Alvocidib Biomarker-driven Phase 2 AML Study

Acute Myeloid Leukemia Clinical Trial

Official title:

Phase 2, Randomized, Biomarker-driven Clinical Study in Patients With Relapsed or Refractory Acute Myeloid Leukemia (AML) With MCL-1 Dependence ≥30%

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02520011
• Other study ID #: TPI-ALV-201
• Status: Terminated
• Phase: Phase 2
• Start date: March 14, 2016
• Est. completion date: February 12, 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 two-stage Phase 2 study is to assess the clinical response (Complete Remission) of ACM (Alvocidib/Cytarabine/Mitoxantrone) compared to CM (Cytarabine/Mitoxantrone) treatment in refractory or relapsed AML patients with demonstrated MCL-1 dependence of ≥ 30% by mitochondrial profiling in bone marrow.

Description:

In Stage 1 of the study, all eligible AML patients with demonstrated MCL-1 dependence of ≥ 30% by mitochondrial profiling in bone marrow will receive treatment with ACM.

In Stage 2, all eligible AML patients with demonstrated MCL-1 dependence of ≥ 30% by mitochondrial profiling in bone marrow will be randomized 1:1 to receive either treatment with ACM or CM.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 104
• Est. completion date: February 12, 2020
• Est. primary completion date: February 12, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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 excluding acute promyelocytic leukemia (APL-M3) with a bone marrow of >5% blasts based on histology or flow cytometry

3. Be in first relapse (within 24 months of CR) or have failed induction therapy* (no CR or CRi after treatment with an intensive regimen (eg, anthracycline/cytarabine ± etoposide, gemtuzumab ozogamicin, or cladribine).

*Induction therapy may involve 1 or 2 cycles of the same regimen. Efficacy assessment of induction therapy must be >21 days from the start of the previous induction cycle.

4. Demonstrate MCL-1 dependence of =30% by mitochondrial profiling in bone marrow.

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

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

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

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

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

10. 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 at least 6 months after completion of study therapy.

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

12. Provide written informed consent prior to any study related procedure.

Exclusion Criteria:

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/m2 equivalents of daunorubicin

7. Have a peripheral blast count of >30,000/mm3 (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. Diagnosed with acute promyelocytic leukemia (APL, M3)

10. Have active central nervous system (CNS) leukemia

11. Have evidence of uncontrolled disseminated intravascular coagulation

12. Have an active, uncontrolled infection

13. Have other life-threatening illness

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

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

16. Are pregnant and/or nursing

17. Have received any live vaccine within 14 days prior to first study drug administration.

Related Conditions & MeSH terms

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

Intervention

Drug:
• Alvocidib

• Cytarabine

• Mitoxantrone

Locations

Country	Name	City	State
Canada	Princess Margaret Cancer Center	Toronto	Ontario
Spain	Complejo Hospitalario Universitario de Albacete	Albacete
Spain	Institut Catala d'Oncologia	Badalona
Spain	Hospital Clinic de Barcelona	Barcelona
Spain	Hospital San Pedro de Alcantara	Cáceres
Spain	Hospital Regional Universitario de Malaga	Málaga	Malaga
Spain	Hospital Universitario Central de Asturias - HUCA	Oviedo
Spain	Hospital Clinico Universitario de Salamanca	Salamanca
Spain	Hospital Universitari i Politècnic La Fe	Valencia
United Kingdom	Univ Hospital of Bristol	Bristol
United Kingdom	University Hospitals of Wales	Cardiff	Wales
United Kingdom	Guys Hospital St. Thomas	London
United States	University of Michigan	Ann Arbor	Michigan
United States	Northside Hospital	Atlanta	Georgia
United States	Sidney Kimmel Cancer Center at Johns Hopkins	Baltimore	Maryland
United States	Roswell Park Cancer Center Institute	Buffalo	New York
United States	University of North Carolina	Chapel Hill	North Carolina
United States	Northwestern Memorial Hospital	Chicago	Illinois
United States	Cleveland Clinic Foundation	Cleveland	Ohio
United States	Ohio State University	Columbus	Ohio
United States	Baylor Sammons Cancer Center	Dallas	Texas
United States	Duke	Durham	North Carolina
United States	East Carolina University	Greenville	North Carolina
United States	Hudson Valley Cancer Center	Hawthorne	New York
United States	MD Anderson Cancer Center	Houston	Texas
United States	University of Iowa	Iowa City	Iowa
United States	Mayo Clinic Florida	Jacksonville	Florida
United States	University of California Los Angeles (UCLA)	Los Angeles	California
United States	Medical College of Wisconsin	Milwaukee	Wisconsin
United States	Morristown Cancer Center	Morristown	New Jersey
United States	Ochsner Clinic Foundation	New Orleans	Louisiana
United States	Columbia University Medical Center	New York	New York
United States	University of Nebraska Medical Center	Omaha	Nebraska
United States	West Penn Allegheny Hospital	Pittsburgh	Pennsylvania
United States	Mayo Clinic Rochester	Rochester	Minnesota
United States	University of California San Diego UCSD	San Diego	California
United States	Honor Health Research Institute	Scottsdale	Arizona
United States	University of Kansas Medical Center	Westwood	Kansas

Sponsors (1)

Lead Sponsor	Collaborator
Sumitomo Pharma America, Inc.

Countries where clinical trial is conducted

United States,  Canada,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Response to Treatment	To determine if treatment with ACM can induce CR in patients with relapsed or refractory AML with MCL-1 dependence of >30% who failed to achieve CR following 1 cycle of CM	Best response after at least 1 cycle through study completion approximately 4 years
Primary	Complete Response (CR) Rate in Patients With Relapsed or Refractory AML	Complete Remission (CR) rate = Percentage of patients achieving CR after Cycle 1 as defined in Stage 1 by the International Working Group (IWG) Criteria and 2010 European LeukemiaNet (EN) criteria in patients with relapsed or refractory AML with MCL-1 dependence >30% and in Stage 2 by the 2017 ELN criteria.; The study was terminated in January 2020 due to a steady and marked reduction in enrollment. Thus, the efficacy endpoints could not be analyzed. As sufficient efficacy results were not available to analyze patients based on the percentage of MCL-1 dependency the treatment efficacy was summarized by distributing the safety population into 6 groups based on whether the patients received the ACM vs CM regimen and their disease stages at study entry.	Best response after at least 1 cycle through study completion approximately 4 years