investigator-initiated study of imipramine hydrochloride and lomustine in recurrent glioblastoma

Conditions: Glioblastoma

Summary: this study is designed as a single center, prospective, open label, single-arm therapeutic trial with both surgical and non-surgical cohorts.


Eligibility criteria:
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.