Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: National Cancer Institute (NCI)
Must be taking: Parp inhibitors
Must not be taking: CYP3A4/5 inhibitors, QTc prolongation drugs
Disqualifiers: Chemotherapy, Radiotherapy, Gilbert syndrome, others
No Placebo Group
Trial Summary
What is the purpose of this trial?This trial tests novobiocin, an antibiotic, in cancer patients with specific DNA repair gene mutations who haven't responded to other treatments. Novobiocin blocks a protein that helps cancer cells repair themselves, leading to their death. Studies show that novobiocin can make other cancer treatments more effective.
Do I need to stop taking my current medications for the trial?
The trial requires that you stop taking certain medications, specifically those that are strong inhibitors or inducers of CYP3A4/5, substrates of certain transport proteins, or those that prolong the QT interval. You should consult with your doctor to review your current medications and see if any need to be stopped before joining the trial.
How does the drug Novobiocin Sodium differ from other cancer treatments?
Novobiocin Sodium is unique because it targets the Hsp90 protein, which is involved in cancer cell growth, and it can enhance the effectiveness of other cancer drugs by making cancer cells more sensitive to them. Unlike many standard treatments, it also has the potential to work in combination with other agents to inhibit cancer cell growth more effectively.
12345Eligibility Criteria
This trial is for adults with advanced or inoperable tumors that have specific mutations in DNA repair genes. Patients must have tried other treatments without success and may or may not have used PARP inhibitors, depending on the type of cancer. They should be relatively healthy otherwise, with adequate blood cell counts and organ function.Inclusion Criteria
Any number of prior therapy regimens is allowed.
Platelets >= 100,000/mcL
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
+7 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive novobiocin sodium orally once daily 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.
Up to 2 years
Biopsies at baseline, day 15 of cycle 1, and at time of progression; imaging every 8 weeks
Follow-up
Participants are monitored for safety and effectiveness after treatment completion
Every 3-6 months for 2 years
Participant Groups
The trial is testing Novobiocin Sodium's safety and optimal dosage. It's an antibiotic thought to kill cancer cells by blocking a protein involved in DNA repair. The study includes biopsies, biospecimen collection, and diagnostic imaging to monitor effects.
1Treatment groups
Experimental Treatment
Group I: Treatment (novobiocin sodium)Experimental Treatment4 Interventions
Patients receive novobiocin sodium PO 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.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Dana-Farber - Harvard Cancer Center LAOBoston, MA
NYU Langone Hospital - Long IslandMineola, NY
Laura and Isaac Perlmutter Cancer Center at NYU LangoneNew York, NY
UCI Health - Chao Family Comprehensive Cancer Center and Ambulatory CareIrvine, CA
More Trial Locations
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Who Is Running the Clinical Trial?
National Cancer Institute (NCI)Lead Sponsor
References
Novobiocin-induced anti-proliferative and differentiating effects in melanoma B16. [2019]The antibiotic drug novobiocin was evaluated for its anti-tumour properties in B16 melanoma cells. Novobiocin is shown to inhibit melanoma B16 cell proliferation. The anti-proliferative effect was gradually reversible upon removal of novobiocin from the culture medium. Growth inhibition by novobiocin was accompanied by phenotypic alterations, that included morphological changes, lipid accumulation and marked increases in the activities of NADPH cytochrome c reductase and gamma glutamyl transpeptidase. In vivo administration of repeated i.p. doses of novobiocin, to mice implanted with B16 melanoma cells resulted in growth retardation. The combined treatment of the B16 melanoma cells with novobiocin and other chemical inducers of differentiation was examined in a cell growth assay. Novobiocin and sodium butyrate inhibited cell growth in a near additive manner, while combination of novobiocin with the GTP-depleting agents, tiazofurin or mycophenolic acid resulted in a synergistic decrease in cell growth. Our results support the contention further that novobiocin and other differentiating agents might be of potential value in melanoma therapy.
Novobiocin analogues with second-generation noviose surrogates. [2021]Hsp90 is a promising therapeutic target for the treatment of cancer. Novobiocin is the first Hsp90 C-terminal inhibitor ever identified and recent structure-activity relationship studies on the noviose sugar identified several commercially available amines as suitable surrogates. In an effort to further understand this region of the molecule, analogues containing various N'-amino substituents were prepared and evaluated against two breast cancer cell lines for determination of their efficacy. Compound 37j manifested the most potent anti-proliferative activity from these studies and induced Hsp90-dependent client protein degradation at mid nano-molar concentrations.
Cisplatin and novobiocin in the treatment of non-small cell lung cancer. A Southwest Oncology Group study. [2019]Novobiocin, a commercially available oral antibiotic, inhibits DNA topoisomerase II in a manner shown in cell culture to enhance the cytotoxicity of alkylating agents and cisplatin. Thirty-six patients were entered on a Phase II trial using high-dose cisplatin (100 mg/m2 on days 1 and 8 for four cycles) after steady-state dosing with novobiocin (1000 mg or four 250-mg capsules every 12 hours for six doses, four of which were administered before each dose of cisplatin). One patient remains on study and cannot be evaluated for response. No complete responses were seen. Three patients (8%) had partial responses and an additional patient had an unconfirmed partial response. The median survival time of all patients was just less than 7 months. These results are comparable with those of other concurrent Southwest Oncology Group (SWOG) Phase II and III trials of high-dose cisplatin in non-small cell lung cancer (NSCLC). Novobiocin plasma levels were obtained for three patients and were approximately 50% of the optimal concentration as reported in cell culture for potentiation of cytotoxicity. It was concluded that an optimum test of novobiocin as a modulator of cytotoxicity may require the availability of an intravenous preparation.
Diverging Novobiocin Anti-Cancer Activity from Neuroprotective Activity through Modification of the Amide Tail. [2020]Novobiocin is a natural product that binds the Hsp90 C-terminus and manifests Hsp90 inhibitory activity. Structural investigations on novobiocin led to the development of both anti-cancer and neuroprotective agents. The varied pharmacological activity manifested by these novobiocin analogs prompted the investigation of structure-function studies to identify these contradictory effects, which revealed that modifications to the amide side chain produce either anti-cancer or neuroprotective activity. Compounds that exhibit neuroprotective activity contain a short alkyl or cycloalkyl amide side chain. In contrast, anti-cancer agents contain five or more carbons, disrupt interactions between Hsp90α and Aha1, and induce the degradation of Hsp90-dependent client proteins.
Novobiocin sensitizes BCRP/MXR/ABCP overexpressing topotecan-resistant human breast carcinoma cells to topotecan and mitoxantrone. [2018]Novobiocin was shown to sensitize cancer cells to etoposide and alkylating agents. Human breast carcinoma cells exposed to topotecan (MCF7/TPT300 cells) developed resistance to both mitoxantrone and topotecan. An ATP-binding cassette family protein BCRP/MXR/ABCP was overexpressed in MCF7/TPT300 cells. In addition, topotecan efflux was markedly enhanced in the resistant cells. To investigate the possibility that novobiocin may enhance cytotoxicity in BCRP/MXR/ABCP overexpressing cells, we exposed MCF7/TPT300 cells to novobiocin.