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

Phase 2

Terminated

Conditions: Neuroendocrine Tumors
Small Cell Lung Cancer (SCLC)

Interventions: Drug: Desipramine HCL

Registration Number: NCT01719861

Lead Sponsor: Joel Neal

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

Detailed Description: 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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 6

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Desipramine HCl	Desipramine HCL	Desipramine is a tricyclic antidepressant (TCA).

Primary Outcome Measures

Name	Time	Method
Overall Response Rate (ORR)	6 weeks	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.

Secondary Outcome Measures

Name	Time	Method
Median Serum Desipramine Levels During Treatment	Up to 6 weeks	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.
Desipramine Maximum Dose	Up to 6 weeks	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.
Progression-free Survival (PFS), Median	Up to 5 years from enrollment to radiographic progression or drug discontinuation	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.
Median Overall Survival (OS)	From start of enrollment until death, no limit	Median overall survival was defined as time from enrollment to death from any cause calculated using the Kaplan-Meier method.