Topotecan and Doxorubicin in Treating Patients With Small Cell Lung Cancer That Has Relapsed or Not Responded to Treatment

• Safety and efficacy of this regimen as assessed by the maximum tolerated dose (MTD) of the next lowest dose level below where greater than or equal to 2/3 or 3/6 patients experience dose limiting toxicities (DLT) in cohorts of 5 different doses [ Time Frame: After 2 cycles ] [ Designated as safety issue: Yes ]
• DLT of topotecan hydrochloride administered in combination with doxorubicin hydrochloride as assessed by the MTD of the next lowest dose level below where greater than or equal to 2/3 or 3/6 patients experience DLT in cohorts of 5 different doses [ Time Frame: After 2 cycles ] [ Designated as safety issue: Yes ]

• Safety and efficacy of this regimen by RECIST criteria [ Designated as safety issue: Yes ]
• Dose-limiting toxicity of topotecan hydrochloride administered in combination with doxorubicin hydrochloride [ Designated as safety issue: Yes ]

• Correlation of topoisomerase I and II levels in peripheral blood with the presence or absence of grades 3 and 4 hematological toxicity [ Designated as safety issue: Yes ]
• Correlation of topoisomerase I and II levels in peripheral blood with efficacy [ Designated as safety issue: No ]

RATIONALE: Drugs used in chemotherapy, such as topotecan and doxorubicin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Doxorubicin may also stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

PURPOSE: This phase I trial is studying the side effects and best dose of topotecan when given together with doxorubicin in treating patients with small cell lung cancer that has relapsed or not responded to treatment

PRIMARY OBJECTIVES:

I. Evaluate the safety and efficacy, in terms of clinical disease benefit (complete or partial response and stable disease with stable or improved quality of life scores), of treatment with doxorubicin hydrochloride and topotecan hydrochloride in patients with relapsed or refractory small cell lung cancer.

II. Determine the dose-limiting toxicity of topotecan hydrochloride administered in combination with doxorubicin hydrochloride in these patients.

SECONDARY OBJECTIVES:

I. Estimate topoisomerase I and II levels in peripheral blood mononuclear cells and correlate them with the presence or absence of grades 3 and 4 hematological toxicity.

II. Estimate topoisomerase I and II levels in peripheral blood mononuclear cells and correlate them with efficacy.

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

Patients receive doxorubicin hydrochloride IV weekly beginning on day 6 in weeks 1-15. Patients also receive oral topotecan hydrochloride on days 1-5 in weeks 1, 4, 7, 10, and 13 in the absence of disease progression or unacceptable toxicity.

Blood samples are collected at baseline, and at weeks 7 and 16 to measure topoisomerase I and II levels. Patients also complete the FACT-L quality of life questionnaire at baseline, and at weeks 7 and 16.

After completion of study treatment, patients are followed every 2 months

• Drug: doxorubicin hydrochloride
  Given IV
  Other Names:

  • ADM
  • ADR
  • Adria
  • Adriamycin PFS
  • Adriamycin RDF
• Drug: topotecan hydrochloride
  Given orally
  Other Names:

  • hycamptamine
  • Hycamtin
  • SKF S-104864-A
  • TOPO
• Procedure: laboratory biomarker analysis
  Correlative studies
• Procedure: protein analysis
  Correlative studies

Inclusion Criteria:

• Pathologically proven diagnosis of small cell lung cancer (SCLC)
• Have received at least one prior chemotherapy regimen for SCLC
• Primarily refractory or relapsed disease
• Measurable disease in 2 dimensions on imaging studies performed within 4 weeks of starting treatment
• Greater than 2 weeks since last treatment (chemotherapy or radiation) provided subject has recovered from side effects of treatment prior to the study
• Karnofsky score >= 70 (ECOG 0-2)
• No active secondary malignancy; patients with other prior malignancies will be included, provided they have been disease-free for at least five years
• Patients with adequately treated basal cell or squamous cell carcinoma of the skin, adequately treated non-invasive carcinomas will be eligible
• WBC count >= 3,500/mm^3 , OR absolute neutrophil count (ANC) >= 1,500/ul and platelet count >= 100,000/mm^3 within 7 days prior to starting treatment
• Serum creatinine less than 1.5 times the upper limits of normal within 7 days prior to starting treatment
• Serum AST and ALT less than 1.5 times the upper limits of normal, serum alkaline phosphatase less than 2.5 times the upper limits of normal within 7 days prior to starting treatment in the absence of liver metastasis; in the presence of liver metastasis serum AST, ALT and alkaline phosphatase less than or equal to 5.0 times the upper limits of normal within 7 days prior to starting treatment
• Women of child-bearing potential must have a negative pregnancy test within 7 days of initiating study; (no childbearing potential is defined as age 55 years or older and no menses for two years or any age with surgical removal of the uterus and/or both ovaries)
• Non-pregnant and non-nursing; men and women of reproductive potential may not participate unless they have agreed to use an effective contraceptive method while on the study
• Able to return for treatment and follow-up as specified in the protocol
• Able to give informed consent

Exclusion Criteria:

• Known hypersensitivity to any component of topotecan or doxorubicin or other required drugs in the study
• Any co morbidity or condition which, in the opinion of the investigator, may interfere with the assessments and procedures of this protocol
• Ejection fraction below the lower limit of normal (< 50%)
• Uncontrolled intercurrent illnesses including, but not limited to unstable angina or uncontrolled cardiac arrhythmia, chronic liver disease, complete left bundle branch block, obligate use of a cardiac pacemaker, ST depression of > 1 mm in two or more leads and/or T wave inversions in two or more contiguous leads, congenital long QT syndrome, history of or presence of significant ventricular or atrial tachyarrhythmias, clinically significant resting bradycardia (< 50 beats per minute), QTc > 480 ms on screening electrocardiogram that could jeopardize the patient's ability to receive the chemotherapy described in the protocol safely
• Women who are pregnant (confirmed by a serum pregnancy test in females of reproductive potential) or breast-feeding; women of child-bearing potential and sexually active males must be advised to take precautions to prevent pregnancy during treatment (unless the subject or subject's partner(s) is sterile (i.e. women who have had a hysterectomy or have been post-menopausal for at least twelve consecutive months) or remain abstinent, men and women of reproductive potential must agree to use TWO of the following forms of birth control every time they have sex throughout the study and for up to 3 months following discontinuation of study drug: condoms (male or female) with or without a spermicidal agent, diaphragm or cervical cap with spermicidal, IUD, or surgical sterilization while participating in this study; hormonal birth control methods are not permitted
• Inability to co-operate with the requirements of the protocol