Phase 2a Desipramine in Small Cell Lung Cancer and Other High-Grade Neuroendocrine Tumors

Study Overview
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Brief Summary
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Intrapatient dose escalation study of desipramine in subjects with small cell lung cancer (SCLC) and other high-grade neuroendocrine tumors.

Detailed Description
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Participants will start desipramine by mouth nightly (QHS) for 6 weeks, with weekly dose escalation. Starting dose will be 25 to 75 mg. The desipramine dose will be escalated until the maximum dose of 450 mg is reached or a maximum safe dose per subject is established. Dose level may be adjusted (decreased) based on cardiac or general adverse effects. desipramine level will be tapered if the subject experience disease progression, unless physician judges immediate suspension is in the subjects best interest. Assessments will be conducted every 28 days, and will include ECGs, physicians and blood samples. One partial and/or complete response will be sufficient to consider a larger clinical trial.

Official Title
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A Phase 2a Intrapatient Dose Escalation Study of Desipramine in Small Cell Lung Cancer and Other High-Grade Neuroendocrine Tumors

Conditions
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Small Cell Lung Cancer (SCLC), Neuroendocrine Tumors

Intervention / Treatment
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* Drug: Desipramine HCL


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Metastatic small-cell lung cancer Metastatic high-grade neuroendocrine carcinoma of any organ system (high-grade defined by Ki-67 ≥ 20% and/or ≥ 20 mitoses/10 (HPF). Received at least one line of prior chemotherapy treatment for metastatic disease. Daily chemotherapy must be completed ≥ 2 weeks prior to registration Weekly chemotherapy must be completed ≥ 2 weeks prior to registration Chemotherapy every 2 weeks must be completed ≥ 3 weeks prior to registration Chemotherapy every 3 weeks must be completed ≥ 4 weeks prior to registration ECOG Performance Status 0 to 2 Measurable disease by RECIST 1.1 criteria Age at least 18 years Estimated life expectancy at least 3 months Absolute neutrophil count ≥ 1,500/ mm³ Platelets ≥ 100,000/mm³ Hemoglobin ≥ 9 g/dL Total bilirubin ≤ 1.5 mg/dL, OR ≤ 2 X ULN if tumor involves the liver AST(SGOT) ALT(SGPT) ≤ 3 X ULN Creatinine ≤ 1.5 X ULN Creatinine clearance ≥ 45 mL/min/1.73m²) for patients with creatinine levels above institutional normal QT interval corrected using Fridericia's method (QTcF) < 450 msec (males) or < 470 msec (females) PR < 240 msec QRS < 100 msec Brain metastases must be asymptomatic and have been adequately treated with radiation finishing at least 1 week prior to initiation of study treatment. Ability to understand and the willingness to sign a written informed consent document. Exclusion Criteria: Clinically-significant ventricular arrhythmia including cardiac arrest Myocardial infarction from coronary artery disease within 3 months of study enrollment Implantable pacemaker or implantable cardioverter defibrillator NYHA Class III or greater congestive heart failure Other clinically-significant cardiac disorders Family history of long QT syndrome. Concomitant or expected treatment with strong inhibitors of cytochrome p450 CYP2D6, specifically including Bupropion; Fluoxetine; or Paroxetine (must be discontinued at least 2 weeks or 5-half lives prior to the initiation of desipramine, whichever is shortest, except fluoxetine which requires at least a 5-week washout period). Use of medications known to increase risk of torsades de pointes, including Amiodarone; Arsenic trioxide; Astemizole; Azithromycin; Bepridil; Chloroquine; Chlorpromazine; Cisapride; Citalopram; Clarithromycin; Disopyramide; Dofetilide; Domperidone; Droperidol; Erythromycin; Flecainide; Halofantrine; Haloperidol; Ibutilide; Levomethadyl; Mesoridazine; Methadone; Moxifloxacin; Pentamidine; Pimozide; Probucol; Procainamide; Quinidine; Sotalol; Sparfloxacin; Terfenadine; Thioridazine; Vandetanib Other anti-depressant or anti-psychotic medications including selective serotonin re-uptake inhibitors (SSRIs); other tricyclic, monoamine oxidase inhibitors (MAOIs); serotonin-norepinephrine reuptake inhibitors (SNRIs, typical or atypical anti-psychotic) Metoclopramide (Reglan) because of increased risk of extrapyrimidal symptoms and neuroleptic malignant syndrome Symptomatic orthostatic hypotension despite adequate volume resuscitation. Medical history of narrow angle glaucoma Bipolar disorder, ongoing or active within the last 5 years Suicidal ideation, ongoing or active within the last 5 years Suicide attempt, ongoing or active within the last 5 years Pregnancy Breastfeeding Receiving any other investigational agents Any other serious or unstable concomitant systemic disorder that in the opinion of the investigator is incompatible with the clinical study

Ages Eligible for Study
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Minimum Age: 18 Years

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: Desipramine HCl<br>Desipramine is a tricyclic antidepressant (TCA). | Drug: Desipramine HCL<br>* Desipramine is a tricyclic antidepressant (TCA). All patients will start off with a 25 mg dose by mouth nightly (QHS), increasing weekly for 6 weeks. The target dose level at 6 weeks is 450 mg (maximum dosage) or the maximum tolerated dose (MTD) for each subject.<br>* Other names: Desmethylimipramine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) | Overall response rate (ORR) was assessed as the number of patients who achieve either a partial (PR) or complete response (CR) measured by CT scans and Response Evaluation Criteria In Solid Tumors (RECIST 1.1) criteria, divided by the total number of patients treated on the study. CR: Disappearance of all target lesions, all non-target lesions, and no new lesion. PR: At least a 30% decrease in the sum of diameters of target lesions, no progression in non-target lesion, and no new lesion. | 6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Desipramine Maximum Dose | Assessed as the median per patient maximum dose (MD) using intra-patient dose escalation, and reported as the highest dose of desipramine administered continuously for 1 week or greater. | Up to 6 weeks | 
| Median Serum Desipramine Levels During Treatment | Median serum desipramine levels during treatment is reported as the median of the maximum steady state serum concentration observed in all patients. Therapeutic concentration of desipramine is 100 to 300 ng/mL, and toxic concentration is > 300 ng/mL. | Up to 6 weeks | 
| Progression-free Survival (PFS), Median | Median PFS was defined as the time from randomization to disease progression (or death if the patient died before progression) calculated using the Kaplan-Meier method. | Up to 5 years from enrollment to radiographic progression or drug discontinuation | 
| Median Overall Survival (OS) | Median overall survival was defined as time from enrollment to death from any cause calculated using the Kaplan-Meier method. | From start of enrollment until death, no limit |