Date: 2016-06-12
Type of information: Publication of results in a medical journal
phase: 3
Announcement: publication of results in The New English Journal of Medicine
Company: Pfizer (USA - NY)
Product: inotuzumab ozogamicin
Action
mechanism: antibody drug conjugate. Inotuzumab ozogamicin is an antibody drug conjugate (ADC) comprised of a monoclonal antibody targeting CD22, a cell surface antigen expressed on approximately 90 percent of B-cell malignancies, linked to a cytotoxic agent, calicheamicin. CMC-544 is the product of a collaboration between Wyeth and UCB-Celltech. Inotuzumab ozogamicin received Breakthrough Therapy designation from the FDA for ALL in October 2015. Inotuzumab ozogamicin originates from a collaboration between Pfizer and Celltech, now UCB. Pfizer has sole responsibility for all manufacturing, clinical development and commercialization activities for this molecule.
Disease: relapsed or refractory CD22-positive acute lymphoblastic leukemia (ALL)
Therapeutic area: Cancer - Oncology
Country: Argentina, Australia, Canada, China, Czech Republic, Finland, France, Germany, Hungary, Italy, Japan, Republic of Korea, The Netherlands, Poland, Singapore, Spain, Sweden, Taiwan, UK, USA
Trial
details: The INO-VATE ALL Study, also known as Study 1022, is an open-label, randomized, Phase 3 study evaluating the safety and efficacy of inotuzumab ozogamicin as compared with a defined set of chemotherapy choices in adult patients with relapsed or refractory CD22-positive acute lymphoblastic leukemia (ALL). The two primary endpoints are hematologic remission, defined as a complete response with or without platelet and/or neutrophil recovery (CR/CRi), and overall survival. Secondary endpoints include progression-free survival, volume of distribution and systemic clearance for inotuzumab ozogamicin in serum, duration of response, rate of stem-cell transplantation, minimal residual disease, cytogenetics, safety and quality of life (European Organization for Research and Treatment of Cancer, Quality of Life Questionnaire, Core-30 and EuroQual-5D Health Questionnaire). Inotuzumab ozogamicin was administered intravenously once weekly for three weeks for a three to four week cycle up to six cycles. Chemotherapy options included fludarabine, cytarabine and G-CSF (FLAG); high dose cytarabine (HIDAC); or cytarabine and mitoxantrone. There were 326 patients enrolled in the trial. Enrollment is now complete. (NCT01564784)
Latest
news: * On June 12, 2016, Pfizer announced the publication of findings from the Phase 3 INO-VATE ALL study in the online issue of The New England Journal of Medicine. The study is evaluating the safety and efficacy of inotuzumab ozogamicin as compared with investigator-choice chemotherapy in 326 adult patients with relapsed or refractory CD22-positive acute lymphoblastic leukemia. Results showed improvement over chemotherapy on a number of measures including complete hematologic remission and progression-free survival (PFS). Updated results and newly available overall survival (OS) data were also presented as a late-breaking oral presentation (#LB2233) at the 21st Congress of the European Hematology Association (EHA) 2016 Annual Meeting in Copenhagen, Denmark. The INO-VATE ALL study had two independent primary endpoints, complete response with or without hematologic remission and OS. INO-VATE ALL met its first primary endpoint of complete response, which was significantly better with inotuzumab ozogamicin compared to chemotherapy (80.7% [95% CI, 72%-88%] vs. 29.4% [95% CI, 21%-39%], P<0.001). Inotuzumab ozogamicin also significantly extended PFS compared to chemotherapy (HR: 0.45 [97.5% CI, 0.34-0.61], P<0.001; median PFS, 5.0 vs. 1.8 months, in their respective arms). The second primary endpoint of OS showed a strong trend toward longer OS for patients treated with inotuzumab ozogamicin compared to chemotherapy, but did not reach the level of statistical significance (p < 0.0104) for the trial (HR: 0.77 [97.5% CI, 0.58-1.03], one-sided P=0.0203; median OS, 7.7 months [95% CI, 6.0-9.2] vs. 6.7 months [95% CI, 4.9-8.3]). The two-year OS rate for inotuzumab ozogamicin was 23 percent (95% CI, 16%?30%) compared to chemotherapy at 10 percent (95% CI, 5%?16%). Results from INO-VATE ALL also showed patients treated with inotuzumab ozogamicin achieved high rates of minimal residual disease (MRD) negativity (78.4% [95% CI, 68%-87%; P<0.001]), and experienced a duration of response (DOR) of 4.6 months (95% CI, 3.9-5.4; HR: 0.55; P<0.034). In comparison, 28.1 percent (95% CI, 14%-47%; P<0.001) of patients treated with chemotherapy achieved MRD negativity and median DOR was 3.1 months (95% CI, 1.4-4.9; HR: 0.55; P<0.034). More patients also proceeded to stem-cell transplant with inotuzumab ozogamicin compared to standard chemotherapy (41% vs. 11%, P<0.001). The most common adverse events (AEs) observed for both inotuzumab ozogamicin and chemotherapy were cytopenias, including febrile neutropenia (16% vs. 22%). Common nonhematologic treatment-emergent AEs with inotuzumab ozogamicin included nausea (32%), headache (28%) and pyrexia (27%). Patients in the chemotherapy arm experienced nausea (47%), pyrexia (43%) and diarrhea (40%). Additionally, any-grade veno-occlusive liver disease (VOD) occurred more frequently in patients treated with inotuzumab ozogamicin compared to chemotherapy (11% vs. 1%). Five patients taking inotuzumab ozogamicin developed VOD during treatment and 10 patients developed VOD after subsequent stem cell transplant. Among those taking chemotherapy, one patient developed VOD after transplant; no cases of VOD occurred during treatment with chemotherapy. * On April 21, 2015, Pfizer announced that the Phase 3 study investigating the treatment of inotuzumab ozogamicin met its first primary endpoint of demonstrating a higher complete hematologic remission rate in adult patients with relapsed or refractory CD22-positive acute lymphoblastic leukemia (ALL) compared to that achieved with standard of care chemotherapy. The Phase 3 study has two primary endpoints, complete hematologic remission rate and overall survival. Pfizer is continuing the study to allow for the data on overall survival to mature. The company now looks forward to discussing these data with regulatory authorities. No new or unexpected safety issues were identified. Efficacy and safety data from this study will be submitted for presentation at an upcoming medical meeting.
