Safety of Batracylin in Patients With Solid Tumors and Lymphomas

Background:

- Batracylin advanced through the National Cancer Institute (NCI) drug development
pipeline until its evaluation at Stage 3 on July 1989, It was then proposed for a phase
I investigation based on its activity against as TOPO II inhibitor in s.c. mouse colon
38, PANC03, COLO9, and cisplatin- and doxorubicin-resistant P388 tumors.

- IND-directed oral toxicology studies indicated interspecies variation in toxicity. Rats
were found to be highly sensitive to batracylin. Ames et al showed that the interspecies
variation in toxicity was consistent with the pattern of metabolism of the compound by
N-acetyltransferase 2 (NAT2) to the acetylated form, N-Ac-batracylin, (a highly toxic
molecule)

- We hypothesize that batracylin can be administered safely in slow acetylator NAT2
genotype patients and can be rapidly evaluated for its potential as a tumor-suppressing
agent.

Objectives:

- Define the maximum tolerated dose, dose-limiting toxicities, and toxicity profile
associated with the oral administration of batracylin daily for 7 consecutive days,
repeated every 28 days in patients with solid tumors and lymphomas.

- Define the pharmacokinetics of oral batracylin administered daily for 7 consecutive days
every 28 days.

- Obtain preliminary evidence of anti-tumor activity of batracylin in patients with solid
tumors or lymphoma.

- Correlate polymorphisms in slow acetylators NAT2 genotypes (NAT2 5, NAT2 6, NAT2 7, and
NAT2 14) with pharmacokinetics results.

- Evaluate the inter-subject variability and toxicity ratio, (N-Ac-Batra) / (batracylin).

- Evaluate the effect of batracylin treatment on gamma-H2AX levels in tumor biopsies.

Eligibility:

- Patients must have a slow acetylator NAT2 genotype defined as NAT2 5, NAT2 6, NAT2 7, or
NAT2 14.

- Patients with advanced, histologically confirmed malignancies refractory to standard
therapy, or those for whom no standard therapy exists.

- Patients should have adequate liver, renal, and bone marrow function.

Study Design:

- In accordance with the accelerated titration design 4B[3], dose levels will initially be
increased at 100% increments, and one new patient per dose level will be treated
according to a 4-week course.

- The accelerated phase ends when one patient experiences dose limiting toxicity (DLT)
during the first course of treatment, or when two different patients experience grade 2,
batracylin-related toxicity during the first course of treatment, or when the
N-acetyl-batra AUC value reach 0.33 uM-Hour (i.e., the lower end of the range in the
rat).

- When the first instance of grade 2 batracylin-related toxicity is observed, two
additional patients must have been treated at that dose, or a higher dose (during any
course), without experiencing moderate (grade 2) or worse (grade 3) toxicity, in order
for the accelerated phase to continue.

- When the accelerated phase ends, the dose-escalation will revert to a more conservative,
modified Fibonacci scheme with 40% dose-step increments, with at least 3 patients
treated per dose level.

-INCLUSION CRITERIA:

1. Patients must have histologically confirmed (by the NIH pathology department) 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.

2. Patients must have measurable or evaluable disease.

3. Patients must have completed any chemotherapy or biologic therapy greater than or
equal to 4 weeks prior to entering the study (6 weeks for nitrosoureas or mitomycin C,
or UCN-01). Patients must be greater than or equal to 2 weeks since any prior
administration of study drug in a exploratory IND/Phase Zero study. Patients must be
greater than or equal to 1 month since any prior radiation or major surgery. Patients
must have recovered to eligibility levels from prior toxicity or adverse events.
However, patients receiving bisphosphonates for any cancer or undergoing androgen
deprivation therapy for prostate cancer are eligible for this therapy.

4. Age greater than or equal to 18 years.

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

6. Life expectancy greater than 3 months.

7. 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 x institutional upper limit of
normal.

- creatinine less than 1.5 x upper limit of normal

OR

-creatinine clearance greater than or equal to 60 mL/min/1.73 m(2) for patients with
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.

8. The effects of batracylin 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 for adverse events in nursing infants
secondary to treatment of the mother with batracylin, breastfeeding should be
discontinued if the mother is treated with batracylin.

9. Patients must have a slow acetylator NAT2 genotype defined as NAT2 5, NAT2 6, NAT2 7,
or NAT2 14. Theoretically slow acetylators will have lower Ac-BAT concentrations. A
number of different polymorphisms in the NAT2 give rise to amino acid substitutions,
and these have been demonstrated to result in absence of catalytic activity in vitro
(http://www.louisville.edu/medschool/pharmacology/NAT.html). Screening for the four
variant alleles (NAT2 5, NAT2 6, NAT2 7 and NAT2 14) results in the detection of the
vast majority of Caucasian slow acetylators, though additional alleles are also common
in other ethnic groups. The precise percentage of slow acetylators also varies with
ethnic origin, ranging from 90% in North Africans to less than 10% in many Asian
populations, with a frequency of 50% in Caucasians. The incidence of fast acetylators
(potentially with increased toxicity) is as follow: 50% among Caucasians, 50% among
Africans, 90% among Japanese, and 20% among Egyptians. We plan to select the slow
acetylators NAT2 subjects and determine the batracylin MTD in this population. The
screening will occur prior to the study start and before patients sign the informed
consent form. Cogenics will be performing the NAT2 analysis.

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

EXCLUSION CRITERIA:

1. Patients receiving any other investigational agents.

2. 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 6 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.

3. Patients with clinically significant illnesses which could compromise participation in
the study, including, but not limited to, active or uncontrolled infection, immune
deficiencies or confirmed diagnosis of HIV infection, 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.

Inclusion of Women and Minorities

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