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™

3. Acute Myeloid Leukemia

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.  Leukemia – Acute Myeloid (Myelogenous).  Available at:  Accessed November 7, 2016.
Myelodysplastic Syndromes (MDS) are a group of diverse bone marrow disorders in which the bone marrow does not produce enough healthy blood cells. MDS is often referred to as a “bone marrow failure disorder”. MDS is primarily a disease of the elderly (most patients are older than age 65)
FAB – cell type involvement/morphology
WHO classification - cytogenetics
American Cancer Society.  URL:

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
NCCN AML guidelines
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:

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
De novo - De novo DNA synthesis is DNA replication without the need for precursor template DNA. It's also referred to as artificial gene synthesis. Primase is an RNA polymerase, and it can add a primer to an existing strand awaiting replication. DNA polymerase cannot add primers, and therefore, needs primase to add the primer de novo.
National Cancer Institute.  URL:

7. Current treatment options
7+3 Therapy
1st line induction therapy consisting of cytarabine and an anthracycline
Dosing regimen may vary
Daunorubicin may be substituted with doxorubicin, idarubicin, or mitoxantrone
Drug
Dose
Max Dose/Cycle
Mode
Days
Cytarabine
mg/m2
700 mg/m2
IV continuous infusion over 24 hours
1-7
Daunorubicin
17-60 years old: mg/m2
≥ 60 years old: 30 mg/m2
17-60 years old: mg/m2
≥ 60 years old: 90 mg/m2
IV bolus
1-3
7+3 (Cytarabine-Daunorubicin) (AML Induction). Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL.  Available at:  Accessed November 7, 2016.
Cytarabine is a anti-metabolite
7+3 (Cytarabine-Daunorubicin) (AML Induction). Lexi-Drugs. Lexicomp.

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. Wolters Kluwer Health, Inc. Riverwoods, IL.  Available at:  Accessed November 7, 2016.
Cytarabine (conventional). Lexi-Drugs. Lexicomp.

9. daunorubicin
Inhibits DNA and RNA synthesis by intercalating between DNA base pairs and steric obstruction
ADRs:
BBW: Myocardial toxicity
Lifetime maximum dose 550mg/m2 in adults
BBW: Bone marrow suppression
BBW: Extravasation
Hepatic/renal dose adjustments recommended
Daunorubicin (conventional). Lexi-Drugs. Lexicomp.

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
In addition to standard “7+3”
Cortes JE, Goldberg SL, Feldman EJ, et al. Cancer. 2015; 121(2):

11. Vyxeos™

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

13. Vyxeos™ – CombiPlex® Technology
7+3 – free cytarabine and daunorubicin administered – excessive anthracycline has potential for toxicity
Get inactivation and imbalanced drug efflux reducing drug levels in cell
Potential for cell survival and drug resistance
Celator Technology Fact Sheet. URL:

14. Clinical trials

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. 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):
Lancet JE, Cortes JE, Hogge DE, et al. Blood. 2014; 123(21):

16. Phase II Clinical Trial
Inclusion Criteria
60-75 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/m2
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 mg (±10%) cytarabine and mg (±10%) daunorubicin
Induction therapy administered by 90 minute infusion at a dose of U/m2 CPX-351 on days 1, 3, 5
100 mg/m2 cytarabine and 44 mg/m2 daunorubicin with each dose
Second induction and consolidation courses were administered at U/m2 on days 1, 3
Control Group
Cytarabine 100 mg/m2 administered by 7 day continuous infusion and daunorubicin 60 mg/m2 per day administered on days 1, 2, 3
Daunorubicin could be reduced to 45 mg/m2
Choice of consolidation therapy was at discretion of the investigator
Recommended mg/m2 cytarabine for 5-7 days with or without daunorubicin (5+2) or intermediate- dose cytarabine ( mg/m2/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
The primary efficacy end point was complete response (CR+CRi) rate. Enrollment of 120 patients (80 in the CPX-351 arm and 40 in the control arm) was sufficient to detect a 23% increase in response rate with at least 85% power and a one-sided significance level of 0.1. A P value of .1, rather than the traditional P < .05, was used because this study was not intended to replace a formal phase 3 study but rather to provide the basis for designing a subsequent phase 3 study
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. 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
Celator Pharmaceuticals. ClinicalTrials.gov. NLM Identifier: NCT

21. Phase III clinical trial
Inclusion Criteria
60-75 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/m2
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)
PRNewswire.  Celator Pharmaceuticals® Announces VYXEOS™ Granted Breakthrough Therapy Designation.  Available at:  Accessed November 7, 2016.
CPX-351
7+3
% of patients alive 12 months after randomization
41.5%
27.6%
% of patients alive 24 months after randomization
31.3%
12.3%
60 day all-cause mortality
13.7%
21.2%
PRNewswire.  URL: 

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: 

24. Next Steps for Vyxeos™?

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
Breakthrough designation Allows company to submit individual sections of NDA for review as they are completed rather than submitting when entire application as a whole later
PRNewswire.  URL: 

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: 

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

28. Thank you!
Any questions?

29. references
American Cancer Society.  Leukemia – Acute Myeloid (Myelogenous).  Available at:  Accessed November 7, 2016.
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:  November 7, 2016.
American Cancer Society.  Leukemia – Acute Myeloid (Myelogenous) - Statistics.  Available at:  Accessed November 7, 2016.
National Cancer Institute.  Adult Acute Myeloid Leukemia Treatment (PDQ®)–Patient Version.  Available at:  November 7, 2016.
7+3 (Cytarabine-Daunorubicin) (AML Induction). Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL.  Available at:  Accessed November 7, 2016.
Cytarabine (conventional). Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL.  Available at:  Accessed November 7, 2016.
Daunorubicin (conventional). Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL.  Available at:  Accessed November 7, 2016.
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: : Accessed November 7, 2016.
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, 2016.
PRNewswire.  Jazz Pharmaceuticals Initiates Rolling NDA Submission for Vyxeos (CPX-351) Expects to Complete NDA Submission by Early 2017.  Available at:  Accessed November 7, 2016.