Tivozanib for Biliary Tract Cancer
Recruiting in Palo Alto (17 mi)
Overseen byJonathan M Hernandez, M.D.
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
Sponsor: National Cancer Institute (NCI)
Must not be taking: Anti-arrhythmics, Encephalopathy meds
Disqualifiers: Second primary malignancy, Cardiovascular disease, others
No Placebo Group
Approved in 2 Jurisdictions
Trial Summary
What is the purpose of this trial?Background:
Cholangiocarcinoma (CCA) is an aggressive cancer of the bile ducts. People with CCA have few treatment options and poor survival. Researchers want to see if a new drug can stop or slow CCA growth.
Objective:
To find the safest and most effective dose of tivozanib to treat CCA and learn its overall response rate.
Eligibility:
Adults ages 18 and older with CCA not removable with surgery and have been treated with at least one type of chemotherapy.
Design:
Participants will be screened with the following:
* Medical history
* Physical exam
* Assessment of their ability to do daily activities
* Medicine review
* Blood tests, including thyroid function tests
* Urine tests
* Electrocardiogram, to check heart function
* Pregnancy test, if needed
* Tumor biopsy, if needed
* Computed tomography scans
* Magnetic resonance imaging, if needed
Some screening tests may be repeated during the study.
Participants will be asked to enroll in protocol #13C0176. This will allow any remaining tumor or blood samples to be used in future research.
Participants will take tivozanib by mouth, once a day for 21 days per cycle or every other day per cycle. Each cycle is 28 days. They can take the drug until they have bad side effects, their CCA gets worse, or if they become pregnant. They will record their blood pressure twice daily at home. They will also keep a medication diary of each dose of tivozanib they take and any side effects.
Participants will have study visits before starting each new cycle and every 8 weeks. They will also have a follow-up visit 30 days after treatment ends at NIH, or if they are unable to come to NIH by phone, videocall, or other NIH-approved platform. Then they will be contacted 6 and 12 months later, and then once a year.
Do I need to stop my current medications to join the trial?
The trial does not specify if you need to stop taking your current medications, but you cannot have had chemotherapy, small molecule, or radiation therapy within 2 weeks before starting the study drug. It's best to discuss your current medications with the trial team to ensure they don't interfere with the study.
How does the drug Tivozanib differ from other treatments for biliary tract cancer?
Tivozanib is unique because it is a targeted therapy that inhibits specific pathways involved in cancer growth, such as the vascular endothelial growth factor receptor (VEGFR), which is different from traditional chemotherapy that affects all rapidly dividing cells. This approach may offer a more personalized treatment option for patients with biliary tract cancer, especially those who do not respond to standard chemotherapy.
12345Eligibility Criteria
Adults over 18 with inoperable biliary tract cancer (BTC), including cholangiocarcinoma or gallbladder cancer, who have already tried at least one chemotherapy. They must be able to perform daily activities to a certain extent and have adequate organ function. Women of childbearing potential must test negative for pregnancy and agree to use contraception.Inclusion Criteria
- Creatinine clearance > 30
- AST(SGOT)/ALT(SGPT) <= 5 X institutional ULN
I am 18 years old or older.
+15 more
Exclusion Criteria
I have multiple bile duct blockages and need more than one stent or external drainage.
My blood pressure is controlled and hasn't required medication changes for at least 14 days.
I am not pregnant or breastfeeding.
+16 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
1 visit (in-person)
Treatment
Participants receive tivozanib orally once a day for 21 days per 28-day cycle, with dose adjustments as needed
Until disease progression or unacceptable toxicity
Visits before each new cycle and every 8 weeks
Follow-up
Participants are monitored for safety and effectiveness after treatment
12 months
1 visit (in-person or virtual) 30 days post-treatment, then contact at 6 and 12 months, and annually
Participant Groups
The trial is testing the safety and effectiveness of Tivozanib, an oral medication taken once daily for three weeks per cycle, with each cycle lasting four weeks. The goal is to determine the best dose that can manage BTC without causing severe side effects.
2Treatment groups
Experimental Treatment
Group I: 2/ Phase IIExperimental Treatment1 Intervention
Tivozanib at the RP2D established in Phase I
Group II: 1/ Phase IExperimental Treatment1 Intervention
Tivozanib, P.O. daily at 0.89 mg (given on Days 1-21 of every 28-day cycle) with intra-patient escalation to 1.34 mg daily (given on Days 1-21 of every 28-day cycle) and possible dose de-escalation to 0.89 mg every other day (without interruption for a 28-day cycle) if needed to determine RP2D
Tivozanib is already approved in United States, European Union for the following indications:
🇺🇸 Approved in United States as Fotivda for:
- Renal cell carcinoma
🇪🇺 Approved in European Union as Fotivda for:
- Renal cell carcinoma
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
National Institutes of Health Clinical CenterBethesda, MD
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Who Is Running the Clinical Trial?
National Cancer Institute (NCI)Lead Sponsor
References
Continuum of care for advanced biliary tract cancers. [2021]Biliary tract cancers (BTC) are a heterogeneous group of epithelial neoplasms, with a poor prognosis. Advanced BTC remains a challenging, non-curable disease. In this review, we provide an overview of the medical treatment options in advanced BTC and new strategies under development. Gemcitabine plus platinum chemotherapy is the standard first-line therapy in this setting. Recently, 5-fluorouracil, folinic acid plus oxaliplatin (FOLFOX) regimen became the only second-line therapy to be prospectively validated beyond failure of gemcitabine plus cisplatin combination in a phase III study, even though chemotherapy yielded modest survival improvement over best supportive care. Anti-epidermal growth factor receptor and antiangiogenic antibodies have not demonstrated any survival benefit in unselected patient populations. In recent years, knowledge about the molecular heterogeneity of BTC has considerably increased with the advent of large-scale genomic and transcriptomic analyses, opening up new perspectives for so-called personalised targeted therapies. Patients with BTC may be particularly good candidates for biomarker-driven strategies in clinical practice. Among current developments, the targeting of fibroblast growth factor receptor and isocitrate dehydrogenase gene alterations are the most promising avenues, and combination immunotherapies are under investigation.
Current and emerging therapies for advanced biliary tract cancers. [2022]Biliary tract cancers (cholangiocarcinomas and gallbladder cancers) are increasing in incidence and have a poor prognosis. Most patients present with advanced disease, for which the treatment is palliative chemotherapy. Over the past few years, the genomic landscape of biliary tract cancers has been examined and several targeted therapies have been developed. Molecular targets with clinically meaningful activity include fibroblast growth factor receptor (FGFR), isocitrate dehydrogenase (IDH), RAS-RAF-MEK (MAP2K1)-ERK (MAPK3), HER2 (also known as ERBB2), DNA mismatch repair, and NTRK. Pemigatinib, a FGFR1-3 inhibitor, showed encouraging response rates and survival data as second-line treatment and received US Food and Drug Administration (FDA) approval in April, 2020, for previously treated advanced or metastatic cholangiocarcinoma with FGFR2 gene fusion or rearrangements. Ivosidenib, an IDH1 inhibitor, showed improved progression-free survival versus placebo in second-line treatment in the phase 3 ClarIDHy trial. Early phase trials of dabrafenib plus trametinib (BRAF and MEK inhibition) and zanidatamab (a bispecific HER2-antibody) have yielded encouraging response rates. Immunotherapy has mainly produced responses in tumours with deficient mismatch repair or high microsatellite instability (also known as dMMR or MSI-H) or higher PD-L1 score, or both. However, early phase trials of immunotherapy plus chemotherapy in unselected patient populations appear promising. NTRK inhibitors have also shown promise in early phase trials of NTRK-fusion positive solid tumours, including cholangiocarcinoma. In this Review, we discuss current and emerging therapies for advanced biliary tract cancers, with a focus on molecularly targeted therapy.
Multicenter randomized phase II trial of atezolizumab with or without cobimetinib in biliary tract cancers. [2023]BACKGROUNDMEK inhibitors have limited activity in biliary tract cancers (BTCs) as monotherapy but are hypothesized to enhance responses to programmed death ligand 1 (PD-L1) inhibition.METHODSThis open-label phase II study randomized patients with BTC to atezolizumab (anti-PD-L1) as monotherapy or in combination with cobimetinib (MEK inhibitor). Eligible patients had unresectable BTC with 1 to 2 lines of prior therapy in the metastatic setting, measurable disease, and Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 1. The primary endpoint was progression-free survival (PFS).RESULTSSeventy-seven patients were randomized and received study therapy. The trial met its primary endpoint, with a median PFS of 3.65 months in the combination arm versus 1.87 months in the monotherapy arm (HR 0.58, 90% CI 0.35-0.93, 1-tail P = 0.027). One patient in the combination arm (3.3%) and 1 patient in the monotherapy arm (2.8%) had a partial response. Combination therapy was associated with more rash, gastrointestinal events, CPK elevations, and thrombocytopenia. Exploratory analysis of tumor biopsies revealed enhanced expression of antigen processing and presentation genes and an increase in CD8/FoxP3 ratios with combination treatment. Patients with higher baseline or lower fold changes in expression of certain inhibitory ligands (LAG3, BTLA, VISTA) on circulating T cells had evidence of greater clinical benefit from the combination.CONCLUSIONThe combination of atezolizumab plus cobimetinib prolonged PFS as compared with atezolizumab monotherapy, but the low response rate in both arms highlights the immune-resistant nature of BTCs.TRIAL REGISTRATIONClinicalTrials.gov NCT03201458.FUNDINGNational Cancer Institute (NCI) Experimental Therapeutics Clinical Trials Network (ETCTN); F. Hoffmann-La Roche, Ltd.; NCI, NIH (R01 CA228414-01 and UM1CA186691); NCI's Specialized Program of Research Excellence (SPORE) in Gastrointestinal Cancers (P50 CA062924); NIH Center Core Grant (P30 CA006973); and the Passano Foundation.
Precision Oncology Targets in Biliary Tract Cancer. [2023]Targeted therapies in biliary tract cancer (BTC) are emerging as options for patients not who do not respond to first-line treatment. Agents acting on tumor-specific oncogenes in BTC may target fibroblast growth factor receptor 2 (FGFR2), isocitrate dehydrogenase (IDH), B-raf kinase (BRAF), and human epidermal growth factor receptor 2 (HER-2). Additionally, given the heterogeneous genetic landscape of advanced BTCs, many harbor genetic aberrations that are common among solid tumors, including RET fusions, tropomyosin receptor kinase (TRK) fusions, and high tumor mutational burden (TMB). This review aims to provide updates on the evolving array of therapeutics available, and to summarize promising works on the horizon.
A review of molecularly targeted therapy in biliary tract carcinoma: what is the next step? [2023]Patients with unresectable biliary tract carcinomas (BTCs) have a poor prognosis with a median overall survival of fewer than 12 months following systemic chemotherapy. In recent years, the identification of distinct molecular alterations with corresponding targeted therapies is modifying this therapeutic algorithm. The aim of this review is to present an overview of targeted therapy for BTCs, describing published available data and potential future challenges in ongoing trials. From clinicaltrials.gov online database all ongoing trials for BTCs (any stage) was examinated in July 2021, and data regarding study design, disease characteristics and type of treatments were registered. Oncogenic-driven therapy (targeted therapy) was investigated in 67 trials. According to research, 15 ongoing trials (22.4%) are investigating fibroblast growth factor (FGF) receptor (FGFR)-inhibitors in BTCs. Three (18.7%) are open-label randomized multicenter phase 3 trials, 8 (50%) are single-arm phase two trials, and 4 (25%) are phase one studies. Twelve (17.9%) clinical trials dealt with isocitrate dehydrogenase (IDH) 1/2 targeting therapy either in combination with cisplatin (Cis) and gemcitabine (Gem) as first-line treatment for BTCs or in monotherapy in patients with IDH1 mutant advanced malignancies, including cholangiocarcinoma (CCA). Nine (13.4%) clinical trials tested human epidermal growth factor receptor (HER) 2 targeting therapy. Four (44.4%) studies are phase I trials, two (22.2%) are phase I/II trials, and three (33.3%) phase II trials. Rare molecular alterations in BTCs, such as anaplastic lymphoma kinase (ALK), c-ros oncogene1 receptor tyrosine kinase (ROS1), and v-RAF murine sarcoma viral oncogene homologue B1 (BRAF), are also under investigation in a few trials. Forty-four clinical trials (17.2%) are investigating not oncogenic-driven multitarget therapy like multireceptor tyrosin kinase inhibitors and antiangiogenetic agents. In conclusion, this review shows that BTCs management is experiencing important innovations, especially in biomarker-based patient selection and in the new emerging therapeutic approach. Many ongoing trials could answer questions regarding the role of molecular inhibitors leading to new therapeutic frontiers for molecular subcategories of BTCs.