Title
A Phase 1 Study of the Polymerase Theta (POL0) Inhibitor Novobiocin in BRCA-mutant and Other DNA Damage Repair-Deficient Solid Tumors

Description
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.

Objective
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.

Treatment 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 a tumor biopsy at baseline, on day 15 of cycle 1, and at time of progression. Patients undergo medical imaging scans at baseline and every 8 weeks. Patients also undergo blood sample collection on study.

After completion of study treatment, patients are followed up every 3-6 months for 2 years.

Key Eligibility For full study eligibility, see this study's clinicaltrials.gov record.

Applicable Disease Sites
Breast; Gastrointestinal cancers, other; Genitourinary cancers, other; Head and Neck; Lung; Ovary; Pancreas; Prostate

Participating Institutions
UW Health Eastpark Medical Center; UW Health University Hospital