Clinical trial NCT01696084: Phase III Study of CPX-351 Versus 7+3 in Patients 60-75 Years Old With Untreated High Risk (Secondary) Acute Myeloid Leukemia
Official title: Phase III, Multicenter, Randomized, Trial of CPX-351 (Cytarabine:Daunorubicin) Liposome Injection Versus Cytarabine and Daunorubicin in Patients 60-75 Years of Age With Untreated High Risk (Secondary) AML
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: High Risk Acute Myeloid Leukemia
Keywords: AML
Acute Myeloid Leukemia
high risk AML
secondary AML
AML in elderly
Lead sponsor: Jazz Pharmaceuticals
Sponsor class: INDUSTRY
Collaborators: name: The Leukemia and Lymphoma Society
First posted: 2012-09-28
Enrollment: 309
Sex: ALL
Minimum age (years): 60
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: To confirm the efficacy of CPX-351 compared to 7+3 as first line therapy in elderly patients (60-75 yrs) with high risk (secondary) Acute Myeloid Leukemia. The primary efficacy endpoint will be overall survival.


Eligibility criteria: Inclusion Criteria:

* Ability to understand and voluntarily give informed consent
* Age 60-75 years at the time of diagnosis of AML
* Pathological diagnosis of AML according to WHO criteria (with at least 20% blasts in the peripheral blood or bone marrow)
* Confirmation of:

  * Therapy related AML: t-AML must have a documented history of prior cytotoxic therapy or ionizing radiotherapy for an unrelated disease
  * AML with a history of myelodysplasia: MDSAML must have bone marrow documentation of prior MDS
  * AML with a history of CMMoL: CMMoLAML must have bone marrow documentation of prior CMMoL
  * De novo AML with karyotypic abnormalities characteristic of MDS: de novoAML must have cytogenetics with abnormalities per WHO.
* Eastern Cooperative Oncology Group (ECOG) performance status 0-2
* Able to adhere to the study visit schedule and other protocol requirements
* Laboratory values fulfilling the following:

  * Serum creatinine \< 2.0 mg/dL
  * Serum total bilirubin \< 2.0 mg/dL, patients with Gilbert's Syndrome should contact the medical monitor
  * Serum alanine aminotransferase or aspartate aminotransferase \< 3 times the ULN Note: If elevated liver enzymes, above the ULN, are related to disease; contact medical monitor to discuss.
* Cardiac ejection fraction ≥ 50% by echocardiography or MUGA
* Patients with second malignancies in remission may be eligible if there is clinical evidence of disease stability for a period of greater than 6 months off cytotoxic chemotherapy, documented by imaging, tumor marker studies, etc., at screening. Patients maintained on long-term non-chemotherapy treatment, e.g., hormonal therapy, are eligible.

Exclusion Criteria:

* Except for CMMoL, patients with history of myeloproliferative neoplasms (MPN) (defined as a history of essential thrombocytosis or polycythemia vera, or idiopathic myelofibrosis prior to the diagnosis of AML) or combined MDS/MPN are not eligible.
* Acute promyelocytic leukemia \[t(15;17)\] or favorable cytogenetics, including t(8;21) or inv16 if known at the time of randomization.
* Clinical evidence of active CNS leukemia
* Patients with active (uncontrolled, metastatic) second malignancies are excluded.
* Prior treatment intended for induction therapy of AML; only hydroxyurea is permitted for control of blood counts. For example, a patient with MDS that changes HMA dose and schedule after the diagnosis of AML is excluded. AML-type therapy, such as cytarabine alone (\>1g/m2/day) or cytarabine plus an anthracycline as well as prior HSCT are also excluded.
* Administration of any therapy for MDS (conventional or investigational) must be completed by 2 weeks prior to of the first dose of study drug; in the event of rapidly proliferative disease use of hydroxyurea is permitted until 24 hours before the start of study treatment. Toxicities associated with prior MDS therapy must have recovered to grade 1 or less prior to start of treatment.
* Any major surgery or radiation therapy within four weeks.
* Patients with prior cumulative anthracycline exposure of greater than 368 mg/m2 daunorubicin (or equivalent).
* Any serious medical condition, laboratory abnormality or psychiatric illness that would prevent obtaining informed consent
* Patients with myocardial impairment of any cause (e.g. cardiomyopathy, ischemic heart disease, significant valvular dysfunction, hypertensive heart disease, and congestive heart failure) resulting in heart failure by New York Heart Association Criteria (Class III or IV staging)
* Active or uncontrolled infection. Patients with an infection receiving treatment (antibiotic, antifungal or antiviral treatment) may be entered into the study but must be afebrile and hemodynamically stable for ≥72 hrs.
* Current evidence of invasive fungal infection (blood or tissue culture); patients with recent fungal infection must have a subsequent negative cultures to be eligible; known HIV (new testing not required) or evidence of active hepatitis B or C infection (with rising transaminase values)
* Hypersensitivity to cytarabine, daunorubicin or liposomal products
* History of Wilson's disease or other copper-metabolism disorder

Primary outcomes:
measure: Overall Survival
timeFrame: From the date of randomization to death from any cause
Secondary outcomes:
measure: Proportion of Subjects With a Response
timeFrame: Post Induction
measure: Event-free Survival
timeFrame: From the date of randomization to the date that persistent disease was documented or the date of relapse after CR or death, whichever came first
measure: Remission Duration
timeFrame: From the date of achievement of a remission until the date of relapse or death from any cause
measure: Rate of Achieving Morphologic Leukemia-free State
timeFrame: Day 14
measure: Proportion of Subjects Receiving a Stem Cell Transplant
timeFrame: Post Induction
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Los Angeles
country: United States
facility: UCLA
state: California
city: San Diego
country: United States
facility: University of CA San Diego
state: California
city: Stanford
country: United States
facility: Stanford University
state: California
city: New Haven
country: United States
facility: Yale University
state: Connecticut
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Tampa
country: United States
facility: H. Lee Moffitt Cancer Center
state: Florida
city: Atlanta
country: United States
facility: Northside Hospital
state: Georgia
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: Indianapolis
country: United States
facility: Franciscan St. Francis Health
state: Indiana
city: Kansas City
country: United States
facility: University of Kansas Medical Center
state: Kansas
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Columbia
country: United States
facility: University of Missouri
state: Missouri
city: Saint Louis
country: United States
facility: Washington University
state: Missouri
city: Lebanon
country: United States
facility: Dartmouth Hitchcock Medical Center
state: New Hampshire
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: Bronx
country: United States
facility: Montefiore Medical Center
state: New York
city: Long Island City
country: United States
facility: North Shore LIJ Health System
state: New York
city: New York
country: United States
facility: Columbia University
state: New York
city: New York
country: United States
facility: Cornell U, Weill Medical College
state: New York
city: Valhalla
country: United States
facility: New York Medical College
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina at Chapel Hill
state: North Carolina
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest University Health Services
state: North Carolina
city: Portland
country: United States
facility: Providence Portland Medical Center
state: Oregon
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Philadelphia
country: United States
facility: Fox Chase Cancer Center
state: Pennsylvania
city: Pittsburgh
country: United States
facility: UPMC
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Nashville
country: United States
facility: Sarah Cannon Research Institute
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt University
state: Tennessee
city: Dallas
country: United States
facility: Baylor Research Insitute
state: Texas
city: Houston
country: United States
facility: M.D. Anderson Cancer Center
state: Texas
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Research Center
state: Washington
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
city: Edmonton
country: Canada
facility: University of Alberta Hospital
state: Alberta
city: Vancouver
country: Canada
facility: British Columbia Cancer Center
state: British Columbia
city: Toronto
country: Canada
facility: Princess Margaret Hospital
state: Ontario
city: Montreal
country: Canada
facility: Hopital Maisonneuve-Rosemont
state: Quebec
Study officials:
References:
citation: Cortes JE, Lin TL, Asubonteng K, Faderl S, Lancet JE, Prebet T. Efficacy and safety of CPX-351 versus 7 + 3 chemotherapy by European LeukemiaNet 2017 risk subgroups in older adults with newly diagnosed, high-risk/secondary AML: post hoc analysis of a randomized, phase 3 trial. J Hematol Oncol. 2022 Oct 26;15(1):155. doi: 10.1186/s13045-022-01361-w.
citation: Cortes JE, Lin TL, Uy GL, Ryan RJ, Faderl S, Lancet JE. Quality-adjusted Time Without Symptoms of disease or Toxicity (Q-TWiST) analysis of CPX-351 versus 7 + 3 in older adults with newly diagnosed high-risk/secondary AML. J Hematol Oncol. 2021 Jul 13;14(1):110. doi: 10.1186/s13045-021-01119-w.
citation: Lancet JE, Uy GL, Newell LF, Lin TL, Ritchie EK, Stuart RK, Strickland SA, Hogge D, Solomon SR, Bixby DL, Kolitz JE, Schiller GJ, Wieduwilt MJ, Ryan DH, Faderl S, Cortes JE. CPX-351 versus 7+3 cytarabine and daunorubicin chemotherapy in older adults with newly diagnosed high-risk or secondary acute myeloid leukaemia: 5-year results of a randomised, open-label, multicentre, phase 3 trial. Lancet Haematol. 2021 Jul;8(7):e481-e491. doi: 10.1016/S2352-3026(21)00134-4.
citation: Lin TL, Rizzieri DA, Ryan DH, Schiller GJ, Kolitz JE, Uy GL, Hogge DE, Solomon SR, Wieduwilt MJ, Ryan RJ, Faderl S, Cortes JE, Lancet JE. Older adults with newly diagnosed high-risk/secondary AML who achieved remission with CPX-351: phase 3 post hoc analyses. Blood Adv. 2021 Mar 23;5(6):1719-1728. doi: 10.1182/bloodadvances.2020003510.
citation: Kolitz JE, Strickland SA, Cortes JE, Hogge D, Lancet JE, Goldberg SL, Villa KF, Ryan RJ, Chiarella M, Louie AC, Ritchie EK, Stuart RK. Consolidation outcomes in CPX-351 versus cytarabine/daunorubicin-treated older patients with high-risk/secondary acute myeloid leukemia. Leuk Lymphoma. 2020 Mar;61(3):631-640. doi: 10.1080/10428194.2019.1688320. Epub 2019 Nov 25.
citation: Lancet JE, Uy GL, Cortes JE, Newell LF, Lin TL, Ritchie EK, Stuart RK, Strickland SA, Hogge D, Solomon SR, Stone RM, Bixby DL, Kolitz JE, Schiller GJ, Wieduwilt MJ, Ryan DH, Hoering A, Banerjee K, Chiarella M, Louie AC, Medeiros BC. CPX-351 (cytarabine and daunorubicin) Liposome for Injection Versus Conventional Cytarabine Plus Daunorubicin in Older Patients With Newly Diagnosed Secondary Acute Myeloid Leukemia. J Clin Oncol. 2018 Sep 10;36(26):2684-2692. doi: 10.1200/JCO.2017.77.6112. Epub 2018 Jul 19.
citation: Stein EM, Tallman MS. Emerging therapeutic drugs for AML. Blood. 2016 Jan 7;127(1):71-8. doi: 10.1182/blood-2015-07-604538. Epub 2015 Dec 10.