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Testing novobiocin for cancer patients with DNA repair gene alterations

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

Phase 1 Interventional National Cancer Institute (NCI) · NCT05687110

This study is testing a drug called novobiocin to see if it can help cancer patients with certain gene changes in their tumors feel better and fight their cancer.

Quick facts

PhasePhase 1
Study typeInterventional
Enrollment43 (estimated)
Ages18 Years and up
SexAll
SponsorNational Cancer Institute (NCI) NIH
Drugs / interventionschemotherapy
Locations23 sites (Duarte, California and 22 other locations)
Trial IDNCT05687110 on ClinicalTrials.gov

What this trial studies

This phase I trial evaluates the safety and optimal dosing of novobiocin in patients with metastatic or unresectable solid tumors that have alterations in DNA repair genes. The study aims to determine the maximum tolerated dose and assess the drug's anti-tumor activity, safety, and pharmacokinetics. Patients will receive novobiocin on a schedule of five days on treatment followed by two days off, with biopsies taken to evaluate the drug's effects on tumor biology. The trial focuses on patients who are either naïve to or resistant to PARP inhibitors.

Who should consider this trial

Good fit: Ideal candidates include patients with metastatic or unresectable solid tumors that have specific pathogenic mutations in DNA repair genes.

Not a fit: Patients with tumors that do not have alterations in DNA repair genes or those who have already received PARP inhibitors as standard care may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could provide a new therapeutic option for patients with specific genetic alterations in their tumors.

How similar studies have performed: While the approach of using novobiocin in this context is novel, similar studies targeting DNA repair deficiencies have shown promise in the past.

Eligibility criteria

Show full inclusion / exclusion criteria 
Inclusion Criteria:

* 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)
* Age \>= 18 years. Because no dosing or adverse event data are currently available on the use of novobiocin in patients \< 18 years of age, children are excluded from this study
* Eastern Cooperative Oncology Group Performance (ECOG) performance status =\< 2 (Karnofsky \>= 60%)
* Absolute neutrophil count \>= 1,500/mcL
* Leukocytes \>= 3,000/mcL
* Platelets \>= 100,000/mcL
* Total bilirubin =\< 1.5 × institutional upper limit of normal (ULN)
* Aspartate transaminase (AST) (serum glutamic-oxaloacetic transaminase \[SGOT\])/alanine transferase (ALT)(serum glutamate pyruvate transaminase \[SGPT\]) =\< 1.5 × institutional ULN
* Glomerular filtration rate (GFR) \>= 60 mL/min (via the chronic kidney disease epidemiology \[CKD-EPI\] glomerular filtration rate estimation)
* Fridericia's formula-corrected QT interval (QTcF) =\< 480 ms
* Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
* For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
* Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
* Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression, stable and off steroids for 1 month
* Patients with new or progressive brain metastases (active brain metastases) or leptomeningeal disease are eligible if the patient is asymptomatic and the treating physician determines that immediate CNS specific treatment is not required and is unlikely to be required during the first cycle of therapy
* Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
* Patients should be New York Heart Association Functional Classification of class 2B or better
* Patients must have tumors amenable to biopsies, and be willing to undergo biopsies at two time points (pre- and on-treatment)
* The effects of novobiocin on the developing human fetus are unknown. For this reason and because polymerase theta (POLtheta) inhibitor agents have the potential to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation and 4 months after completion of novobiocin administration. Effective contraception is defined as a method that achieves a failure rate of less than 1% per year when used consistently and correctly. (Note: Because of a concern for decreased effectiveness of estrogen-containing oral agents when given with novobiocin, barrier methods and abstinence are the preferred methods for contraception). Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately
* Ability to understand and the willingness to sign a written informed consent document. Participants with impaired decision-making capacity who have a legally-authorized representative (LAR) and/or family member available will also be eligible

Exclusion Criteria:

* 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
* Patients receiving any medications or substances that are strong inhibitors or inducers of CYP3A4/5 are ineligible. Patients receiving any medications or substances that are known to be substrates of breast cancer resistance protein (BCRP/ABCG2) and/or organic anion transporting polypeptides (OATP1B1, OATP1B3 and OATP2B1) and/or organic anion transporters (OAT1 and OAT3) within 14 days prior to the first dose of study drug are ineligible. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product
* Patients using herbal/dietary supplements with known hepatotoxicity risk are ineligible
* Patients receiving concurrent medications associated with a risk of corrected QT interval (QTc) prolongation and/or Torsades de Pointes are not allowed within 14 days of initiation of study treatment. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently updated medical reference such as CredibleMeds or Lexicomp. Drugs listed in the "drugs to avoid in CLQTS (congenital long QT syndrome)" and "known risk of TdP (torsade de pointes)" should be excluded. Granisetron is an acceptable antiemetic on this study. If a patient must take ondansetron, they may NOT take any other concomitant agents which might impact their QTc
* Patients must have UGT1A1 testing at screening. Patients homozygous for A(TA)7TAA in the promoter region (also known as UGT1A1 \*28), homozygous for the G71R allele (also known as UGT1A1\*6), or with compound alterations of \*28 and \*6, are excluded as they are at risk for further reduction of UGT1A1 activity that may disrupt bilirubin clearance

  * UGT1A1 testing must address both \*28 and \*6 alterations
* Patients with uncontrolled intercurrent illness. Additionally, patients with acute liver disease, poorly controlled liver disease, or cirrhosis are excluded
* Patients with (known) active or poorly controlled alcohol use disorder are excluded
* Pregnant women are excluded from this study because novobiocin is a POLtheta inhibitor agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with novobiocin, breastfeeding should be discontinued if the mother is treated with novobiocin

Where this trial is running

Duarte, California and 22 other locations

Study contacts

How to participate

  1. Review the eligibility criteria above with your treating physician.
  2. Visit the official trial page on ClinicalTrials.gov for the most current contact information and recruitment status.
  3. Contact the listed study coordinator or principal investigator to request pre-screening. Pre-screening is free and never obligates you to enroll.
View on ClinicalTrials.gov → Find more trials like this →
Conditions Metastatic Malignant Solid NeoplasmUnresectable Malignant Solid Neoplasm
Last reviewed 2026-06-13 by the Find a Trial editorial team. Information on this page is for educational purposes and is not medical advice. Always consult qualified healthcare professionals about clinical trial participation.