Filgrastim, Cladribine, Cytarabine, and Mitoxantrone With Sorafenib in Treating Patients With Newly-Diagnosed, Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome

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

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.

Study Overview

• Status: Completed
• Conditions: Acute Myeloid Leukemia; Myelodysplastic Syndrome; Myeloproliferative Neoplasm; de Novo Myelodysplastic Syndrome; Acute Biphenotypic Leukemia
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Other: Quality-of-Life Assessment; Drug: Cytarabine; Drug: Mitoxantrone; Biological: Filgrastim; Drug: Sorafenib; Drug: Cladribine

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.

• Study Type: Interventional
• Enrollment (Actual): 84
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Washington
    • Seattle, Washington, United States, 98109
      • Fred Hutch/University of Washington Cancer Consortium

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age 18-60 years, inclusive
• 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, 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment (sorafenib, G-CLAM); See Detailed Description.

Other: Laboratory Biomarker Analysis; Correlative studies; Other: Quality-of-Life Assessment; Ancillary studies; Other Names: Quality of Life Assessment; Drug: Cytarabine; Given IV; Other Names: .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; CHX-3311; Cytarabinum; Cytarbel; Cytosar; Cytosine Arabinoside; Cytosine-.beta.-arabinoside; Cytosine-beta-arabinoside; Erpalfa; Starasid; Tarabine PFS; U 19920; U-19920; Udicil; WR-28453; Beta-cytosine Arabinoside; Drug: Mitoxantrone; Given IV; Other Names: Dihydroxyanthracenedione; Mitozantrone; Biological: Filgrastim; Given SC; Other Names: G-CSF; r-metHuG-CSF; Neupogen; Filgrastim-aafi; Nivestym; Recombinant Methionyl Human Granulocyte Colony Stimulating Factor; rG-CSF; Tevagrastim; FILGRASTIM, LICENSE HOLDER UNSPECIFIED; Drug: Sorafenib; Given PO; Other Names: BAY 43-9006; Bay-439006; 284461-73-0; Drug: Cladribine; Given IV; Other Names: 2-CdA; CdA; 2CDA; Cladribina; Leustat; Leustatin; Leustatine; RWJ-26251

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 1: Maximum Tolerated Dose (MTD)/Recommended Phase 2 Dose (RP2D) of Mitoxantrone	MTD/RP2D will be defined as the highest dose studied in which the incidence of dose-limiting toxicity (DLT) is < 33% assuming at least 6 patients have been treated at this dose. DLTs were defined as: 1) grade ≥3 non-hematologic toxicity lasting >48 hours leading to >7-day delay of the next cycle; 2) grade ≥4 non-hematologic toxicity if no recovery to grade ≤2 in 14 days (both excluding febrile neutropenia/ infection); 3) Absolute neutrophil count <500/ µL or platelet count <50,000/µL for >49 days after CLAGM+S without marrow evidence of AML. Doses were escalated up to dose level six if <2/6 patients out of each cohort of 6 had a DLT (some cohorts were expanded to 12 patients while awaiting completion of DLT monitoring period). The dose level at which dose escalation was stopped was the recommended phase 2 dose (RP2D).	First 28 days of treatment
Phase 1: Maximum Tolerated Dose (MTD)/Recommended Phase 2 Dose (RP2D) of Sorafenib	MTD/RP2D will be defined as the highest dose studied in which the incidence of dose-limiting toxicity (DLT) is < 33% assuming at least 6 patients have been treated at this dose. DLTs were defined as: 1) grade ≥3 non-hematologic toxicity lasting >48 hours leading to >7-day delay of the next cycle; 2) grade ≥4 non-hematologic toxicity if no recovery to grade ≤2 in 14 days (both excluding febrile neutropenia/ infection); 3) Absolute neutrophil count <500/ µL or platelet count <50,000/µL for >49 days after CLAGM+S without marrow evidence of AML. Doses were escalated up to dose level six if <2/6 patients out of each cohort of 6 had a DLT (some cohorts were expanded to 12 patients while awaiting completion of DLT monitoring period). The dose level at which dose escalation was stopped was the recommended phase 2 dose (RP2D).	First 28 days of treatment
Phase I and II: Rate of Minimal Residual Disease Negative (MRDneg) Complete Response (CR)	We will determine if the addition of sorafenib to CLAG-M improves the rate of MRDneg CR compared to our institution's historical control of CLAG-M alone in adults with newly-diagnosed AML/high-risk MDS.	56 days (2 cycles of induction chemotherapy)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete Remission (CR)	Complete remission (CR) is defined as bone marrow blasts <5%; absence of circulating blasts; absence of extramedullary disease; ANC ≥1.0 x 10^9/L; platelet count ≥100 x 10^9/L. CR with incomplete hematologic recovery (CRi) is CR with ANC <1.0 x10^9/L or platelet count <100 x 10^9/L. Measurable residual disease (MRD) is assessed by multiparameter flow cytometry and PCR. Morphologic leukemia free state (MLFS) is bone marrow blasts <5%; absence of circulating blasts; absence of extramedullary disease; no hematologic recovery. Resistant disease is defined as not not meeting the criteria for CR, CRi, MLFS.	Up to 5 years
Overall Response Rate (ORR)	ORR, defined as CR+CRi, rates of patients treated with CLAG-M with sorafenib.	Up to 5 years
Overall Survival (OS)	12-month overall survival	12 months
Event-free Survival (EFS)	12-month event free survival	12 months
Relapse-free Survival (RFS)	12-month relapse free survival (RFS)	12 months
Number of Participants With Adverse Events	Will be assessed using National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.	Up to 5 years

Collaborators and Investigators

• Sponsor: University of Washington
• Collaborators: National Cancer Institute (NCI); Bayer
• Investigators: Principal Investigator: Anna Halpern, Fred Hutch/University of Washington Cancer Consortium

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2016
• Primary Completion (Actual): February 3, 2022
• Study Completion (Actual): April 4, 2023

Study Registration Dates

• First Submitted: March 14, 2016
• First Submitted That Met QC Criteria: March 30, 2016
• First Posted (Estimated): April 5, 2016

Study Record Updates

• Last Update Posted (Actual): July 5, 2023
• Last Update Submitted That Met QC Criteria: June 30, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Disease; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Leukemia, Lymphoid; Syndrome; Myelodysplastic Syndromes; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Preleukemia; Myeloproliferative Disorders; Leukemia, Biphenotypic, Acute; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Peripheral Nervous System Agents; Antiviral Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Protein Kinase Inhibitors; Adjuvants, Immunologic; Sorafenib; Lenograstim; Cytarabine; Mitoxantrone; Cladribine; 2-chloro-3'-deoxyadenosine
• Other Study ID Numbers: 9510 (Other Identifier: Fred Hutch/University of Washington Cancer Consortium); P30CA015704 (U.S. NIH Grant/Contract); NCI-2016-00286 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); RG1016000 (Other Identifier: Fred Hutch/University of Washington Cancer Consortium)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No