VYXEOS : CHEMOTHERAPY LIPOSOME INJECTION FOR ACUTE MYELOID LEUKEMIA

Transcription

1 VYXEOS : CHEMOTHERAPY LIPOSOME INJECTION FOR ACUTE MYELOID LEUKEMIA Sarah Mae Rogado PharmD Candidate 2017 Preceptors: Rozena Varghese, PharmD, CMPP; Rachel Brown, PharmD MedVal Scientific Information Services, LLC November 10, 2016

2 OBJECTIVES Discuss the epidemiology and pathophysiology of acute myeloid leukemia Describe Vyxeos and potential role in AML treatment Review clinical trials regarding the safety and efficacy of Vyxeos Discuss future plans to obtain FDA approval for Vyxeos 2

3 ACUTE MYELOID LEUKEMIA 3

4 ACUTE MYELOID LEUKEMIA (AML) Hematologic cancer characterized by the clonal expansion of myeloid blasts in the peripheral blood and bone marrow producing abnormal myeloblasts, red blood cells, or platelets Several subtypes described by cell type involvement and/or cytogenetics Secondary acute myeloid leukemia may occur due to myelodysplastic syndrome (MDS) or exposure to a leukemogenic agent American Cancer Society. URL: 4

5 EPIDEMIOLOGY Most common form of acute leukemia diagnosed in adults Age adjusted annual incidence rate 3.7 per 100,000 persons Largest number of annual deaths from leukemia in US 2016 United States estimates: 19,950 new cases of AML 10,430 deaths from malignancy Only 20-25% of patients survive past the first 5 years of diagnosis Patients > 60 years old often have poorer prognosis O Donnell MR, Tallman MS, Abboud CN, et al. J Natl Compr Canc Netw. 2013; 11(9): National Cancer Institute. URL: American Cancer Society. URL: 5

6 PATHOPHYSIOLOGY Normal cell differentiation is interrupted in myeloid stem cells Occurs due to either de novo events, association with a previous therapy, or multiple genetic events Leukemic cells build up in bone marrow and blood Less room for healthy cells Leukemic cells may spread outside blood to other parts of body National Cancer Institute. URL: 6

7 CURRENT TREATMENT OPTIONS 7+3 Therapy 1 st line induction therapy consisting of cytarabine and an anthracycline Dosing regimen may vary Drug Dose Max Dose/Cycle Mode Days Cytarabine mg/m mg/m 2 IV continuous infusion over 24 hours Daunorubicin years old: mg/m 2 60 years old: 30 mg/m years old: mg/m 2 60 years old: 90 mg/m 2 IV bolus 1-3 Daunorubicin may be substituted with doxorubicin, idarubicin, or mitoxantrone (Cytarabine-Daunorubicin) (AML Induction). Lexi-Drugs. Lexicomp. 7

8 CYTARABINE Pyrimidine analog that inhibits DNA polymerase and thus DNA synthesis/repair (S phase) ADRs: BBW: Myelosuppression Gastrointestinal toxicity: Nausea Vomiting Diarrhea Oral Ulcerations Abdominal pain Hepatic dysfunction Cytarabine (conventional). Lexi-Drugs. Lexicomp. 8

9 DAUNORUBICIN Inhibits DNA and RNA synthesis by intercalating between DNA base pairs and steric obstruction ADRs: BBW: Myocardial toxicity Lifetime maximum dose 550mg/m 2 in adults BBW: Bone marrow suppression BBW: Extravasation Hepatic/renal dose adjustments recommended Daunorubicin (conventional). Lexi-Drugs. Lexicomp. 9

10 ISSUES WITH 7+3 THERAPY No new therapies have been more successful than 7+3 in over 40 years May require additional therapy to improve survival Addition of 1 or more new agents has had limited success, especially in patients with poor-risk characteristics Alternative solution may be to maximize cytarabine and anthracycline combination treatment Cortes JE, Goldberg SL, Feldman EJ, et al. Cancer. 2015; 121(2):

11 VYXEOS 11

12 VYXEOS (CPX-35) Cytarabine:Daunorubicin (5:1) Liposome Injection Investigational drug by Celator Pharmaceuticals Celator Pharmaceuticals was acquired by Jazz Pharmaceuticals in July 2016 Potential treatment for AML with improved survival outcomes compared to 7+3 therapy 12

13 VYXEOS COMBIPLEX TECHNOLOGY Celator Technology Fact Sheet. URL: 13

14 CLINICAL TRIALS 14

15 PHASE II CLINICAL TRIAL Lancet JE, Cortes JE, Hogge DE, et al. Phase 2 trial of CPX-351, a fixed 5:1 molar ratio of cytarabine/daunorubicin, vs cytarabine/daunorubicin in older adults with untreated AML. Blood. 2014; 123(21): Phase IIB, multicenter, randomized, open label, parallel-arm trial in untreated AML patients (60-75 years old) ClinicalTrial.gov number NCT Objective: To compare if CPX 351 will be more effective and more tolerable than the standard treatment for AML Lancet JE, Cortes JE, Hogge DE, et al. Blood. 2014; 123(21):

16 PHASE II CLINICAL TRIAL Inclusion Criteria years old with newly diagnosed, confirmed AML Patients with secondary AML Exclusion Criteria Patients with prior treatment of AML Active leukemia in CNS/uncontrolled malignancy Prior anthracycline exposure > 368 mg/m 2 Cardiovascular disease resulting in heart failure Patients were not permitted to receive any treatment within 4 weeks of the first dose of study drug, except for hydroxyurea Hydroxyurea had to be discontinued 24 hours before start of study treatment Lancet JE, Cortes JE, Hogge DE, et al. Blood. 2014; 123(21):

17 PHASE II CLINICAL TRIAL Primary Outcome Complete response rate (complete + incomplete remission) Secondary Outcomes Complete response rate duration Event free survival Overall survival Lancet JE, Cortes JE, Hogge DE, et al. Blood. 2014; 123(21):

18 PHASE II CLINICAL TRIAL Treatment Group Each unit of CPX-351 contained 1.0 mg (±10%) cytarabine and 0.44 mg (±10%) daunorubicin Induction therapy administered by 90 minute infusion at a dose of 100 U/m 2 CPX-351 on days 1, 3, mg/m 2 cytarabine and 44 mg/m 2 daunorubicin with each dose Second induction and consolidation courses were administered at 100 U/m 2 on days 1, 3 Control Group Cytarabine 100 mg/m 2 administered by 7 day continuous infusion and daunorubicin 60 mg/m 2 per day administered on days 1, 2, 3 Daunorubicin could be reduced to 45 mg/m 2 Choice of consolidation therapy was at discretion of the investigator Recommended mg/m 2 cytarabine for 5-7 days with or without daunorubicin (5+2) or intermediatedose cytarabine ( mg/m 2 /dose) Lancet JE, Cortes JE, Hogge DE, et al. Blood. 2014; 123(21):

19 PHASE II CLINICAL TRIAL Results 126 patients enrolled CPX-351 produced overall higher response rates than control 66.7% vs 51.2%, p = 0.07 Analysis of secondary AML subgroup demonstrated an improved response rate 57.6% vs 31.6%, p = 0.06 Recovery from cytopenias was slower after CPX-351 Increased occurrences of grade 3-4 infection but without increase in infection-related deaths Conclusions CPX-351 may have a clinical benefit among patients with secondary AML Provided rationale for Phase 3 trial Lancet JE, Cortes JE, Hogge DE, et al. Blood. 2014; 123(21):

20 PHASE III CLINICAL TRIAL ClinicalTrials.gov NCT Ongoing Phase III, multicenter, randomized trial Primary completion of final data collection: March 2016 Estimated study completion date: December 2016 Objective: To confirm efficacy of CPX-351 compared to 7+3 as first line therapy in elderly patients with high risk (secondary) AML Primary outcome: Overall survival Celator Pharmaceuticals. ClinicalTrials.gov. NLM Identifier: NCT

21 PHASE III CLINICAL TRIAL Inclusion Criteria years at time of diagnosis Pathological diagnosis of AML according to WHO criteria (>20% blasts) Confirmation of secondary AML ECOG performance status 0-2 Exclusion Criteria APL t(15;17) or favorable cytogenetics (including t(8;21) ) Clinical evidence of active CNS leukemia/second malignancies Prior treatment intended for induction (only hydroxyurea permitted for control of blood counts) Prior anthracycline exposure > 368 mg/m 2 Cardiovascular disease resulting in heart failure Active/uncontrolled infection Celator Pharmaceuticals. ClinicalTrials.gov. NLM Identifier: NCT

22 PHASE III PRELIMINARY RESULTS Efficacy CPX 351 demonstrated statistically significant improvement in overall survival Median overall survival 9.56 months CPX 351 compared to 5.95 months 7+3 HR 0.69 (p = 0.005) CPX % of patients alive 12 months after randomization % of patients alive 24 months after randomization 41.5% 27.6% 31.3% 12.3% 60 day all-cause mortality 13.7% 21.2% PRNewswire. URL: 22

23 PHASE III PRELIMINARY RESULTS Safety No substantial difference in grade 3-5 adverse events between both arms Grade 3-5 hematologic adverse events were similar for overall infections, febrile neutropenia, and bleeding events Grade 3-5 non-hematologic events were similar across all organ systems PRNewswire. URL: 23

24 NEXT STEPS FOR VYXEOS? 24

25 BREAKTHROUGH THERAPY DESIGNATION FDA granted Breakthrough Therapy designation for treatment of adults with therapy-related AML/AML with myelodysplasia-related changes Granted May 2016 based on results of Phase III trial Expedites the development and review of new medicines intended to treat serious/life-threatening diseases Must have demonstrated substantial improvement over available therapies in at least one clinically significant endpoint or significant unmet medical need PRNewswire. URL: 25

26 NEW DRUG APPLICATION Jazz Pharmaceuticals initiated rolling submission of NDA to FDA on September 30, 2016 Expected complete submission by early 2017 Requesting priority review PRNewswire. URL: 26

27 SUMMARY 7+3 therapy has been the mainstay of AML treatment for over 40 years due to no other significant advancements Vyxeos has potential to be the next chemotherapy agent for secondary AML however more data is needed 27

28 THANK YOU! Any questions? 28

29 REFERENCES 1. American Cancer Society. Leukemia Acute Myeloid (Myelogenous). Available at: Accessed November 7, O Donnell MR, Tallman MS, Abboud CN, et al. Acute myeloid leukemia, Version : Featured updates to the NCCN guidelines. J Natl Compr Canc Netw. 2013; 11(9): National Cancer Institute. SEER Stat Fact Sheets: Acute Myeloid Leukemia (AML). Available at: Accessed November 7, American Cancer Society. Leukemia Acute Myeloid (Myelogenous) - Statistics. Available at: Accessed November 7, National Cancer Institute. Adult Acute Myeloid Leukemia Treatment (PDQ ) Patient Version. Available at: Accessed November 7, (Cytarabine-Daunorubicin) (AML Induction). Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: Accessed November 7, Cytarabine (conventional). Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: Accessed November 7, Daunorubicin (conventional). Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: Accessed November 7, Cortes JE, Goldberg SL, Feldman EJ, et al. Phase II, multicenter, randomized trial of CPX-351 (cytarabine:daunorubicin) liposome injection versus intensive salvage therapy in adults with first relapse AML. Cancer. 2015; 121(2): Celator Pharmaceuticals. Celator Technology Fact Sheet. Available at: : EB2132F1EFF7/Celator_Technology_Fact_Sheet.pdf. Accessed November 7, Lancet JE, Cortes JE, Hogge DE, et al. Phase 2 trial of CPX-351, a fixed 5:1 molar ratio of cytarabine/daunorubicin, vs cytarabine/daunorubicin in older adults with untreated AML. Blood. 2014; 123(21): Celator Pharmaceuticals. Phase III Study of CPX-351 Versus 7+3 in Patients Years Old With Untreated High Risk (Secondary) Acute Myeloid Leukemia (301). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US) [cited 2016 Nov 7]. Available from: NLM Identifier: NCT PRNewswire. Celator Pharmaceuticals Announces VYXEOS Granted Breakthrough Therapy Designation. Available at: Accessed November 7, PRNewswire. Jazz Pharmaceuticals Initiates Rolling NDA Submission for Vyxeos (CPX-351) Expects to Complete NDA Submission by Early Available at: Accessed November 7,