Topotecan Hydrochloride and Doxorubicin Hydrochloride in Treating Patients With Relapsed or Refractory Small Cell Lung Cancer

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
combination of oral topotecan (topotecan hydrochloride) when given with weekly doxorubicin
(doxorubicin hydrochloride) in patients with SCLC.

II. Determine the dose limiting toxicity of oral topotecan when given with weekly doxorubicin
in patients with SCLC.

SECONDARY OBJECTIVES:

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

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

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

Patients receive doxorubicin hydrochloride intravenously (IV) over 3-5 minutes on day 6 of
course 1 and on days 6, 13, and 20 of courses 2-5. Patients also receive topotecan
hydrochloride orally (PO) on days 1-5. Treatment repeats every 21 days for up to 5 courses in
the absence of disease progression or unacceptable toxicity.

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

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 or evaluable 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; (Eastern Cooperative Oncology Group [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

- White blood cell (WBC) count >= 3,500/mm^3 within 7 days prior to starting treatment,
OR

- Absolute neutrophil count (ANC) >= 1,500/ul within 7 days prior to starting treatment

- 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 aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than
1.5 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 and ALT
less than or equal to 5.0 times the upper limits of normal within 7 days prior to
starting treatment

- 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 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),
corrected QT (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,
intrauterine device (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