Bisantrene Combination for Resistant AML

An Open-label, Phase II, Two-stage, Study of Bisantrene(Xantrene) in Combination With Fludarabine and Clofarabine as Salvage Therapy for Adult Patients With Relapsed or Refractory Acute Myeloid Leukemia (AML)

An Open-label, Phase II, Two-stage, Study of Xantrene® (Bisantrene) in combination with Fludarabine and Clofarabine as Salvage Therapy for Adult Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML) Lead-in stage: up to 12 (up to 2 cohorts in a 3+3 dose escalation design) Efficacy stage: up to 17 (Simon 2-stage design 9+8)

Study Objectives:

• Confirm safety and tolerability of the combination regimen
• Time to response with combination treatment
• Overall survival

The treatment regimen will comprise daily IV infusion of Fludarabine (Flu), Clofarabine (Clo) and Bisantrene (Xan) administered via central venous line and controlled-rate infusion pump with a 1-hour break between each agent infusion, amounting to a total of 6 hours for each daily FluCloXan treatment in the following sequence:

• First, infusion over 60 minutes of Fludarabine (Flu) at 10 mg/m2
• Followed by infusion of Clofarabine (Clo) at 30 mg/m2 over 60 minutes
• Followed by infusion of Bisantrene (Xan) at 250 mg/m2 over 2 hours. One cycle will comprise daily IV infusion of the combination treatment course for 4 or 5 consecutive days and rest period to between Day 30 and Day 42, based on patient performance and disease status.

Study Overview

• Status: Recruiting
• Conditions: Myelogenous Leukemia, Acute
• Intervention / Treatment: Drug: Bisantrene; Drug: Fludarabine; Drug: Clofarabine

• Study Type: Interventional
• Enrollment (Estimated): 29
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Arnon Nagler, MD; Phone Number: 972-3-530-58-30; Email: Arnon.Nagler@sheba.health.gov.il

Study Locations

• Israel
  • Ramat Gan, Israel, 57261
    • Recruiting
    • Chaim Sheba Medical Center
    • Contact: Arnon Nagler, M.D.; Phone Number: +97235305830; Email: Arnon.Nagler@sheba.health.gov.il
    • Contact: M.D.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written Informed Consent and privacy language as per national regulations.
2. Age 18 -65 (inclusive) years
3. Diagnosis of AML by World Health Organization (WHO) classification (WHO, 2016) and have received at least one line of therapy prior to enrollment into this study.
4. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.0
5. Life expectancy ≥ 3 months.
6. Adequate organ function as evidenced by serum total bilirubin ≤ 2.0 mg/dL, alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤4 × the upper limit of normal (ULN), serum albumin >2.8 g/dL, serum creatinine ≤2 mg/dL.
7. Cardiac ejection fraction ≥50%, assessed by 2-Dimensional echocardiogram.
8. Pulmonary function ≥50% assessed by diffusing capacity for carbon monoxide (DLCO), and any clinically significant decrease in DLCO must not be caused by infection.
9. Negative for serum markers for HIV, Hepatitis -B, -C, and HTLV-1
10. Clinically significant non-hematologic toxicity after prior chemotherapy has recovered to Grade 1 per Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
11. Females must be surgically or biologically sterile or postmenopausal (amenorrhoeic for at least 12 months) or if of childbearing potential, must have a negative urine or serum pregnancy test within 14 days before study entry, and must agree to use an adequate method of contraception, i.e. barrier method, during the study until 30 days after the last treatment. Males must be surgically or biologically sterile or agree to use an adequate method of contraception, i.e. barrier method, during the study until 30 days after the last treatment.

Exclusion Criteria:

1. Acute promyelocytic leukemia (APML, APL) M3 subtype of AML.
2. Other active malignancy (including other hematologic malignancies) or other malignancy within the last 12 months except non-melanoma skin cancer or cervical intraepithelial neoplasia.

3. Prior or current therapy:

   1. Hydroxyurea or other oral medications to reduce blast count within 72 hours before the first dose of study drug
   2. Treatment with an investigational agent within 14 days before the first dose of study drug, or not recovered from all acute effects of previous investigational therapy
   3. Last treatment was with a drug of long elimination half-life (e.g. enasidenib), as such a wash out period 5x elimination half-life is necessary prior to enrollment
4. For patients who have undergone hematopoietic stem cell transplantation (HSCT), procedure-related medications (e.g. immunosuppressive therapy) administered within 2 weeks prior to first dose of study drug.
5. Any medical, psychological, or social condition that may interfere with study participation or compliance or may compromise the patient's safety in the opinion of the investigator.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Bisantrene combined with Fludarabine and Clofarabine; Bisantrene 250 mg at final concentration of 0.5 mg/mL will be administrated by intravenous (IV) infusion, delivered by a controlled-rate programmable pump via a central line over 2 hours. Fludarabine (generic) and Clofarabine (generic) are commercially available as injection for intravenous infusion. The treatment regimen will comprise daily IV infusion of Fludarabine (Flu), Clofarabine (Clo) and Bisantrene (Xan) administered via central venous line and controlled-rate infusion pump with a 1-hour break between each agent infusion, amounting to a total of 6 hours for each daily FluCloXan treatment in the following sequence: First, infusion over 60 minutes of Fludarabine (Flu) at 10 mg/m2; Followed by infusion of Clofarabine (Clo) at 30 mg/m2 over 60 minutes; Followed by infusion of Bisantrene (Xan) at 250 mg/m2 over 2 hours.

Drug: Bisantrene; Combined escalated dose chemotherapy; Drug: Fludarabine; Combined escalated dose chemotherapy; Drug: Clofarabine; Combined escalated dose chemotherapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The recommended Phase 2 dose (RP2D) , assessed by the number of treatment days of FluCloXan		12 months
The maximum tolerated dose (MTD) of Bisantre in mg per day	To evaluate safety and tolerability	12 months
The overall response rate (ORR)	Overall Response Rate (ORR) defined as the proportion of patients with complete remission (CR) and complete remission with incomplete blood count recovery (CRi) between Day 30 to Day 42.	between Day 30 to Day 42.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants with treatment-related adverse events as assessed by CTCAE v4.0.	Confirm safety and tolerability of the combination regimen.	12 months
Time of respons in months	Number of months for each patient with no evidence of diseases.	12 months
Overall survival	Median surviving months for each patients.	12 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
MRD status	To determine the MRD status of patients post completion of FluCloXan. MRD will be asset in patients with defiant mutations by Polymerase Chain Techniques(PCR).	12 months

Collaborators and Investigators

• Sponsor: Sheba Medical Center
• Collaborators: Race Oncology Ltd
• Investigators: Principal Investigator: Arnon Nagler, MD, Sheba Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): August 2, 2021
• Primary Completion (Estimated): December 1, 2024
• Study Completion (Estimated): December 1, 2025

Study Registration Dates

• First Submitted: July 7, 2021
• First Submitted That Met QC Criteria: August 3, 2021
• First Posted (Actual): August 4, 2021

Study Record Updates

• Last Update Posted (Actual): November 28, 2023
• Last Update Submitted That Met QC Criteria: November 27, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: AML, Resistance relapsing ,Anti Leukemic effect , Bisantrene
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Antibiotics, Antineoplastic; Clofarabine; Fludarabine; Bisantrene
• Other Study ID Numbers: RAC-002

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No