Study to investigate oral Asciminib compared to selected tyrosine kinase inhibitors (TKI) in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) with Philadelphia chromosome

Australia, Austria, Belgium, Bulgaria, Canada, China, Czechia, Denmark, Finland, France, Germany, Hungary, India, Israel, Italy, Japan, Malaysia, Netherlands, Norway, Portugal, Russia, Singapore, Slovakia, South Korea, Spain, Sweden, Switzerland, Taiwan, United Kingdom, United States (ICTRP)

ICTRP Trial ID
NCT04971226 (ICTRP)

Official title (approved by ethics committee)
A phase III, multi-center, open-label, randomized study of oral Asciminib versus Investigator selected TKI in patients with newly diagnosed Philadelphia Chromosome Positive Chronic Myelogenous Leukemia in Chronic Phase - ASC4First (BASEC)

Academic title
A Phase III, Multi-center, Open-label, Randomized Study of Oral Asciminib Versus Investigator Selected TKI in Patients With Newly Diagnosed Philadelphia Chromosome Positive Chronic Myelogenous Leukemia in Chronic Phase (ICTRP)

Public title
A Study of Oral Asciminib Versus Other TKIs in Adult Patients With Newly Diagnosed Ph+ CML-CP (ICTRP)

Disease under investigation
Chronic Myeloid Leukemia (CML) Philadelphia Chromosome Positive (ICTRP)

Intervention under investigation
Drug: ImatinibDrug: NilotinibDrug: BosutinibDrug: DasatinibDrug: Asciminib (ICTRP)

Type of trial
Interventional (ICTRP)

Trial design
Allocation: Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: None (Open Label). (ICTRP)

Inclusion/Exclusion criteria
Inclusion Criteria for treatment period:

Participants eligible for inclusion in this study must meet all of the following
criteria:

- Male or female patients = 18 years of age.

- Participants with CML-CP within 3 months of diagnosis.

- Diagnosis of CML-CP (ELN 2020 criteria) with cytogenetic confirmation of
Philadelphia chromosome

Documented chronic phase CML will meet all the below criteria (Hochhaus et al 2020):

- < 15% blasts in peripheral blood and bone marrow,

- < 30% blasts plus promyelocytes in peripheral blood and bone marrow,

- < 20% basophils in the peripheral blood,

- Platelet count = 100 x 10^9/L (= 100,000/mm^3),

- No evidence of extramedullary leukemic involvement, with the exception of
hepatosplenomegaly.

- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

- Adequate end organ function as defined by:

- Total bilirubin < 3 x ULN patients with Gilbert's syndrome may only be included if
total bilirubin = 3.0 x ULN or direct bilirubin = 1.5 x ULN

- Creatinine clearance (CrCl) = 30 mL/min as calculated using Cockcroft-Gault formula,

- Serum lipase = 1.5 x ULN. For serum lipase > ULN - = 1.5 x ULN, value must be
considered not clinically significant and not associated with risk factors for acute
pancreatitis

- Participants must have the following laboratory values within normal limits or
corrected to within normal limits with supplements prior to randomization:

- Potassium (potassium increase of up to 6.0 mmol/L is acceptable if associated with
CrCl* = 90 mL/min)

- Total calcium (corrected for serum albumin) (calcium increase of up to 12.5 mg/dl
or 3.1 mmol/L is acceptable if associated with CrCl* = 90 mL/min)

- Magnesium (magnesium increase of up to 3.0 mg/dL or 1.23 mmol/L if associated with
CrCl* = 90 mL/min)

- For patients with mild to moderate renal impairment (CrCl* = 30 mL/min and <90
mL/min) - potassium, total calcium (corrected for serum albumin) and magnesium
should be = LLN or corrected to within normal limits with supplements prior to
randomization.

- *CrCl as calculated using Cockcroft-Gault formula

- Ability to provide written informed consent prior to any study related
screening procedures being performed.

- Evidence of typical BCR-ABL1 transcript [e14a2 and/or e13a2] at the time of
screening which is amenable to standardized Real time quantitative polymerase
chain reaction (RQ-PCR) quantification.

Exclusion Criteria for Treatment period:

- Previous treatment of CML with any other anticancer agents including chemotherapy
and/or biologic agents or prior stem cell transplant, with the exception of
hydroxyurea and/or anagrelide. Treatment with either imatinib, or nilotinib, or
dasatinib or bosutinib for =2 weeks is allowed, but no other treatment with other
tyrosine kinase inhibitors prior to randomization is permitted.

- Known cytopathologically confirmed CNS infiltration (in absence of suspicion of CNS
involvement, lumbar puncture not required).

- Impaired cardiac function or cardiac repolarization abnormality including but not
limited to any one of the following:

- History within 6 months prior to starting study treatment of myocardial
infarction (MI), angina pectoris, coronary artery bypass graft (CABG)

- Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia),
complete left bundle branch block, high-grade AV block (e.g., bifascicular
block, Mobitz type II and third degree AV block)

- QTc = 450 ms (male patients), =460 ms (female patients) on the average of three
serial baseline ECG (using the QTcF formula) as determined by central reading.
If QTcF = 450 ms and electrolytes are not within normal ranges, electrolytes
should be corrected and then the patient re-screened for QTc.

- Long QT syndrome, family history of idiopathic sudden death or congenital long
QT syndrome, or any of the following:

- Risk factors for Torsades de Pointes (TdP) including uncorrected hypokalemia or
hypomagnesemia, history of cardiac failure, or history of clinically
significant/symptomatic bradycardia

- Concomitant medication(s) with a "Known risk of Torsades de Pointes" per
www.crediblemeds.org/ that cannot be discontinued or replaced 7 days prior to
starting study drug by safe alternative medication.Inability to determine the
QTcF interval

- Severe and/or uncontrolled concurrent medical disease that in the opinion of the
investigator could cause unacceptable safety risks or compromise compliance with the
protocol (e.g. uncontrolled diabetes, active or uncontrolled infection uncontrolled
arterial or pulmonary hypertension, uncontrolled clinically significant
hyperlipidemia). Please refer to Section 6.3.1

- History of significant congenital or acquired bleeding disorder unrelated to cancer.

- Major surgery within 4 weeks prior to study entry or who have not recovered from
prior surgery.

- History of other active malignancy within 3 years prior to study entry with the
exception of previous or concomitant basal cell skin cancer and previous carcinoma
in situ treated curatively

- History of acute pancreatitis within 1 year prior to randomization or medical
history of chronic pancreatitis.

- History of chronic liver disease leading to severe hepatic impairment, or ongoing
acute liver disease.

- Known hypersensitivity to the study treatment

Other protocol-defined Inclusion/exclusion criteria will apply.

Inclusion Criteria for optional TFR period:

Participants meeting the following additional criteria are not eligible to enter the TRI
Period:

- Willingness and ability to comply with scheduled visits, treatment plans, laboratory
tests and other study procedures

- A minimum of 5 years of study treatment up to maximum of 6 years of study treatment
(i.e. participants are eligible to enter TFR any time between year 5 and year 6 of
their study treatment

- Sustained MR 4.0 (BCR::ABL1 IS =0.01%) or better, assessed by central laboratory for
at least 2 years (equivalent to 104 weeks) which includes MR 4.5 (BCR::ABL1 IS
=0.0032%) for at least 1 year (equivalent to 52 weeks) immediately prior to entry
into the TFR Period, with the 5 last consecutive RQ-PCR (every 12 weeks) assessments
at/or below MR 4.5. Entry into TFR Period should be no later than 12 weeks from the
last MR 4.5 RQ-PCR assessment

- Separate signed informed consent must be obtained prior to participation in the TFR
Period

Exclusion Criteria for optional TFR period:

- Participants meeting the following additional criterion are not eligible for the
inclusion in the optional TFR Period:

- Participants in the treatment re-initiation (TRI) Period cannot re-enter TFR for a
second TFR attempt

Exclusion Criteria for Treatment Re-initiation (TRI) Period

Participants meeting the following additional criterion are not eligible to enter the TRI
Period:

- In case of (ICTRP)

not available

Primary and secondary end points
Percentage of Participants With Major Molecular Response (MMR) at Week 48 - Ascimimib vs. Investigator Selected TKI;Percentage of Participants With Major Molecular Response (MMR) at Week 48 - Asciminib (Imatinib Stratum) vs Investigator Selected TKI (Imatinib Stratum) (ICTRP)

Major Molecular Response at Week 96;Time to Discontinuation of Study Treatment Due to Adverse Events (TTDAE);Major Molecular Response at Scheduled Data Collection Time Points;Major Molecular Response by Scheduled Data Collection Time Points;MR4.0 at Scheduled Data Collection Time Points;MR4.5 at All Scheduled Data Collection Time Points;MR4.0 by Scheduled Data Collection Time Points;MR4.5 by All Scheduled Data Collection Time Points;Complete Hematological Response (CHR) at All Scheduled Data Collection Time Points;Complete Hematological Response (CHR) by All Scheduled Data Collection Time Points;Percentage of Participants With Complete Cytogenic Response (CCyR) by Week 48 & Week 96;Duration of MMR;Duration of MR4.0;Duration of MR4.5;Time to First MMR;Time to First MR4.0;Time to First MR4.5;BCR-ABL1=1% at Scheduled Data Collection Time Points;BCR-ABL1=1% by Scheduled Data Collection Time Points;Time to Treatment Failure (TTF);Failure Free Survival (FFS);Event Free Survival (EFS);Progression Free Survival (PFS);Overall Survival (OS);Trough Plasma Concentrations.;Pharmacokinetics (PK) of Asciminib: Cmax;PK of Asciminib: Tmax;PK of Asciminib: AUCtau and AUClast;PK of Asciminib: CL/F;Change From Baseline in Overall Scores (Global Health Status) and Individual Scales of the EORTC QLQ-C30 at Week 48 and Week 96;Change From Baseline in EORTC QLQ-CML24 Scales at Week 48 and Week 96 (ICTRP)

Registration date
not available

Incorporation of the first participant
not available

Secondary sponsors
not available

Additional contacts
Novartis Pharmaceuticals, Novartis Pharmaceuticals (ICTRP)

Secondary trial IDs
2023-508838-33-00, CABL001J12301 (ICTRP)

Results-Individual Participant Data (IPD)
not available

Further information on the trial
https://clinicaltrials.gov/study/NCT04971226 (ICTRP)