Indenoisoquinoline LMP400 for Advanced Solid Tumors and Lymphomas

Background:

- Indenoisoquinolines are non-camptothecin topoisomerase (Top1) inhibitors that form
stable DNA-Top1 cleavage-complexes, have a preference for unique DNA cleavage sites, and
are active against camptothecin-resistant cell lines. Unlike camptothecins,
indenoisoquinolines are chemically stable and active in cells that over-express
ATP-binding cassette (ABC) transporters ABCG2 and multidrug resistance (MDR-1). Top1
inhibitors are potent anticancer agents because stabilizing cleavage complex formation
induces replication-and transcription-mediated DNA damage and delays DNA repair, leading
to apoptosis. Preclinical and clinical data indicate that baseline tumor levels of Top1
correlate strongly with ability to respond to Top1 inhibitor therapy.

- A first-in-human Phase I study conducted at the NCI of the indenoisoquinoline LMP400
(NSC 743400) on a QD x 5 q28 schedule in patients with refractory solid tumors and
lymphomas (10-C-0056) established that this agent is well tolerated. LMP400 shows linear
pharmacokinetics with evidence of drug accumulation following 5 days of dosing. We
hypothesize that weekly dosing (days 1, 8, 15 q28-day cycle) will increase LMP400 peak
levels and exposures, improving clinical activity and safety.

Primary Objectives:

- To establish the safety and tolerability of weekly (days 1, 8, 15 q28-day cycle) LMP400
in patients with refractory solid tumors and lymphomas.

- To establish the maximum tolerated dose (MTD) of weekly LMP400 in patients with
refractory solid tumors and lymphomas.

- To evaluate the pharmacokinetic profile of weekly LMP400.

Secondary Objectives:

- Evaluate the level of Top1 in tumor biopsies pre- and post- administration of LMP400.

- Evaluate the effect of LMP400 on markers of DNA damage and apoptosis, such as >=H2AX and
caspase 3, in tumor biopsies pre- and post- LMP400 administration.

Eligibility:

-Patients with histologically confirmed metastatic solid tumors and lymphomas; adequate organ
function.

Study Design:

- This is an open-label Phase I trial evaluating weekly administration of LMP400, on days
1, 8, and 15, in 28-day cycles.

- Starting dose is based on the MTD determined from the QD x 5, q28 day schedule currently
being evaluated. The study will follow a 3 plus 3 design.

- Once the MTD is established, 10 additional patients will be enrolled at the MTD to
further define the pharmacokinetics and evaluate effect of study drug on DNA damage and
apoptosis.

- INCLUSION CRITERIA:

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

- The Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to
2

- Life expectancy >3 months.

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

- Leukocytes greater than or equal to 3,000/mcL

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

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

- Total bilirubin less than or equal to 2.0 x institutional upper limit of normal
(we will allow patients with Gilbert s syndrome with total bilirubin up to 2.5
mg/dL)

- AST (SGOT)/ALT (SGPT) less than or equal to 3 x institutional upper limit of
normal

---patients with metastatic disease in the liver less than or equal to 5 x ULN

- Creatinine <1.5 x upper limit of normal

- OR

- Creatinine clearance

- greater than or equal to 60 mL/minute for patients with creatinine levels

- greater than or equal to 1.5 x institutional upper limit of normal

- Age greater than or equal to 18

- 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; abstinence) prior to study
entry, for the duration of study participation, and for 3 months after completion of
indenoisoquinolines administration. Should a woman become pregnant or suspect she is
pregnant while she or her partner is participating in this study, she should inform
her treating physician immediately. Men treated or enrolled on this protocol must also
agree to use adequate contraception prior to the study, for the duration of study
participation, and 3 months after completion of indenoisoquinolines administration

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

EXCLUSION CRITERIA:

- 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 major surgery, chemotherapy, radiotherapy, or biologic therapy within 3 weeks (6
weeks for nitrosoureas and mitomycin C, or 2 months for UCN-01). Patients must be
greater than or equal to2 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 subtherapeutic dose of drug is administered) at the PI s discretion, and
should have recovered to eligibility levels from any toxicities. 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.

- Patients who are receiving any other investigational agents.

- Patients with known active brain metastases are excluded from this clinical trial
because of their poor prognosis and because they often develop progressive neurologic
dysfunction that would confound the evaluation of neurologic and other adverse events.
Patients with brain metastasis stable for at least 4 weeks following surgery and/or
radiation are eligible.

- Uncontrolled incurrent illness including, but not limited to, symptomatic congestive
heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric
illness/social situations that would limit compliance with study requirements.

- HIV-positive patients on combination antiretroviral therapy are ineligible because of
the potential for pharmacokinetic interactions with LMP400. Appropriate studies will
be undertaken in patients receiving combination antiretroviral therapy when indicated.

INCLUSION OF WOMEN AND MINORITIES:

- Both men and women of all races and ethnic groups are eligible for this trial.