A Phase III, Randomized, Controlled, Global Multicenter Study to Evaluate the Efficacy and Safety of Oral Tinengotinib versus Physician’s Choice in Subjects with Fibroblast Growth Factor Receptor (FGFR) altered, Chemotherapy- and FGFR Inhibitor-Refractory/Relapsed Cholangiocarcinoma (FIRST-308)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Transthera Sciences (Nanjing) Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

24 Apr 2024 → ongoing

Decision date (initial)

2024-03-04

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

TransThera Sciences (Nanjing), Inc.

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Pharmacokinetic, Efficacy

Part A
• To assess the safety and tolerability of tinengotinib in 8 mg QD and 10 mg once daily (QD) in subjects with FGFR altered, chemotherapy- and FGFR inhibitor-refractory/relapsed CCA
Part B
• To evaluate the efficacy of tinengotinib at the selected Part B dose based on progression-free survival (PFS) per blinded independent central review (BICR) compared to Physician’s Choice in subjects with FGFR altered, chemotherapy- and FGFR inhibitor-refractory/relapsed CCA.

Secondary objectives 1

1. Part A • To assess the preliminary efficacy of tinengotinib in 8 mg QD and 10 mg QD based on objective response rate (ORR), and duration of response (DOR) assessed by the investigators in subjects with FGFR-altered, chemotherapy- and FGFR inhibitor- refractory/relapsed CCA • To assess the PK of tinengotinib in 8 mg QD and 10 mg QD in subjects with FGFR-altered, chemotherapy- and FGFR inhibitor- refractory/relapsed CCA. Part B • To evaluate the efficacy of tinengotinib at the selected Part B dose based on overall survival (OS), compared to Physician’s Choice in subjects with FGFR-altered, chemotherapy- and FGFR inhibitor- refractory/relapsed CCA. • To evaluate the efficacy of tinengotinib at the selected Part B dose based on ORR, DOR, with response assessed by BICR and investigator compared to Physician’s Choice in subjects with FGFR-altered, chemotherapy- and FGFR inhibitor- refractory/relapsed CCA. • To evaluate PFS of tinengotinib at the selected Part B per investigator assessment in subjects with FGFR-altered, chemotherapy- and FGFR inhibitor- refractory/relapsed CCA. • To evaluate the safety of tinengotinib at the selected Part B dose versus Physician’s Choice. • To assess health-related quality of life (HRQOL) by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaires (EORTC QLQ-C30) global HRQOL, functioning (physical) and symptoms (fatigue), and EORTC QLQ-BIL21 in tinengotinib at the selected Part B dose vs. Physician’s Choice for Part B. • To assess the Population PK of tinengotinib in all treated and PK-evaluable subjects.

Conditions and MedDRA coding

Cholangiocarcinoma (LTT, 26.0)

Study design 2 periods

Regulatory references

Scientific advice from competent authorities

European Medicines Agency, Food And Drug Administration

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. 1. ≥ 18 years of age at the time of signing the informed consent form (ICF).
2. 10. Able to understand and sign the ICF and comply with the protocol.
3. 2. Histologically or cytologically confirmed CCA/adenocarcinoma of biliary origin with radiological evidence of unresectable or metastatic disease.
4. 3. Documentation of presence FGFR2 fusion/rearrangement gene status
5. 4. Subjects must have received at least one line of prior chemotherapy and exactly one FGFR inhibitor.
6. 5. 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.
7. 6. Must agree to blood collection for liquid biopsy genomic testing.
8. 7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
9. 8. 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
10. 9. 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.
11. 11. Life expectancy≥12 weeks.

Exclusion criteria 12

1. 1. Prior receipt of two or more FGFR inhibitors, either approved or investigational drugs.
2. 11. Subjects with a fistula, impairment of gastrointestinal function, or gastrointestinal disease that may significantly alter the absorption, metabolism, or excretion of tinengotinib.
3. 3. 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.
4. 4. 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.
5. 5. 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.
6. 6. Concurrent anticancer therapy including chemo-, immune-, or radiotherapy. Hormone therapy may be allowed with Sponsor approval.
7. 7. 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.
8. 8. Subjects who have undergone major surgery ≤ 4 weeks prior to starting the study drug or who have not recovered from AEs of prior therapy.
9. 9. 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.
10. 10. 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).
11. 2. Prior receipt of both FOLFOX and FOLFIRI chemotherapy regimens.
12. 20. 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Part A • Incidence, duration, and severity of adverse events (AEs), as assessed per Common Terminology Criteria for Adverse Events (CTCAE) v5.0 (or the most current version).
2. Part B • Progression-free survival (PFS) by BICR: PFS is defined as the time from date of randomization to the date of first documented disease progression as assessed by BICR per Response Evaluation Criteria in Solid Tumors (RECIST) v1.116, or date of death due to any cause, whichever is earlier.

Secondary endpoints 9

1. Part A • ORR，DOR by Investigator
2. • PK analysis
3. Part B • Overall survival (OS): OS is defined as the time from date of randomization to date of death of any cause.
4. • Objective Response Rate (ORR) by BICR and by Investigator: ORR is defined as the proportion of subjects with a best overall response of complete response (CR) or partial response (PR), as assessed by BICR and by the investigator, per RECIST v1.1.
5. • Duration of Response (DOR) by BICR and by Investigator: DOR is defined as the time from date of first documented CR or PR to the date of first documented progressive disease (PD) or death due to any cause by BICR and by investigator’s assessment per RECIST v1.1.
6. • PFS by Investigators per RECIST v1.1.
7. • Incidence, duration, and severity of AEs: as assessed per CTCAE v5.0 (or the most current version).
8. • European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire: global HRQOL, functioning (physical) and symptoms (fatigue); and EORTC QLQ-BIL21 in tinengotinib vs. Physician’s Choice.
9. • Population PK: for the tinengotinib arm.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Comparator 8

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Transthera Sciences (Nanjing) Inc.

Sponsor organisation

Transthera Sciences (Nanjing) Inc.

Address

Floor 3, Building 9 Accelerator Phase 2, Jiangbei New Area Building 9 Accelerator Phase 2 Jiangbei New Area

City

Nanjing

Postcode

210032

Country

China

Scientific contact point

Organisation

Transthera Sciences (Nanjing) Inc.

Contact name

Clinical Trial RA Desk

Public contact point

Organisation

Transthera Sciences (Nanjing) Inc.

Contact name

Clinical Project Team

Third parties 8

Locations

8 EU/EEA countries · 44 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 108 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

15 submissions — initial application plus substantial / non-substantial modifications