A Study of Bisantrene Combined With Cytarabine or With Decitabine for Adult Subjects With Extramedullary AML and MDS

NCT05456269 | Withdrawn Phase 1 DMC

• 1 other identifier: RAC-006
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

This is a two strata Phase 1b study to assess the safety and efficacy of bisantrene (RC110) in combination with a) cytarabine arabinoside (Ara-C) treatment for patients with relapsed or refractory (R/R) Acute Myeloid Leukemia (AML) with extramedullary disease and able to tolerate intensive chemotherapy; b) in combination with decitabine/cedazuridune (ASTX727) new or relapsed or refractory AML or high risk MDS or CMML with extramedullary disease and unable or not willing to have intensive chemotherapy.

Conditions

Acute Myeloid Leukemia; Recurrent Acute Myeloid Leukemia; Refractory Acute Myeloid Leukemia; Higher Risk Myelodysplastic Syndrome; Chronic Myelomonocytic Leukemia

Keywords

combination treatment intervention

Outcome Measures

Primary Outcomes (3)

• Stratum 1, Stage 1: Dose confirmation

  Maximum tolerated dose (MTD) based on occurence dose limiting toxicity (DLT) graded according to the National Cancer Institute Common Terminology Criteria (NCI CTCAE) for Adverse Events v5.0 after completion of 2 cycles of treatment

  8 weeks

• Stratum 1 Stage 2: Overall response

  Morphological overall response, defined as complete remission (CR), CR with incomplete hematologic recovery or morphologic leukemia free state (MLFS), after completion of first treatment cycle 1

  4 weeks

• Stratum 2: Safety and tolerabillity

  Assessed based on the occurence of non-hematological Dose limiting toxicity (DLT) as graded according to the National Cancer Institute Common Terminology Criteria (NCI CTCAE) for Adverse Events v5.0 at the completion of cycle 1.

  4 weeks

Secondary Outcomes (15)

• Stratum 1: Minimal Residual Disease (MRD) response

  4 weeks

• Stratum 1: Radiologic response

  4, 8 and 16 weeks

• Stratum 1: Dermal clinical response

  4, 8, 12, and 16 weeks

• Stratum 1: Dermal therapeutic response

  4, 8, 12, and 16 weeks

• Stratum 1: Safety and tolerability

  4, 8, 12 and 16 weeks

Study Arms (2)

Stratum 1

EXPERIMENTAL

Bisantrene infused daily for 7 days of induction cycle 1; followed by bisantrene infusion on Days 1 and 2 and cytarabine arabinoside continuous infusion on Days 1 to 5 of each consolidation cycle for up to 3 cycles. Each cycle is 28 days, with a potential to expand to 42 days to allow for full hematologic recovery.

Drug: Bisantrene Dihydrochloride (high dose); Drug: Cytarabine Hydrochloride

Stratum 2

EXPERIMENTAL

Decitabine/cedazuridine daily on Days 1-5, Bisantrene infusion on Days 3 and 5 in 28 day cycle. Treatment repeats every 28 days up to 12 cycles in the absence of disease progression or unacceptable toxicity. Each has potential to expand to 42 days to allow for full hematologic recovery.

Drug: Bisantrene Dihydrochloride (low dose); Drug: Decitabine and cedazuridine

Interventions

Bisantrene Dihydrochloride (high dose) DRUG

Induction monotherapy cycle: IV bisantrene daily on Days 1 to 7, starting at 250 mg/m2 then adjusted to either 275 mg/m2 or 225 mg/m2 based on confirmed dose (Run-in) Consolidation combination cycle/s: IV bisantrene daily on Days 1 to 2

Also known as: RC110, Zantrene®, Xantrene®

Stratum 1

Bisantrene Dihydrochloride (low dose) DRUG

IV bisantrene at escalating doses for 3 dose levels of 50, 65, 85 mg/m2 on Days 3 and 5 until Maximum tolerated dose (MTD) reached.

Also known as: RC110, Zantrene®, Xantrene®

Stratum 2

Cytarabine Hydrochloride DRUG

Consolidation cycles: continuous IV cytarabine (100mg/m2) on Days 1 to 5

Also known as: Ara-C, Cytarabine arabinoside, Cytosar-U®

Stratum 1

Decitabine and cedazuridine DRUG

PO fixed-dose decitabine/cedazuridine 35/100 mg tablet daily for 5 days (Days 1 to 5), 1 hour prior bisantrene infusion

Also known as: ASTX727

Stratum 2

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• \[Both Stratums\]
• Patients must be able to understand and provide informed written consent.
• Patients must be of age ≥ 18 years at the time of signing the informed consent.
• Extramedullary disease (i.e., AML) by 18F-FDG PET/CT and/or clinical morphology (histopathology of chloroma, leukemia cutis or AML) at pre-screening
• Patients who have undergone stem cell transplantation (SCT), maybe included if they are ≥ 8 weeks from stem cell infusion (autologous or allogeneic), have no active graft versus host disease (GVHD), are off immune suppression for at least 2 weeks, and do not have a history of veno occlusive disease (VOD).
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.0 for intensive Stratum 1 patients and ≤ 3.0 for low intensity treatment Stratum 2 patients.
• Life expectancy estimated to be \> 3 months.
• Adequate organ function as evidenced by serum total bilirubin ≤ 2.0 mg/dL, alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤ 5 × the upper limit of normal (ULN), serum creatinine ≤ 1.5 mg/dL or calculated creatinine clearance of ≥ 60 mL/min.
• Cardiac ejection fraction ≥ 50%, assessed by 2-Dimensional (2D) echocardiogram.
• Females of childbearing potential must have a negative serum pregnancy test at enrolment or 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.
• \[Stratum 1 only\]
• Diagnosis of R/R AML, defined as ≥ 5% blasts in a patient with known prior history of AML according to World Health Organization (WHO) criteria. Patients with AML that have relapsed at least once or are primary induction failure will be eligible.
• \[Stratum 2 only\]
• Patients with diagnosis of de novo AML with EMD, or R/R AML with EMD.
• Patients with MDS or CMML, diagnosed according to the 2016 WHO classification with high-risk disease per the International Prognostic Scoring System (IPSS) of intermediate 2 or higher for both MDS and CMML. Revised IPSS intermediate risk patients can be considered after discussion with the Investigator.

You may not qualify if:

• \[Both Stratums\]
• Acute promyelocytic leukemia (APML) M3 subtype of AML.
• Central nervous system manifestations of AML, unless treated and with no residual manifestations (either by cerebrospinal fluid (CSF) cytology, radiologically or by other clinical assessments) in the last 2 weeks.
• Evidence or recent history of CNS disease, including primary or metastatic brain tumors, seizure disorders unless there is evidence for clearance of CNS leukemia (2 leukemia free CSFs by morphology and /or flow cytometry 1 week apart).
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, cirrhosis, chronic obstructive or restrictive pulmonary disease, symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia.
• Other active malignancy (including other hematologic malignancies) or other malignancy within the last 12 months except non-melanoma skin cancer or cervical intraepithelial neoplasia.
• Major surgery within 4 weeks of treatment.
• Any medical, psychological, or social condition that may interfere with study patient or compliance or may compromise the patient's safety in the opinion of the Investigator.

Sponsors & Collaborators

• Race Oncology Ltd: lead
• Astex Pharmaceuticals, Inc.: collaborator

Study Sites (1)

Calvary Mater

Newcastle, New South Wales, 2298, Australia

Location

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Leukemia, Myelomonocytic, Chronic

Interventions

bisantrene; Cytarabine; Arabinofuranosylcytosine Triphosphate; decitabine and cedazuridine drug combination

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Myelodysplastic-Myeloproliferative Diseases; Bone Marrow Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Cytosine Nucleotides; Pyrimidine Nucleotides; Arabinonucleotides; Nucleotides

Study Officials

• Marinella Messina, PhD

  Clinical Director

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 4, 2022
• First Posted: July 13, 2022
• Study Start: July 29, 2022
• Primary Completion: August 31, 2023
• Study Completion: August 31, 2023
• Last Updated: October 3, 2023

Record last verified: 2023-09

Data Sharing

• IPD Sharing: Will not share

Locations

AU (1)