A Phase 2, Randomized, Biomarker-Driven, Clinical Study in Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML) with an Exploratory Arm in Patients with Newly Diagnosed High-Risk AML
The goal of the pre-screening part of this clinical research study is to learn if your bone marrow expresses a certain protein called NOXA. This test may show which patients could be more affected by the study drug, alvocidib. The goal of the main part of this study is to learn if adding alvocidib to the combination of cytarabine and mitoxantrone can help to control AML. The safety of the study drug combinations will also be studied.
Disease Group: Leukemia
Treatment Agent: Alvocidib,Cytarabine,Mitoxantrone
Treatment Location: Both at MDACC & and Other Sites
Sponsor: Tolero Pharmaceuticals, Inc
Stage 1: To determine the CR rate in patients with relapsed or refractory AML with NOXA BH3 priming >/= 40%. Stage 2: To compare CR rates between patients with relapsed or refractory AML with NOXA BH3 priming >/=40% receiving 1-2 cycles of Alvocidib/Cytarabine/Mitoxantrone (ACM - previously refered to as FLAM) treatment and those receiving 1-2 cycles of Cytarabine/Mitoxantrone (CM - previously referred to as AM). Exploratory Objective (Stage 2): To determine if treatment with ACM can induce CR in patients with relapsed or refractory AML with NOXA BH3 priming >/=40% who failed to achieve CR following 1-2 cycles of CM. NDHR Exploratory Arm: To determine the CR rate in patients with newly diagnosed high-risk AML with NOXA BH3 priming >/= 40% following 1-2 cycles of ACM treatment. NOXA Exploratory Arm: To determine the CR rate in patients with relapsed or refractory AML with NOXA BH3 priming 30-39% following 1-2 cycles of ACM treatment.
IRB Review and Approval Date: 05/16/2016
Recruitment Status: Open
Projected Accrual: 99
1) During Prescreening: Be between the ages of >/=18 and </=65 years
2) During Prescreening: Have an established, pathologically confirmed diagnoses of AML by World Health Organization (WHO) criteria excluding acute promyelocytic leukemia (APL-M3) with a bone marrow of >5% blasts based on histology or flow cytometry
3) During Prescreening: Be in first relapse (within 24 months of CR) or have primary refractory AML (refractory to initial induction therapy using 1 or 2 cycles of intensive anthracycline/cytarabine +/- etoposide or cladribine induction) or have newly diagnosed high-risk AML as defined in this protocol.
4) During Prescreening: Demonstrate NOXA BH3 priming of >/=40% by mitochondrial profiling in bone marrow or 30-39% for NOXA Exploratory Arm.
5) During Screening: Have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) </=2
6) During Screening: Have a serum creatinine level </=1.8 mg/dL
7) During Screening: Have an alanine aminotransferase (ALT)/aspartate aminotransferase (AST) level </=5 times upper limit of normal (ULN)
8) During Screening: Have a total bilirubin level </=2.0 mg/dL (unless secondary to Gilbert syndrome, hemolysis, or leukemia)
9) During Screening: Have a left ventricular ejection fraction (LVEF) >45% by echocardiogram (ECHO) or multigated acquisition (MUGA) scan
10) During Screening: Be nonfertile or agree to use an adequate method of contraception. Sexually active patients and their partners must use an effective method of contraception associated with a low failure rate during and for 6 months after completion of study therapy
11) During Screening: Be able to comply with the requirements of the entire study.
12) During Screening: Provide written informed consent prior to any study related procedure. (In the event that the patient is re-screened for study participation or a protocol amendment alters the care of an ongoing patient, a new informed consent form must be signed.)
1) Received more than 2 cycles of induction therapy for AML.
Investigational agents as part of front-line therapy for AML may by
acceptable following discussion with the Medical Monitor. Hydroxyurea is
permitted (see #5 below).
2) Received any previous treatment with alvocidib or any other CDK inhibitor
3) Received a hematopoietic stem cell transplant within the previous 2 months
4) Have clinically significant graft versus host disease (GVHD), or GVHD requiring initiation or escalation of treatment within the last 21 days
5) Require concomitant chemotherapy, radiation therapy, or immunotherapy. Hydroxyurea is allowed up to the evening before starting (but not within 12 hours) of starting treatment on either arm.
6) Received >360 mg/m(2) equivalents of daunorubicin
7) Have a peripheral blast count of >30,000/mm(3) (may use hydroxyurea as in #5 above)
8) Received antileukemic therapy within the last 3 weeks (with the exception of hydroxyurea or if the patient has definite refractory disease). Refractory patients who received therapy within the last 3 weeks may be eligible with prior approval of the Medical Monitor.
9) Received active immunosuppressive therapy for GVHD within 2 weeks before randomization
10) Diagnosed with acute promyelocytic leukemia (APL, M3)
11) Have active central nervous system (CNS) leukemia
12) Have evidence of uncontrolled disseminated intravascular coagulation
13) Have an active, uncontrolled infection
14) Have other life-threatening illness
15) Have other active malignancies or diagnosed with other malignancies within the last 6 months, except nonmelanoma skin cancer or cervical intraepithelial neoplasia
16) Have mental deficits and/or psychiatric history that may compromise the ability to give written informed consent or to comply with the study protocol.
17) Are pregnant and/or nursing
Information and next steps
For general questions about clinical trials: