Clinical trial NCT01719861: Phase 2a Desipramine in Small Cell Lung Cancer and Other High-Grade Neuroendocrine Tumors
Official title: A Phase 2a Intrapatient Dose Escalation Study of Desipramine in Small Cell Lung Cancer and Other High-Grade Neuroendocrine Tumors
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Small Cell Lung Cancer (SCLC)
Neuroendocrine Tumors
Lead sponsor: Stanford University
Sponsor class: OTHER
First posted: 2012-11-01
Enrollment: 6
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Overall Response Rate (ORR)
timeFrame: 6 weeks
Secondary outcomes:
measure: Desipramine Maximum Dose
timeFrame: Up to 6 weeks
measure: Median Serum Desipramine Levels During Treatment
timeFrame: Up to 6 weeks
measure: Progression-free Survival (PFS), Median
timeFrame: Up to 5 years from enrollment to radiographic progression or drug discontinuation
measure: Median Overall Survival (OS)
timeFrame: From start of enrollment until death, no limit
Other outcomes:
Locations:
city: Stanford
country: United States
facility: Stanford University Cancer Institute
state: California
Study officials:
affiliation: Stanford University
name: Joel W Neal, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: