Phase III Randomized Controlled Trial Evaluating Tinengotinib Versus Physician's Choice in FGFR-Altered, Chemotherapy- and FGFR Inhibitor-Refractory Cholangiocarcinoma
- Trial ID
- 2023-505660-11-00
- Protocol
- TT420C2308
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this Phase III, randomized, controlled, global multicenter study is to assess the **safety** and tolerability of tinengotinib at doses of 8 mg and 10 mg once daily in subjects with fibroblast growth factor receptor (FGFR) altered, chemotherapy- and FGFR inhibitor-refractory/relapsed **cholangiocarcinoma** (CCA). Additionally, the study aims to evaluate the efficacy of tinengotinib at the selected Part B dose based on progression-free survival (PFS) as determined by blinded independent central review (BICR) compared to Physician’s Choice in the same patient population. The clinical relevance of these objectives lies in the potential to provide a new therapeutic option for patients with limited treatment alternatives due to resistance or relapse following standard therapies.
Secondary objectives include:
- Assessing the preliminary efficacy of tinengotinib in 8 mg and 10 mg doses based on objective response rate (ORR) and duration of response (DOR) as evaluated by investigators in Part A.
- Evaluating the pharmacokinetics (PK) of tinengotinib in the same dosing regimen in Part A.
- In Part B, evaluating the efficacy of tinengotinib at the selected dose based on overall survival (OS) compared to Physician’s Choice.
- Assessing ORR and DOR with response evaluated by BICR and investigators compared to Physician’s Choice in Part B.
- Evaluating PFS per investigator assessment in Part B.
- Assessing the safety of tinengotinib at the selected Part B dose versus Physician’s Choice.
- Evaluating health-related quality of life (HRQOL) using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaires (EORTC QLQ-C30) and EORTC QLQ-BIL21 in Part B.
- Assessing the population PK of tinengotinib in all treated and PK-evaluable subjects.
Participants
The clinical trial involves a total of **105 participants** diagnosed with **cholangiocarcinoma**, specifically those with FGFR altered, chemotherapy- and FGFR inhibitor-refractory/relapsed conditions. The study population includes both male and female subjects aged **18 years and older**. Participants were selected based on their confirmed diagnosis of cholangiocarcinoma or adenocarcinoma of biliary origin, with radiological evidence of unresectable or metastatic disease. The trial includes individuals who have previously undergone at least one line of chemotherapy and exactly one FDA-approved FGFR inhibitor. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Adequate organ function and agreement to blood collection for genomic testing are necessary. The trial population is not limited by gender, and both male and female subjects are included. Participants must adhere to contraceptive measures to prevent pregnancy during the study and for a specified period after treatment. The trial does not exclude vulnerable populations, indicating inclusivity in the selection process. Lifestyle factors such as diet and physical activity are not specified as part of the selection criteria.
Plans and Procedures
The clinical trial is a **Phase III**, randomized, controlled, global multicenter study designed to evaluate the efficacy and safety of oral **tinengotinib** compared to the physician's choice in subjects with **cholangiocarcinoma** that is refractory or relapsed after chemotherapy and FGFR inhibitor treatment. The trial employs a double-blind methodology to ensure unbiased results. The estimated duration of the trial is from December 31, 2023, to August 1, 2026, with participant involvement expected to last up to 280 days, depending on individual response and treatment tolerance.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, confirmed diagnosis of cholangiocarcinoma, and previous treatment history. Following successful screening, participants will be randomized to receive either tinengotinib or a treatment of the physician's choice. The trial includes multiple follow-up visits to monitor safety, efficacy, and any adverse events, as assessed per the Common Terminology Criteria for Adverse Events (CTCAE) v5.0. The primary endpoint is progression-free survival (PFS) as determined by blinded independent central review (BICR), with secondary endpoints including overall survival (OS) and objective response rate (ORR).
The end-of-study visit will occur after the completion of the treatment period or upon early termination, which may be necessitated by factors such as disease progression, unacceptable toxicity, or withdrawal of consent. Participants are required to comply with protocol guidelines, including the use of contraceptive measures to prevent pregnancy during the study and for at least three months after the end of treatment. The trial aims to provide comprehensive data on the safety and efficacy of tinengotinib in this patient population, contributing to the understanding and management of cholangiocarcinoma.
Treatment
The clinical trial involves the administration of **Tinengotinib**, an experimental medication, in various dosages. Tinengotinib is available in tablet form with strengths of 4 mg, 5 mg, and 6 mg. The medication is administered orally with a maximum daily dose of 10 mg and a total maximum dose of 2800 mg over a treatment period of 280 days. The active substance, tinengotinib, is of chemical origin and is provided by TRANSTHERA SCIENCES (NANJING), INC. Participant compliance with the dosing schedule is monitored throughout the trial.
In addition to the experimental medication, the study includes several comparator treatments. **Oxaliplatin** is administered as a solution for infusion, with a concentration of 5 mg/ml. The maximum daily dose is 85 mg/m², with a total maximum dose of 510 mg/m² over a 3-day treatment period. The active substance, oxaliplatin, is of chemical origin and is provided by AQVIDA GMBH and HIKMA FARMACÊUTICA (PORTUGAL), S.A.
**Irinotecan Hydrochloride** is another comparator treatment, available as a concentrate for solution for infusion with a concentration of 20 mg/ml. The maximum daily dose is 180 mg/m², with a total maximum dose of 16200 mg/m² over a 3-day treatment period. The active substance is of chemical origin and is provided by AQVIDA GMBH and HIKMA FARMACÊUTICA (PORTUGAL), S.A.
**Folinic Acid**, also known as leucovorin, is administered as a solution for injection. The maximum daily dose is 200 mg/m², with a total maximum dose of 18000 mg/m² over a 3-day treatment period. The active substance is of chemical origin and is provided by HIKMA FARMACÊUTICA (PORTUGAL), S.A. and BENDALIS GMBH.
**Fluorouracil** is administered as a solution for injection or infusion, with a concentration of 50 mg/ml. The maximum daily dose is 2800 mg/m², with a total maximum dose of 252000 mg/m² over a 3-day treatment period. The active substance is of chemical origin and is provided by BENDALIS GMBH and EBEWE PHARMA.
Efficacy
The efficacy of the clinical trial will be assessed primarily through **progression-free survival (PFS)**, as evaluated by a blinded independent central review (BICR). PFS is defined as the time from the date of randomization to the date of first documented disease progression, as assessed by BICR per the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, or the date of death due to any cause, whichever occurs earlier. Secondary efficacy endpoints include overall survival (OS), objective response rate (ORR), and duration of response (DOR), all assessed by BICR and by the investigator per RECIST v1.1. ORR is defined as the proportion of subjects with a best overall response of complete response (CR) or partial response (PR). DOR is defined as the time from the date of first documented CR or PR to the date of first documented progressive disease (PD) or death due to any cause.
Additional secondary endpoints include PFS as assessed by investigators, incidence, duration, and severity of adverse events (AEs) as per Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, and quality of life measures using the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ). The trial will also conduct pharmacokinetic (PK) analysis for the tinengotinib arm. Efficacy assessments will be conducted at specified intervals throughout the trial, with data collection and analysis performed in accordance with the trial protocol to ensure accuracy and reliability of the results.
Inclusion and Exclusion Criteria
Inclusion Criteria
- ≥ 18 years of age at the time of signing the informed consent form (ICF).
- Able to understand and sign the ICF and comply with the protocol.
- Histologically or cytologically confirmed CCA/adenocarcinoma of biliary origin with radiological evidence of unresectable or metastatic disease.
- Documentation of presence FGFR2 fusion/rearrangement gene status
- Subjects must have received at least one line of prior chemotherapy and exactly one FGFR inhibitor.
- Radiographically measurable disease per RECIST v1.1, as confirmed by central imagining review (BICR). • At least one target lesion of ≥ 10 mm in the longest diameter for a non lymph node or ≥ 15 mm in the short-axis diameter for a lymph node using computed tomography (CT)/magnetic resonance imaging (MRI). If there is only one target lesion and it is a non-lymph node, it should have the longest diameter of ≥ 15 mm. • A target lesion must not be chosen from a previously irradiated area, unless it is a new lesion that appeared after completion of radiotherapy or show evidence of disease progression after completion of radiotherapy based on RECIST v1.1.
- Must agree to blood collection for liquid biopsy genomic testing.
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
- Adequate organ function as evidenced by: • Absolute neutrophil count ≥ 1.5 × 109/L • Hemoglobin ≥ 9 g/dL • Platelet count ≥ 75 × 109/L • Aspartate aminotransferase (AST/SGOT) and alanine aminotransferase (ALT/SGPT) ≤ 2.5 × upper limit of normal (ULN) or ≤ 5.0 × ULN if liver metastases are present • Total bilirubin ≤ 1.5 × ULN; or < 2.5 × ULN if Gilbert syndrome or disease involving liver • Creatinine clearance >30 mL/min (Cockcroft Gault formula) • Adequate blood coagulation function as evidence by an international normalized ratio (INR) ≤ 1.5 unless subject is on anticoagulants
- Must agree to take sufficient contraceptive measures to avoid pregnancy (including male and female subjects) during the study and for at least 3 months after the end of treatment (EOT) for subjects randomized to the tinengotinib arm, and for at least 6 months after the EOT for subjects randomized to Physician’s Choice arm. (Note: for subjects who receive oxaliplatin to be at least 9 months for women of child-bearing potential and 6 months for men; for subjects who receive irinotecan to be at least 6 months for women of child-bearing potential and 3 months for men). Subjects will be considered to be of childbearing potential unless surgically sterile with a hysterectomy and/or bilateral oophorectomy or ≥ 12 months of amenorrhea.
- Life expectancy≥12 weeks.
Exclusion Criteria
- Prior receipt of two or more FGFR inhibitors, either approved or investigational drugs.
- Subjects with a fistula, impairment of gastrointestinal function, or gastrointestinal disease that may significantly alter the absorption, metabolism, or excretion of tinengotinib.
- Subjects with known brain or central nervous system (CNS) metastases that have radiologically or clinically progressed in the 28 days prior to initiation of therapy (e.g., evidence of new or enlarging brain metastasis or new neurological symptoms attributable to brain/CNS metastases, no adequate treatment with radiotherapy, symptomatic, requiring treatment with anticonvulsants). Subjects with asymptomatic brain/CNS metastases or treated brain/CNS metastases that have been clinically stable for 14 days on steroids without escalation of steroids are eligible for enrollment.
- Subjects with a known concurrent malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, carcinoma in situ of the cervix, or other noninvasive or indolent malignancy, including those that have previously undergone potentially curative therapy.
- Subjects who have received prior systemic therapy or investigational study drug ≤ 5 half-lives or 14 days, whichever is shorter, prior to starting the study drug.
- Concurrent anticancer therapy including chemo-, immune-, or radiotherapy. Hormone therapy may be allowed with Sponsor approval.
- Subjects who have received wide field radiotherapy ≤ 4 weeks or limited field radiation for palliation ≤ 2 weeks prior to starting the study drug or who have not recovered from AEs of prior therapy.
- Subjects who have undergone major surgery ≤ 4 weeks prior to starting the study drug or who have not recovered from AEs of prior therapy.
- Impaired cardiac function or significant diseases, including but not limited to any of the following: • History of congestive heart failure with New York Heart Association (NYHA) Class III or IV. • History of risk factors for Torsades de Pointes (TdP) including hypokalemia, or congenital long QT syndrome, or familial history of prolonged QT syndrome, etc. • QT interval with Fredericia’s correction (QTcF) ≥ 480 msec on screening electrocardiogram (ECG) (If QTcF measurement is not available, please consult with the cardiologist to exclude the risk of TdP). • Unstable angina pectoris ≤ 3 months prior to starting study drug. • Acute myocardial infarction or stroke ≤ 6 months prior to starting study drug. • Cardiac arrhythmia that is unstable requiring antiarrhythmic medical treatment (rate control medication, i.e. beta blockers, are permitted). Subjects with a pacemaker or well-controlled rhythm for at least 1 month prior to the first dose will be allowed.
- Subjects with uncontrolled hypertension (defined as blood pressure of ≥ 150 mmHg systolic and/or ≥ 90 mmHg diastolic despite adequate treatment with antihypertensive medications at screening).
- Prior receipt of both FOLFOX and FOLFIRI chemotherapy regimens.
- Subjects who have not recovered (grade ≤ 1 or at pretreatment baseline except tolerable grade 2 alopecia, fatigue/asthenia, and neuropathy due to trauma including chemotherapy) from adverse events (AEs) of prior therapy.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Recruiting | 31 Dec 2023 | 7 |
 Belgium | Recruiting | 31 Dec 2023 | 3 |
 France | Recruiting | 31 Dec 2023 | 14 |
 Germany | Recruiting | 31 Dec 2023 | 17 |
 Italy | Recruiting | 31 Dec 2023 | 24 |
 Poland | Recruiting | 31 Dec 2023 | 3 |
 Portugal | Recruiting | 31 Dec 2023 | 5 |
 Spain | Recruiting | 31 Dec 2023 | 22 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Irinotecan Hikma 20 mg/ml Konzentrat zur Herstellung einer Infusionslösung | Comparator | KONZENTRAT ZUR HERSTELLUNG EINER INFUSIONSLÖSUNG | INTRAVENOUS INFUSION | 180 | 3 | PRD6796264 |
Benda-5 FU 50 mg/ml Injektionslösung | Comparator | INJEKTIONSLÖSUNG | INTRAVENOUS BOLUS INJECTION/IV INFUSION | 2800 | 3 | PRD2947832 |
Oxaliplatin Hikma 5 mg/ml Konzentrat zur Herstellung einer Infusionslösung | Comparator | KONZENTRAT ZUR HERSTELLUNG EINER INFUSIONSLÖSUNG | INTRAVENOUS INFUSION | 85 | 3 | PRD9467155 |
BENDAFOLIN 10 mg/ml Injektionslösung | Comparator | INJEKTIONSLÖSUNG | INTRAVENOUS | 200 | 3 | PRD2832960 |
Oxaliplatin AqVida 5 mg/ml Konzentrat zur Herstellung einer Infusionslösung | Comparator | KONZENTRAT ZUR HERSTELLUNG EINER INFUSIONSLÖSUNG | INTRAVENOUS INFUSION | 85 | 3 | PRD1874310 |
Tinengotinib 5 mg | Test | TABLET | ORAL USE | 10 | 280 | PRD10494408 |
Ribofolin® 10 mg/ml Injektionslösung | Comparator | INJEKTIONSLÖSUNG | INTRAVENOUS | 200 | 3 | PRD10286539 |
5-Fluorouracil Ebewe 50 mg/ml - Konzentrat zur Herstellung einer Infusionslösung | Comparator | KONZENTRAT ZUR HERSTELLUNG EINER INFUSIONSLÖSUNG | INTRAVENOUS BOLUS INJECTION/IV INFUSION | 2800 | 3 | PRD746769 |
Irinotecan HCl AqVida 20 mg/ml Konzentrat zur Herstellung einer Infusionslösung | Comparator | KONZENTRAT ZUR HERSTELLUNG EINER INFUSIONSLÖSUNG | INTRAVENOUS INFUSION | 180 | 3 | PRD3022873 |
Tinengotinib 4 mg | Test | TABLET | ORAL USE | 10 | 280 | PRD10494407 |