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

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.

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