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Metastatic Malignant Solid NeoplasmPhase 1NCT05687110

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 testing Biopsy Procedure, Biospecimen Collection and Diagnostic Imaging Testing in people with Metastatic Malignant Solid Neoplasm and Unresectable Malignant Solid Neoplasm, run by National Cancer Institute (NCI) at 23 sites in 2 countries.

Recruiting

Looking for participants now. Contact the study team or a site below to ask about taking part.

Sites and contacts
Official record
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Trial 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… Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Biopsy Procedure, Biospecimen Collection and Diagnostic Imaging Testing
Type of treatment
Surgery or procedure
Could I receive a placebo?
No, everyone receives an active treatment
How many people
43 participants
Where
23 sitesin 2 countries
Study dates
6 Jul 2023to 1 Jul 2028
Phase
Phase 1
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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%)
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  • 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

Who cannot join

  • 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
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  • 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

Trial locations and contacts

23 sites in 2 countries. Contact the study team or a site near you to ask about taking part.

23 sites in 2 countries

United States22 sites, 18 recruiting

  • National Cancer Institute Developmental Therapeutics Clinic

    Bethesda, Maryland, 20892

    Site Public Contact, 800-411-1222

    A P. Chen

    Recruiting

  • National Institutes of Health Clinical Center

    Bethesda, Maryland, 20892

    Active, not recruiting

  • Beth Israel Deaconess Medical Center

    Boston, Massachusetts, 02215

    Site Public Contact, 617-667-9925

    Gerburg M. Wulf

    Recruiting

  • Dana-Farber Cancer Institute

    Boston, Massachusetts, 02215

    Site Public Contact, 877-442-3324

    Geoffrey I. Shapiro

    Recruiting

  • University of Chicago Comprehensive Cancer Center

    Chicago, Illinois, 60637

    Site Public Contact, 773-702-8222, cancerclinicaltrials@bsd.uchicago.edu

    Gini F. Fleming

    Recruiting

  • Ohio State University Comprehensive Cancer Center

    Columbus, Ohio, 43210

    Site Public Contact, 800-293-5066, Jamesline@osumc.edu

    John L. Hays

    Recruiting

  • City of Hope Comprehensive Cancer Center

    Duarte, California, 91010

    Site Public Contact, 800-826-4673, becomingapatient@coh.org

    Sharonlin Bhardwaj

    Recruiting

  • UCI Health - Chao Family Comprehensive Cancer Center and Ambulatory Care

    Irvine, California, 92612

    Active, not recruiting

  • UC San Diego Moores Cancer Center

    La Jolla, California, 92093

    Site Public Contact, 858-822-5354, cancercto@ucsd.edu

    Shumei Kato

    Recruiting

  • Los Angeles General Medical Center

    Los Angeles, California, 90033

    Site Public Contact, 323-865-0451, uscnorrisinfo@med.usc.edu

    Varsha Tulpule

    Recruiting

  • USC / Norris Comprehensive Cancer Center

    Los Angeles, California, 90033

    Site Public Contact, 323-865-0451

    Varsha Tulpule

    Recruiting

  • University of Wisconsin Carbone Cancer Center - Eastpark Medical Center

    Madison, Wisconsin, 53718

    Site Public Contact, 800-622-8922, clinicaltrials@cancer.wisc.edu

    Jeremy Kratz

    Recruiting

  • University of Wisconsin Carbone Cancer Center - University Hospital

    Madison, Wisconsin, 53792

    Site Public Contact, 800-622-8922, clinicaltrials@cancer.wisc.edu

    Jeremy Kratz

    Recruiting

  • NYU Langone Hospital - Long Island

    Mineola, New York, 11501

    Site Public Contact, 212-263-4432, cancertrials@nyulangone.org

    Nancy Chan

    Recruiting

  • Laura and Isaac Perlmutter Cancer Center at NYU Langone

    New York, New York, 10016

    Site Public Contact, CancerTrials@nyulangone.org

    Nancy Chan

    Recruiting

  • University of Oklahoma Health Sciences Center

    Oklahoma City, Oklahoma, 73104

    Site Public Contact, 405-271-8777, ou-clinical-trials@ouhsc.edu

    Debra L. Richardson

    Recruiting

  • UC Irvine Health/Chao Family Comprehensive Cancer Center

    Orange, California, 92868

    Active, not recruiting

  • University of California Davis Comprehensive Cancer Center

    Sacramento, California, 95817

    Active, not recruiting

  • Huntsman Cancer Institute/University of Utah

    Salt Lake City, Utah, 84112

    Site Public Contact, 888-424-2100, cancerinfo@hci.utah.edu

    Vaia Florou

    Recruiting

  • UC San Diego Medical Center - Hillcrest

    San Diego, California, 92103

    Site Public Contact, rhabbaba@health.ucsd.edu

    Shumei Kato

    Recruiting

  • Fred Hutchinson Cancer Center

    Seattle, Washington, 98109

    Site Public Contact, 800-804-8824

    Michael Schweizer

    Recruiting

  • University of Washington Medical Center - Montlake

    Seattle, Washington, 98195

    Site Public Contact, 800-804-8824

    Michael Schweizer

    Recruiting

Other trials in United States

Canada1 site

  • University Health Network-Princess Margaret Hospital

    Toronto, Ontario, M5G 2M9

    Active, not recruiting

Other trials in Canada

About this study

Official title: A Phase 1 Study of the Polymerase Theta (POLθ) 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.

Read the detailed description

PRIMARY OBJECTIVE:

  1. 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:

  1. 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.

  1. To conduct a preliminary assessment of anti-tumor activity of novobiocin administered on a 5-days on/2-days off schedule.

EXPLORATORY OBJECTIVES:

  1. 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.

Being tested
Biopsy Procedure, Biospecimen Collection, Diagnostic Imaging Testing, Novobiocin Sodium
Medical subject headings
Neoplasm Metastasis

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Biopsy ProcedureProcedure or surgery

    Also called Biopsy, BIOPSY_TYPE, Bx

    Undergo tumor biopsy

  • Biospecimen CollectionProcedure or surgery

    Also called Biological Sample Collection, Biospecimen Collected, Sample Collection, Specimen Collection

    Undergo blood sample collection

  • Diagnostic Imaging TestingProcedure or surgery

    Also called Diagnostic Imaging, Medical Imaging

    Undergo medical imaging scans

  • Novobiocin SodiumBiological

    Given PO

Study groups in NCT05687110
Study groupRoleWhat they receive
Treatment (novobiocin sodium)ExperimentalPatients receive novobiocin sodium PO 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.
Receives: Procedure: Biopsy Procedure; Procedure: Biospecimen Collection; Procedure: Diagnostic Imaging Testing; Biological: Novobiocin Sodium

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: Up to 2 years

Secondary outcomes (7)

  1. 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.

    Measured: Up to 2 years

  2. Response rate

    Response rate (CR + PR) will be summarized by frequencies and percentages, by dose level.

    Measured: Up to 2 years

  3. Clinical benefit rate

    Clinical benefit rate (CR + PR + SD > 24 weeks) will be summarized by frequencies and percentages, by dose level.

    Measured: Up to 2 years

  4. Progression free survival

    Will be summarized using Kaplan-Meier curves by dose-level (for dose levels with sufficient sample size to permit estimation).

    Measured: From study enrollment until the identification of disease progression or death, assessed up to 2 years

  5. Median duration of response

    Median duration of response will be reported with ranges.

    Measured: Up to 2 years

  6. Plasma concentrations of novobiocin

    Will be quantitatively measured using liquid chromatography with tandem mass spectrometry to derive standard pharmacokinetic parameters.

    Measured: Days 1 & 17 of cycle 1 (pre-treatment and 0.5, 1, 2, 4, 6, 8, & 24 hours post-treatment) and days 2 & 25 of cycle 2 (pre-dose and 24 hours post-treatment)

  7. Biological effectiveness

    Biological effectiveness will be defined as an increase in the percentage of RAD51-foci positive cells (> 5 foci/nucleus) from =< 10% on the pre-treatment biopsy to >= 30% at the on-treatment biopsy in patients with poly (ADP-ribose) polymerase inhibitor-resistant tumors. A biologically effective dose will be one that induces an increase in gamma-H2AX in the on-treatment compared to the pre-treatment biopsy.

    Measured: Up to 2 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted18 Jan 2023
  2. Study start6 Jul 2023
  3. Primary completion1 Jul 2028 (estimated)
  4. Study completion1 Jul 2028 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
43 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT05687110
Sponsor's protocol ID
NCI-2022-06608
Other IDs
NCI-2022-06608, DF/HCC 23-235, 10528, 10528, UM1CA186709
Status last verified
Jul 2026
First submitted
14 Jan 2023
Last updated
3 Aug 2026
Results posted
No
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
Yes: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Biopsy Procedure, Biospecimen Collection and Diagnostic Imaging Testing in people with Metastatic Malignant Solid Neoplasm and Unresectable Malignant Solid Neoplasm, run by National Cancer Institute (NCI) at 23 sites in 2 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 23 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: looking for participants now, as of the sponsor's last update on 3 Aug 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 23 sites in United States, Canada. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

Each site lists its own contact: choose the nearest one under Trial locations. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Maximum tolerated dose (MTD) and recommended phase 2 dose of continuous novobiocin administration (time frame: Up to 2 years). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT05687110.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 3 Aug 2026.

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