Clinical trial NCT05456269: A Study of Bisantrene Combined With Cytarabine or With Decitabine for Adult Subjects With Extramedullary AML and MDS
Official title: An Open-label Two Strata Study of Bisantrene in Combination With Cytarabine Arabinoside or Bisantrene in Combination With Oral Decitabine/Cedazuridine for the Treatment of Acute Myeloid Leukemia Patients With Extramedullary Disease
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE1
Conditions: Acute Myeloid Leukemia
Recurrent Acute Myeloid Leukemia
Refractory Acute Myeloid Leukemia
Higher Risk Myelodysplastic Syndrome
Chronic Myelomonocytic Leukemia
Keywords: combination treatment intervention
Lead sponsor: Race Oncology Ltd
Sponsor class: INDUSTRY
Collaborators: name: Astex Pharmaceuticals, Inc.
First posted: 2022-07-13
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.

Detailed description: The study is a multicenter, open label in patients with haematological malignancy / myeloproliferative disease (AML, MDS and CMML) and extramedullary disease (EMD) investigating 2 treatment regimens:

1. Stratum 1 will investigate use of high dose intravenous (IV) bisantrene (RC110) in combination with IV Ara-C for R/R AML with EMD able to tolerate intensive chemotherapy. This includes a run-in stage to confirm the dose of bisantrene (RC110) for induction and in combination with Ara-C for consolidation cycles and an expansion and an expansion stage that will treat additional patients at the confirmed bisantrene dose for induction and in combination with Ara-C consolidation cycles;
2. Stratum 2 will investigate use lower doses intravenous (IV) bisantrene (RC-110) in combination with fixed-dose oral decitabine/cedazuridine (ASTX727) to determine the maximum tolerated dose (MTD) for new or R/R AML and HR-MDS/CMML unable to tolerate intensive chemotherapy.

Pre-screening will be conducted to identify patients with EMD diagnosed by standard clinical practice including histology and by fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography (18F FDG-PET/CT) imaging.

Eligibility criteria: Inclusion Criteria:

\[Both Stratums\]

1. Patients must be able to understand and provide informed written consent.
2. Patients must be of age ≥ 18 years at the time of signing the informed consent.
3. Extramedullary disease (i.e., AML) by 18F-FDG PET/CT and/or clinical morphology (histopathology of chloroma, leukemia cutis or AML) at pre-screening
4. 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).
5. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.0 for intensive Stratum 1 patients and ≤ 3.0 for low intensity treatment Stratum 2 patients.
6. Life expectancy estimated to be \> 3 months.
7. 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.
8. Cardiac ejection fraction ≥ 50%, assessed by 2-Dimensional (2D) echocardiogram.
9. 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.

   \[Stratum 1 only\]
10. 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.

    \[Stratum 2 only\]
11. Patients with diagnosis of de novo AML with EMD, or R/R AML with EMD.
12. 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.

Exclusion Criteria:

\[Both Stratums\]

1. Acute promyelocytic leukemia (APML) M3 subtype of AML.
2. 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.
3. 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).
4. 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.
5. Other active malignancy (including other hematologic malignancies) or other malignancy within the last 12 months except non-melanoma skin cancer or cervical intraepithelial neoplasia.
6. Major surgery within 4 weeks of treatment.
7. 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.

Primary outcomes:
measure: Stratum 1, Stage 1: Dose confirmation
timeFrame: 8 weeks
measure: Stratum 1 Stage 2: Overall response
timeFrame: 4 weeks
measure: Stratum 2: Safety and tolerabillity
timeFrame: 4 weeks
Secondary outcomes:
measure: Stratum 1: Minimal Residual Disease (MRD) response
timeFrame: 4 weeks
measure: Stratum 1: Radiologic response
timeFrame: 4, 8 and 16 weeks
measure: Stratum 1: Dermal clinical response
timeFrame: 4, 8, 12, and 16 weeks
measure: Stratum 1: Dermal therapeutic response
timeFrame: 4, 8, 12, and 16 weeks
measure: Stratum 1: Safety and tolerability
timeFrame: 4, 8, 12 and 16 weeks
measure: Stratum 1: Number of participants that recieve subsequent allogeneic hematopoietic stem cell transplant
timeFrame: 5 years
measure: Stratum 1:Event free survival (EFS)
timeFrame: Day 1 (treatment start) to 5 years
measure: Stratum 1: Overall Survival (OS)
timeFrame: Day 1 (treatment start) to 5 years
measure: Stratum 2: Overall response
timeFrame: 4 weeks
measure: Stratum 2: Minimal Residual Disease (MRD) response
timeFrame: 16 weeks
measure: Stratum 2: Radiologic response
timeFrame: 16, 36 and 48 weeks
measure: Stratum 2: Dermal clinical response
timeFrame: 4, 24, 36 and 48 weeks
measure: Stratum 2: Dermal therapeutic response
timeFrame: 4, 24, 36 and 48 weeks
measure: Stratum 2: Event free survival (EFS)
timeFrame: Day 1 (treatment start) up to 5 years
measure: Stratum 2: Overall survival (OS)
timeFrame: Day 1 (treatment start) to 5 years
Other outcomes:
Locations:
city: Newcastle
country: Australia
facility: Calvary Mater
state: New South Wales
Study officials:
affiliation: Clinical Director
name: Marinella Messina, PhD
role: STUDY_DIRECTOR
References: