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 of the Polymerase Theta (POLθ) Inhibitor Novobiocin in BRCA- Mutant and Other DNA Damage Repair-Deficient Solid Tumors
4 other identifiers
interventional
43
2 countries
23
Brief 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 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.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P50-P75 for phase_1
Started Jul 2023
Typical duration for phase_1
23 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
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Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
January 14, 2023
CompletedFirst Posted
Study publicly available on registry
January 18, 2023
CompletedStudy Start
First participant enrolled
July 6, 2023
CompletedPrimary Completion
Last participant's last visit for primary outcome
August 1, 2026
ExpectedStudy Completion
Last participant's last visit for all outcomes
September 1, 2026
April 30, 2026
April 1, 2026
3.1 years
January 14, 2023
April 29, 2026
Conditions
Outcome Measures
Primary Outcomes (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.
Up to 2 years
Secondary Outcomes (7)
Radiological response
Up to 2 years
Response rate
Up to 2 years
Clinical benefit rate
Up to 2 years
Progression free survival
From study enrollment until the identification of disease progression or death, assessed up to 2 years
Median duration of response
Up to 2 years
- +2 more secondary outcomes
Other Outcomes (2)
POLQ messenger ribonucleic acid level (mRNA)
Up to 2 years
ATM immunohistochemistry (IHC)
Up to 2 years
Study Arms (1)
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.
Interventions
Undergo tumor biopsy
Undergo blood sample collection
Undergo medical imaging scans
Eligibility Criteria
You may qualify if:
- 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
- +8 more criteria
You may not qualify if:
- 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
Contact the study team to confirm eligibility.
Sponsors & Collaborators
Study Sites (23)
City of Hope Comprehensive Cancer Center
Duarte, California, 91010, United States
UCI Health - Chao Family Comprehensive Cancer Center and Ambulatory Care
Irvine, California, 92612, United States
UC San Diego Moores Cancer Center
La Jolla, California, 92093, United States
Los Angeles General Medical Center
Los Angeles, California, 90033, United States
USC / Norris Comprehensive Cancer Center
Los Angeles, California, 90033, United States
UC Irvine Health/Chao Family Comprehensive Cancer Center
Orange, California, 92868, United States
University of California Davis Comprehensive Cancer Center
Sacramento, California, 95817, United States
UC San Diego Medical Center - Hillcrest
San Diego, California, 92103, United States
University of Chicago Comprehensive Cancer Center
Chicago, Illinois, 60637, United States
National Cancer Institute Developmental Therapeutics Clinic
Bethesda, Maryland, 20892, United States
National Institutes of Health Clinical Center
Bethesda, Maryland, 20892, United States
Beth Israel Deaconess Medical Center
Boston, Massachusetts, 02215, United States
Dana-Farber Cancer Institute
Boston, Massachusetts, 02215, United States
NYU Langone Hospital - Long Island
Mineola, New York, 11501, United States
Laura and Isaac Perlmutter Cancer Center at NYU Langone
New York, New York, 10016, United States
Ohio State University Comprehensive Cancer Center
Columbus, Ohio, 43210, United States
University of Oklahoma Health Sciences Center
Oklahoma City, Oklahoma, 73104, United States
Huntsman Cancer Institute/University of Utah
Salt Lake City, Utah, 84112, United States
Fred Hutchinson Cancer Center
Seattle, Washington, 98109, United States
University of Washington Medical Center - Montlake
Seattle, Washington, 98195, United States
University of Wisconsin Carbone Cancer Center - Eastpark Medical Center
Madison, Wisconsin, 53718, United States
University of Wisconsin Carbone Cancer Center - University Hospital
Madison, Wisconsin, 53792, United States
University Health Network-Princess Margaret Hospital
Toronto, Ontario, M5G 2M9, Canada
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Study Officials
- PRINCIPAL INVESTIGATOR
Geoffrey I Shapiro
Dana-Farber - Harvard Cancer Center LAO
Study Design
- Study Type
- interventional
- Phase
- phase 1
- Allocation
- NA
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- SINGLE GROUP
- Sponsor Type
- NIH
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
January 14, 2023
First Posted
January 18, 2023
Study Start
July 6, 2023
Primary Completion (Estimated)
August 1, 2026
Study Completion (Estimated)
September 1, 2026
Last Updated
April 30, 2026
Record last verified: 2026-04
Data Sharing
- IPD Sharing
- Will share
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