Randomized, Double-Blind, Phase 2 Study of Ramucirumab or Merestinib or Placebo Plus Cisplatin and Gemcitabine as First-Line Treatment in Patients With Advanced or Metastatic Biliary Tract Cancer
Overview
- Phase
- Phase 2
- Intervention
- Ramucirumab
- Conditions
- Biliary Tract Cancer
- Sponsor
- Eli Lilly and Company
- Enrollment
- 309
- Locations
- 79
- Primary Endpoint
- Progression Free Survival (PFS)
- Status
- Active, not recruiting
- Last Updated
- 9 months ago
Overview
Brief Summary
The main purpose of this study is to evaluate the efficacy and safety of ramucirumab or merestinib or placebo plus cisplatin and gemcitabine in participants with advanced or metastatic biliary tract cancer.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Have an Eastern Cooperative Oncology Group performance status of 0 or
- •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) .
- •Have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST).
- •Have adequate biliary drainage.
- •Have adequate organ function.
- •Males and females are sterile, postmenopausal, or compliant with a highly effective contraceptive method.
- •Female participants of childbearing potential must have a negative serum pregnancy test within 7 days prior to first dose.
- •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.
Exclusion Criteria
- •Previous systemic therapy for locally advanced or metastatic disease is not allowed.
- •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.
- •Have ongoing or recent (≤6 months) hepatorenal syndrome.
- •Have had a major surgical procedure or significant traumatic injury including nonhealing wound, peptic ulcer, or bone fracture ≤28 days prior to randomization.
- •Anticipate having a major surgical procedure during the course of the study.
- •Has documented brain metastases, leptomeningeal disease, or uncontrolled spinal cord compression.
- •Within 6 months prior to randomization, have had any arterial thrombotic event, including myocardial infarction, unstable angina, cerebrovascular accident, or transient ischemic attack.
- •Have an uncontrolled arterial hypertension with systolic blood pressure ≥150 or diastolic blood pressure ≥90 millimeters of mercury (mm Hg) despite standard medical management.
- •Have a previous malignancy within 5 years of study entry or a concurrent malignancy.
- •Have a history of gastrointestinal perforation and/or fistulae within 6 months prior to randomization.
Arms & Interventions
8 mg/kg Ramucirumab + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine
Participants received 8 mg/kg ramucirumab plus 25 mg/square meter (mg/m²) cisplatin and 1000 mg/m² gemcitabine intravenously (IV) on days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for ramucirumab therapy).
Intervention: Ramucirumab
8 mg/kg Ramucirumab + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine
Participants received 8 mg/kg ramucirumab plus 25 mg/square meter (mg/m²) cisplatin and 1000 mg/m² gemcitabine intravenously (IV) on days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for ramucirumab therapy).
Intervention: Cisplatin
8 mg/kg Ramucirumab + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine
Participants received 8 mg/kg ramucirumab plus 25 mg/square meter (mg/m²) cisplatin and 1000 mg/m² gemcitabine intravenously (IV) on days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for ramucirumab therapy).
Intervention: Gemcitabine
Placebo IV + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine
Participants received placebo (indistinguishable and equivalent volume to ramucirumab) plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for placebo therapy).
Intervention: Cisplatin
Placebo IV + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine
Participants received placebo (indistinguishable and equivalent volume to ramucirumab) plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for placebo therapy).
Intervention: Gemcitabine
Placebo IV + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine
Participants received placebo (indistinguishable and equivalent volume to ramucirumab) plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for placebo therapy).
Intervention: Placebo IV
80 mg Merestinib + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine
Participants received 80 mg merestinib orally each day, plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on Days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for merestinib therapy).
Intervention: Merestinib
80 mg Merestinib + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine
Participants received 80 mg merestinib orally each day, plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on Days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for merestinib therapy).
Intervention: Cisplatin
80 mg Merestinib + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine
Participants received 80 mg merestinib orally each day, plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on Days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for merestinib therapy).
Intervention: Gemcitabine
Placebo Oral + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine
Participants received placebo (indistinguishable to merestinib) orally each day, plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on Days 1 and 8, every 21 days. Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for placebo therapy).
Intervention: Cisplatin
Placebo Oral + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine
Participants received placebo (indistinguishable to merestinib) orally each day, plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on Days 1 and 8, every 21 days. Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for placebo therapy).
Intervention: Gemcitabine
Placebo Oral + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine
Participants received placebo (indistinguishable to merestinib) orally each day, plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on Days 1 and 8, every 21 days. Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for placebo therapy).
Intervention: Placebo Oral
Outcomes
Primary Outcomes
Progression Free Survival (PFS)
Time Frame: Randomization to Progressive Disease or Death from Any Cause (Up To 20 Months)
PFS time was measured from the date of randomization until the first radiographic documentation of progression as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, or death from any cause. Progressive Disease (PD) was at least a 20% increase in the sum of the diameters of target lesions, with reference being the smallest sum on study and an absolute increase of at least 5 mm, or unequivocal progression of non-target lesions, or 1 or more new lesions. If a participant does not have a complete baseline disease assessment, then the PFS time was censored at the date of first dose, regardless of whether or not objectively determined disease progression or death has been observed for the participant. If a participant was not known to have died or have objective progression as of the data inclusion cutoff date for the analysis, the PFS time was censored at the last adequate tumor assessment date.
Secondary Outcomes
- Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab(C1 D8, C2 D1, C3 D1, C4 D1,C5 D1,C7 D1, C9 D1 and C13 D1: Within 3 days Prior to Infusion(PTI))
- Change From Baseline in Functional Assessment of Cancer Therapy Hepatobiliary Questionnaire (FACT-Hep)(Baseline, Follow Up (Up To 48 Months))
- Change From Baseline on the EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) Index Score(Baseline, Follow Up (Up To 48 Months))
- Overall Survival (OS)(Randomization to Date of Death from Any Cause (Up To 48 Months))
- Percentage of Participants With a Best Overall Response of Complete Response (CR) or Partial Response (PR): Objective Response Rate (ORR)(Randomization to Disease Progression (Up To 30 Months))
- Percentage of Participants With a Best Overall Response of CR, PR, or Stable Disease (SD): Disease Control Rate (DCR)(Randomization to Disease Progression (Up To 30 Months))
- PK: Plasma Concentration of Merestinib(C1 D8; C2 D1; C4 D1; C6 D1; C8 D1; C2 D8; C4 D8; C6 D8; C8 D8: Morning)
- Change From Baseline in Participant-Reported EQ-5D-5L Visual Analog Scale (VAS) Score(Baseline, Follow Up (Up To 48 Months))
- Number of Participants With Treatment-Emergent Anti-Ramucirumab Antibodies(Predose Cycle 1 Day 1 through Follow Up (Up To 48 Months))