Metastatic Malignant Solid Neoplasm Clinical Trial
Official title:
A Phase 1 Study of the Polymerase Theta (POLQ) Inhibitor Novobiocin in BRCA-Mutant and Other DNA Damage Repair-Deficient Solid Tumors
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.
PRIMARY OBJECTIVE: I. To determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of continuous novobiocin sodium (novobiocin) 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 continuous novobiocin in patients with solid tumors carrying HR or DDR alterations that are PARP inhibitor-naïve or -resistant. III. To characterize the pharmacokinetic parameters of continuous novobiocin administration 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-naïve 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 daily. 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 (m)RNA 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) twice daily (BID) on days 1-28 of each cycle. Cycles repeat 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. ;
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