Indenoisoquinoline LMP744 in Adults With Relapsed Solid Tumors and Lymphomas

Background:

- Indenoisoquinolines are non-camptothecin inhibitors of topoisomerase 1 (top1)
withimproved 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:

-To establish the safety, tolerability and the maximum tolerated dose (MTD) of LMP744 (NSC
706744) administered intravenously (IV) daily for 5 days (QD x 5) schedule in patients with
refractory solid tumors and lymphomas.

Secondary Objectives:

- Characterize the pharmacokinetic (PK) profile of LMP744.

- Evaluate the effect of LMP744 on markers of DNA damage ( >=H2AX, pNbs1, pATR, ERCC1,
RAD51) and epithelial-mesenchymal transition (EMT) in circulating tumor cells (CTCs) and
pre- and post- treatment tumor biopsies in patients at the expansion cohort.

- Assess preliminary antitumor activity of LMP744.

Eligibility:

-Adult patients must have histologically documented, relapsed solid tumors that are
metastatic or unresectable, or lymphoma which had progressed after all FDA-approved therapy,
therapy associated with overall survival benefit, or for which no standard of care therapy
exists.

Study Design:

- Cycle 1 and subsequent cycles: Patients will receive LMP744 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. Tumor biopsies will be optional during the
escalation phase and mandatory during the expansion phase and mandatory during the
expansion phase.

- ELIGIBILITY CRITERIA:

1. Patients must have histologically documented metastatic solid tumors which have
progressed after one line of therapy, or lymphoma which has progressed after all
FDA-approved therapy.

2. Patients must have measurable or evaluable disease

3. Age greater than or equal to 18 years.

4. ECOG performance status less than or equal to 2

5. Life expectancy of greater than 3 months.

6. Patients must have normal 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/mcL

platelets greater than or equal to 100,000/mcL

total bilirubin within normal institutional limits

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

Serum creatinine less than or equal to 1.5 (SqrRoot) institutional ULN

OR

creatinine clearance greater than or equal to 60 mL/min/1.73 m2 for patients with
serum creatinine levelsgreater than 1.5 x higher than institutional normal.

7. Anticoagulation with low-molecular-weight heparin (LMWH) will be permitted.
Patients receiving treatment with warfarin or any of the NOACs (rivaroxaban,
apixaban, dabigatran, or edoxaban) will be given the option to switch to LMWH.

8. Patients must have recovered to grade 1 or baseline from adverse events (AEs)
and/or toxicity of prior chemotherapy or biologic therapy. They must not have had
chemotherapy, biologic therapy, or definitive radiotherapy within 4 weeks (6
weeks for nitrosoureas and mitomycin C) or 5 half-lives, whichever is shorter,
prior to entering the study. Palliative-intent radiotherapy (30 Gy or less) must
be completed at least 2 weeks prior to start of treatment, and may not be to a
lesion that is included as measurable disease. Patients must be greater than or
equal to 2 weeks since any investigational agent administered as part of a Phase
0 study (where a sub-therapeutic dose of drug is administered) at the PI s
discretion, and should have recovered to grade 1 or baseline from any toxicities.

9. Patients receiving denosumab or bisphosphonates for any cancer or undergoing
androgen deprivation therapy for prostate cancer are eligible for this therapy.

10. Prior therapy with topoisomerase I inhibitors is allowed.

11. HIV-positive patients are eligible provided the following criteria are met: CD4
count >350/mm3, an undetectable viral load, and not receiving prophylaxis
antibiotics.

12. The effects of LMP744 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
and for the duration of study participation. 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. Women and 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 4 months after completion
of LMP744 administration.

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

14. Willingness to provide blood and new tumor biopsy samples for research purposes
if on the expansion phase of the study.

EXCLUSION CRITERIA:

1. Patients who are receiving any other investigational agents.

2. Patients with clinically significant illnesses which would compromise participation in
the study, including, but not limited to active or uncontrolled infection, immune
deficiencies, 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.

3. Patients with known brain metastases or carcinomatous meningitis 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 1 month after treatment of the
brain metastases. Patients on anti-seizure medications or steroid therapy may be
enrolled at the discretion of the Principal Investigator.

4. Pregnant women are excluded from this study because LMP744 is an agent with the
potential for teratogenic or abortifacient effects. Because there is an unknown but
potential risk for adverse events in nursing infants secondary to treatment of the
mother with LMP744, breastfeeding should be discontinued if the mother is treated.

INCLUSION OF WOMEN AND MINORITIES:

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