A Phase I Study of Indenoisoquinolines LMP400 and LMP776 in Adults With Relapsed Solid Tumors and Lymphomas

Background:

- Indenoisoquinolines are non-camptothecin inhibitors of topoisomerase 1 (top1) with
improved characteristics over their predecessors. Indenoisoquinolines have better
chemical stability, producing stable DNA-top1 cleavage complexes, and exhibit a
preference for unique DNA cleavage sites, compared with their camptothecin counterparts.

- They have demonstrated activity against camptothecin-resistant cell lines and produce
DNA-protein crosslinks, which are resistant to reversal. They also show less or no
resistance to cells overexpressing the ATP-binding cassette (ABC) transporters, ABCG2,
and multidrug resistance (MDR-1).

Primary Objectives:

- Define the maximum tolerated dose (MTD) of LMP400 (NSC 743400) and LMP776 (NSC 725776)
administered intravenously (IV) daily for 5 days (QDx5).

- Define the dose-limiting toxicities (DLTs) and toxicity profile associated with
administration of LMP400 and LMP776.

- Evaluate the effect of LMP400 and LMP776 on the pharmacodynamic (PD) endpoint,
gamma-H2AX, in tumor biopsy pre- and post-treatment. In particular, compare the PD
response, defined as the mean percent nuclear area that is gamma-H2AX positive (%NAP) in
tumor biopsies, at the MTD for LMP400 and LMP776, and the toxicity profile versus PD
dose-response relationship.

Secondary Objectives:

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

- Characterize the pharmacokinetic (PK) profile of LMP400 and LMP776.

Eligibility:

-Adult patients must have histologically confirmed relapsed solid tumor malignancy or
lymphoma that is metastatic or unresectable for which standard curative measures do not exist
or are associated with minimal patient survival benefit.

Study Design:

- Cycle 1 and subsequent cycles: Patients will be randomized to receive either LMP400 or
LMP776 administered IV QD over 1 hour on days 1-5 followed by 23 days without drug
(28-day cycle).

- PK and PD samples will be collected in cycle 1 only. Tumor biopsies will not be
collected during the escalation phase; however, tumor biopsies will be mandatory during
the expansion phase.

- INCLUSION CRITERIA:

- Patients must have histologically documented (confirmed at the Laboratory of
Pathology, NCI), relapsed solid tumor malignancy or Hodgkin s disease/non-Hodgkin
lymphoma that is metastatic or unresectable for which standard curative measures do
not exist, or are associated with minimal patient survival benefit.

- Patients must have measurable or evaluable disease.

- Patients must have recovered to at least eligibility levels due to adverse events
(AEs) and/or toxicity of prior chemotherapy or biologic therapy. They must not have
had chemotherapy or biologic therapy within 4 weeks (6 weeks for nitrosoureas and
mitomycin C, or 2 months for UCN-01), or therapy with tyrosine kinase inhibitors
within 5 times the half-life of the inhibitors prior to entering the study. Patients
must be (Bullet)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.

- Patients must have recovered to at least a Grade less than or equal to toxicity
eligibility levels due to adverse events (AEs) and/or toxicity of prior chemotherapy
or biologic therapy. They must not have had chemotherapy or biologic therapy within 4
weeks (6 weeks for nitrosoureas and mitomycin C, or 2 months for UCN-01), or therapy
with tyrosine kinase inhibitors within 5 times the half-life of the inhibitors prior
to entering the study. Patients must be greater than or equal to 2 weeks since any
prior administration of study drug in an exploratory IND/Phase 0 study. Patients must
be greater than or equal to 1 month since completion of any prior radiation (greater
than or equal to 2 weeks for palliative radiation therapy). However, patients
receiving bisphosphonates for any cancer or undergoing androgen deprivation therapy
for prostate cancer are eligible for this therapy. Prior therapy with topoisomerase I
inhibitors is allowed.

- Age greater than or equal to 18 years.

- The Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to
2 (Karnofsky greater than or equal to 60%).

- Life expectancy greater than 3 months.

- Patients must have normal or adequate organ and marrow function as defined below:

- Absolute neutrophil count greater than or equal to 1,500/microL

- Platelets greater than or equal to 100,000/microL

- Total bilirubin* within less than or equal to 1.5 normal institutional limits

- AST (SGOT)/ALT (SGPT) less than or equal to 2.5 times institutional upper limit
of normal

- Creatinine less than 1.5 times upper limit of normal

OR

- Creatinine clearance greater than or equal to 60 mL/minute for patients with
(measured) creatinine levels greater than or equal to 1.5 times upper limit of normal

*we will allow patients with Gilbert s syndrome with total bilirubin up to 2.5 mg/dL

- The effects of indenoisoquinolines on the developing human fetus are unknown. For
this reason, women of child-bearing potential and men must agree to use adequate
contraception (hormonal or barrier method of birth control or abstinence) prior
to study entry, for the duration of study participation, and for 2 months after
discontinuation from the study. Women of child bearing potential must have a
negative pregnancy test in order to be eligible. Should a woman become pregnant
or suspect she is pregnant while participating in this study, she should inform
her treating physician immediately. Because there is an unknown but potential
risk to nursing infants secondary to treatment of the mother with
indenoisoquinolines, breastfeeding should be discontinued if the mother is
treated with indenoisoquinolines.

- Willingness to undergo skin biopsies.

- At the point when tumor biopsies become mandatory rather than optional, disease
amenable to biopsy and willingness to undergo biopsies or patient will be
undergoing a procedure due to medical necessity during which the tissue may be
collected, or tumor biopsy tissue from a previous research study or medical care
is available for submission at registration. Criteria for the submission of
tissue are:

- Tissue must have been collected within 3 months prior to registration

- Patient has not received any intervening therapy for their cancer since the collection
of the tumor sample

- Tumor tissue must meet the minimum requirements outlined in Section 9.1.

- Ability to understand and the willingness to sign a written informed consent
document.

EXCLUSION CRITERIA:

- Patients receiving any other investigational agents.

- Patients with known brain metastases are excluded from this clinical trial, with the
exception of patients whose brain metastatic disease status has remained stable for
greater than or equal to 2 months after treatment of the brain metastases, without
steroids or anti-seizure medications. These patients may be enrolled at the discretion
of the principal investigator.

- Patients with clinically significant illnesses which could compromise participation in
the study, including, but not limited to, active or uncontrolled infection, immune
deficiencies, known HIV infection requiring antiretroviral therapy, Hepatitis B,
Hepatitis C, uncontrolled diabetes, uncontrolled hypertension, symptomatic congestive
heart failure, unstable angina pectoris, myocardial infarction within the past 6
months, uncontrolled cardiac arrhythmia, or psychiatric illness/social situations that
would limit compliance with study requirements.