Imipramine Hydrochloride and Lomustine for the Treatment of 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 Institutional Review Board (IRB)/Ethics Committee
• The subject has histologically confirmed glioblastoma (including IDH-mutant glioblastoma [GBM] but not grade II or III IDH-wt glioma)
• The subject has progression following standard combined modality treatment with radiation and temozolomide chemotherapy
• The subject has an Karnofsky performance status ≥ 60
• The subject has a life expectancy of at least 3 months
• Bilirubin =< 1.5 times upper limit of normal (ULN)
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 times upper limit of normal (ULN)
• Serum creatinine =< ULN
• Absolute neutrophil count (ANC) >= 1500 cells/uL (without hematologic support)
• Platelet count >= 100,000/uL (without hematologic support)
• Hemoglobin >= 9.0 g/dL (without hematologic support)
• 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 intrauterine device [IUD]) with their partner from entry into the study through 6 months after the last dose
• Must have measurable disease by Response Assessment in Neuro-Oncology (RANO) criteria
• Conditions or situations which, in the opinion of the investigator imply the patient will be unable or not suitable to complete trial requirements or at excessive risk from trial participation

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 magnetic resonance imaging (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) version (v)5.0 grade =< 1 from adverse events (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 corrected QT (QTc) rhythm noted during initial electrocardiography (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
• Uncontrolled mood disorder which in the opinion of the investigator would jeopardize welfare of patient or others, or that which would jeopardize study compliance or integrity
• 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 serotonin reuptake inhibitor (SSRI), serotonin–norepinephrine reuptake inhibitor (SNRI), monoamine oxidase (MAO) inhibitor, tramadol or trazodone who are unwilling to undergo taper