Clinical trial NCT01253070: Sorafenib Tosylate and Chemotherapy in Treating Older Patients With Acute Myeloid Leukemia
Official title: A Phase II Study Incorporating Sorafenib (NSC 724772) Into the Therapy of Patients &gt;/= 60 Years of Age With FLT3 Mutated Acute Myeloid Leukemia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Acute Myeloid Leukemia With FLT3/ITD Mutation
Acute Myeloid Leukemia With Inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11
Acute Myeloid Leukemia With t(8;21); (q22; q22.1); RUNX1-RUNX1T1
Acute Promyelocytic Leukemia With PML-RARA
FLT3 Gene Mutation
Therapy-Related Acute Myeloid Leukemia
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2010-12-03
Enrollment: 54
Sex: ALL
Minimum age (years): 60
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This phase II trial studies how well sorafenib tosylate and chemotherapy work in treating older patients with acute myeloid leukemia (AML). Sorafenib tosylate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as daunorubicin hydrochloride and cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving sorafenib tosylate and combination chemotherapy may be an effective treatment for AML.

Detailed description: PRIMARY OBJECTIVES:

I. To determine if the 1-year overall survival rate of patients age \>= 60 with FLT3-ITD AML treated with a sorafenib (sorafenib tosylate) containing induction and post-remission therapy is significantly higher than the historical 1-year overall survival rate of similar patients who were not treated with sorafenib.

SECONDARY OBJECTIVES:

I. To determine the rates of complete remission (CR), CR with incomplete count recovery (CRi), and cytogenetic complete remission (CCyR) to induction chemotherapy.

II. To determine the overall survival, event-free survival, and remission duration in patients treated on this study.

III. To describe the frequency and severity of adverse events for patients treated on this study.

IV. To describe the interaction of pre-treatment disease and patient characteristics including morphology, cytogenetics, immunophenotype, molecular genetic features, white blood cell (WBC) count and hemogram, and performance status on clinical outcomes.

V. To assess FLT3 ligand concentrations and FLT3 plasma inhibitory activity during treatment and determine the relationship to clinical outcomes. (Cancer and Leukemia Group B \[CALGB\] 21003) VI. To describe the interaction of FLT3 mutation type (tyrosine kinase domain \[TKD\] vs. ITD) and allelic ratio on clinical outcomes. (CALGB 21003) VII. To characterize geriatric assessment measures in the context of a treatment trial for AML defined by: the observed distribution and number of missing values for each measurement. (CALGB 361006) VIII. To identify specific geriatric assessment measures which are independently associated with overall survival (OS), 30-day treatment-related mortality and key quality of life outcomes (number of days hospitalized, number of oncology clinic visits, admission to a nursing facility) in patients receiving induction chemotherapy for AML. (CALGB 361006) IX. To explore the impact of induction chemotherapy on physical, cognitive, psychosocial factors. (CALGB 361006)

OUTLINE:

INDUCTION THERAPY: Patients receive daunorubicin hydrochloride intravenously (IV) on days 1-3, cytarabine IV continuously on days 1-7, and sorafenib tosylate orally (PO) twice daily (BID) on days 1-7. Patients then undergo a bone marrow aspirate or biopsy on day 14.

Patients with persistent disease undergo a second remission induction therapy comprising daunorubicin hydrochloride IV on days 1-2, cytarabine IV continuously on days 1-5, and sorafenib tosylate PO BID on days 1-7. Patients who achieve complete response (CR)\* proceed to consolidation therapy.

CONSOLIDATION THERAPY: Patients\*\* receive cytarabine IV over 3 hours on days 1-5 and sorafenib tosylate PO BID on days 1-28. Treatment repeats every 28 days for 2 cycles in the absence of disease progression or unacceptable toxicity. Patients with continued CR proceed to maintenance therapy.

MAINTENANCE THERAPY: Patients receive sorafenib tosylate PO BID on days 1-28. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.

NOTE: \*Patients who achieve CR and who are eligible for hematopoietic stem cell transplant (HSCT) are encouraged to enroll in Cancer and Leukemia Group B (CALGB) 100103. Patients in CR who are unable or unwilling to undergo HSCT receive two cycles of remission consolidation therapy.

NOTE: \*\* Patients in CR/complete remission with incomplete count recovery (CRi) who are unable or unwilling to complete remission consolidation therapy may proceed directly to maintenance therapy after consulting with the CALGB study chair.

After completion of study therapy, patients are followed up every 2 months for 2 years, every 3 months for 2 years, and then yearly for a maximum of 10 years.

Eligibility criteria: Inclusion Criteria:

* Unequivocal histologic diagnosis of AML according to World Health Organization (WHO) criteria, EXCLUDING:

  * Acute promyelocytic leukemia t(15;17)(q22;q12); promyelocytic leukemia (PML)-retinoic acid receptor, alpha (RARA)
  * Acute myeloid leukemia with t(8;21)(q22;q22); runt-related transcription factor 1 (RUNX1-RUNXT1) as determined by the Ohio State University (OSU) Molecular Reference Laboratory, per CALGB 20202
  * Acute myeloid leukemia with inv(16)(p13.1;q22) or t(16;16(p13.1;q22); core-binding factor, beta subunit (CBFB)-myosin, heavy chain 11, smooth muscle (MYH11) as determined by the OSU Molecular Reference Laboratory, per CALGB 20202
* AML patients with an antecedent hematologic disorder are eligible for treatment on this trial provided that they have not received chemotherapy, including lenalidomide, azacitidine or decitabine for their hematologic disorder; patients with therapy-related AML are eligible if there had been no further exposure to chemotherapy or radiation therapy for \> 3 years and their primary malignancy is in remission
* FLT3 mutation (ITD or point mutation) determined by the OSU Molecular Reference Laboratory, per CALGB 20202
* No prior chemotherapy for AML with the following exceptions:

  * Emergency leukapheresis
  * Emergency treatment for hyperleukocytosis with hydroxyurea
  * Cranial radiation therapy (RT) for central nervous system (CNS) leukostasis (one dose only)
  * Growth factor/cytokine support
  * All-trans retinoic acid (ATRA)

Primary outcomes:
measure: Overall Survival (OS) Rate
timeFrame: 1 year
Secondary outcomes:
measure: OS
timeFrame: Time from registration to death (up to 10 years)
measure: Event-free Survival
timeFrame: Time from registration to death or relapse (up to 10 years)
Other outcomes:
Locations:
city: Lewes
country: United States
facility: Beebe Medical Center
state: Delaware
city: Newark
country: United States
facility: Christiana Care Health System-Christiana Hospital
state: Delaware
city: Orlando
country: United States
facility: AdventHealth Orlando
state: Florida
city: Chicago
country: United States
facility: University of Chicago Comprehensive Cancer Center
state: Illinois
city: Evanston
country: United States
facility: NorthShore University HealthSystem-Evanston Hospital
state: Illinois
city: Fort Wayne
country: United States
facility: Fort Wayne Medical Oncology and Hematology Inc-Parkview
state: Indiana
city: Iowa City
country: United States
facility: University of Iowa/Holden Comprehensive Cancer Center
state: Iowa
city: Augusta
country: United States
facility: Harold Alfond Center for Cancer Care
state: Maine
city: Bangor
country: United States
facility: Eastern Maine Medical Center
state: Maine
city: Baltimore
country: United States
facility: University of Maryland/Greenebaum Cancer Center
state: Maryland
city: Elkton
country: United States
facility: Christiana Care - Union Hospital
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital Cancer Center
state: Massachusetts
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Battle Creek
country: United States
facility: Bronson Battle Creek
state: Michigan
city: Big Rapids
country: United States
facility: Spectrum Health Big Rapids Hospital
state: Michigan
city: Grand Rapids
country: United States
facility: Cancer Research Consortium of West Michigan NCORP
state: Michigan
city: Grand Rapids
country: United States
facility: Mercy Health Saint Mary's
state: Michigan
city: Grand Rapids
country: United States
facility: Spectrum Health at Butterworth Campus
state: Michigan
city: Muskegon
country: United States
facility: Mercy Health Mercy Campus
state: Michigan
city: Reed City
country: United States
facility: Spectrum Health Reed City Hospital
state: Michigan
city: Traverse City
country: United States
facility: Munson Medical Center
state: Michigan
city: Columbia
country: United States
facility: University of Missouri - Ellis Fischel
state: Missouri
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Lebanon
country: United States
facility: Dartmouth Hitchcock Medical Center
state: New Hampshire
city: Camden
country: United States
facility: Cooper Hospital University Medical Center
state: New Jersey
city: Lake Success
country: United States
facility: Northwell Health NCORP
state: New York
city: Lake Success
country: United States
facility: Northwell Health/Center for Advanced Medicine
state: New York
city: Manhasset
country: United States
facility: North Shore University Hospital
state: New York
city: New Hyde Park
country: United States
facility: Long Island Jewish Medical Center
state: New York
city: New York
country: United States
facility: NYP/Weill Cornell Medical Center
state: New York
city: Syracuse
country: United States
facility: State University of New York Upstate Medical University
state: New York
city: Goldsboro
country: United States
facility: Wayne Memorial Hospital
state: North Carolina
city: Kinston
country: United States
facility: Vidant Oncology-Kinston
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest University Health Sciences
state: North Carolina
city: Columbus
country: United States
facility: Ohio State University Comprehensive Cancer Center
state: Ohio
city: Norman
country: United States
facility: Cancer Care Associates-Norman
state: Oklahoma
city: Oklahoma City
country: United States
facility: Mercy Hospital Oklahoma City
state: Oklahoma
city: Pittsburgh
country: United States
facility: West Penn Hospital
state: Pennsylvania
city: Charleston
country: United States
facility: Roper Hospital
state: South Carolina
city: Berlin
country: United States
facility: Central Vermont Medical Center/National Life Cancer Treatment
state: Vermont
city: Burlington
country: United States
facility: University of Vermont and State Agricultural College
state: Vermont
city: Richmond
country: United States
facility: Virginia Commonwealth University/Massey Cancer Center
state: Virginia
Study officials:
affiliation: Alliance for Clinical Trials in Oncology
name: Geoffrey L Uy
role: PRINCIPAL_INVESTIGATOR
References:
citation: Mims AS, Kohlschmidt J, Borate U, Blachly JS, Orwick S, Eisfeld AK, Papaioannou D, Nicolet D, Mromicronzek K, Stein E, Bhatnagar B, Stone RM, Kolitz JE, Wang ES, Powell BL, Burd A, Levine RL, Druker BJ, Bloomfield CD, Byrd JC. A precision medicine classification for treatment of acute myeloid leukemia in older patients. J Hematol Oncol. 2021 Jun 23;14(1):96. doi: 10.1186/s13045-021-01110-5.
citation: Klepin HD, Ritchie E, Major-Elechi B, Le-Rademacher J, Seisler D, Storrick L, Sanford BL, Marcucci G, Zhao W, Geyer SA, Ballman KV, Powell BL, Baer MR, Stock W, Cohen HJ, Stone RM, Larson RA, Uy GL. Geriatric assessment among older adults receiving intensive therapy for acute myeloid leukemia: Report of CALGB 361006 (Alliance). J Geriatr Oncol. 2020 Jan;11(1):107-113. doi: 10.1016/j.jgo.2019.10.002. Epub 2019 Oct 24.
citation: Yin J, LaPlant B, Uy GL, Marcucci G, Blum W, Larson RA, Stone RM, Mandrekar SJ. Evaluation of event-free survival as a robust end point in untreated acute myeloid leukemia (Alliance A151614). Blood Adv. 2019 Jun 11;3(11):1714-1721. doi: 10.1182/bloodadvances.2018026112.
citation: Uy GL, Mandrekar SJ, Laumann K, Marcucci G, Zhao W, Levis MJ, Klepin HD, Baer MR, Powell BL, Westervelt P, DeAngelo DJ, Stock W, Sanford B, Blum WG, Bloomfield CD, Stone RM, Larson RA. A phase 2 study incorporating sorafenib into the chemotherapy for older adults with FLT3-mutated acute myeloid leukemia: CALGB 11001. Blood Adv. 2017 Jan 24;1(5):331-340. doi: 10.1182/bloodadvances.2016003053.