LMP400 and LMP776 in Treating Patients With Relapsed Solid Tumors or Lymphomas

OBJECTIVES:

Primary

- Define the maximum tolerated dose (MTD) of topoisomerase I inhibitors LMP400 and LMP776
in patients with relapsed solid tumors or lymphomas.

- Define the dose-limiting toxicities and toxicity profile of topoisomerase I inhibitors
LMP400 and LMP776 in these patients.

- Evaluate the effect of topoisomerase I inhibitors LMP400 and LMP776 on the
pharmacodynamic (PD) endpoint, γ-H2AX, in pre- and post-treatment tumor biopsy samples.

- Compare topoisomerase I inhibitors LMP400 and LMP776 (when administered at the MTD), in
terms of the PD response, defined as the mean percent nuclear area that is γ-H2AX
positive in tumor biopsies, and the risk-benefit relationship, defined by the toxicity
profile vs PD dose-response relationship.

Secondary

- Obtain preliminary evidence of anti-tumor activity of topoisomerase I inhibitors LMP400
and LMP776.

- Characterize the pharmacokinetic profile of topoisomerase I inhibitors LMP400 and
LMP776.

OUTLINE: Patients are alternately assigned to 1 of 2 treatment groups.

- Group I: Patients receive topoisomerase I inhibitor LMP400 IV over 1 hour on days 1-5.
Courses repeat every 28 days in the absence of disease progression or unacceptable
toxicity.

- Group II: Patients receive topoisomerase I inhibitor LMP776 IV over 1 hour on days 1-5.
Courses repeat every 28 days in the absence of disease progression or unacceptable
toxicity.

Patients undergo blood, urine, and tumor tissue sample collection periodically for
correlative laboratory studies, including pharmacodynamic and pharmacokinetic studies and
γ-H2AX marker expression. Patients may also undergo hair follicle sample collection for
correlative laboratory studies.

After completion of study therapy, patients are followed up for 30 days.

DISEASE CHARACTERISTICS:

- Histologically confirmed relapsed solid tumor malignancy or Hodgkin or non-Hodgkin
lymphoma

- Metastatic or unresectable disease for which standard curative measures do not
exist or are associated with minimal patient survival benefit

- Measurable or evaluable disease

- Disease amenable to biopsy

- No known brain metastases

- Patients whose brain metastases have remained stable for ≥ 2 months after
treatment AND do not require steroids or anti-seizure medications may be
eligible at the discretion of the investigator

PATIENT CHARACTERISTICS:

- ECOG performance status (PS) 0-2 or Karnofsky PS 60-100%

- Life expectancy > 3 months

- ANC ≥ 1,500/μL

- Platelet count ≥ 100,000/μL

- Total bilirubin ≤ 1.5 mg/dL (≤ 2.5 mg/dL for patients with Gilbert's syndrome)

- AST and ALT ≤ 2.5 times upper limit of normal (ULN)

- Creatinine < 1.5 times ULN OR creatinine clearance ≥ 60 mL/min

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception prior to, during, and for ≥ 2
months after completion of study therapy

- Willing to undergo skin biopsies

- No clinically significant illness that could compromise participation in the study,
including, but not limited to any of the following:

- Active or uncontrolled infection

- Immune deficiencies

- Known HIV infection requiring antiretroviral therapy

- Hepatitis B or C

- Uncontrolled diabetes

- Uncontrolled hypertension

- Symptomatic congestive heart failure

- Unstable angina pectoris

- Myocardial infarction within the past 6 months

- Uncontrolled cardiac arrhythmia

- Psychiatric illness and/or social situation that would limit compliance with
study requirements

PRIOR CONCURRENT THERAPY:

- More than 4 weeks since prior chemotherapy or biological therapy (6 weeks for
nitrosoureas or mitomycin C; 2 months for UCN-01) and recovered

- No prior tyrosine kinase inhibitors within 5 times the half-life of the inhibitors

- Patients must be ≥ 2 weeks since any investigational agent administered as part of a
Phase 0 study (also referred to as an "early Phase I study" or "pre-Phase I study"
where a sub-therapeutic dose of drug is administered) at the PI's discretion, and
should have recovered to eligibility levels from any toxicities

- At least 1 month since prior radiotherapy

- Prior topoisomerase I inhibitors allowed

- Concurrent bisphosphonates for any cancer allowed

- Concurrent androgen deprivation therapy for prostate cancer allowed

- No other concurrent investigational agents