14 days, or other cytotoxic chemotherapy within 28 days, prior to first dose of study drug.

• - Prior treatment with carmustine wafers.

• - Any current psychosis, uncontrolled mood disorder (as assessed by investigator) or suicidal ideation.

Additionally, current or history of bipolar disorder is excluded.

• - Patients currently using SSRI, SNRI, MAO inhibitors, tramadol or trazodone who are unwilling to undergo taper.

Arms

Experimental: Imipramine Hydrochloride/Lomustine

Interventions

Drug: - Lomustine

For surgical cohort patients, lomustine will be initiated (C1D1) within 6 weeks of surgery as soon as patient is deemed by the investigator (or designee) to be recovered enough for chemotherapy. Initiation of lomustine must be initiated within 6 weeks. If patient cannot be safely initiated on lomustine within this timeframe then they will be replaced. For non-surgical cohort patients (the decision for surgery is made independent of study participation), lomustine will be initiated on C1D1. For both cohorts, lomustine will be administered as 110 mg/m2 PO once every 6 weeks.

Drug: - Imipramine Hydrochloride

For the surgical cohort, imipramine hydrochloride will be initiated within a minimum of 16 days to a maximum of 3 weeks prior to surgery. Imipramine hydrochloride will be administered as 50mg PO (oral) QHS (at bedtime) for 4 days followed by a dose increase (taper-up) of 50mg/day every fourth day to attain a maximum dose of 200mg/day in 16 days. For non-surgical cohort patients (the decision for surgery is made independent of study participation), imipramine hydrochloride will be initiated on Cycle 1 Day 1. Imipramine hydrochloride will be administered as 50mg PO (oral) QHS (at bedtime) for 4 days followed by a dose increase (taper-up) of 50mg/day every fourth day, if tolerated, to attain a maximum dose of 200mg/day in 16 days.