The Janssen Pharmaceutical Companies of Johnson & Johnson today announced important new data from the Phase 3 CASSINI study on the use of oral anticoagulant XARELTO (rivaroxaban) in the management and prevention of VTE (or blood clots) in high-risk patients with cancer.
The composite primary endpoint of VTE occurrence did not reach statistical significance during the full study period. However, use of XARELTO resulted in a clinically meaningful and nominally significant 60 percent reduction of VTE events compared to placebo during the time patients were actively receiving treatment. Bleeding rates were low, though higher with XARELTO. These late-breaking results, presented this week at the 60th American Society of Hematology (ASH) Annual Meeting in San Diego, add to the robust research from prior XARELTO trials.
'We want patients to focus on treating their cancer and getting better, without the concern and burden of blood clots,' said Alok Khorana, M.D., FACP, Sondra and Stephen Hardis Chair in Oncology, Vice Chair for Clinical Services, Director of the GI Malignancies Program, Cleveland Clinic, and CASSINI lead investigator. 'Building on prior research supporting the use of rivaroxaban for the treatment of VTE in patients with cancer, this new CASSINI data signal the role of rivaroxaban in preventing blood clots.' Dr. Khorana was compensated by Janssen for his role as chair of the CALLISTO advisory council and co-chair of the CASSINI steering committee.
Despite being largely preventable, blood clots remain the second leading cause of death in patients with cancer. The risk of VTE, which comprises deep vein thrombosis (DVT) and pulmonary embolism (PE), is five times greater in people with cancer, and that risk is magnified in those receiving certain types of chemotherapy.1 VTE risk is also highest in the newly diagnosed and in those with more advanced, metastatic disease.2 Recent guidelines issued by the International Society on Thrombosis and Haemostasis (ISTH) and National Comprehensive Cancer Network (NCCN) recommend XARELTO as an option for the treatment of cancer-associated VTE. Currently, no medicine is approved for the primary prevention of VTE in high-risk, ambulatory cancer patients, due to limited clinical data.
'We are very encouraged by the CASSINI results and look forward to discussing them with the Food & Drug Administration,' said Paul Burton, M.D., Ph.D., FACC, Vice President, Medical Affairs, Internal Medicine, Janssen Scientific Affairs, LLC. 'This study underscores our longstanding commitment to exploring the full potential of XARELTO through our EXPLORER program. Most recently, XARELTO became the first and only Factor Xa inhibitor indicated for people with chronic coronary or peripheral artery disease.'
In the intent to treat (ITT) population, the primary efficacy composite endpoint (symptomatic or asymptomatic lower-extremity proximal DVT, symptomatic upper-extremity or distal lower-extremity DVT, symptomatic or incidental PE, and VTE-related death) occurred during the study period in 8.79 percent of patients in the placebo group and in 5.95 percent of patients treated with XARELTO 10 mg once daily; however, this result was not statistically significant (HR=0.66; 95% CI, 0.40-1.09; p=0.101). Approximately 62.4 percent of patients completed the double-blind trial period from randomization through the end of the study's 180-day observation period, regardless of whether they discontinued the study medication. Withdrawal of consent and death were the primary reasons for discontinuation.
Researchers also examined the primary efficacy composite endpoint in all randomized patients, during the time they were actively taking treatment, known as the 'on-treatment' period. For this pre-specified analysis, XARELTO was associated with a statistically significant 60 percent reduction in VTE events compared to placebo (2.62 percent vs. 6.41 percent; HR=0.40; 95% CI, 0.20-0.80; p=0.007). The primary safety outcome, ISTH major bleeding, during the on-treatment period was low across both treatment arms and occurred in 4/404 (0.99 percent) patients treated with placebo and 8/405 (1.98 percent) patients treated with XARELTO; this result was not statistically significant, though the study was not powered to detect a significant difference. (HR=1.96; 95% CI, 0.59-6.49; p=0.265).
The following observations were also made: Of the total VTE events that occurred, approximately 39 percent were experienced by patients who had prematurely discontinued treatment.
All-cause mortality, a secondary efficacy endpoint, was similar between both groups at the end of the 180-day observation period (20.0 percent for XARELTO vs. 23.8 percent for placebo; HR=0.83; 95% CI, 0.62-1.11). Many patients died as a result of their cancer, with a small number of VTE-related deaths.
Efficacy and safety outcomes were consistent across all prespecified subgroups.
Prior XARELTO Research in Cancer-Associated VTE
The CASSINI results add to prior research on the use of XARELTO in people with cancer. A prospective, randomized, open-label, multicenter pilot trial of 406 patients with cancer diagnosed with acute VTE, SELECT-D, found XARELTO was associated with significantly lower rates of recurrent VTE compared to low-molecular weight heparin (LMWH) (4 percent vs. 11 percent; HR=0.43; 95% CI, 0.19-0.99). However, six-month cumulative major bleeding rates were higher in the XARELTO group (6 percent vs. 4 percent; HR=1.83; 95% CI, 0.68-4.96) as were rates of clinically relevant non-major bleeding (13 percent vs. 4 percent; HR=3.76; 95% CI, 1.63-8.69).
Additional Information About CASSINI
CASSINI is a Phase 3b, randomized, double-blind, placebo-controlled, parallel-group superiority study comparing the efficacy and safety of XARELTO with placebo for the primary prevention of VTE in adult patients with active cancer who were scheduled to receive systemic cancer therapy, like chemotherapy, outside the hospital setting. A total of 841 patients were randomized in a 1:1 ratio, with 420 receiving XARELTO10 mg once daily and 421 receiving placebo. Of all patients randomized, 43.7 percent prematurely discontinued XARELTO and 50.2 percent prematurely discontinued placebo during the study's 180-day observation period; reasons for discontinuation were similar between groups. Patients were at high risk of developing VTE, with a baseline Khorana risk score of 2 (a recognized scoring system for predicting VTE in cancer patients). Patients had various types of solid cancers or lymphoma and were stratified by tumor type (advanced pancreatic cancer (APC) or non-APC). Patients also had an expected survival of greater than six months with a plan to start a new systemic regimen within one week of initiating study treatment. A total of 1,080 patients from 143 sites across 11 countries were enrolled and underwent a screening compression ultrasound prior to randomization; of these, 49 patients had evidence of DVT and were excluded from the study.
CASSINI consisted of three periods: a two-week screening period; a 180-day double-blind treatment period and a 30-day post-treatment follow-up period with a day 210/end-of-study visit. During the double-blind treatment period, study visits occurred during week 8, week 16 and week 26/end of treatment, with compression ultrasounds conducted at each visit to assess VTE occurrence. The study used an ITT population, which means that all participants were followed during the 180-day observation period, regardless of whether they took or prematurely discontinued study medicine.
About CALLISTO and EXPLORER
CASSINI is part of the CALLISTO research program, the largest and broadest prospective clinical program evaluating a Factor Xa inhibitor, specifically XARELTO, for the prevention and treatment of cancer-associated VTE. It includes clinical trials and registries in more than 4,000 patients. CALLISTO also further examines findings from the Phase 3 EINSTEIN clinical program, which was used by regulatory authorities worldwide to approve XARELTO for the treatment of VTE and reduction of risk of recurrent VTE.
CALLISTO is part of the EXPLORER clinical research program for XARELTO. A collaborative effort between Janssen and its development partner Bayer, EXPLORER seeks to generate important clinical evidence on the safety and efficacy of XARELTO and its potential role in addressing critical medical needs. Several studies in the program are designed to seek additional indications or expand the label for XARELTO to benefit more patients in need of additional therapies for their cardiovascular disease. By the time of its completion, more than 275,000 patients will have participated in the EXPLORER clinical development program, other completed and ongoing clinical trials, investigative registries and non-interventional studies.
About the Janssen Pharmaceutical Companies
At the Janssen Pharmaceutical Companies of Johnson & Johnson, we are working to create a world without disease. Transforming lives by finding new and better ways to prevent, intercept, treat and cure disease inspires us. We bring together the best minds and pursue the most promising science.
Cautions Concerning Forward-Looking Statements
This press release contains 'forward-looking statements,' as defined in the Private Securities Litigation Reform Act of 1995, regarding product development and the presentation of new data and analyses regarding XARELTO (rivaroxaban). The reader is cautioned not to rely on these forward-looking statements. These statements are based on current expectations of future events. If underlying assumptions prove inaccurate or known or unknown risks or uncertainties materialize, actual results could vary materially from the expectations and projections of Janssen Pharmaceuticals, Inc., Janssen Scientific Affairs, LLC, any of the other Janssen Pharmaceutical Companies and/or Johnson & Johnson. Risks and uncertainties include, but are not limited to: challenges and uncertainties inherent in product research and development, including the uncertainty of clinical success and of obtaining regulatory approvals; uncertainty of commercial success; manufacturing difficulties and delays; competition, including technological advances, new products and patents attained by competitors; challenges to patents; product efficacy or safety concerns resulting in product recalls or regulatory action; changes in behavior and spending patterns of purchasers of health care products and services; changes to applicable laws and regulations, including global health care reforms and trends toward health care cost containment. A further list and descriptions of these risks, uncertainties and other factors can be found in Johnson & Johnson's Annual Report on Form 10-K for the fiscal year ended December 31, 2017, including in the sections captioned 'Cautionary Note Regarding Forward-Looking Statements' and 'Item 1A. Risk Factors,' and in the company's most recently filed Quarterly Report on Form 10-Q, and the company's subsequent filings with the Securities and Exchange Commission. Copies of these filings are available online at www.sec.gov, www.jnj.com or on request from Johnson & Johnson.
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