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

NCT02728050 | Completed Phase 1 Results FDA Drug

• 4 other identifiers: 9510NCI-2016-00286P30CA015704RG1016000
• Study Type: interventional
• Target: 84
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Acute Biphenotypic Leukemia; Acute Myeloid Leukemia; de Novo Myelodysplastic Syndrome; Myelodysplastic Syndrome; Myeloproliferative Neoplasm

Outcome Measures

Primary Outcomes (3)

• 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 Outcomes (6)

• Complete Remission (CR)

  Up to 5 years

• Overall Response Rate (ORR)

  Up to 5 years

• Overall Survival (OS)

  12 months

• Event-free Survival (EFS)

  12 months

• Relapse-free Survival (RFS)

  12 months

Study Arms (1)

Treatment (sorafenib, G-CLAM)

EXPERIMENTAL

See Detailed Description.

Drug: Cladribine; Drug: Cytarabine; Biological: Filgrastim; Other: Laboratory Biomarker Analysis; Other: Quality-of-Life Assessment; Drug: Mitoxantrone; Drug: Sorafenib

Interventions

Cladribine DRUG

Given IV

Also known as: 2-CdA, 2CDA, CdA, Cladribina, Leustat, Leustatin, Leustatine, RWJ-26251

Treatment (sorafenib, G-CLAM)

Cytarabine DRUG

Given IV

Also known as: .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 BIOLOGICAL

Given SC

Also known as: 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)

Laboratory Biomarker Analysis OTHER

Correlative studies

Treatment (sorafenib, G-CLAM)

Quality-of-Life Assessment OTHER

Ancillary studies

Also known as: Quality of Life Assessment

Treatment (sorafenib, G-CLAM)

Mitoxantrone DRUG

Given IV

Also known as: Dihydroxyanthracenedione, Mitozantrone

Treatment (sorafenib, G-CLAM)

Sorafenib DRUG

Given PO

Also known as: 284461-73-0, BAY 43-9006, Bay-439006

Treatment (sorafenib, G-CLAM)

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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)

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Washington: lead
• National Cancer Institute (NCI): collaborator
• Bayer: collaborator

Study Sites (1)

Fred Hutch/University of Washington Cancer Consortium

Seattle, Washington, 98109, United States

Location

Related Publications (1)

• Halpern AB, Rodriguez-Arboli E, Othus M, Garcia KA, Percival MM, Cassaday RD, Oehler VG, Becker PS, Appelbaum JS, Abkowitz JL, Orozco JJ, Keel SB, Hendrie PC, Scott BL, Ghiuzeli MC, Estey EH, Walter RB. Phase 1/2 study of sorafenib added to cladribine, high-dose cytarabine, G-CSF, and mitoxantrone in untreated AML. Blood Adv. 2023 Sep 12;7(17):4950-4961. doi: 10.1182/bloodadvances.2023010392.

  PMID: 37339483 DERIVED

MeSH Terms

Conditions

Leukemia, Biphenotypic, Acute; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Myeloproliferative Disorders

Interventions

Cladribine; Cytarabine; Filgrastim; Granulocyte Colony-Stimulating Factor; Mitoxantrone; Sorafenib

Condition Hierarchy (Ancestors)

Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Leukemia, Myeloid; Bone Marrow Diseases

Intervention Hierarchy (Ancestors)

2-Chloroadenosine; Adenosine; Purine Nucleosides; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Deoxyadenosines; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Arabinonucleosides; Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors; Anthraquinones; Anthrones; Anthracenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Quinones; Polycyclic Compounds; Phenylurea Compounds; Urea; Amides; Benzene Derivatives; Niacinamide; Nicotinic Acids; Acids, Heterocyclic; Pyridines

Limitations and Caveats

Study was limited by its single-institution and non-randomized nature

Results Point of Contact

• Title: Anna Halpern, MD
• Organization: University of Washington

halpern2@uw.edu

206-606-1978

Study Officials

• Anna Halpern

  Fred Hutch/University of Washington Cancer Consortium

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor

Study Record Dates

• First Submitted: March 14, 2016
• First Posted: April 5, 2016
• Study Start: December 1, 2016
• Primary Completion: February 3, 2022
• Study Completion: April 4, 2023
• Last Updated: July 5, 2023
• Results First Posted: June 29, 2023

Record last verified: 2023-06

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)