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

Acute Myeloid Leukemia Clinical Trial

Official title:

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03298984
• Other study ID #: TPI-ALV-101
• Status: Completed
• Phase: Phase 1
• Start date: September 25, 2017
• Est. completion date: March 20, 2020

Study information

• Verified date: November 2023
• Source: Sumitomo Pharma America, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 32
• Est. completion date: March 20, 2020
• Est. primary completion date: March 20, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria:

• To be eligible for participation in the study, patients must meet all of the following inclusion criteria:

1. Be between the ages of =18 and =65 years

2. 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

3. Be newly diagnosed and previously untreated

4. Have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) =2

5. Have a serum creatinine level =1.8 mg/dL

6. Have an alanine aminotransferase (ALT) and aspartate aminotransferase (AST) level =5 times upper limit of normal (ULN)

7. Have a total bilirubin level =2.0 mg/dL (unless secondary to Gilbert syndrome, hemolysis, or leukemia)

8. Have a left ventricular ejection fraction (LVEF) >45% by echocardiogram (ECHO) or multigated acquisition (MUGA) scan

9. 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.

10. Be able to comply with the requirements of the entire study.

11. 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.

1. Received any previous treatment for AML

2. Diagnosed with APL-M3 or CBF-AML

3. 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.

4. Received >200 mg/m2 equivalents of daunorubicin

5. Have a peripheral blast count of >30,000/mm3 (may use hydroxyurea as in #3 above)

6. Have active central nervous system (CNS) leukemia

7. Have evidence of uncontrolled disseminated intravascular coagulation

8. Have an active, uncontrolled infection

9. Have other life-threatening illness

10. Have other active malignancies or diagnosed with other malignancies within the last 6 months, except nonmelanoma skin cancer or cervical intraepithelial neoplasia

11. Have mental deficits and/or psychiatric history that may compromise the ability to give written informed consent or to comply with the study protocol.

12. Are pregnant and/or nursing

Related Conditions & MeSH terms

• Acute Myeloid Leukemia
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute

Intervention

Drug:
• Alvocidib
IV bolus followed by IV infusion
• Cytarabine
continuous infusion
• Daunorubicin
IV bolus

Locations

Country	Name	City	State
United States	Sidney Kimmel Cancer Center at Johns Hopkins	Baltimore	Maryland
United States	University of North Carolina	Chapel Hill	North Carolina
United States	Columbia University	New York	New York

Sponsors (1)

Lead Sponsor	Collaborator
Sumitomo Pharma America, Inc.

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Minimal Residual Disease (MRD) Using Standardized Techniques	Percentage of participants with a CRMRD- response at the end of Cycle 1	During duration of study
Primary	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
Primary	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	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
Secondary	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