| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Substudy 1
Inoperable or advanced FGFR2 gene fusion positive iCCA
Substudy 2:
Inoperable or advanced iCCA harboring FGFR2 mutations or amplifications |
|
| E.1.1.1 | Medical condition in easily understood language |
| A type of bile duct cancer that is inoperable or has spread, in patients that test positive for FGFR2 gene fusion, or, FGFR2 gene mutations or amplifications |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10073077 |
| E.1.2 | Term | Intrahepatic cholangiocarcinoma |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10073078 |
| E.1.2 | Term | Intrahepatic cholangiocarcinoma recurrent |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Substudy 1: To evaluate the anti-cancer activity by Objective Response Rate (ORR) by central radiology review as per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 in subjects with inoperable or advanced iCCA whose tumors harbor FGFR2 gene fusions (by FISH performed by a central laboratory) and who received at least one prior regimen of systemic therapy.
Substudy 2: To evaluate the anti-tumor activity of derazantinib by progression-free survival at 3 months (PFS 3) based on survival status or central radiology review (RECIST 1.1) in patients with inoperable or advanced iCCA whose tumors
harbor FGFR2 gene mutations or amplifications, and who received at least one prior regimen of systemic therapy.
|
|
| E.2.2 | Secondary objectives of the trial |
Substudy 1 and Substudy 2
• To evaluate progression free survival (PFS) by central radiology review and overall survival (OS)
• To evaluate duration of response (DoR) by central radiology review
• To evaluate the safety profile (toxicities) of derazantinib in this subject population
• To evaluate changes, and assess the minimally important difference, in health-related quality-of-life (HRQOL) and symptom response from baseline using the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and QLQ-BIL21, Global-Self Evaluated Transition (G-SET) / Health Transition Index (HTI) and the EQ-5D visual analog scale (VAS).
Substudy 2
• To evaluate the anti-cancer activity by ORR by central radiology review as per RECIST version 1.1 in patients with inoperable or advanced iCCA whose tumors harbor FGFR2 gene mutations or amplifications, and who received at least one prior regimen of systemic therapy |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Tissue samples for genetic testing will be obtained from subjects who meet the following pre-screening eligibility criteria:
1. Signed written informed consent to permit tissue analysis
2. 18 years of age or older
3. No medical history that is excluded per the study treatment eligibility criteria
4. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1 (Appendix 2)
5. Eligible for or receiving systemic therapy for inoperable or advanced iCCA
6. Not currently eligible for curative local or surgical therapy
To be enrolled in the study, once the FGFR2 genomic aberration status is determined, each prospective subject must meet all of the following inclusion criteria and none of the exclusion criteria.
1. Signed written informed consent granted prior to initiation of any study-specific procedures
2. 18 years of age or older
3. Histologically or cytologically confirmed locally advanced, inoperable (where surgery is not indicated due to disease extension, co-morbidities, or other technical reasons), or metastatic iCCA or mixed histology tumors (combined hepatocellular-cholangiocarcinoma [cHCC-CCA])
4. Substudy 1:
FGFR2 gene fusion status based on the following assessments:
a) If central laboratory designated by the Sponsor:
Positive FISH test; and/or
b) If non-central laboratory:*
i) Positive FISH or NGS test: patients may be enrolled and may start dosing, but central confirmation is required**
* Using standard protocols and approved by local IRB/IEC, CLIA, or other similar agency. For enrollment of patients in the EU, assays must be fully CE-marked.
** The patient must not be enrolled if a negative FISH test is obtained from the central laboratory prior to commencing study treatment. Patients without central confirmation of an FGFR2 fusion by the central FISH test will be assessed on a case-by-case basis.
ii) Negative FISH or NGS test: tissue may be submitted to the central laboratory designated by the Sponsor, and patients may only be enrolled if the central test is positive
Substudy 2:
FGFR2 mutation status based on local NGS testing performed or commissioned by the respective study site using a validated test listed Section 6.7. For enrollment of patients in the EU, assays must be fully CE-marked. For NGS testing, no central laboratory will be established for the purpose of Substudy 2.
5. Received at least one regimen of prior systemic therapy and then experienced documented radiographic progression (for Substudy 1), and have no satisfactory treatment alternatives (for Substudy 2).
6. Measurable disease by RECIST version 1.1 criteria
7. ECOG performance status ≤ 1 (Appendix 2 of protocol)
8. Adequate organ functions as indicated by the following laboratory values (based on screening visit values from the central laboratory).
◦ Hematological
◦ Hemoglobin (Hgb) ≥ 9.0 g/dL
◦ Absolute neutrophil count (ANC) ≥ 1.5 x 10 to the power of 9/L
◦ Platelet count ≥ 75 x 10 to the power of 9/L
◦ International normalized ratio (INR) 0.8 to upper limit of normal (ULN) or ≤ 3 for subjects receiving anticoagulant therapy such as warfarin or heparin
- Hepatic
◦ Total bilirubin ≤ 2 x ULN
◦ Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 ULN (≤ 5 x ULN for subjects with liver metastases)
◦ Albumin ≥ 2.8 g/dL
- Renal
◦ Serum creatinine ≤ 1.5 x ULN, or
◦ Creatinine clearance of ≥ 60 mL/min as estimated by the Cockcroft-Gault equation
9. Female and male patients of child-producing potential must agree to avoid becoming pregnant or impregnating a partner, respectively during the study, and for at least 120 days after the last dose of derazantinib.
Male patients are considered not to be of child-producing potential if they have azoospermia (whether due to vasectomy or an underlying medical condition). Female patients are considered not to be of child-producing potential if they are:
• postmenopausal , or
• have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or bilateral tubal ligation/occlusion, at least 6 weeks prior to screening, or
• have a congenital or acquired condition that prevents childbearing.
Male or female patients of child-producing potential must agree to comply with one of the following until at least 120 days after the last dose of derazantinib:
a) Abstinence from heterosexual activity
b) Using (or having their partner use) a highly effective method of contraception during heterosexual activity.
Highly effective methods of contraception are:
• an intrauterine device (IUD)
•vasectomy of a female patient’s male partner
•a contraceptive rod implanted into the skin
• Combined (estrogen- and progestogen-containing) or progestogen-only hormonal contraception associated with inhibition of ovulation (oral contraceptive pill [estrogen/progestin pill or progestin-only pill] contraceptive skin patch/implant, vaginal contraceptive ring, or subcutaneous contraceptive injection) |
|
| E.4 | Principal exclusion criteria |
1. Systemic anti-cancer therapy, such as chemotherapy, immunotherapy, hormonal, targeted therapy, or investigational agents within four weeks of the first dose of derazantinib, or within five half-lives of the respective anticancer therapy, whichever is the longer period.
2. Major surgery, locoregional therapy, or radiation therapy within four weeks of the first dose of derazantinib
3. Previous treatment with any FGFR inhibitor (e.g., ponatinib, dovitinib, nintedanib, AZD4547, NVP-BGJ398, LY2784455, BAY1163877)
- Subjects who received less than four weeks of therapy and were unable to continue therapy due to toxicity will be allowed to participate
4. Unable or unwilling to swallow the complete daily dose of derazantinib capsules
5. Clinically unstable central nervous system (CNS) metastases (to be eligible, subjects must have stable disease ≥ 3 months, confirmed by magnetic resonance imaging (MRI) or computed tomography (CT) scan, and/or have CNS metastases well controlled by low-dose steroids, anti-epileptics, or other symptom-relieving medications)
6. Current evidence of corneal or retinal disorder, including but not limited to bullous/band keratopathy, keratoconjunctivitis, corneal abrasion, inflammation/ulceration, confirmed by ophthalmologic examination
7. Concurrent uncontrolled or active hepatobiliary disorders, untreated or ongoing complications after laparoscopic procedures or stent placement, including but not limited to active cholangitis, biloma or abscess (to be eligible, the subjects have to be treated and disorders/complications should be resolved within 2 weeks prior to the first dose of derazantinib [ARQ 087])
8. History of significant cardiac disorders:
- Myocardial infarction (MI) or congestive heart failure defined as Class II to IV per the New York Heart Association (NYHA) classification within 6 months of the first dose of derazantinib (MI that occurred > 6 months prior to the first dose of derazantinib are permitted)
- QTcF > 450 msec for men and QTcF > 460 msec for women
9.Serum electrolyte abnormalities defined as follows:
• Hyperphosphatemia: serum phosphate > institutional ULN
•Hyperkalemia: serum potassium > institutional ULN
•Hypokalemia: serum potassium < institutional lower limit of normal (LLN)
• Hypercalcemia: corrected serum calcium > 3.1 mmol/L (>12.5 mg/dL)
• Hypocalcemia: corrected serum calcium < 1.75 mmol/L (<7.0 mg/dL)
• Hypomagnesemia: < 0.4 mmol/L (< 0.9 mg/dL)
10. Significant gastrointestinal disorder(s) that could, in the opinion of the Investigator, interfere with the absorption, metabolism, or excretion of derazantinib (e.g., Crohn’s disease, ulcerative colitis, extensive gastric resection)
11. Previous malignancy within 2 years of the first dose of derazantinib, except curatively treated or low grade malignancies such as non-melanoma skin cancer, carcinoma in-situ of the breast, cervix, and superficial bladder tumors
12. Concurrent uncontrolled illness not related to cancer, including but not limited to:
- Psychiatric illness/substance abuse/social situation that would limit compliance with study requirements
- Known uncontrolled human immunodeficiency virus (HIV) infection
13. Blood or albumin transfusion within 5 days of the blood draw being used to confirm eligibility
14. Pregnant or breast feeding
15. Known hypsersensitivity to derazantinib, or to any of the study drug excipients (starch, lactose, crospovidone, magnesium stearate). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary efficacy endpoint (Substudy 1)
ORR will be the proportion of subjects with confirmed complete responses and partial responses by central radiology review as per RECIST version 1.1
Primary efficacy endpoint (Substudy 2)
PFS 3 will be the proportion of patients who have progression-free survival at 3 months from the first date of receiving study drug as assessed by survival status and central radiology review as per RECIST version 1.1. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Tumor assessments (CT or MRI scan) of the chest, abdomen, and pelvis will be done at screening, once every 8 weeks (every 2 cycles) from the day of the first dose for the first 6 cycles (C3D1, C5D1, C7D1), and once every 12 weeks (every 3 cycles) thereafter (C10D1, C13D1, etc.). The End of Treatment scan will be done if the previous scan was not done within four weeks (28 days) prior to the End of Treatment visit or if the previous scan did not show radiographic disease progression. |
|
| E.5.2 | Secondary end point(s) |
Secondary efficacy endpoints (Substudy 1 and Substudy 2)
• DoR will be calculated from the first date of documented tumor response to disease progression by central radiology review
• PFS will be calculated from the first date of receiving study drug until radiographic disease progression by central radiology review or death
• OS will be calculated from the first date of receiving study drug until death
• Changes in HRQOL and symptom response will be evaluated using the EORTC QLQ-C30, QLQ-BIL21, and EQ-5D VAS.
Secondary efficacy endpoint (Substudy 2)
• ORR will be the proportion of patients with confirmed complete responses and partial responses by central radiology review as per RECIST version 1.1. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
DoR and PFS - Tumor assessments (CT or MRI scan) of the chest, abdomen, and pelvis will be done at screening, once every 8 weeks (every 2 cycles) from the day of the first dose for the first 6 cycles (C3D1, C5D1, C7D1), and once every 12 weeks (every 3 cycles) thereafter (C10D1, C13D1, etc.). The End of Treatment scan will be done if the previous scan was not done within four weeks (28 days) prior to the End of Treatment visit or if the previous scan did not show radiographic disease progression.
OS - from the first date of receiving study drug until death |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 19 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Belgium |
| Canada |
| France |
| Germany |
| Ireland |
| Italy |
| Korea, Republic of |
| Spain |
| Switzerland |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
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