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

Study Overview
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Brief Summary
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This study is designed as a single center, prospective, open label, single-arm therapeutic trial with both surgical and non-surgical cohorts.

Official Title
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A Phase II, Investigator-Initiated Study of Imipramine Hydrochloride and Lomustine in Recurrent Glioblastoma

Conditions
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Glioblastoma

Intervention / Treatment
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* Drug: Lomustine
* Drug: Imipramine Hydrochloride


Participation Criteria
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Eligibility Criteria
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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.
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Imipramine Hydrochloride/Lomustine<br> | Drug: Lomustine<br>* 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.<br>* Other names: Gleostine;Drug: Imipramine Hydrochloride<br>* 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.<br>* Other names: Trofranil;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival |  | 6 months |