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

• ClinicalTrials.gov Identifier: NCT01719861
• Recruitment Status: Terminated
• First Posted: November 1, 2012
• Results First Posted: April 17, 2017
• Last Update Posted: April 17, 2017
• Sponsor: Joel Neal
• Information provided by (Responsible Party): Joel Neal, Stanford University

Tracking Information

• First Submitted Date: October 29, 2012
• First Posted Date: November 1, 2012
• Results First Submitted Date: January 12, 2017
• Results First Posted Date: April 17, 2017
• Last Update Posted Date: April 17, 2017
• Study Start Date: October 2012
• Actual Primary Completion Date: May 2014 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 2, 2017)

Overall Response Rate (ORR) [ Time Frame: 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.

• Original Primary Outcome Measures (submitted: October 30, 2012): Overall Response Rate (ORR): Number of patients who achieve either a partial or complete response divided by the total number of patients treated on the study as measured by CT scans and RECIST 1.1 criteria. [ Time Frame: At baseline and every 8 weeks up to 3 years. ]

Current Secondary Outcome Measures (submitted: March 2, 2017)

• Desipramine Maximum Dose [ Time Frame: 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.
• Median Serum Desipramine Levels During Treatment [ Time Frame: 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.
• Progression-free Survival (PFS), Median [ Time Frame: 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) [ Time Frame: 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.

• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• 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.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Small Cell Lung Cancer (SCLC)
• Neuroendocrine Tumors

Intervention

Drug: Desipramine HCL

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.

Other Names:

• Norpramin
• Pertofrane
• Desmethylimipramine

Study Arms

Experimental: Desipramine HCl

Desipramine is a tricyclic antidepressant (TCA).

Intervention: Drug: Desipramine HCL

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: May 21, 2014): 6
• Original Estimated Enrollment (submitted: October 30, 2012): 10
• Actual Study Completion Date: May 2015
• Actual Primary Completion Date: May 2014 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01719861
• Other Study ID Numbers: IRB-25491; VAR0087 ( Other Identifier: OnCore )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Joel Neal, Stanford University
• Original Responsible Party: Joel Neal, Stanford University, Joel Neal MD, PhD
• Current Study Sponsor: Joel Neal
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Joel W Neal, MD, PhD; Stanford University

• PRS Account: Stanford University
• Verification Date: March 2017