| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced or Metastatic Biliary Tract Cancer |
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| E.1.1.1 | Medical condition in easily understood language |
| Advanced or Metastatic Biliary Tract Cancer |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Evaluate the efficacy, in terms of PFS, in patients with advanced or metastatic BTC, for
• ramucirumab (8 mg/kg, IV) versus placebo, in combination with cisplatin (25 mg/m2, IV) and gemcitabine (1000 mg/m2, IV), on Days 1 and 8 of a 21-day cycle.
• merestinib (80 mg, oral each day) versus placebo, in combination with cisplatin (25 mg/m2, IV) and gemcitabine (1000 mg/m2 IV), on Days 1 and 8 of a 21-day cycle.
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| E.2.2 | Secondary objectives of the trial |
- Evaluate the efficacy, in combination with cisplatin and gemcitabine, in terms of OS, for ramucirumab versus placebo and merestinib versus placebo.
- Evaluate the efficacy, in combination with cisplatin and gemcitabine, in terms of ORR and DCR for ramucirumab versus placebo and merestinib versus placebo.
- Safety profile of merestinib
- Safety profile of ramucirumab
- PK of ramucirumab
- PK of merestinib
- Immunogenicity of ramucirumab
- Evaluate PRO measures of disease-specific symptoms, in combination with cisplatin and gemcitabine, for ramucirumab versus placebo and merestinib versus placebo.
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
I3O-MC-JSBF(1): Drug Drug Interaction addendum
An additional secondary objective for the DDI substudy will be to assess the PK of gemcitabine and cisplatin with and without ramucirumab or merestinib. |
|
| E.3 | Principal inclusion criteria |
[1] Are of an acceptable age to provide informed consent according to the local regulations and are at least 18 years of age.
[2] Have an estimated life expectancy ≥3 months.
[3] Have an Eastern Cooperative Oncology Group performance status of 0 or 1 at the time of randomization (refer to Appendix 7).
[4] Have a histologically or cytologically confirmed diagnosis of non-resectable, recurrent, or metastatic biliary tract adenocarcinoma (intrahepatic or extrahepatic cholangiocarcinoma, gallbladder cancer, or Ampulla of Vater).
[5] Have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 on computed tomography (CT) or magnetic resonance imaging (MRI) assessments performed ≤ 28 days prior to Cycle 1 Day 1.
[6] Have resolution of all clinically significant toxic effects of prior therapy to Grade ≤1 by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), Version 4.0.
[7] Have adequate biliary drainage (per investigator’s discretion), with no evidence of ongoing infection.
[8] Have adequate organ function as determined by:
a. Hepatic: Total bilirubin, aspartate transaminase (AST), and alanine transaminase (ALT) are all ≤ 3 times upper limit of institutional normal value (ULN) on 2 measurements separated by at least 5 days.
b. Renal:
i. Glomerular filtration rate (GFR) of ≥50 ml/min/1.73 m2. GFR should be calculated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation (refer to Appendix 6), or may be measured using 24 hour urine collection or clearance of exogenous filtration markers (such as iothalamate or 51-CrEDTA or Tc99m-DTPA).
ii. The patient’s urinary protein is ≤1+ on dipstick or routine urinalysis. If urine dipstick or routine analysis indicates proteinuria ≥2+, then a 24-hour urine must be collected and must demonstrate <2 g of protein in 24 hours to allow participation in the study.
c. Hematologic:
i. Absolute neutrophil count (ANC) ≥1.5 x 109/L,
ii. hemoglobin ≥9 g/dL (5.58 mmol/L; packed red blood cell transfusions are not allowed within 1 week prior to baseline hematology profile), and
iii. platelets ≥ 100 x 109/L.
d. Coagulation: The patient must have adequate coagulation function as defined by International Normalized Ratio (INR) ≤1.5 and a partial thromboplastin time (PTT/aPTT) ≤5 seconds above the ULN. Patients receiving low-dose anticoagulant therapy at prophylactic doses (such as prophylaxis with low-molecular weight heparin) are eligible, provided that INR ≤1.5 and PTT/aPTT ≤5 seconds above the ULN. Treatment with acetylsalicylic acid (aspirin) at a daily dose of ≤325 mg is permitted.
[9] Males and females are sterile, postmenopausal, or compliant with a highly effective contraceptive method during study participation and for 3 months following the last dose of study drug.
[10] Female patients of childbearing potential must have a negative serum pregnancy test within 7 days prior to first dose.
[11] The patient has provided signed informed consent and authorization for release of health information for research prior to any study-specific procedures and is amenable to compliance with protocol schedules and testing.
[12] Are willing to provide blood/serum/plasma and tumor tissue samples for research purposes. Submission of blood/serum/plasma and tumor tissue samples is mandatory for participation in this study, unless restricted per local regulations. Tumor tissue biopsies may be taken by either core needle or excisional biopsy.
[13] Are able to swallow tablets. Patients who have a nontemporary gastric or enteral feeding tube may be permitted to participate in the study with prior approval from the Sponsor’s CRP/CRS. |
|
| E.4 | Principal exclusion criteria |
[14] Previous systemic therapy for locally advanced or metastatic disease is not allowed. Transarterial chemoembolization (TACE) or radiotherapy, including use of radioactive beads, is not allowed unless otherwise addressed in the Exclusion Criterion 18. See protocol for previous allowed treatments:
[15] Have a history of or have current hepatic encephalopathy of any grade, or ascites of Grade >1, or cirrhosis with Child-Pugh Stage B or higher.
[16] Have ongoing or recent (≤6 months) hepatorenal syndrome
[17] Have had a major surgical procedure or significant traumatic injury including non-healing wound, peptic ulcer, or bone fracture ≤28 days prior to randomization, or anticipate having a major surgical procedure during the course of the study. Randomization should only occur after complete wound healing. Subcutaneous venous access device placement should not be considered a significant surgery, but should be placed greater than 7 days prior to randomization.
[18] Have had radiation to any site (for example, bone) within 14 days prior to randomization. Palliative radiation to symptomatic metastatic sites (for example, bone) is permitted, provided it is performed >14 days prior to randomization. If any tumor lesion is administered radiotherapy, then it cannot be considered for response assessment.
[19] Has documented brain metastases, leptomeningeal disease, or uncontrolled spinal cord compression. Screening of asymptomatic patients without history of central nervous system (CNS) metastases is not required. However, patients with findings consistent with CNS malignancy or metastasis should be evaluated fully before study participation.
[20] Have had any previous systemic therapy with VEGF inhibitors or VEGF-Receptor inhibitors (including investigational agents).
[21] Are receiving therapeutic dose anticoagulation with warfarin, low-molecular-weight heparin, or similar agents (see also Inclusion Criterion 8d).
[22] Are receiving chronic therapy with nonsteroidal anti-inflammatory agents (NSAIDs: for example, indomethacin, ibuprofen, naproxen, or similar agents) or other anti-platelet agents (for example, clopidogrel, ticlopidine, dipyridamole, anagrelide). Aspirin use at doses up to 325 mg/day is permitted
[23] Symptomatic congestive heart failure (New York Heart Association III-IV are excluded, Class I and II are eligible), unstable angina pectoris, or symptomatic or poorly controlled cardiac arrhythmia.
[24] Within 6 months prior to randomization, have had any arterial thrombotic event, including myocardial infarction, unstable angina, cerebrovascular accident, or transient ischemic attack.
[25] Have an uncontrolled arterial hypertension with systolic blood pressure ≥150 or diastolic blood pressure ≥90 mm Hg despite standard medical management.
[26] Have a previous malignancy within 5 years of study entry or a concurrent malignancy. Patients with carcinoma in situ of any origin and patients with prior malignancies who are in remission and whose likelihood of recurrence is very low, as judged by the Lilly CRP/CRS in consultation with the treating investigator, are eligible for this study. The approval by the CRP/CRS of such patients is required before these patients may be enrolled.
[28] Have a history of gastrointestinal perforation and/or fistulae within 6 months prior to randomization.
[29] Have a known allergy or hypersensitivity reaction to any of the treatment components.
[30] Have a history of uncontrolled hereditary or acquired thrombotic disorder.
[31] Have uncontrolled metabolic disorders or other nonmalignant organ or systemic diseases or secondary effects of cancer that induce a high medical risk and/or make assessment of survival uncertain. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, and in the judgment of the investigator would make the patient ineligible for entry into this study.
[32] Have mixed hepatocellular biliary tract cancer histology.
[33] Females who are pregnant or lactating.
[34] Have a QTc interval >470 msec as calculated be the Fredericia equation.
[35] The patient experienced any bleeding episode considered life-threatening, or any Grade 3 or 4 gastrointestinal/variceal bleeding episode in the 3 months prior to randomization requiring transfusion or endoscopic or operative intervention
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| PFS (objective progression or death), as determined by investigator assessment per RECIST 1.1 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| From randomization until the first radiographic documentation of progression or death from any cause in the absence of progressive disease |
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| E.5.2 | Secondary end point(s) |
OS
ORR and DCR
The safety endpoints evaluated will include but are not limited to the following:
• TEAEs, AESIs, SAEs, and hospitalizations
• Clinical laboratory tests, vital signs, and physical examinations
• Minimum ramucirumab concentration in serum
• Postdose merestinib concentration in plasma
Blood samples for immunogenicity testing will be collected to determine antibody production against ramucirumab.
Functional Assessment of Cancer Therapy Hepatobiliary Questionnaire (FACT-Hep)
EuroQol 5-Dimension 5-Level (EQ-5D-5L)
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|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Time period for OS is from randomization until death from any cause.
For ORR/DCR from randomization until the first radiographic documentation of progression or death from any cause in the absence of progressive disease |
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| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| 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 | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 47 |
| 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 |
| Argentina |
| Australia |
| Austria |
| Belgium |
| Czech Republic |
| Denmark |
| France |
| Germany |
| Hungary |
| Italy |
| Korea, Republic of |
| Mexico |
| Russian Federation |
| Spain |
| Sweden |
| Taiwan |
| Turkey |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 5 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 5 |
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