Safety of Batracylin in Patients With Solid Tumors and Lymphomas

Neoplasms Clinical Trial

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

Status Completed

Clinical Trial Summary

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 x7 consecutive days, repeated every 28 days in patients with solid tumors and lymphomas.

• Define the pharmacokinetics of oral batracylin administered daily x7 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.

Clinical Trial Description

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. ;

Related Conditions & MeSH terms

• Lymphoma
• Neoplasms

• NCT number: NCT00450502
• Study type: Interventional
• Source: National Institutes of Health Clinical Center (CC)
• Status: Completed
• Phase: Phase 1
• Start date: February 24, 2007
• Completion date: April 24, 2011