Neuroendocrine Tumors, Small Cell Lung Cancer (SCLC)
Conditions
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.
Interventions
DRUGDesipramine 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.
Sponsors
Joel Neal
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
Countries
United States
Participant flow
Recruitment details
10 participants total were to be enrolled at Stanford Medical Center between December 2012 - December 2013
Participants by arm
| Arm | Count |
|---|---|
| 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. By the end of the 6 weeks, patients will be taking 450 mg (maximum dosage) or a tolerable dose of desipramine without serious side effects. | 6 |
| Total | 6 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Cycle 1 | Death | 4 |
| Cycle 2 | Death | 1 |
Baseline characteristics
| Characteristic | Desipramine HCl |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 2 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Histology Large Cell Neuroendocrine Carcinoma of Lung | 2 participants |
| Histology Large Cell Neuroendocrine Carcinoma of Pancreas | 1 participants |
| Histology Small Cell Carcinoma of Lung | 3 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 5 Participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 6 / 6 |
| serious Total, serious adverse events | 6 / 6 |
Outcome results
Primary
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.
Time frame: 6 weeks
Population: All patients who were enrolled and started therapy.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Desipramine HCl 25 mg | Overall Response Rate (ORR) | 0 percentage of participants |
Secondary
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.
Time frame: Up to 6 weeks
Population: All patients who were enrolled and started therapy.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Desipramine HCl 25 mg | Desipramine Maximum Dose | 75 mg daily |
Secondary
Median Overall Survival (OS)
Median overall survival was defined as time from enrollment to death from any cause calculated using the Kaplan-Meier method.
Time frame: From start of enrollment until death, no limit
Population: All patients who were enrolled and started therapy.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Desipramine HCl 25 mg | Median Overall Survival (OS) | 2.7 Months |
Secondary
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.
Time frame: Up to 6 weeks
Population: All patients who were enrolled and started therapy.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Desipramine HCl 25 mg | Median Serum Desipramine Levels During Treatment | 132 ng/mL |
Secondary
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.
Time frame: Up to 5 years from enrollment to radiographic progression or drug discontinuation
Population: All patients who were enrolled and started therapy.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Desipramine HCl 25 mg | Progression-free Survival (PFS), Median | 1.2 Months |