Clinical Trials Logo

Clinical Trial Details — Status: Completed

Administrative data

NCT number NCT02728050
Other study ID # 9510
Secondary ID NCI-2016-0028695
Status Completed
Phase Phase 1/Phase 2
First received
Last updated
Start date December 1, 2016
Est. completion date April 4, 2023

Study information

Verified date June 2023
Source University of Washington
Contact n/a
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial 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.


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.


Recruitment information / eligibility

Status Completed
Enrollment 84
Est. completion date April 4, 2023
Est. primary completion date February 3, 2022
Accepts healthy volunteers No
Gender All
Age group 18 Years to 60 Years
Eligibility 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 Design


Intervention

Drug:
Cladribine
Given IV
Cytarabine
Given IV
Biological:
Filgrastim
Given SC
Other:
Laboratory Biomarker Analysis
Correlative studies
Quality-of-Life Assessment
Ancillary studies
Drug:
Mitoxantrone
Given IV
Sorafenib
Given PO

Locations

Country Name City State
United States Fred Hutch/University of Washington Cancer Consortium Seattle Washington

Sponsors (3)

Lead Sponsor Collaborator
University of Washington Bayer, National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type Measure Description Time frame Safety issue
Primary 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
Primary 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
Primary 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 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
Secondary Overall Response Rate (ORR) ORR, defined as CR+CRi, rates of patients treated with CLAG-M with sorafenib. Up to 5 years
Secondary Overall Survival (OS) 12-month overall survival 12 months
Secondary Event-free Survival (EFS) 12-month event free survival 12 months
Secondary Relapse-free Survival (RFS) 12-month relapse free survival (RFS) 12 months
Secondary 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
See also
  Status Clinical Trial Phase
Recruiting NCT05400122 - Natural Killer (NK) Cells in Combination With Interleukin-2 (IL-2) and Transforming Growth Factor Beta (TGFbeta) Receptor I Inhibitor Vactosertib in Cancer Phase 1
Recruiting NCT04460235 - Immunogenicity of an Anti-pneumococcal Combined Vaccination in Acute Leukemia or Lymphoma Phase 4
Completed NCT04022785 - PLX51107 and Azacitidine in Treating Patients With Acute Myeloid Leukemia or Myelodysplastic Syndrome Phase 1
Completed NCT03678493 - A Study of FMT in Patients With AML Allo HSCT in Recipients Phase 2
Recruiting NCT05424562 - A Study to Assess Change in Disease State in Adult Participants With Acute Myeloid Leukemia (AML) Ineligible for Intensive Chemotherapy Receiving Oral Venetoclax Tablets in Canada
Terminated NCT03224819 - Study of Emerfetamab (AMG 673) in Adults With Relapsed/Refractory Acute Myeloid Leukemia (AML) Early Phase 1
Completed NCT03197714 - Clinical Trial of OPB-111077 in Patients With Relapsed or Refractory Acute Myeloid Leukaemia Phase 1
Active, not recruiting NCT03844048 - An Extension Study of Venetoclax for Subjects Who Have Completed a Prior Venetoclax Clinical Trial Phase 3
Active, not recruiting NCT04070768 - Study of the Safety and Efficacy of Gemtuzumab Ozogamicin (GO) and Venetoclax in Patients With Relapsed or Refractory CD33+ Acute Myeloid Leukemia:Big Ten Cancer Research Consortium BTCRC-AML17-113 Phase 1
Active, not recruiting NCT04107727 - Trial to Compare Efficacy and Safety of Chemotherapy/Quizartinib vs Chemotherapy/Placebo in Adults FMS-like Tyrosine Kinase 3 (FLT3) Wild-type Acute Myeloid Leukemia (AML) Phase 2
Recruiting NCT04385290 - Combination of Midostaurin and Gemtuzumab Ozogamicin in First-line Standard Therapy for Acute Myeloid Leukemia (MOSAIC) Phase 1/Phase 2
Recruiting NCT04920500 - Bioequivalence of Daunorubicin Cytarabine Liposomes in Naive AML Patients N/A
Recruiting NCT03897127 - Study of Standard Intensive Chemotherapy Versus Intensive Chemotherapy With CPX-351 in Adult Patients With Newly Diagnosed AML and Intermediate- or Adverse Genetics Phase 3
Active, not recruiting NCT04021368 - RVU120 in Patients With Acute Myeloid Leukemia or High-risk Myelodysplastic Syndrome Phase 1
Recruiting NCT03665480 - The Effect of G-CSF on MRD After Induction Therapy in Newly Diagnosed AML Phase 2/Phase 3
Completed NCT02485535 - Selinexor in Treating Patients With Intermediate- and High-Risk Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome After Transplant Phase 1
Enrolling by invitation NCT04093570 - A Study for Participants Who Participated in Prior Clinical Studies of ASTX727 (Standard Dose), With a Food Effect Substudy at Select Study Centers Phase 2
Recruiting NCT04069208 - IA14 Induction in Young Acute Myeloid Leukemia Phase 2
Recruiting NCT05744739 - Tomivosertib in Relapsed or Refractory Acute Myeloid Leukemia (AML) Phase 1
Recruiting NCT04969601 - Anti-Covid-19 Vaccine in Children With Acute Leukemia and Their Siblings Phase 1/Phase 2