Clinical trial NCT00742625: Bortezomib, Daunorubicin, and Cytarabine in Treating Older Patients With Previously Untreated Acute Myeloid Leukemia
Official title: Dose Escalation and Phase II Study of Bortezomib (IND #58443) Added to Standard Daunorubicin and Cytarabine Therapy for Patients With Previously Untreated Acute Myeloid Leukemia Age 60-75 Years
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Acute Myeloid Leukemia
Adult Acute Megakaryoblastic Leukemia (M7)
Adult Acute Minimally Differentiated Myeloid Leukemia (M0)
Adult Acute Monoblastic Leukemia (M5a)
Adult Acute Monocytic Leukemia (M5b)
Adult Acute Myeloblastic Leukemia With Maturation (M2)
Adult Acute Myeloblastic Leukemia Without Maturation (M1)
Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities
Adult Acute Myeloid Leukemia With Inv(16)(p13;q22)
Adult Acute Myeloid Leukemia With t(16;16)(p13;q22)
Adult Acute Myeloid Leukemia With t(8;21)(q22;q22)
Adult Acute Myelomonocytic Leukemia (M4)
Adult Erythroleukemia (M6a)
Adult Pure Erythroid Leukemia (M6b)
Untreated Adult Acute Myeloid Leukemia
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2008-08-28
Enrollment: 95
Sex: ALL
Minimum age (years): 60
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This phase II trial studies the side effects and best dose of bortezomib when given together with daunorubicin and cytarabine and to see how well it works in treating older patients with previously untreated acute myeloid leukemia. Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as daunorubicin 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 bortezomib together with combination chemotherapy may kill more cancer cells.

Detailed description: PRIMARY OBJECTIVES:

I. To define the remission induction response rate (complete response \[CR\] and CR with incomplete platelet recovery \[CRp\]) in older patients with previously untreated acute myeloid leukemia treated with induction therapy comprising bortezomib in combination with daunorubicin hydrochloride and cytarabine.

II. To define the maximum tolerated dose of bortezomib when administered in combination with intermediate-dose cytarabine after induction therapy.

SECONDARY OBJECTIVES:

I. To describe the disease-free survival of patients treated with this regimen. II. To describe the overall survival of patients treated with this regimen. III. To evaluate the treatment-related toxicities in these patients.

OUTLINE: This is a multicenter, dose-escalation study of bortezomib. Doses of bortezomib are escalated during remission consolidation therapy.

REMISSION INDUCTION THERAPY: Remission induction course 1: Patients receive bortezomib IV over 3-5 seconds on days 1, 4, 8, and 11; daunorubicin hydrochloride IV on days 1-3; and cytarabine IV continuously over 168 hours on days 1-7.

After completion of remission induction course 1, patients undergo bone marrow aspiration and biopsy for evaluation of response. Patients achieving a complete response (CR) or partial response (PR) proceed to remission consolidation therapy. Patients achieving a CR with incomplete platelet recovery (CRp) proceed to remission consolidation therapy after platelet counts recover. Patients with persistent leukemia (\>= 20% bone marrow cellularity and \>= 5% bone marrow myeloblasts) proceed to remission induction course 2.

REMISSION INDUCTION COURSE 2: Patients receive bortezomib IV over 3-5 seconds on days 1 and 4; daunorubicin hydrochloride IV on days 1 and 2; and cytarabine IV continuously over 120 hours on days 1-5.

After completion of remission induction course 2, patients undergo bone marrow aspiration and biopsy for evaluation of response. Patients achieving a CR or PR proceed to remission consolidation therapy. Patients achieving a CRp proceed to remission consolidation therapy after platelet counts recover. Patients with residual leukemia who do not meet the criteria for PR are removed from the study.

REMISSION CONSOLIDATION THERAPY: Patients receive bortezomib IV over 3-5 seconds on days 1, 4, 8, and 11 and intermediate-dose cytarabine IV over 3 hours on days 1-5. Patients then undergo bone marrow aspiration and biopsy for evaluation of response. Patients achieving a CR or who demonstrate continuing CR receive a second course of remission consolidation therapy beginning 2-4 weeks after blood counts recover.

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

Eligibility criteria: Inclusion Criteria:

* Unequivocally histologically confirmed acute myeloid leukemia (AML)
* At least 20% blasts in the bone marrow based on WHO criteria
* No acute promyelocytic leukemia (M3)
* Antecedent hematologic disorder or myelodysplastic syndromes allowed provided the patient did not receive cytotoxic chemotherapy, including azacitidine and decitabine, for their pre-leukemic disorder
* Concurrent enrollment on CALGB-8461 required
* Not pregnant or nursing
* Fertile patients must use effective contraception
* No ataxia, cranial neuropathy, or peripheral neuropathy \>= grade 2
* LVEF \>= 40% by ECHO or MUGA scan
* No signs or symptoms of congestive heart failure
* DLCO \>= 50% (corrected for hemoglobin)
* No prior therapy for leukemia or pre-leukemic disorders, except for the following:

  * emergency leukapheresis;
  * emergency treatment for hyperleukocytosis with hydroxyurea;
  * cranial radiotherapy for CNS leukostasis (one dose only);
  * growth factor/cytokine support
* No other concurrent chemotherapy, except for the following:

  * I) steroids administered for adrenal failure, hypersensitivity reactions, or septic shock;
  * II) hormones administered for non-disease-related conditions (e.g., insulin for diabetes or estrogens or progestins for gynecologic indications)
* No concurrent palliative radiotherapy

Primary outcomes:
measure: Remission Induction Response
timeFrame: 2 months
measure: Participants Experiencing a Dose-limiting Toxicity (DLT) of Bortezomib When Administered in Combination With Intermediate-dose Cytarabine
timeFrame: during consolidation cycle 1 (42 days)
Secondary outcomes:
measure: Disease-free Survival
timeFrame: Duration of study (up to 10 years)
measure: Overall Survival
timeFrame: Duration of study (up to 10 years)
Other outcomes:
Locations:
city: Washington
country: United States
facility: Washington Hospital Center
state: District of Columbia
city: Washington
country: United States
facility: Lombardi Comprehensive Cancer Center at Georgetown University
state: District of Columbia
city: Orlando
country: United States
facility: Florida Hospital
state: Florida
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
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: 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: Columbia
country: United States
facility: University of Missouri - Ellis Fischel
state: Missouri
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: Manhasset
country: United States
facility: North Shore University Hospital
state: New York
city: Manhasset
country: United States
facility: North Shore-LIJ Health System CCOP
state: New York
city: New Hyde Park
country: United States
facility: Long Island Jewish Medical Center
state: New York
city: New Hyde Park
country: United States
facility: North Shore-LIJ Health System/Center for Advanced Medicine
state: New York
city: New York
country: United States
facility: Mount Sinai Medical Center
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina
state: North Carolina
city: Kinston
country: United States
facility: Kinston Medical Specialists PA
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest University Health Sciences
state: North Carolina
city: Columbus
country: United States
facility: Arthur G. James Cancer Hospital and Solove Research Institute at Ohio State University Medical Center
state: Ohio
city: Richmond
country: United States
facility: Virginia Commonwealth University
state: Virginia
Study officials:
affiliation: Cancer and Leukemia Group B
name: Eyal Attar
role: PRINCIPAL_INVESTIGATOR
References:
citation: Walker CJ, Kohlschmidt J, Eisfeld AK, Mrozek K, Liyanarachchi S, Song C, Nicolet D, Blachly JS, Bill M, Papaioannou D, Oakes CC, Giacopelli B, Genutis LK, Maharry SE, Orwick S, Archer KJ, Powell BL, Kolitz JE, Uy GL, Wang ES, Carroll AJ, Stone RM, Byrd JC, de la Chapelle A, Bloomfield CD. Genetic Characterization and Prognostic Relevance of Acquired Uniparental Disomies in Cytogenetically Normal Acute Myeloid Leukemia. Clin Cancer Res. 2019 Nov 1;25(21):6524-6531. doi: 10.1158/1078-0432.CCR-19-0725. Epub 2019 Aug 2.