Investigator-Initiated Study of Imipramine Hydrochloride and Lomustine in Recurrent Glioblastoma

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.