NCT05687110

Studying the Safety and Determining the Optimal Dose of Novobiocin in Patients With Tumors That Have Alterations in DNA Repair Genes

A Phase 1 Study of the Polymerase Theta (POLθ) Inhibitor Novobiocin in BRCA- Mutant and Other DNA Damage Repair-Deficient Solid Tumors

• Status: Recruiting
• Phase: Phase 1
• Study type: Interventional
• Enrollment: 43 (estimated)
• Sponsor: National Cancer Institute (NCI) · NIH
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

Summary

This phase I trial tests the safety, side effects, and best dose of novobiocin in treating cancer patients with alterations in deoxyribonucleic acid (DNA) repair genes. Novobiocin is an antibiotic that blocks the activity of a protein called DNA polymerase theta, which helps repair DNA that has become damaged as cells grow and divide. Cancer cells that cannot repair their damaged DNA die. This medication may help shrink or stabilize cancer with a mutation in DNA repair genes.

Detailed description

PRIMARY OBJECTIVE: I. To determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of novobiocin sodium (novobiocin) administered on a 5-days on/2-days off schedule in patients with solid tumors carrying homologous recombination (HR) or DNA damage repair (DDR) alterations that are poly (ADP-ribose) polymerase (PARP) inhibitor-naïve or -resistant. SECONDARY OBJECTIVES: I. To observe and record anti-tumor activity. II. To evaluate the safety and tolerability of novobiocin administered on a 5-days on/2-days off schedule in patients with solid tumors carrying HR or DDR alterations that are PARP inhibitor-naïve or -resistant. III. To characterize the pharmacokinetic parameters of novobiocin administered on a 5-days on/2-days off schedule in patients with solid tumors carrying HR or DDR alterations that are PARP inhibitor- naïve or -resistant. IV. To determine the minimally biologically effective dose of novobiocin in patients with solid tumors carrying HR or DDR alterations that are PARP inhibitor-naive or -resistant using pre- and on-treatment biopsies to characterize novobiocin-mediated pharmacodynamic effects. V. To conduct a preliminary assessment of anti-tumor activity of novobiocin administered on a 5-days on/2-days off schedule. EXPLORATORY OBJECTIVES: I. Whole exome sequencing (WES) of pre- and time-of-progression biopsies to characterize tumors for HR deficiency (deleterious mutations/deletions in genes known to be involved in HR) and genomic changes mediating acquired resistance to novobiocin. II. Ribonucleic acid sequencing (RNAseq) on pre- and on-treatment biopsies, as well as time-of-progression biopsies for serial analysis of gene expression to identify determinants of response, resistance, and pathway adaptation to novobiocin. III. Correlation of baseline level of POLQ messenger ribonucleic acid (mRNA) with clinical outcome (complete response \[CR\], partial response \[PR\] or stable disease \[SD\] versus \[vs.\] progressive disease \[PD\]). IV. Correlation of ATM immunohistochemistry (IHC) with clinical outcome in patients with ATM-mutant cancers. OUTLINE: This is a dose-escalation study. Patients receive novobiocin sodium orally (PO) once daily (QD) for 5 days in a row followed by 2 days off each week. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo tumor biopsy, medical imaging scans, and collection of blood samples throughout the trial. After completion of study treatment, patients are followed up every 3-6 months for 2 years.

Conditions

• Metastatic Malignant Solid Neoplasm
• Unresectable Malignant Solid Neoplasm

Interventions

Type	Name	Description
PROCEDURE	Biopsy Procedure	Undergo tumor biopsy
PROCEDURE	Biospecimen Collection	Undergo blood sample collection
PROCEDURE	Diagnostic Imaging Testing	Undergo medical imaging scans
BIOLOGICAL	Novobiocin Sodium	Given PO

Timeline

• Start date: 2023-07-06
• Primary completion: 2026-08-01
• Completion: 2026-09-01
• First posted: 2023-01-18
• Last updated: 2026-04-13

Locations

23 sites across 2 countries: United States, Canada

Regulatory

• FDA-regulated drug study