A Phase 1 Study of the Polymerase Theta (POL-theta) 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.

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. 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

- 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 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