A Randomized, Multicenter Open Label Phase II Trial of Paclitaxel + Ramucirumab Versus Paclitaxel Alone in Patients With Squamous-cell Carcinoma of the Esophagus, Refractory or Intolerant to Combination Therapy With Fluoropyrimidine and Platinum-based Drugs - The RAMOS STUDY
Overview
- Phase
- Phase 2
- Intervention
- Ramucirumab
- Conditions
- Squamous Cell Carcinoma of the Esophagus
- Sponsor
- Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest
- Enrollment
- 21
- Locations
- 2
- Primary Endpoint
- Overall survival (OS) at 6 months
- Status
- Completed
- Last Updated
- 3 years ago
Overview
Brief Summary
This is a multicenter, randomized, controlled, open-label phase II study including patients with squamous-cell carcinoma of the esophagus, refractory or intolerant to combination therapy with Fluoropyrimidine and Platinum-based drugs.
Detailed Description
This is a phase II, randomized, open-label multi-center study comparing treatment of paclitaxel plus ramucirumab with paclitaxel monotherapy in patients with advanced squamous-cell carcinoma (SCC) of the esophagus. Adult patients with histologically or cytologically confirmed advanced squamous-cell carcinoma of the esophagus and refractory or intolerant to combination therapy with Fluoropyrimidine and Platinum-based drugs will be enrolled in the study. A total number of 186 patients will be enrolled (Randomization 1:1). 93 patients will be treated with paclitaxel + ramucirumab (Arm A) and 93 with paclitaxel (Arm B). Randomization will be stratified by time of progression during or after end of first-line therapy (≤3 months vs. \>3 months). The primary objective is to compare overall survival (OS) after 6 months in patients with squamous-cell carcinoma of the esophagus, refractory or intolerant to combination therapy with Fluoropyrimidine and Platinum-based drugs receiving paclitaxel with ramucirumab versus paclitaxel alone in the intent-to-treat population (ITT). OS is defined as the time from randomization to death from any cause. Patients in Arm A (investigational arm) receive Paclitaxel 80 mg/m2 on day 1, 8, 15 plus Ramucirumab 8 mg/kg i.v. infusion on day 1 and 15 every 4 weeks. Patients in Arm B (control arm) receive Paclitaxel 80 mg/m2 on day 1, 8, 15 every 4 weeks. Study treatment will be continued until progression or intolerable toxicity, but for a maximum of 1 year. Tumor assessment will be performed according to clinical routine at screening / baseline and every 8 weeks. After discontinuation of study medication, patients will be followed for up to 1 year. Tumor assessments per CT or MRI will be performed every 2 months for 6 months or until documentation of disease progression. Follow-up for survival will be done and documented every 2 months for the 1 year follow-up period after end of treatment. During treatment, clinical visits (blood cell counts, detection of toxicity) will be performed prior to every treatment dose. Safety of paclitaxel +/- ramucirumab will be monitored continuously by careful monitoring of all adverse events (AEs) and serious adverse events (SAEs) reported. Prior to the start of each cycle and at the 30-day safety follow-up visit Quality of life (QoL) will be assessed using the European Organization for Research and treatment of Cancer Quality of Life Questionnaire-C30 (EORTC-QLQ-C30).
Investigators
Eligibility Criteria
Inclusion Criteria
- •Signed written informed consent;
- •Male or female\* ≥ 18 years of age; Patients in reproductive age must be willing to use adequate contraception during the study and for 6 months after the end of ramucirumab treatment (Appropriate contraception is defined as surgical sterilization (e.g., bilateral tubal ligation, vasectomy), hormonal contraception (implantable, patch, oral), and double-barrier methods (any double combination of: IUD, male or female condom with spermicidal gel, diaphragm, sponge, cervical cap)). Female patients with childbearing potential need to have a negative pregnancy test within 7 days before study start.
- •\*There are no data that indicate special gender distribution. Therefore, patients will be enrolled in the study gender-independently.
- •Histologically proven squamous cell carcinoma of the esophagus
- •Adult patients with metastatic or locally advanced squamous-cell carcinoma of the esophagus, not amenable to potentially curative resection, who are refractory to or intolerant of prior platinum/fluoropyrimidine combination therapy. The definition of refractory should be defined as follows:
- •Patients whose PD or recurrence was confirmed by imaging during their initial chemotherapy (including chemoradiation) or within 8 weeks after the last dose of chemotherapy will be assessed as "refractory".
- •Patients after radical resection in conjunction with chemotherapy, including neoadjuvant/adjuvant therapy and chemoradiation, whose recurrence was confirmed by imaging within 24 weeks after the last dose of chemotherapy, will be determined "refractory".
- •Measurable or non-measurable but evaluable disease determined using guidelines in RECIST 1.1 as confirmed within 28 days before randomization
- •ECOG performance status 0-1;
- •Life expectancy \> 12 weeks;
Exclusion Criteria
- •Other tumor type than squamous carcinoma (e.g. leiomyosarcoma, lymphoma) or a second cancer except in patients with squamous or basal cell carcinoma of the skin or carcinoma in situ of the cervix that has been effectively treated. Patients curatively treated and disease-free for at least 5 years will be discussed with the sponsor before inclusion.
- •Patients with significant malnutrition who receive intravenous hyperalimentation or require continuous infusion therapy with hospitalization.
- •Patients with apparent tumor invasion on organs located adjacent to the esophageal disease. Patients will be excluded if they are receiving stent therapy in esophagus or respiratory tract.
- •Concurrent chronic systemic immune therapy, chemotherapy, or hormone therapy not indicated in the study protocol.
- •Previous therapy with paclitaxeI
- •Current treatment with any anti-cancer therapy ≤ 2 weeks prior to study treatment start, unless rapidly progressing disease is measured
- •Concurrent treatment with any other anti-cancer therapy
- •Previous exposure to a VEGF or VEGFR inhibitor or any antiangiogenic agent, or prior enrolment in this study
- •Patient has undergone major surgery within 28 days prior to first dose of protocol therapy, or minor surgery/subcutaneous venous access device placement within 7 days prior to first dose of protocol therapy. The patient has elective or planned major surgery to be performed during the course of the clinical trial.
- •Grade 3-4 GI bleeding within 3 months prior to enrollment
Arms & Interventions
Arm A (Paclitaxel + Ramucirumab)
Paclitaxel 80 mg/m2 as 1 hour intravenous infusion on day 1, 8, 15 plus Ramucirumab 8 mg/kg as 1 hour intravenous infusion on day 1 and 15 qd 28
Intervention: Ramucirumab
Arm A (Paclitaxel + Ramucirumab)
Paclitaxel 80 mg/m2 as 1 hour intravenous infusion on day 1, 8, 15 plus Ramucirumab 8 mg/kg as 1 hour intravenous infusion on day 1 and 15 qd 28
Intervention: Paclitaxel
Arm B (control arm)
Paclitaxel 80 mg/m2 as 1 hour intravenous infusion on day 1, 8, 15 qd 28
Intervention: Paclitaxel
Outcomes
Primary Outcomes
Overall survival (OS) at 6 months
Time Frame: 6 months
OS rate at 6 months, defined as patients who are alive after at 6 months
Secondary Outcomes
- Tumor control rate(Up to 2 years)
- Overall survival(Up to 2 years)
- Progression-free survival (PFS)(Up to 2 years)
- Objective response rate(Up to 2 years)
- Quality of life (QoL)(Up to 1 year and 30 days)
- Incidence and severity of adverse events(Up to 1 year and 30 days)