Studying the Safety and Determining the Optimal Dose of Novobiocin in Patients With Tumors That Have Alterations in DNA Repair Genes

• ClinicalTrials.gov Identifier: NCT05687110
• Recruitment Status: Recruiting
• First Posted: January 18, 2023
• Last Update Posted: April 23, 2024
• Sponsor: National Cancer Institute (NCI)
• Information provided by (Responsible Party): National Cancer Institute (NCI)

Tracking Information

• First Submitted Date: January 14, 2023
• First Posted Date: January 18, 2023
• Last Update Posted Date: April 23, 2024
• Actual Study Start Date: July 6, 2023
• Estimated Primary Completion Date: May 31, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 14, 2023)

Maximum tolerated dose (MTD) and recommended phase 2 dose of continuous novobiocin administration [ Time Frame: Up to 2 years ]

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.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: April 29, 2023)

• Plasma concentrations of novobiocin [ Time Frame: 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) ]
  Will be quantitatively measured using liquid chromatography with tandem mass spectrometry to derive standard pharmacokinetic parameters.
• Biological effectiveness [ Time Frame: Up to 2 years ]
  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.

Original Secondary Outcome Measures (submitted: January 14, 2023)

• Plasma concentrations of novobiocin [ Time Frame: Days 1 & 14 of cycle 1 (pre-treatment and 0.5, 1, 2, 4, 6, & 8 hours post-treatment) and day 1 of cycles 2, 4, & 6 (pre-dose only) ]
  Will be quantitatively measured using liquid chromatography with tandem mass spectrometry to derive standard pharmacokinetic parameters.
• Biological effectiveness [ Time Frame: Up to 2 years ]
  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.

Current Other Pre-specified Outcome Measures (submitted: January 14, 2023)

• POLQ messenger ribonucleic acid level (mRNA) [ Time Frame: Up to 2 years ]
  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.
• ATM immunohistochemistry (IHC) [ Time Frame: Up to 2 years ]
  Other pharmacodynamic data will be captured using descriptive statistics. In an exploratory fashion, we will analyze correlations between ATM IHC and genomic alterations.

• Original Other Pre-specified Outcome Measures: Same as current

Descriptive Information

• Brief Title: Studying the Safety and Determining the Optimal Dose of Novobiocin in Patients With Tumors That Have Alterations in DNA Repair Genes
• Official Title: A Phase 1 Study of the Polymerase Theta (POLQ) Inhibitor Novobiocin in BRCA-Mutant and Other DNA Damage Repair-Deficient Solid Tumors
• 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.

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
• Study Phase: Phase 1
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Metastatic Malignant Solid Neoplasm
• Unresectable Malignant Solid Neoplasm

Intervention

• Procedure: Biopsy
  Undergo tumor biopsy
  Other Names:

  • BIOPSY_TYPE
  • Bx
• Procedure: Biospecimen Collection
  Undergo blood sample collection
  Other Names:

  • Biological Sample Collection
  • Biospecimen Collected
  • Specimen Collection
• Procedure: Diagnostic Imaging
  Undergo medical imaging scans
  Other Name: Medical Imaging
• Biological: Novobiocin Sodium
  Given PO

Study Arms

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.

Interventions:

• Procedure: Biopsy
• Procedure: Biospecimen Collection
• Procedure: Diagnostic Imaging
• Biological: Novobiocin Sodium

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: January 14, 2023): 30
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: May 31, 2024
• Estimated Primary Completion Date: May 31, 2024 (Final data collection date for primary outcome measure)

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]) =< 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT05687110
• Other Study ID Numbers: NCI-2022-06608; NCI-2022-06608 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); 10528 ( Other Identifier: Dana-Farber - Harvard Cancer Center LAO ); 10528 ( Other Identifier: CTEP ); UM1CA186709 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• 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.
• URL: https://grants.nih.gov/policy/sharing.htm

• Current Responsible Party: National Cancer Institute (NCI)
• Original Responsible Party: Same as current
• Current Study Sponsor: National Cancer Institute (NCI)
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Geoffrey I Shapiro; Dana-Farber - Harvard Cancer Center LAO

• PRS Account: National Cancer Institute (NCI)
• Verification Date: April 2024