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 (POLQ) 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.

Study Overview

• Status: Recruiting
• Conditions: Unresectable Malignant Solid Neoplasm; Metastatic Malignant Solid Neoplasm
• Intervention / Treatment: Procedure: Biopsy; Procedure: Biospecimen Collection; Procedure: Diagnostic Imaging; Biological: Novobiocin Sodium

Detailed Description

PRIMARY OBJECTIVE:

I. To determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of continuous novobiocin sodium (novobiocin) 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 continuous novobiocin in patients with solid tumors carrying HR or DDR alterations that are PARP inhibitor-naïve or -resistant.

III. To characterize the pharmacokinetic parameters of continuous novobiocin administration 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-naïve 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 daily.

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) twice daily (BID) on days 1-28 of each cycle. Cycles repeat 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.

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • Recruiting
      • National Institutes of Health Clinical Center
      • Contact: Site Public Contact; Phone Number: 800-411-1222
      • Principal Investigator: A P. Chen
    • Bethesda, Maryland, United States, 20892
      • Recruiting
      • National Cancer Institute Developmental Therapeutics Clinic
      • Contact: Site Public Contact; Phone Number: 800-411-1222
      • Principal Investigator: A P. Chen
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Recruiting
      • Dana-Farber Cancer Institute
      • Contact: Site Public Contact; Phone Number: 877-442-3324
      • Principal Investigator: Geoffrey I. Shapiro

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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]) =< 3 × 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 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 with uncontrolled intercurrent illness
• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment (novobiocin sodium); Patients receive novobiocin sodium PO BID on days 1-28 of each cycle. Cycles repeat 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.

Procedure: Biopsy; Undergo tumor biopsy; Other Names: Bx; BIOPSY_TYPE; Procedure: Biospecimen Collection; Undergo blood sample collection; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection; Procedure: Diagnostic Imaging; Undergo medical imaging scans; Other Names: Medical Imaging; Biological: Novobiocin Sodium; Given PO

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Up to 2 years
Plasma concentrations of novobiocin	Will be quantitatively measured using liquid chromatography with tandem mass spectrometry to derive standard pharmacokinetic parameters.	Days 1 & 14 of cycle 1 (pre-treatment and 0.5, 1, 2, 4, 6, & 8 hours post-treatment), days 8 & 22 of cycle 1 (pre-treatment), day 1 of cycle 2 (pre-dose), day 15 of cycle 2 (pre-treatment) and day 1 of cycles 3, 4, & 6 (pre-treatment)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
POLQ messenger ribonucleic acid level (mRNA)	Other pharmacodynamic data will be captured using descriptive statistics. In an exploratory fashion, we will analyze correlations between baseline POLQ mRNA level and clinical outcome.	Up to 2 years
ATM immunohistochemistry (IHC)	Other pharmacodynamic data will be captured using descriptive statistics. In an exploratory fashion, we will analyze correlations between ATM IHC and genomic alterations.	Up to 2 years

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Geoffrey I Shapiro, Dana-Farber - Harvard Cancer Center LAO

Study record dates

Study Major Dates

• Study Start (Actual): July 6, 2023
• Primary Completion (Estimated): May 31, 2024
• Study Completion (Estimated): May 31, 2024

Study Registration Dates

• First Submitted: January 14, 2023
• First Submitted That Met QC Criteria: January 14, 2023
• First Posted (Actual): January 18, 2023

Study Record Updates

• Last Update Posted (Actual): April 23, 2024
• Last Update Submitted That Met QC Criteria: April 20, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-Bacterial Agents; Novobiocin
• Other Study ID Numbers: NCI-2022-06608 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); UM1CA186709 (U.S. NIH Grant/Contract); 10528 (Other Identifier: CTEP)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: 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.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No