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

• ClinicalTrials.gov Identifier: NCT02728050
• Recruitment Status: Recruiting
• First Posted: April 5, 2016
• Last Update Posted: January 8, 2021
• Sponsor: University of Washington
• Collaborators: National Cancer Institute (NCI); Bayer
• Information provided by (Responsible Party): University of Washington

Tracking Information

• First Submitted Date: March 14, 2016
• First Posted Date: April 5, 2016
• Last Update Posted Date: January 8, 2021
• Actual Study Start Date: December 1, 2016
• Estimated Primary Completion Date: October 31, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 17, 2020)

• Maximum tolerated dose (MTD) (Phase I) [ Time Frame: 28 days ]
  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.
• Minimal residual disease negative (MRDneg) complete response (CR) rate (Phase II) [ Time Frame: 56 days (2 cycles of induction chemotherapy) ]

Original Primary Outcome Measures (submitted: March 30, 2016)

• Minimal residual disease negative (MRDneg) complete response (CR) rate (Phase II) [ Time Frame: 56 days (2 courses of induction chemotherapy) ]
• Maximum tolerated dose (MTD), 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 (Phase I) [ Time Frame: 28 days ]

Current Secondary Outcome Measures (submitted: March 17, 2020)

• Complete response (CR) [ Time Frame: Up to 5 years ]
• Overall response rate (ORR) [ Time Frame: Up to 5 years ]
• Overall survival (OS) [ Time Frame: Up to 5 years ]
• Event-free survival (EFS) [ Time Frame: Up to 5 years ]
• Relapse-free survival (RFS) [ Time Frame: Up to 5 years ]
• Incidence of toxicity [ Time Frame: Up to 5 years ]
  Will be assessed using National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.
• Quality of life (QOL) scores [ Time Frame: Up to 5 years ]
  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).
• Costs, obtained by cost records [ Time Frame: Up to 5 years ]
  Will be recorded and summarized using descriptive methods including boxplots, histograms, and statistical summary measures (medians, means, standard deviation, N, and proportions).
• Number of days in hospital [ Time Frame: Up to 5 years ]
• Number of hospital admissions [ Time Frame: Up to 5 years ]
• Mean duration of hospital stays [ Time Frame: Up to 5 years ]
• Number of days in the intensive care unit [ Time Frame: Up to 5 years ]
• Number of blood product transfusions received [ Time Frame: Up to 5 years ]
• Number of episodes of febrile neutropenia [ Time Frame: Up to 5 years ]
• Number of days requiring antibiotic use [ Time Frame: Up to 5 years ]
• Number of visits to the emergency department [ Time Frame: Up to 5 years ]
• Number of clinic visits [ Time Frame: Up to 5 years ]

Original Secondary Outcome Measures (submitted: March 30, 2016)

• Costs, obtained by cost records [ Time Frame: Up to 5 years ]
  This will be a composite measure. Will be recorded and summarized using descriptive methods including boxplots, histograms, and statistical summary measures (medians, means, standard deviation, N, and proportions).
• Complete response (CR) [ Time Frame: Up to 5 years ]
• Event-free survival (EFS) [ Time Frame: Up to 5 years ]
• Incidence of toxicity using National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 [ Time Frame: Up to 5 years ]
• Overall response rate (ORR) [ Time Frame: Up to 5 years ]
• Overall survival (OS) [ Time Frame: Up to 5 years ]
• Quality of life (QOL) scores, assessed by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 [ Time Frame: Up to 5 years ]
  Will be recorded and summarized using descriptive methods including boxplots, histograms, and statistical summary measures (medians, means, standard deviation, N, and proportions).
• Relapse-free survival (RFS) [ Time Frame: Up to 5 years ]
• Number of days in hospital [ Time Frame: Up to 5 years ]
• Number of hospital admissions [ Time Frame: Up to 5 years ]
• Mean duration of hospital stays [ Time Frame: Up to 5 years ]
• Number of days in the intensive care unit [ Time Frame: Up to 5 years ]
• Number of blood product transfusions received [ Time Frame: Up to 5 years ]
• Number of episodes of febrile neutropenia [ Time Frame: Up to 5 years ]
• Number of days requiring antibiotic use [ Time Frame: Up to 5 years ]
• Number of visits to the emergency department [ Time Frame: Up to 5 years ]
• Number of clinic visits [ Time Frame: Up to 5 years ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• 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
• 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.

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
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

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

Intervention

• Drug: Cladribine
  Given IV
  Other Names:

  • 2-CdA
  • 2CDA
  • CdA
  • Cladribina
  • Leustat
  • Leustatin
  • Leustatine
  • RWJ-26251
• 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
  • 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
• Biological: Filgrastim
  Given SC
  Other Names:

  • FILGRASTIM, LICENSE HOLDER UNSPECIFIED
  • G-CSF
  • Neupogen
  • r-metHuG-CSF
  • Recombinant Methionyl Human Granulocyte Colony Stimulating Factor
  • rG-CSF
  • Tevagrastim
• Other: Laboratory Biomarker Analysis
  Correlative studies
• Other: Quality-of-Life Assessment
  Ancillary studies
  Other Name: Quality of Life Assessment
• Drug: Mitoxantrone
  Given IV
  Other Names:

  • Dihydroxyanthracenedione
  • Mitozantrone
• Drug: Sorafenib
  Given PO
  Other Names:

  • 284461-73-0
  • BAY 43-9006
  • Bay-439006

Study Arms

Experimental: Treatment (sorafenib, G-CLAM)

See Detailed Description.

Interventions:

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

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: March 13, 2019): 82
• Original Estimated Enrollment (submitted: March 30, 2016): 77
• Estimated Study Completion Date: October 31, 2025
• Estimated Primary Completion Date: October 31, 2022 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 60 Years (Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Anna Halpern; 206-606-1978; halpern2@uw.edu

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02728050
• Other Study ID Numbers: 9510; NCI-2016-00286 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); 9510 ( Other Identifier: Fred Hutch/University of Washington Cancer Consortium ); P30CA015704 ( U.S. NIH Grant/Contract ); RG1016000 ( Other Identifier: Fred Hutch/University of Washington Cancer Consortium )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Responsible Party: University of Washington
• Study Sponsor: University of Washington

Collaborators

• National Cancer Institute (NCI)
• Bayer

Investigators

• Principal Investigator: Anna Halpern; Fred Hutch/University of Washington Cancer Consortium

• PRS Account: University of Washington
• Verification Date: January 2021