Ph I Study of Alvocidib and Cytarabine/Daunorubicin (7+3) in Patients With Newly Diagnosed Acute Myeloid Leukemia (AML).

Study Overview
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Brief Summary
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The purpose of this Phase I study is to determine the safety and tolerability including the maximum dose (MTD) and dose-limiting toxicities (DLTs) of alvocidib when administered over a range of doses on Days 1-3 followed by cytarabine/daunorubicin (7+3) on Days 5-11 in adults with newly diagnosed and previously untreated AML

Detailed Description
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Primary Objective: • To determine the safety and tolerability including the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of alvocidib when administered over a range of doses on Days 1-3 followed by cytarabine/daunorubicin (7+3) on Days 5-11 in adults with newly diagnosed and previously untreated AML Secondary Objectives: To observe patients for any evidence of antileukemic activity of alvocidib plus 7+3 using the 2017 ELN response criteria To establish the Recommended Phase 2 Dose (RP2D) for future studies with alvocidib in combination with 7+3 Exploratory Objective: • To assess levels of minimal residual disease (MRD) using standardized techniques (ie, multiparametric flow cytometry [MPFC] and next generation sequencing [NGS] and evaluate other potential biomarkers including, but not limited to, MCL-1 dependency.

Official Title
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A Phase 1, Open-label, Dose-escalation, Safety and Biomarker Prediction of Alvocidib and Cytarabine/Daunorubicin (7+3) in Patients With Newly Diagnosed Acute Myeloid Leukemia (AML)

Conditions
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Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: Alvocidib
* Drug: Cytarabine
* Drug: Daunorubicin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: To be eligible for participation in the study, patients must meet all of the following inclusion criteria: Be between the ages of ≥18 and ≤65 years Have an established, pathologically confirmed diagnoses of AML by World Health Organization (WHO) criteria with ≥20% bone marrow blasts based on histology or flow cytometry Be newly diagnosed and previously untreated Have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤2 Have a serum creatinine level ≤1.8 mg/dL Have an alanine aminotransferase (ALT) and aspartate aminotransferase (AST) level ≤5 times upper limit of normal (ULN) Have a total bilirubin level ≤2.0 mg/dL (unless secondary to Gilbert syndrome, hemolysis, or leukemia) Have a left ventricular ejection fraction (LVEF) >45% by echocardiogram (ECHO) or multigated acquisition (MUGA) scan 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 prior to study entry, for the duration of study participation, and for at least 6 months after the last dose of study drug. Be able to comply with the requirements of the entire study. 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.) Exclusion Criteria: Patients meeting any one of these exclusion criteria will be prohibited from participating in this study. Received any previous treatment for AML Diagnosed with APL-M3 or CBF-AML Require concomitant chemotherapy, radiation therapy, or immunotherapy. Hydroxyurea is allowed up to the evening before starting (but not within 12 hours) of starting Induction therapy. Received >200 mg/m2 equivalents of daunorubicin Have a peripheral blast count of >30,000/mm3 (may use hydroxyurea as in #3 above) Have active central nervous system (CNS) leukemia Have evidence of uncontrolled disseminated intravascular coagulation Have an active, uncontrolled infection Have other life-threatening illness Have other active malignancies or diagnosed with other malignancies within the last 6 months, except nonmelanoma skin cancer or cervical intraepithelial neoplasia Have mental deficits and/or psychiatric history that may compromise the ability to give written informed consent or to comply with the study protocol. Are pregnant and/or nursing

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Alvocidib and Cytarabine/Daunorubicin<br>The starting dose of alvocidib will be 20 mg/m2 as a 30-minute intravenous (IV) bolus followed by 30 mg/m2 over 4 hours as an IV infusion administered daily on Days 1-3 of Induction. Patients will have a one day drug holiday (Day 4) before initiation of the 7+3 regimen. Beginning on Day 5, cytarabine will be administered as a 100 mg/m2/day continuous IV infusion for seven consecutive days (Days 5-11) plus daunorubicin administered at a dosage of 60 mg/m2 IV on Days 5-7. | Drug: Alvocidib<br>* IV bolus followed by IV infusion<br>Drug: Cytarabine<br>* continuous infusion<br>Drug: Daunorubicin<br>* IV bolus<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) of Alvocidib | Determine the safety and tolerability including the maximum tolerated dose (MTD) of alvocidib when administered over a range of doses on Days 1-3 followed by Ara-c/daunorubicin (7+3) on Days 5-11 in adults with newly diagnosed and previously untreated AML | During the first cycle | 
| Number of Participants Who Experienced Dose Limiting Toxicities (DLTs) of Alvocidib | Determine the safety and tolerability including dose-limiting toxicities (DLTs) of alvocidib when administered over a range of doses on Days 1-3 followed by Ara-c/daunorubicin (7+3) on Days 5-11 in adults with newly diagnosed and previously untreated AML | During the first cycle | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Antileukemic Activity of Alvocidib Plus 7+3 - Response to Treatment Based on 2017 ELN Response Criteria | CR: Measurable residual disease is positive or unknown; BM blasts (bls) <5%; no circulating bls and bls w/ Auer rods; no extramedullary disease; ANC >1.0 x 109/L; platelets >100 x 109/L. CRMRD-: CR w/ negativity genetic marker. CRi: CR except residual neutropenia or thrombocytopenia. MLFS: BM bls <5%; no bls with Auer rods; no extramedullary disease; no hematologic recovery required. PR: all hematologic CR criteria; decrease (dec) BM bls % to 5-25%; dec pretreatment BM bls % by >50%. SD: no CRMRD-/CR/CRi/PR/MLFS; PD criteria not met. PD: increase (inc) BM bls % and/or inc absolute bls in blood: 50% inc BM bls over baseline (>15% point inc required in cases w/ <30% bls at baseline or persistent BM bls % of >70% over at least 3 months; without at least 100% improvement in ANC to absolute level [>0.5 x 109/L and/or platelet count to >50 x 109/L non-transfused); or >50% inc in peripheral bls to >25 x 109/L (in the absence of differentiation syndrome); or new extramedullary disease. | Best response during duration of study | 
| Recommended Phase 2 Dose (RP2D) of Alvocidib in Combination With 7+3 | The dose at which < 1 of 6 patients experience a DLT during Cycle 1 with the next higher dose having at least 2 of 3 to 6 patients experiencing a DLT during Cycle 1 | During Cycle 1 beginning at 1st dose of study drug through Day 50 + or - 3 days |