- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01892371
Quizartinib With Azacitidine or Cytarabine in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome
Phase I/II Study of the Combination of Quizartinib (AC220) With 5-Azacytidine or Low-Dose Cytarabine for the Treatment of Patients With Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS)
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
PRIMARY OBJECTIVES:
I. To determine the dose limiting toxicity (DLT) and maximum tolerated dose (MTD) of the combination of quizartinib (AC220) with either azacitidine (5-azacitidine [AZA]) or low-dose cytarabine (LDAC) in patients with acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS). (Phase I) II. To determine the clinical activity of the combination of quizartinib with either AZA or LDAC in patients with AML or MDS. (Phase II)
SECONDARY OBJECTIVES:
I. To determine the clinical activity of the combination of quizartinib with either AZA or LDAC in patients with AML or MDS. (Phase I) II. To determine the safety of the combination of quizartinib with either AZA or LDAC in patients with AML or MDS. (Phase II) III. To determine the induction of hypomethylation, deoxyribonucleic acid (DNA) damage and FLT3 signaling during therapy with this combination and its correlation with response. (Phase I and II) IV. To determine the effect of this combination therapy on plasma levels of FLT3-ligand. (Phase I and II) V. To determine the pharmacodynamics of this combination therapy in patients with AML or high-risk MDS. (Phase I and II)
OUTLINE: This is a phase I, dose-escalation study of quizartinib followed by a phase II study. Participants are assigned to 1 of 2 arms.
ARM I: Patients receive quizartinib orally (PO) once daily (QD) on days 5-28 of cycle 1 and on days 1-28 of subsequent cycles and azacitidine subcutaneously (SC) or intravenously (IV) over 10-40 minutes on days 1-7. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
ARM II: Patients receive quizartinib PO QD on days 5-28 of cycle 1 and on days 1-28 of subsequent cycles and cytarabine SC twice daily (BID) on days 1-10. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 6-12 months.
Study Type
Enrollment (Actual)
Phase
- Phase 2
- Phase 1
Contacts and Locations
Study Locations
-
-
Texas
-
Houston, Texas, United States, 77030
- M D Anderson Cancer Center
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
Inclusion Criteria:
- PHASE I
- Refractory or relapsed disease defined as follows: patients with MDS or chronic myelomonocytic leukemia (CMML) should have failed prior therapy (e.g., with a hypomethylating agent, clofarabine, and/or with lenalidomide); patients with AML should have failed any prior induction therapy or have relapsed after prior therapy; patients (any age) with MDS or CMML who received therapy with a hypomethylating agent and progress to AML are eligible at the time of diagnosis of AML regardless any prior therapy for AML. The World Health Organization (WHO) classification will be used for AML; patients with any of the eligible diagnoses who have received no prior therapy are eligible if not candidates to receive standard intensive therapy (i.e., high-dose cytarabine-based chemotherapy).
- Patients are eligible regardless of their FLT3 mutation status.
- PHASE II
- COHORT 2A: Patients with MDS, CMML or AML who are either: age 60 years or older and newly diagnosed, previously untreated. Prior therapy with hydroxyurea or single agent ara-C for the purpose of control of white blood cells (WBC) is acceptable.; age 18 years or older and with refractory or relapse disease who have received no more than one prior treatment regimen and will be receiving first salvage. For this purpose, a second induction cycle with the same drugs used during the first cycle, consolidation chemotherapy or stem cell transplant in complete remission (CR) (or complete response with incomplete platelet recovery [CRp] or complete response with incomplete bone marrow recovery [CRi]) will be considered part of the prior regimen. Prior therapy for MDS (or other malignancies) is not considered a prior regimen for AML in patients who progress from MDS (or other malignancies).
- COHORT 2A: Patients (any age) with MDS or CMML who received therapy with a hypomethylating agent and progress to AML are eligible at the time of diagnosis of AML regardless any prior therapy for AML. The WHO classification will be used for AML.
- COHORT 2A: Patients must have evidence of FLT3 ITD in their most recent assessment.
- COHORT 2B: Patients with MDS, CMML or AML who are either: Age 60 years or older and newly diagnosed, previously untreated. Prior therapy with hydroxyurea or single agent ara-C for the purpose of control of WBC is acceptable or age 18 years or older and with refractory or relapse disease who have received no more than two prior treatment regimens and will be receiving second salvage, or who have received a prior SCT and will be receiving their first salvage. For this purposes, a second induction cycle with the same drugs used during the first cycle, consolidation chemotherapy or stem cell transplant in CR (or CRp or CRi) will be considered part of the prior regimen. Prior therapy for MDS (or other malignancies) is not considered a prior regimen for AML in patients who progress from MDS (or other malignancies)
- COHORT 2B: Patients (any age) with MDS or CMML who received therapy with a hypomethylating agent and progress to AML are eligible at the time of diagnosis of AML regardless any prior therapy for AML. The WHO classification will be used for AML
- COHORT 2B: Patients must have no evidence of FLT3 mutations in their most recent assessment
- PHASE I AND II
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2.
- Bilirubin =< 2 x upper limit of normal (ULN).
Alanine aminotransferase (ALT) =< 2.5 x ULN.
- For patients with suspected liver infiltration from leukemia ALT should be =< 5 ULN.
- Creatinine =< 2 x ULN.
- Serum potassium, magnesium, and calcium (normalized for albumin) levels should be at least within institutional normal limits.
- Patients must provide written informed consent.
- Patients must have been off chemotherapy for 2 weeks prior to entering this study, unless there is evidence of rapidly progressive disease, and must have recovered from the toxic effects of that therapy to at least grade 1. Use of hydroxyurea for patients with rapidly proliferative disease is allowed before the start of study therapy and for the first four weeks on therapy. The additional days of hydrea after 28 is permitted as clinically indicated, on case by case basis after discussion with the principal investigator (PI). Other agents given transiently with the intention to control rapid proliferation such as 1-2 doses of single agent ara-C or few doses of sorafenib are also allowed.
- Women of childbearing potential must practice contraception. Women considered not of childbearing potential include any of the following: no menses for at least 2 years or menses within 2 years but amenorrheic for at least 2 months and luteinizing hormone (LH) and follicular stimulating hormone (FSH) values within normal range (according to definition of postmenopausal for laboratory used) or bilateral oophorectomy or radiation castration and amenorrheic for at least 3 months. Females of childbearing potential should practice effective methods of contraception. Effective methods of contraception include barrier methods (e.g., condoms, diaphragm), spermicidal jelly or foam, oral, depo provera, or injectable contraceptives, intrauterine devices, tubal ligation, and abstinence. Male patients with female partners who are of childbearing potential should also practice contraception.
- Negative urine or serum pregnancy test.
Exclusion Criteria:
- Patients with known allergy or hypersensitivity to quizartinib, mannitol, AZA, cytarabine or any of their components.
- Serum potassium < 3.5 mEq/L despite supplementation, or > 5.5 mEq/L.
- Serum magnesium above or below the institutional normal limit despite adequate management.
- Serum calcium (corrected for albumin levels) above or below institutional normal limit despite adequate management.
- Patients with known significant impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of quizartinib.
- Patients with any other known disease concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled diabetes, cardiovascular disease including congestive heart failure, myocardial infarction within 6 months and poorly controlled hypertension, chronic renal disease, or active uncontrolled infection) which could compromise participation in the study. Patients with current active malignancies or any remission for < 6 months, except patients with carcinoma in situ or with non-melanoma skin cancer who may have active disease or be in remission for less than 6 months.
- Patients with a known confirmed diagnosis of human immunodeficiency virus (HIV) infection or active viral hepatitis.
- Patients who have had any major surgical procedure within 14 days of day 1.
- Patients with known malignant disease of the central nervous system.
- Impaired cardiac function including any of the following: screening electrocardiography (ECG) with a corrected QT (QTc) > 450 msec. The QTc interval will be calculated by Fridericia's correction factor (QTcF) at screening and on day 5 prior to the first dose of AC220. The QTcF will be derived from the average QTcF in triplicate; if QTcF > 450 msec on day 5, AC220 will not be given; patients with congenital long QT syndrome; history or presence of sustained ventricular tachycardia requiring medical intervention; any history of clinically significant ventricular fibrillation or torsades de pointes; Known history of second or third degree heart block (may be eligible if the patient currently has a pacemaker); sustained heart rate of < 50/minute on pre-entry ECG; right bundle branch block + left anterior hemiblock (bifascicular block); patients with myocardial infarction or unstable angina within 6 months prior to starting study drug; congestive heart failure (CHF) New York (NY) Heart Association class III or IV. Atrial fibrillation documented within 2 weeks prior to first dose of study drug; patients who require treatment with concomitant drugs that prolong QT/QTc interval or strong CYP3A4 inhibitors or inducers with the exception of antibiotics, antifungals, and antivirals that are used as standard of care to prevent or treat infections and other such drugs that are considered absolutely essential for the care of the subject.
- Known family history of congenital long QT syndrome.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Non-Randomized
- Interventional Model: Parallel Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Phase 1 Arm I (quizartinib, azacitidine)
Patients receive quizartinib PO QD on days 5-28 of cycle 1 and on days 1-28 of subsequent cycles and azacitidine SC or IV over 10-40 minutes on days 1-7.
Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
|
Given SC or IV
Other Names:
Given PO
Other Names:
|
Experimental: Phase 1 Arm II (quizartinib, cytarabine)
Patients receive quizartinib PO QD on days 5-28 of cycle 1 and on days 1-28 of subsequent cycles and cytarabine SC BID on days 1-10.
Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
|
Given PO
Other Names:
Given SC
Other Names:
|
Experimental: Phase 2 Arm I (quizartinib, azacitidine)
Patients receive quizartinib PO QD on days 5-28 of cycle 1 and on days 1-28 of subsequent cycles and azacitidine SC or IV over 10-40 minutes on days 1-7.
Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
|
Given SC or IV
Other Names:
Given PO
Other Names:
|
Experimental: Phase 2 Arm II (quizartinib, cytarabine)
Patients receive quizartinib PO QD on days 5-28 of cycle 1 and on days 1-28 of subsequent cycles and cytarabine SC BID on days 1-10.
Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
|
Given SC
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Maximum Tolerated Dose of Quizartinib (Phase I)
Time Frame: At 28 days
|
At 28 days
|
|
Participants With a Response
Time Frame: At 56 days
|
(complete remission [CR]+complete response with incomplete bone marrow recovery [CRI]+partial remission [PR]+ hematologic improvement [HI]).
Complete Rmission (CR) is bone marrow blasts of </= 5%, platelets >/= 100 and Absolute Neutrophil Count of >/= 1000.
complete response with incomplete bone marrow recovery [CRI] is is bone marrow blasts of </= 5%, platelets >/= 100 or Absolute Neutrophil Count of >/= 1000.
Hematologic improvement [HI]) is Bone Marrow Blasts </= 5%.
Partial remission [PR] is bone marrow blasts of </= 5% with > 50% reduction, platelets >/= 100 and Absolute Neutrophil Count of >/= 1000.
|
At 56 days
|
Secondary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
Incidence of adverse events (Phase II)
Time Frame: Up to 12 months
|
Up to 12 months
|
Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Principal Investigator: Yesid Alvarado, MD, M.D. Anderson Cancer Center
Publications and helpful links
Helpful Links
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimated)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Pathologic Processes
- Neoplasms by Histologic Type
- Neoplasms
- Disease Attributes
- Disease
- Bone Marrow Diseases
- Hematologic Diseases
- Precancerous Conditions
- Myelodysplastic-Myeloproliferative Diseases
- Chronic Disease
- Syndrome
- Myelodysplastic Syndromes
- Leukemia
- Leukemia, Myeloid
- Leukemia, Myeloid, Acute
- Recurrence
- Preleukemia
- Leukemia, Myelomonocytic, Acute
- Leukemia, Myelomonocytic, Chronic
- Leukemia, Myelomonocytic, Juvenile
- Physiological Effects of Drugs
- Molecular Mechanisms of Pharmacological Action
- Anti-Infective Agents
- Antiviral Agents
- Enzyme Inhibitors
- Antimetabolites, Antineoplastic
- Antimetabolites
- Antineoplastic Agents
- Immunosuppressive Agents
- Immunologic Factors
- Azacitidine
- Cytarabine
Other Study ID Numbers
- 2012-1047 (Other Identifier: M D Anderson Cancer Center)
- NCI-2018-01813 (Registry Identifier: CTRP (Clinical Trial Reporting Program))
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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