Description:
This phase I/II trial studies the side effects and best dose of filgrastim (granulocyte
colony-stimulating factor [G-CSF]), cladribine, cytarabine, and mitoxantrone, when given
together with sorafenib and to see how well they work in treating patients with
newly-diagnosed acute myeloid leukemia or high-risk myelodysplastic syndrome (likely to be
more aggressive). Drugs used in chemotherapy, such as cladribine, cytarabine, and
mitoxantrone work in different ways to stop the growth of cancer cells, either by killing the
cells, by stopping them from dividing, or by stopping them from spreading. Colony-stimulating
factors, such as filgrastim, may increase the production of blood cells and may help the
immune system recover from the side effects of chemotherapy. Sorafenib may stop the growth of
cancer cells by blocking some of the enzymes needed for cell growth. Giving filgrastim,
cladribine, cytarabine, and mitoxantrone together with sorafenib may kill more cancer cells.
Title
- Brief Title: Filgrastim, Cladribine, Cytarabine, and Mitoxantrone With Sorafenib in Treating Patients With Newly-Diagnosed, Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome
- Official Title: Addition of Sorafenib to G-CSF, Cladribine, Cytarabine and Mitoxantrone (G-CLAM) in Adults With Newly-Diagnosed Acute Myeloid Leukemia (AML) Independent of FLT3-ITD Status: A Phase 1/2 Study
Clinical Trial IDs
- ORG STUDY ID:
9510
- SECONDARY ID:
NCI-2016-00286
- SECONDARY ID:
9510
- SECONDARY ID:
P30CA015704
- SECONDARY ID:
RG1016000
- NCT ID:
NCT02728050
Conditions
- Acute Biphenotypic Leukemia
- Acute Myeloid Leukemia
- de Novo Myelodysplastic Syndrome
- Myelodysplastic Syndrome
- Myeloproliferative Neoplasm
Interventions
Drug | Synonyms | Arms |
---|
Cladribine | 2-CdA, 2CDA, CdA, Cladribina, Leustat, Leustatin, Leustatine, RWJ-26251 | Treatment (sorafenib, G-CLAM) |
Cytarabine | .beta.-Cytosine arabinoside, 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone, 1-.beta.-D-Arabinofuranosylcytosine, 1-Beta-D-arabinofuranosyl-4-amino-2(1H)pyrimidinone, 1-Beta-D-arabinofuranosylcytosine, 1.beta.-D-Arabinofuranosylcytosine, 2(1H)-Pyrimidinone, 4-Amino-1-beta-D-arabinofuranosyl-, 2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl-, Alexan, Ara-C, ARA-cell, Arabine, Arabinofuranosylcytosine, Arabinosylcytosine, Aracytidine, Aracytin, Aracytine, Beta-cytosine Arabinoside, CHX-3311, Cytarabinum, Cytarbel, Cytosar, Cytosine Arabinoside, Cytosine-.beta.-arabinoside, Cytosine-beta-arabinoside, Erpalfa, Starasid, Tarabine PFS, U 19920, U-19920, Udicil, WR-28453 | Treatment (sorafenib, G-CLAM) |
Filgrastim | FILGRASTIM, LICENSE HOLDER UNSPECIFIED, G-CSF, Neupogen, r-metHuG-CSF, Recombinant Methionyl Human Granulocyte Colony Stimulating Factor, rG-CSF, Tevagrastim, Nivestym, Filgrastim-aafi | Treatment (sorafenib, G-CLAM) |
Mitoxantrone | Dihydroxyanthracenedione, Mitozantrone | Treatment (sorafenib, G-CLAM) |
Sorafenib | 284461-73-0, BAY 43-9006, Bay-439006 | Treatment (sorafenib, G-CLAM) |
Purpose
This phase I/II trial studies the side effects and best dose of filgrastim (granulocyte
colony-stimulating factor [G-CSF]), cladribine, cytarabine, and mitoxantrone, when given
together with sorafenib and to see how well they work in treating patients with
newly-diagnosed acute myeloid leukemia or high-risk myelodysplastic syndrome (likely to be
more aggressive). Drugs used in chemotherapy, such as cladribine, cytarabine, and
mitoxantrone work in different ways to stop the growth of cancer cells, either by killing the
cells, by stopping them from dividing, or by stopping them from spreading. Colony-stimulating
factors, such as filgrastim, may increase the production of blood cells and may help the
immune system recover from the side effects of chemotherapy. Sorafenib may stop the growth of
cancer cells by blocking some of the enzymes needed for cell growth. Giving filgrastim,
cladribine, cytarabine, and mitoxantrone together with sorafenib may kill more cancer cells.
Detailed Description
OUTLINE: This is a phase I, dose-escalation study of mitoxantrone and sorafenib followed by a
phase II study.
INDUCTION: Patients receive mitoxantrone intravenously (IV) over 60 minutes on days 1-3 and
sorafenib orally (PO) twice daily (BID) on days 10-19 in the absence of disease progression
or unacceptable toxicity. Patients also receive filgrastim subcutaneously (SC) once daily
(QD) on days 0-5, cladribine IV QD over 2 hours on days 1-5, and cytarabine IV QD over 2
hours on days 1-5 in the absence of disease progression or unacceptable toxicity. Patients
achieving partial remission (including MRD positive [pos] CR, CR with incomplete platelet
recovery [CRp], and CR with incomplete count recovery [CRi]) or persistent AML may receive up
to 2 cycles of induction therapy per the discretion of the treating physician.
POST-REMISSION: Patients receive sorafenib PO BID on days 8-27 or 3 days prior to next cycle
of treatment, whichever occurs first. Patients also receive filgrastim subcutaneously SC QD
on days 0-5, cladribine IV QD over 2 hours on days 1-5, and cytarabine IV QD over 2 hours on
days 1-5 in the absence of disease progression or unacceptable toxicity. Patients achieving
MRDneg CR may receive up to 4 cycles of post-remission therapy. Patients achieving disease
response (MRDpos CR, CRi/CRp, or persistent disease) may receive up to two induction cycles
and 1 cycle of post-remission therapy with mitoxantrone omitted in cycle 3. If they then
enter MRDneg CR, they can proceed with up to a total of 4 cycles of post-remission therapy.
MAINTENANCE THERAPY: Patients achieving MRDneg CR may receive maintenance therapy of
sorafenib PO BID for up to 1 year.
After completion of study treatment, patients are followed up every 3 months for up to 5
years.
Trial Arms
Name | Type | Description | Interventions |
---|
Treatment (sorafenib, G-CLAM) | Experimental | See Detailed Description. | - Cladribine
- Cytarabine
- Filgrastim
- Mitoxantrone
- Sorafenib
|
Eligibility Criteria
Inclusion Criteria:
- Newly diagnosed disease with either a diagnosis of "high-risk" MDS (>= 10% blasts in
marrow or blood), high-risk myeloproliferative neoplasm (MPN; >= 10% blasts in blood
or bone marrow), or AML other than acute promyelocytic leukemia (APL) with
t(15;17)(q22;q12) or variants according to the 2008 World Health Organization (WHO)
classification; patients with biphenotypic AML are eligible; such "high-risk" MDS or
MPN have natural history much closer to AML than to lower risk MDS or MPN and have
responded similarly to "AML-type" therapy
- Outside diagnostic material is acceptable as long as peripheral blood and/or bone
marrow slides are reviewed at the study institution by appropriate clinical staff;
flow cytometric analysis of peripheral blood and/or bone marrow should be performed
according to institutional practice guidelines
- Treatment-related mortality (TRM) score =< 13.1 as calculated with simplified model
- The use of hydroxyurea prior to study registration is allowed; patients with
symptoms/signs of hyperleukocytosis or white blood cell (WBC) > 100,000/uL, or acute
symptoms can be treated with leukapheresis or may receive up to 2 doses of cytarabine
(up to 500 mg/m^2/dose) prior to study day 0 enrollment
- Bilirubin =< 2 times institutional upper limit of normal unless elevation is thought
to be due to hepatic infiltration by AML, Gilbert's syndrome, or hemolysis (assessed
within 10 days prior to study day 0)
- Serum creatinine =< 2.0 mg/dL (assessed within 10 days prior to study day 0)
- Left ventricular ejection fraction >= 45%, assessed within 3 months prior to study day
0, e.g. by multi gated acquisition scan (MUGA) scan or echocardiography, or other
appropriate diagnostic modality and no clinical evidence of congestive heart failure
- Women of childbearing potential and men must agree to use adequate contraception
beginning at the signing of the consent until at least 3 months after the last dose of
study drug
- Provide written informed consent (or legal representative)
Exclusion Criteria:
- Myeloid blast crisis of chronic myeloid leukemia (CML), unless patient is not
considered candidate for CML-directed tyrosine kinase inhibitor treatment (excluding
sorafenib)
- Concomitant illness associated with a likely survival of < 1 year
- Active systemic fungal, bacterial, viral, or other infection, unless disease is under
treatment with anti-microbials and/or controlled or stable (e.g. if specific,
effective therapy is not available/feasible or desired [e.g. chronic viral hepatitis,
human immunodeficiency virus (HIV)]); patient needs to be clinically stable as defined
as being afebrile and hemodynamically stable for 24-48 hours prior to study day 0,
unless fever is thought to be secondary to the underlying hematologic disease
- Active or clinically significant (or symptomatic) cardiac disease, including active
coronary artery disease, cardiac arrhythmias requiring anti-arrhythmic therapy other
than beta blockers or digoxin within the last 3 months, unstable angina (anginal
symptoms at rest), new-onset angina within 3 months before randomization, or
myocardial infarction within 6 months before study day 0
- Previous receipt of azacitidine, decitabine, anthracyclines, cytarabine, or other
nucleoside analogues for treatment of AML or MPN/MDS other than as noted for
cytarabine
- Pregnancy or lactation
- Concurrent treatment with any other investigational agent that has anti-leukemia
activity or another drug with anti-AML-activity
Maximum Eligible Age: | 60 Years |
Minimum Eligible Age: | 18 Years |
Eligible Gender: | All |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | Maximum tolerated dose (MTD) (Phase I) |
Time Frame: | 28 days |
Safety Issue: | |
Description: | Will be defined as the highest dose studied in which the incidence of dose-limiting toxicity is < 33% assuming at least 6 patients have been treated at this dose. |
Secondary Outcome Measures
Measure: | Complete response (CR) |
Time Frame: | Up to 5 years |
Safety Issue: | |
Description: | |
Measure: | Overall response rate (ORR) |
Time Frame: | Up to 5 years |
Safety Issue: | |
Description: | |
Measure: | Overall survival (OS) |
Time Frame: | Up to 5 years |
Safety Issue: | |
Description: | |
Measure: | Event-free survival (EFS) |
Time Frame: | Up to 5 years |
Safety Issue: | |
Description: | |
Measure: | Relapse-free survival (RFS) |
Time Frame: | Up to 5 years |
Safety Issue: | |
Description: | |
Measure: | Incidence of toxicity |
Time Frame: | Up to 5 years |
Safety Issue: | |
Description: | Will be assessed using National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. |
Measure: | Quality of life (QOL) scores |
Time Frame: | Up to 5 years |
Safety Issue: | |
Description: | Will be assessed by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30. Will be recorded and summarized using descriptive methods including boxplots, histograms, and statistical summary measures (medians, means, standard deviation, N, and proportions). |
Measure: | Costs, obtained by cost records |
Time Frame: | Up to 5 years |
Safety Issue: | |
Description: | Will be recorded and summarized using descriptive methods including boxplots, histograms, and statistical summary measures (medians, means, standard deviation, N, and proportions). |
Measure: | Number of days in hospital |
Time Frame: | Up to 5 years |
Safety Issue: | |
Description: | |
Measure: | Number of hospital admissions |
Time Frame: | Up to 5 years |
Safety Issue: | |
Description: | |
Measure: | Mean duration of hospital stays |
Time Frame: | Up to 5 years |
Safety Issue: | |
Description: | |
Measure: | Number of days in the intensive care unit |
Time Frame: | Up to 5 years |
Safety Issue: | |
Description: | |
Measure: | Number of blood product transfusions received |
Time Frame: | Up to 5 years |
Safety Issue: | |
Description: | |
Measure: | Number of episodes of febrile neutropenia |
Time Frame: | Up to 5 years |
Safety Issue: | |
Description: | |
Measure: | Number of days requiring antibiotic use |
Time Frame: | Up to 5 years |
Safety Issue: | |
Description: | |
Measure: | Number of visits to the emergency department |
Time Frame: | Up to 5 years |
Safety Issue: | |
Description: | |
Measure: | Number of clinic visits |
Time Frame: | Up to 5 years |
Safety Issue: | |
Description: | |
Details
Phase: | Phase 1/Phase 2 |
Primary Purpose: | Interventional |
Overall Status: | Recruiting |
Lead Sponsor: | University of Washington |
Last Updated
June 29, 2021