Trial Title:
Studying the Safety and Determining the Optimal Dose of Novobiocin in Patients With Tumors That Have Alterations in DNA Repair Genes
NCT ID:
NCT05687110
Condition:
Metastatic Malignant Solid Neoplasm
Unresectable Malignant Solid Neoplasm
Conditions: Official terms:
Neoplasms
Novobiocin
Study type:
Interventional
Study phase:
Phase 1
Overall status:
Recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Procedure
Intervention name:
Biopsy
Description:
Undergo tumor biopsy
Arm group label:
Treatment (novobiocin sodium)
Other name:
BIOPSY_TYPE
Other name:
Bx
Intervention type:
Procedure
Intervention name:
Biospecimen Collection
Description:
Undergo blood sample collection
Arm group label:
Treatment (novobiocin sodium)
Other name:
Biological Sample Collection
Other name:
Biospecimen Collected
Other name:
Specimen Collection
Intervention type:
Procedure
Intervention name:
Diagnostic Imaging
Description:
Undergo medical imaging scans
Arm group label:
Treatment (novobiocin sodium)
Other name:
Medical Imaging
Intervention type:
Biological
Intervention name:
Novobiocin Sodium
Description:
Given PO
Arm group label:
Treatment (novobiocin sodium)
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.
Detailed description:
PRIMARY OBJECTIVE:
I. 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:
I. 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.
V. To conduct a preliminary assessment of anti-tumor activity of novobiocin administered
on a 5-days on/2-days off schedule.
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) 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 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.
Criteria for eligibility:
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
- 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)
- Corrected QT interval by Fridericia (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 4 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 or heterozygous
for A(TA)7TAA in the promoter region, or homozygous or heterozygous for the G71R
allele (also known as UGT1A1*6) are excluded (i.e., patients with Gilbert syndrome
or Gilbert carriers) as they are at risk for further reduction of UGT1A1 activity
that may disrupt bilirubin clearance
- 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
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
UCI Health - Chao Family Comprehensive Cancer Center and Ambulatory Care
Address:
City:
Irvine
Zip:
92612
Country:
United States
Status:
Recruiting
Contact:
Last name:
Site Public Contact
Phone:
877-827-8839
Email:
ucstudy@uci.edu
Investigator:
Last name:
Jennifer B. Valerin
Email:
Principal Investigator
Facility:
Name:
Los Angeles General Medical Center
Address:
City:
Los Angeles
Zip:
90033
Country:
United States
Status:
Recruiting
Contact:
Last name:
Site Public Contact
Phone:
323-865-0451
Email:
uscnorrisinfo@med.usc.edu
Investigator:
Last name:
Varsha Tulpule
Email:
Principal Investigator
Facility:
Name:
USC / Norris Comprehensive Cancer Center
Address:
City:
Los Angeles
Zip:
90033
Country:
United States
Status:
Recruiting
Contact:
Last name:
Site Public Contact
Phone:
323-865-0451
Investigator:
Last name:
Varsha Tulpule
Email:
Principal Investigator
Facility:
Name:
UC Irvine Health/Chao Family Comprehensive Cancer Center
Address:
City:
Orange
Zip:
92868
Country:
United States
Status:
Recruiting
Contact:
Last name:
Site Public Contact
Phone:
877-827-8839
Email:
ucstudy@uci.edu
Investigator:
Last name:
Jennifer B. Valerin
Email:
Principal Investigator
Facility:
Name:
University of California Davis Comprehensive Cancer Center
Address:
City:
Sacramento
Zip:
95817
Country:
United States
Status:
Recruiting
Contact:
Last name:
Site Public Contact
Phone:
916-734-3089
Investigator:
Last name:
Nancy T. Nguyen
Email:
Principal Investigator
Facility:
Name:
National Cancer Institute Developmental Therapeutics Clinic
Address:
City:
Bethesda
Zip:
20892
Country:
United States
Status:
Recruiting
Contact:
Last name:
Site Public Contact
Phone:
800-411-1222
Investigator:
Last name:
A P. Chen
Email:
Principal Investigator
Facility:
Name:
National Institutes of Health Clinical Center
Address:
City:
Bethesda
Zip:
20892
Country:
United States
Status:
Active, not recruiting
Facility:
Name:
Beth Israel Deaconess Medical Center
Address:
City:
Boston
Zip:
02215
Country:
United States
Status:
Recruiting
Contact:
Last name:
Site Public Contact
Phone:
617-667-9925
Investigator:
Last name:
Geoffrey I. Shapiro
Email:
Principal Investigator
Facility:
Name:
Dana-Farber Cancer Institute
Address:
City:
Boston
Zip:
02215
Country:
United States
Status:
Recruiting
Contact:
Last name:
Site Public Contact
Phone:
877-442-3324
Investigator:
Last name:
Geoffrey I. Shapiro
Email:
Principal Investigator
Facility:
Name:
NYU Langone Hospital - Long Island
Address:
City:
Mineola
Zip:
11501
Country:
United States
Status:
Recruiting
Contact:
Last name:
Site Public Contact
Phone:
212-263-4432
Email:
cancertrials@nyulangone.org
Investigator:
Last name:
Nancy Chan
Email:
Principal Investigator
Facility:
Name:
Laura and Isaac Perlmutter Cancer Center at NYU Langone
Address:
City:
New York
Zip:
10016
Country:
United States
Status:
Recruiting
Contact:
Last name:
Site Public Contact
Email:
CancerTrials@nyulangone.org
Investigator:
Last name:
Nancy Chan
Email:
Principal Investigator
Facility:
Name:
University of Wisconsin Carbone Cancer Center - Eastpark Medical Center
Address:
City:
Madison
Zip:
53718
Country:
United States
Status:
Recruiting
Contact:
Last name:
Site Public Contact
Phone:
800-622-8922
Email:
clinicaltrials@cancer.wisc.edu
Investigator:
Last name:
Jeremy Kratz
Email:
Principal Investigator
Facility:
Name:
University of Wisconsin Carbone Cancer Center - University Hospital
Address:
City:
Madison
Zip:
53792
Country:
United States
Status:
Recruiting
Contact:
Last name:
Site Public Contact
Phone:
800-622-8922
Email:
clinicaltrials@cancer.wisc.edu
Investigator:
Last name:
Jeremy Kratz
Email:
Principal Investigator
Start date:
July 6, 2023
Completion date:
September 1, 2026
Lead sponsor:
Agency:
National Cancer Institute (NCI)
Agency class:
NIH
Source:
National Cancer Institute (NCI)
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05687110
