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A Phase I Study of Batracylin (NSC320846) in Subjects With Solid Tumors and Lymphomas

Phase 1
18 Years
Not Enrolling

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Trial Information

A Phase I Study of Batracylin (NSC320846) in Subjects With Solid Tumors and Lymphomas


- 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


- 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.


- 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

- 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

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

- creatinine less than 1.5 x upper limit of normal


-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

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
( 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


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

Type of Study:


Study Design:

Primary Purpose: Treatment

Outcome Measure:

Define the maximum tolerated dose of batracylin administered daily x7 consecutive days, repeated every 28 days in slow acetylator NAT2 genotype (NAT2 5, NAT2 6, NAT2 7, or NAT2 14) patients with solid tumors and lymphomas.

Principal Investigator

Shivaani Kummar, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute (NCI)


United States: Federal Government

Study ID:




Start Date:

February 2007

Completion Date:

April 2011

Related Keywords:

  • Neoplasms
  • Cytotoxic
  • Pharmacokinetics
  • Toxicity
  • Neoplasms
  • Pharmacogenomics
  • Solid Tumor
  • Lymphoma
  • Neoplasms
  • Lymphoma



National Institutes of Health Clinical Center, 9000 Rockville Pike Bethesda, Maryland  20892