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

Eligibility 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.
• * 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.