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.
Patients must have histologically confirmed malignancy that is metastatic or unresectable and for which standard curative or palliative measures do not exist or are no longer effective
Patients must have histologically confirmed solid tumor with a known pathogenic mutation in BRCA1/2, PALB2, RAD51C, RAD51D, ATM, BARD1, BLM, BRIP1, CDK12, FANCA, FANCC, FANCD2, FANCE, FANCF, FANCM, MRE11A, NBN (NBS1), RAD50 and RAD51B as confirmed by a Clinical Laboratory Improvement Amendments (CLIA)-certified method. Patients with alterations defined only by germline testing are eligible. Other qualifying HRD alterations may be considered if approved by the principal investigator and the Cancer Therapy Evaluation Program (CTEP) monitor
Any number of prior therapy regimens is allowed
Patients with cancers for which PARP inhibitors have been approved as standard-of-care must have received a PARP inhibitor prior to enrollment on this study. Other patients may be either PARP inhibitor-naïve (i.e., never have received a PARP inhibitor) or have disease that is PARP inhibitor-resistant (i.e., disease that has progressed radiologically based on Response Evaluation Criteria in Solid Tumors [RECIST] 1.1 while receiving any PARP inhibitor)
Patients who have had chemotherapy or radiotherapy within 2 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study
Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1) with the exception of alopecia
Patients who are receiving any other investigational agents
History of allergic reactions attributed to compounds of similar chemical or biologic composition to novobiocin
Single group
Biopsy Procedure
Procedure/SurgeryUndergo tumor biopsy
Biospecimen Collection
Procedure/SurgeryUndergo blood sample collection
Diagnostic Imaging Testing
Procedure/SurgeryUndergo medical imaging scans
Novobiocin Sodium
Biological/VaccineGiven PO
Maximum tolerated dose (MTD) and recommended phase 2 dose of continuous novobiocin administration
The MTD will be identified as the dose for which the isotonic estimate of the toxicity rate is closest to the target toxicity rate. Standard hematological and non-hematologic parameters, scored using Common Terminology Criteria for Adverse Events version 5.0, will be used to define dose limiting toxicity.
Radiological response
Radiological response will be assessed by Response Evaluation Criteria in Solid Tumors version 1.1 criteria and will be graded as complete response (CR), partial response (PR), stable disease (SD) and progressive disease.
Response rate
Response rate (CR + PR) will be summarized by frequencies and percentages, by dose level.
Clinical benefit rate
Clinical benefit rate (CR + PR + SD \> 24 weeks) will be summarized by frequencies and percentages, by dose level.
Progression free survival
Will be summarized using Kaplan-Meier curves by dose-level (for dose levels with sufficient sample size to permit estimation).
POLQ messenger ribonucleic acid level (mRNA)
Other pharmacodynamic data will be captured using descriptive statistics. In an exploratory fashion, will analyze correlations between baseline POLQ mRNA level and clinical outcome.
ATM immunohistochemistry (IHC)
Other pharmacodynamic data will be captured using descriptive statistics. In an exploratory fashion, will analyze correlations between ATM IHC and genomic alterations.
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