Ivosidenib for Bile Duct Cancer
(ProvIDHe Trial)
Recruiting in Palo Alto (17 mi)
+34 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 3
Recruiting
Sponsor: Servier
Must not be taking: IDH1 inhibitors, Steroids
Disqualifiers: Transplant, Brain metastases, Hepatitis, others
No Placebo Group
Pivotal Trial (Near Approval)
Prior Safety Data
Breakthrough Therapy
Approved in 2 Jurisdictions
Trial Summary
What is the purpose of this trial?A Phase 3b research study to consolidate the data that ivosidenib is safe and effective in adult patients with previously treated, locally advanced, or metastatic cholangiocarcinoma (CCA). All patients who meet inclusion criteria will be enrolled to receive ivosidenib tablets orally once daily for 28 day cycles, continuing as long as clinical benefit and consent for participation is maintained. There will be a minimum of 6 study visits from screening until the final follow-up, if one cycle of treatment is completed and consent is maintained through 18 months of follow-up. Each additional cycle completed will add one study visit, on the first day of each cycle.
Do I need to stop my current medications for the trial?
The trial protocol does not specify if you need to stop taking your current medications. However, you cannot have received systemic cancer treatment or radiotherapy within 2 weeks before starting the trial, and certain other treatments within 4 weeks.
What data supports the effectiveness of the drug Ivosidenib for bile duct cancer?
Ivosidenib has been shown to improve progression-free survival and overall survival in patients with advanced cholangiocarcinoma (a type of bile duct cancer) that have IDH1 mutations. In a phase III study, patients taking Ivosidenib lived longer without their cancer getting worse compared to those who took a placebo.
12345Is ivosidenib safe for humans?
Ivosidenib is generally well tolerated in humans, with most side effects being mild, such as diarrhea, nausea, and fatigue. Serious side effects are rare, and the treatment is associated with a low rate of discontinuation due to toxicity, making it a safe option for patients with certain conditions.
12567How is the drug Ivosidenib unique in treating bile duct cancer?
Ivosidenib is unique because it specifically targets and inhibits mutant IDH1, a genetic mutation found in some bile duct cancers, which helps slow down cancer progression and improve survival. Unlike standard chemotherapy, it is an oral medication and is particularly beneficial for patients whose cancer has progressed after initial treatments.
12356Eligibility Criteria
This trial is for adults with advanced or metastatic cholangiocarcinoma (bile duct cancer) that can't be removed by surgery. Participants must have tried at least one systemic therapy, carry a specific IDH1 gene mutation, and have recovered from previous treatment side effects. Women of childbearing age and men with partners of childbearing potential must agree to use two forms of contraception.Inclusion Criteria
I agree to use two forms of birth control during and for 1 month after the study.
I have had one treatment for bile duct cancer and recovered from side effects.
My disease has a specific IDH1 gene mutation.
+2 more
Exclusion Criteria
I have been treated with an IDH1 inhibitor before.
I have had an organ or tissue transplant.
I've had liver treatments like radiation or ablation within the last 4 weeks.
+5 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
1 visit (in-person)
Treatment
Participants receive ivosidenib tablets orally once daily for 28-day cycles, continuing as long as clinical benefit and consent are maintained
28 days per cycle
1 visit per cycle (in-person)
Withdrawal
A withdrawal visit occurs within 42 days of stopping treatment
6 weeks
1 visit (in-person)
Follow-up
Participants are monitored for safety and effectiveness after treatment, with follow-up visits every 6 months for up to 18 months
18 months
3 visits (in-person)
Participant Groups
The study tests the safety and effectiveness of Ivosidenib oral tablets in treating bile duct cancer. Patients take the medication daily in 28-day cycles, continuing if beneficial. The study includes a minimum of six visits over an initial cycle plus follow-up visits on day one of each additional cycle up to 18 months.
1Treatment groups
Experimental Treatment
Group I: IvosidenibExperimental Treatment1 Intervention
Ivosidenib 500 mg, taken orally as two 250 mg tablets once daily for an unlimited amount of continuous 28-day cycles
Ivosidenib is already approved in United States, European Union for the following indications:
🇺🇸 Approved in United States as Tibsovo for:
- Acute myeloid leukemia (AML) with IDH1 mutation
🇪🇺 Approved in European Union as Tibsovo for:
- Acute myeloid leukemia (AML) with IDH1 mutation
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Tom Baker Cancer CenterCalgary, Canada
NSHA, QEII Health Sciences CentreHalifax, Canada
London Regional Cancer ProgramLondon, Canada
Princess Margaret Cancer CenterToronto, Canada
More Trial Locations
Loading ...
Who Is Running the Clinical Trial?
ServierLead Sponsor
Servier Affaires MédicalesLead Sponsor
References
Ivosidenib in IDH1-mutated cholangiocarcinoma: Clinical evaluation and future directions. [2022]To date, treatment options for patients with chemorefractory cholangiocarcinoma (CCA) are limited. However, the advancements in molecular techniques have recently increased the opportunity to offer molecularly targeted therapies to patients with several cancer types and some targetable oncogenic alterations have been identified also in CCA. Among these potentially actionable molecular alterations, isocitrate dehydrogenase-1 (IDH1) mutations have been detected in approximately 10-20% of intrahepatic CCA (iCCA). IDH1 is responsible for the accumulation of oncometabolites inducing epigenetic changes that are involved in various signaling pathways. Ivosidenib is the first IDH1 inhibitor which significantly improved progression-free survival (PFS) (2.7 vs 1.4 months) and overall survival (OS) (10.3 vs 5.1 months [adjusted median OS]) compared with placebo in chemorefractory IDH1-mutated CCA. The very low incidence of grade (G) 3-4 adverse events (AEs) and treatment discontinuation due to toxicity, associated with a significantly less marked decline in health-related quality of life for patients in the ivosidenib group than in placebo group, facilitates patient adherence and clinician confidence. Here, we review the development of ivosidenib in CCA patients and evaluate the clinical impact of the results of the phase III ClarIDHy trial which was responsible for the Food and Drug Administration (FDA) approval for patients with IDH1-mutated CCA whose disease progressed after standard chemotherapy (CT). We also discuss the known primary and secondary resistance mechanisms, including concomitant and acquired mutations in other genes (e.g. IDH2 mutations), second-site mutation in IDH1, and enhanced activation of other pathways (e.g. PI3K/AKT/mTOR pathway). Finally we examine the future directions, as the opportunity to combine ivosidenib with other synergistic agents, including standard chemotherapy (CT), immune checkpoint inhibitors (ICIs), and IDH2 inhibitors.
Ivosidenib: A Review in Advanced Cholangiocarcinoma. [2023]Ivosidenib (Tibsovo®), a first-in-class, oral small molecule, potent and selective inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1), is approved in the EU and USA for the treatment of adults with pretreated, advanced, mIDH1 cholangiocarcinoma (CCA). It is presumed to exert its cytostatic effects in this setting by suppressing 2-hydroxyglutarate, an oncometabolite produced by mIDH1 that impairs cellular differentiation and promotes tumorigenesis. In the multinational phase 3 ClarIDHy study in patients with pretreated, advanced mIDH1 CCA, monotherapy with ivosidenib once daily significantly prolonged progression-free survival (PFS) and almost doubled the disease control rate compared with placebo. Moreover, it had a favourable effect on overall survival (OS), which was also significantly prolonged after correcting for a high rate of crossover from the placebo group (permitted by the trial protocol). Ivosidenib treatment preserved health-related quality of life (HRQOL) relating to physical function, pain and appetite loss/eating and was generally well tolerated, with the most common treatment-emergent adverse events being low-grade diarrhoea, nausea and fatigue. Thus, ivosidenib represents a novel and valuable targeted therapy for the subset of patients with pretreated, advanced CCA tumors harbouring mIDH1.
Ivosidenib Boosts OS in Cholangiocarcinoma. [2022]Ivosidenib extends overall survival in patients with previously treated, advanced cholangiocarcinoma whose disease harbors IDH1 mutations. Median overall survival was 10.3 months in patients who received the drug, versus 7.5 months in the placebo group. The difference was even larger-5.1 months-when researchers accounted for patient crossover into the treatment group.
IDH Signalling Pathway in Cholangiocarcinoma: From Biological Rationale to Therapeutic Targeting. [2020]Biliary tract cancers are anatomically distinct and genetically diverse tumors, evenly characterized by poor response to standard treatments and a bleak outlook. The advent of comprehensive genomic profiling using next-generation sequencing has unveiled a plethora of potentially actionable aberrations, changing the view of biliary tract cancers from an "orphan" to a "target-rich" disease. Recently, mutations in isocitrate dehydrogenase genes (IDH1/2) and fusions of the fibroblast growth factor receptor have emerged as the most amenable to molecularly targeted inhibition, with several compounds actively investigated in advanced-phase clinical trials. Specifically, the IDH1 inhibitor ivosidenib has been the first targeted agent to show a survival benefit in a randomized phase III trial of cholangiocarcinoma patients harboring IDH1 mutations. In this review article, we will focus on the IDH1/IDH2 pathway, discussing the preclinical rationale of its targeting as well as the promises and challenges of the clinical development of IDH inhibitors in biliary tract cancers.
Ivosidenib: an investigational drug for the treatment of biliary tract cancers. [2021]Introduction: Biliary tract cancers (BTCs) [including cholangiocarcinoma and gallbladder cancer] are rare cancers associated with poor survival; most patients have advanced disease at diagnosis. Current chemotherapy reference regimens include cisplatin and gemcitabine as first-line; and oxaliplatin and 5-fluorouracil (FOLFOX) in second-line. Molecular profiling has identified several actionable therapeutic targets including isocitrate dehydrogenase (IDH)1 mutations. Ivosidenib is a reversible inhibitor of mutant IDH1; it is currently approved for the treatment of acute myeloid leukemia and has been studied in patients with advanced cholangiocarcinoma.Areas covered: This article introduces current treatments for BTC and sheds light on the mechanism of action, pharmacodynamics, pharmacokinetics, clinical efficacy, and safety of ivosidenib in advanced cholangiocarcinoma. The authors conclude with insights on the changing treatment paradigm created by emerging drugs and precision approaches.Expert opinion: Ivosidenib is well tolerated, with good oral exposure and long half-life as shown by phase I data. In a phase III study, ivosidenib has demonstrated improved progression-free survival compared to placebo (median 2.7 vs 1.4 months; hazard ratio 0.37; 95% confidence interval 0.25-0.54; one-sided p < 0.0001); it has also demonstrated a trend toward increased overall survival in patients with cholangiocarcinoma and disease progression on prior chemotherapy. Final survival data from this study are pending presentation. Increased use of molecular profiling will continue to identify potential therapeutic targets and improve the prognosis of patients with these cancers.
Clinical Utility of Ivosidenib in the Treatment of IDH1-Mutant Cholangiocarcinoma: Evidence To Date. [2023]Ivosidenib is an isocitrate dehydrogenase 1 (IDH1) inhibitor that is FDA approved for patients with IDH1 mutation and acute myeloid leukemia and previously treated locally advanced or metastatic cholangiocarcinoma. In the Phase III trial ClarIDHy ivosidenib improved progression-free survival, 2.7 months versus 1.4 months (p
Real-World Data on Ivosidenib in Patients with Previously Treated Isocitrate Dehydrogenase 1-Mutated Intrahepatic Cholangiocarcinomas: An Early Exploratory Analysis. [2022]The results of the phase III ClarIDHy trial have led to US FDA approval of ivosidenib as a therapeutic option for patients with locally advanced or metastatic cholangiocarcinoma (CCA) harboring isocitrate dehydrogenase 1 (IDH1) mutations.