Paclitaxel and Nortriptyline Hydrochloride in Treating Patients With Relapsed Small Cell Carcinoma

A Phase 1 Study of Weekly Paclitaxel and Nortriptyline for Relapsed Small Cell Carcinoma

This phase I trial studies the side effects and best dose of nortriptyline hydrochloride when given together with paclitaxel in treating patients with small cell carcinoma that has come back. Nortriptyline hydrochloride, may help disrupt survival signals and cause cancer cell death. Drugs used in chemotherapy, such as paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving nortriptyline hydrochloride and paclitaxel may work better in treating patients with small cell carcinoma.

Study Overview

• Status: Completed
• Conditions: Small Cell Carcinoma
• Intervention / Treatment: Drug: Paclitaxel; Drug: Nortriptyline Hydrochloride

Detailed Description

PRIMARY OBJECTIVES:

I. To determine the maximally tolerated dose (MTD) of nortriptyline hydrochloride (nortriptyline) combined with weekly paclitaxel (PC).

SECONDARY OBJECTIVES:

I. To assess the overall response rate (ORR) to nortriptyline combined with PC.

II. To assess progression free survival (PFS) and overall survival (OS).

OUTLINE: This is a dose-escalation study of nortriptyline hydrochloride.

Patients receive paclitaxel intravenously (IV) on days 1, 8, and 15. Patients also receive nortriptyline hydrochloride orally (PO) once daily (QD) on days 1-7, twice daily (BID) on days 8-14, and thrice daily (TID) on days 15-28 of course 1 and TID on days 1-28 of subsequent courses. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 28 days and every 3 months for 2 years.

• Study Type: Interventional
• Enrollment (Actual): 2
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Washington
    • Seattle, Washington, United States, 98109
      • Fred Hutch/University of Washington Cancer Consortium

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Ability to understand and the willingness to sign a written informed consent
• Pathologically-confirmed small cell carcinoma of any primary site
• Relapse following platinum-based chemotherapy or documented progressive disease while on platinum-based chemotherapy
• Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2 at time of informed consent
• Absolute neutrophil count >= 1.5 x 10^9 cells/L
• Hemoglobin (Hgb) >= 9.0 g/dL
• Platelets >= 100,000 x 10^9/L
• Aspartate aminotransferase (AST), alanine aminotransferase (ALT) =< 2.5 x upper limit of normal (ULN)
• Alkaline phosphatase levels =< 2.5 x upper limit of normal (ULN)
• Total bilirubin =< 1.5 x ULN
• Serum creatinine < 1.5 mg/dL
• At least one site of measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria on computed tomography (CT) scan done within 30 days prior to study start
• Women of child-bearing potential and sexually active men must agree to use adequate contraception (hormonal, barrier method, or abstinence) prior to study entry, during treatment, and for three months after completing treatment
• Baseline electrocardiogram demonstrating all of the following: corrected QT (QTc) < 450 milliseconds (msec) (men) and < 470 msec (women), PR < 240 msec, QRS < 100 msec

Exclusion Criteria:

• Untreated active major depression
• Bipolar disorder
• Pregnancy and lactation; refusal to use adequate contraception
• History of seizures in the past 3 years
• Concurrent therapy with monoamine oxidase inhibitors (MAOI), selective serotonin reuptake inhibitors (SSRI), or other tricyclic antidepressants (TCA) or use within 2 weeks study start
• Concomitant therapy with any drugs shown to have major interactions with nortriptyline (i.e. known inhibitors of cytochrome P450 family 2 subfamily D member 6 [CYP2D6]) and use during the 30-day period prior to study start
• Myocardial infarction in preceding 4 weeks; history of uncontrolled cardiac arrhythmias or family history of sudden cardiac death
• Peripheral neuropathy grade 2 or greater
• Progressive or symptomatic central nervous system (CNS) metastases; patients with known brain metastasis must have stable disease following treatment surgery, radiation, or both
• Glaucoma

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment (paclitaxel, nortriptyline hydrochloride); Patients receive paclitaxel IV on days 1, 8, and 15. Patients also receive nortriptyline hydrochloride PO QD on days 1-7, BID on days 8-14, and TID on days 15-28 of course 1 and TID on days 1-28 of subsequent courses. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.	Drug: Paclitaxel; Given IV; Other Names: Taxol; Anzatax; Asotax; Bristaxol; Praxel; Taxol Konzentrat; Drug: Nortriptyline Hydrochloride; Given PO; Other Names: Pamelor; Allegron; Norpress

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum tolerated dose, determined by the number of patients who experience a dose limiting toxicity	Maximum tolerated dose defined as the highest dose level of nortriptyline (in combination with weekly paclitaxel) where < 1/3 or < 2/6 patients experience a dose-limiting toxicity evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.	Up to 28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective tumor response evaluated according to Response Evaluation Criteria in Solid Tumors version 1.1	Objective tumor response will be assessed with a 95% confidence interval.	Up to 2 years
Overall Survival	Overall Survival will be described using Kaplan-Meier curves.	Up to 2 years
Progression free survival	Progression free survival will be described using Kaplan-Meier curves.	Up to 2 years

Collaborators and Investigators

• Sponsor: University of Washington
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Robert Montgomery, Fred Hutch/University of Washington Cancer Consortium

Study record dates

Study Major Dates

• Study Start (Actual): November 3, 2016
• Primary Completion (Actual): January 1, 2018
• Study Completion (Actual): November 30, 2019

Study Registration Dates

• First Submitted: August 23, 2016
• First Submitted That Met QC Criteria: August 23, 2016
• First Posted (Estimate): August 26, 2016

Study Record Updates

• Last Update Posted (Actual): December 17, 2019
• Last Update Submitted That Met QC Criteria: December 16, 2019
• Last Verified: December 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms by Histologic Type; Neoplasms; Lung Diseases; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma; Small Cell Lung Carcinoma; Carcinoma, Small Cell; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Psychotropic Drugs; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Antidepressive Agents; Antidepressive Agents, Tricyclic; Adrenergic Uptake Inhibitors; Paclitaxel; Albumin-Bound Paclitaxel; Nortriptyline
• Other Study ID Numbers: 9618 (Fred Hutch/University of Washington Cancer Consortium); P30CA015704 (U.S. NIH Grant/Contract); NCI-2016-01197 (Registry Identifier: CTRP (Clinical Trial Reporting Program))