| Eligibility |
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
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