Clinical Trials

Date: 2017-09-10

Type of information: update on patient enrollment

phase: 3

Announcement: presentation of results at the European Society for Medical Oncology (ESMO) 2017 Congress

Company: Eli Lilly (USA - IN)

Product: Cyramza® (ramucirumab)

Action mechanism:

• monoclonal antibody. Cyramza® (ramucirumab) is an antiangiogenic therapy. This vascular endothelial growth factor (VEGF) Receptor 2 antagonist specifically binds and blocks activation of VEGF Receptor 2 by blocking the binding of VEGF receptor ligands VEGF-A, VEGF-C, and VEGF-D.
• Ramucirumab has been granted Orphan Drug Designation for treatment of hepatocellular carcinoma in the U.S. and EU. Orphan drug status is given - in the U.S. by the FDA's Office of Orphan Products Development (OOPD) and in the EU by the European Commission - to medicines that have demonstrated promise for the treatment of rare diseases.

Disease: urothelial carcinoma

Therapeutic area: Cancer - Oncology

Country: Australia, Belgium, Canada, Denmark, France, Germany, Greece, Hungary, Israel, Italy, Japan, Republic of Korea, Mexico, The Netherlands, Poland, Romania, Russian Federation, Spain, Taiwan, Turkey, Ukraine, UK, USA

Trial details:

• The Phase III RANGE study is a randomized, double-blind, placebo-controlled study of ramucirumab and docetaxel versus placebo and docetaxel in patients with locally advanced or unresectable metastatic urothelial carcinoma whose disease progressed on or after platinum-based chemotherapy. The main purpose of this study is to evaluate the safety and efficacy of the study drug ramucirumab in combination with docetaxel in participants with urothelial cancer who failed prior platinum-based therapy.
• The trial enrolled 531 patients globally. It includes:
• 1) patients who progressed following adjuvant and/or neoadjuvant therapy;
• 2) patients who progressed following first-line metastatic therapy; and
• 3) patients who had received prior platinum-based and immune checkpoint inhibitor regimens.
• The trial's primary endpoint is progression-free survival and other secondary endpoints include overall survival, objective response rate, disease control rate and duration of response.(NCT02426125 )

Latest news:

• • On September 10, 2017, phase 3 RANGE data from Eli Lilly  were presented in the Presidential Symposium  at the European Society for Medical Oncology (ESMO) 2017 Congress (abstract#: LBA4_PR). These are the first detailed results from the RANGE study of Cyramza® (ramucirumab), in combination with docetaxel, in patients with advanced or metastatic urothelial carcinoma whose disease progressed on or after platinum-based chemotherapy. The data showed a statistically significant improvement in progression-free survival (PFS) in patients treated with ramucirumab plus docetaxel when compared to those who received placebo plus docetaxel, with a 46 percent prolongation in median PFS. These RANGE data will be published online in The Lancet on Tuesday, September 12, 2017 at 6:30 p.m. EDT.
• RANGE shows superior PFS over chemotherapy in a post-platinum setting in urothelial cancer. Also, ramucirumab is the first anti-angiogenic agent to extend PFS in a Phase 3 trial in urothelial cancer. Patients previously treated with a checkpoint inhibitor were allowed to enroll in the RANGE study. Patients treated on the ramucirumab-plus-docetaxel arm (n=263) achieved a median PFS of 4.1 months compared to 2.8 months for patients on the placebo-plus-docetaxel arm (n=267). The PFS hazard ratio (HR) was 0.757 (95% CI, 0.607-0.943, p=0.0118), which corresponds to a 24 percent reduction in the rate of disease progression or death. These investigator-assessed PFS results were confirmed by a blinded central radiographic review (HR, 0.672; 95% CI, 0.536-0.842; p=0.0005). In addition, PFS results were consistent across pre-specified subgroups.
• Importantly, the PFS HR was consistent across three subgroups defined by poor prognostic factors (HR, 0.694-0.764)--patients with ECOG 1 performance status, liver metastases or a short interval of < 3 months since prior therapy. The majority of patients (415 of 530) had at least one risk factor--44 percent had two or more.
• An analysis of the PFS data in the first 437 patients of the intent-to-treat (ITT) population showed that the ramucirumab-plus-docetaxel arm had an ORR of 24.5 percent (95% CI, 18.8-30.3) compared to 14.0 percent in the placebo-plus-docetaxel arm (95% CI, 9.4-18.6). Given the gated statistical design of the protocol, statistical analysis for significance of ORR will be assessed following the OS endpoint (at the time of the primary PFS analysis, OS data were immature). Although the number of enrolled patients that had received a prior immune checkpoint inhibitor was relatively small--as this trial was initiated in 2015 when several other such trials were ongoing and no approved agents were available--the ORR at this PFS readout in those patients was consistent with the ITT population. Disease control in the ITT population occurred in 63.4 percent (95% CI, 57.0-69.8) of patients in the ramucirumab-plus-docetaxel arm and 56.1 percent (95% CI, 49.6-62.7) in the placebo-plus-docetaxel arm.
• The safety profile observed in the RANGE study at this data readout was consistent with what has previously been observed for ramucirumab. Grade ?3 adverse events were reported at a similar frequency in both arms. The grade ?3 adverse events occurring at a rate of five percent or greater, and that were higher on the ramucirumab-plus-docetaxel arm compared to the placebo-plus-docetaxel arm, were neutropenia (15.1% vs. 13.6%), febrile neutropenia (9.7% vs. 6.4%), and hypertension (5.8% vs. 1.9%). Grade ?3 cardiovascular events, including arterial or venous thromboembolism and congestive heart failure, were rare in both arms, affecting ? 2% of patients.
• RANGE OS data are immature and final OS results are currently expected in mid-2018. Investigators, patients and Lilly study personnel involved in patient-level decision-making will remain blinded to patient-treatment assignments until that time.Overall, RANGE is the sixth positive Phase 3 trial of ramucirumab to date. Previously completed Phase 3 studies of ramucirumab have demonstrated benefit in advanced forms of gastric, non-small cell lung and colorectal cancer--three of the world's leading causes of cancer-related deaths.
• • On May 31, 2017, Eli Lilly announced that its Phase 3 RANGE study of Cyramza® (ramucirumab) met its primary endpoint of progression-free survival (PFS), demonstrating a statistically significant improvement. With these results, RANGE is the first Phase 3 study of any therapy to show superior PFS over chemotherapy in a post-platinum setting in urothelial cancer. Also, ramucirumab is the first antiangiogenic agent to extend PFS in a Phase 3 trial in urothelial cancer. Patients previously treated with a checkpoint inhibitor were allowed to enroll in the RANGE study.
• The safety profile observed in the RANGE study at this analysis was consistent with what has been previously observed for ramucirumab. Grade ?3 adverse events occurring at a rate of five percent or greater and that were higher on the ramucirumab-plus-docetaxel arm compared to the placebo-plus-docetaxel arm were neutropenia, febrile neutropenia and hypertension. Detailed efficacy and safety results will be submitted for presentation at a future medical meeting.
• Although the primary endpoint has been met, Lilly anticipates that overall survival (OS) results are likely to be required for global regulatory submissions. Final OS results are currently expected in mid-2018. Investigators, patients and Lilly study personnel involved in patient-level decision making will remain blinded to patient-treatment assignments until that time.
• • On September 28, 2015, Eli Lilly announced that a phase II study of  Cyramza® (ramucirumab) in combination with docetaxel met its primary endpoint, demonstrating a statistically significant increase in progression-free survival (PFS) for patients with locally advanced or metastatic urothelial carcinoma who failed prior platinum-based therapy. Final results of the Phase II trial were presented at the European Cancer Congress (ECC2015) in Vienna, Austria (Abstract #2508). Based on these findings, Lilly recently initiated a Phase III trial called RANGE, which has begun to enroll patients. The three-arm trial evaluated 140 patients with advanced carcinoma of the urothelial tract (bladder, urethra, ureter, or renal pelvis) who, after a first-line platinum-based chemotherapy regimen, had relapsed up to one year following the initial treatment. Patients were randomized to receive either a combination of ramucirumab and docetaxel (n=46), docetaxel alone (n=45), or a combination of icrucumab and docetaxel (n=49). Treatment continued until disease progression or toxicity levels resulted in an interruption of treatment with one or more of the study medicines.
• Median PFS, the study's primary endpoint, was 5.4 months (HR 0.389; 95% CI: 0.389 0.235-0.643; p < 0.001) on the ramucirumab-docetaxel arm as compared to 2.8 months for patients treated with docetaxel alone, and 1.6 months for those treated with icrucumab and docetaxel. Objective response rate (ORR) results - or patients who achieved either a complete response or partial response to treatment - also favored the ramucirumab combination arm with a significantly higher confirmed ORR (24%) compared to those on the docetaxel arm (9%) and the icrucumab combination arm (12%). A statistically significant benefit in disease control rate - or patients who achieved complete response, partial response, or stable disease - was identified on the ramucirumab arm (78%) versus the docetaxel arm (58%) and the icrucumab arm (45%). While the study was not powered for overall survival (OS), results favored the ramucirumab combination arm, but were not statistically significant, with 10.4 months median OS identified on the ramucirumab arm compared to 9.2 months on the docetaxel arm and 6.7 months on the icrucumab arm.
• The observed safety findings are consistent with prior Phase III studies of ramucirumab and docetaxel. The most common ( > 5% incidence) grade ?3 adverse events occurring at a higher rate on the ramucirumab-plus-docetaxel arm compared to the docetaxel arm were fatigue (35% vs. 13%), febrile neutropenia (17% vs. 13%), pneumonia (13% vs. 9%), anemia (13% vs. 7%), sepsis (11% vs. 7%), edema (9% vs. 2%), diarrhea (7% vs. 2%), intestinal obstruction (7% vs. 2%), urinary tract infection (7% vs. 2%), hypertension (7% vs. 0%), stomatitis (7% vs. 0%), and thrombocytopenia (7% vs. 0%).

 

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