A Study to Investigate Tolerability and Efficacy of Asciminib (Oral) Versus Nilotinib (Oral) in Adult Participants (≥18 Years of Age) With Newly Diagnosed Philadelphia Chromosome Positive Chronic Myelogenous Leukemia in Chronic Phase (Ph+ CML-CP)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Novartis Pharma AG

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04], Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

21 Nov 2022 → ongoing

Decision date (initial)

2024-08-02

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

External identifiers

EU CT number

2024-510947-71-00

EudraCT number

2022-000995-21

ClinicalTrials.gov

NCT05456191

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy, Therapy, Others

To assess the tolerability of asciminib versus nilotinib, in participants with newly diagnosed Chronic Myelogenous Leukemia in Chronic Phase, with respect to the time to discontinuation of study treatment due to adverse event (TTDAE)

Secondary objectives 4

1. Secondary objective on efficacy: - To compare the efficacy of asciminib versus nilotinib at and by all scheduled data collection time points
2. Time to Treatment Discontinuation (TTD) for selected reasons of discontinuation.
3. Secondary objective on PRO: To assess the effect of asciminib versus nilotinib on patient-reported disease-related symptoms, functioning, and health-related quality of life (HRQoL).
4. Secondary objective on safety: To characterize the safety and tolerability profile of asciminib versus nilotinib during the course of study.

Conditions and MedDRA coding

Chronic Myeloid Leukemia

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. Signed informed consent must be obtained prior to participation in the study.
2. Male or female patients ≥ 18 years of age
3. Patients with CML-CP within 3 months of diagnosis
4. Diagnosis of CML-CP (European Leukemia Network [ELN] 2020 criteria) with cytogenetic confirmation of the Philadelphia (Ph) chromosome. A cryptic Ph chromosome should be confirmed by metaphase Fluorescence in situ Hybridization (FISH) •Documented chronic phase CML will meet all the below criteria (Baccarani et al 2013): •< 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 (PLT) count ≥ 100 x 109/L (≥ 100,000/mm3) •No evidence of extramedullary leukemic involvement, with the exception of hepatosplenomegaly.
5. Evidence of typical BCR::ABL1 transcript [e14a2 and/or e13a2] which is amenable to standardized RQ-PCR quantification by the central laboratory assessment. However, if a local qualitative assay, validated according to local regulation, from an accredited local laboratory has confirmed evidence of typical BCR::ABL1 transcript [e14a2 and/or e13a2], these results can be used for eligibility if the central Real Time Quantitative Polymerase Chain Reaction (RQ-PCR) results arrived are not available at the time of randomization.
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
7. Adequate end organ function as defined by: •Total bilirubin (TBL) < 3 x Upper Limit of Normal (ULN); patients with Gilbert’s syndrome may only be included if TBL ≤ 3.0 x ULN or direct bilirubin ≤ 1.5 x ULN, •Creatinine Clearance (CrCl) ≥ 30 milliliters per minute (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.
8. Patients 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 within normal limits or corrected to within normal limits with supplements prior to randomization. *CrCl as calculated using Cockcroft-Gault formula. ** pseudohyperkaliemia in case of thrombocytosis is not an exclusion criterion

Exclusion criteria 16

1. 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.
2. Known cytopathologically confirmed CNS infiltration (in absence of suspicion of CNS involvement, lumbar puncture not required).
3. Impaired cardiac function or cardiac repolarization abnormality including but not limited to any one of the following: • History of myocardial infarction (MI), angina pectoris, coronary artery bypass graft (CABG) within 6 months prior to starting study treatment. • 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). • QTcF ≥ 450 ms on the average of three serial baseline ECG (using the QTcF formula). If QTcF ≥ 450 ms and electrolytes are not within normal ranges, electrolytes should be corrected and then the patient re-screened for QTcF. • 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 crediblemeds.org that cannot be discontinued or replaced 7 days prior to starting study treatment by safe alternative medication. • Inability to determine the QTcF interval.
4. 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).
5. History of significant congenital or acquired bleeding disorder unrelated to cancer.
6. Major surgery within 4 weeks prior to study entry or patients who have not recovered from prior surgery.
7. 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.
8. History of acute pancreatitis within 1 year prior to randomization or medical history of chronic pancreatitis.
9. History of chronic liver disease leading to severe hepatic impairment, or ongoing acute liver disease.
10. Known history of chronic Hepatitis B (HBV), or chronic Hepatitis C (HCV) infection. Testing for Hepatitis B surface antigen (HBs Ag) and Hepatitis B core antibody (HBc Ab/anti HBc) will be performed at screening. If anti-HBc is positive, HBV-DNA evaluation will be carried out at screening. A patient having positive HBV-DNA will not be enrolled in the study. Also, a patient with positive HBsAg will not be enrolled in the study. HCV Ab testing will also be performed at screening. For details on the criteria see Appendix 4.
11. History of Human Immunodeficiency Virus (HIV) unless well-controlled on a stable dose of anti-retroviral therapy at the time of screening.
12. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study treatment (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection, or gastric bypass surgery).
13. Participation in a prior investigational study within 30 days prior to randomization or within 5 half-lives of the investigational product, whichever is longer.
14. Pregnant or nursing (lactating) women
15. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception while taking study treatment and for a period of time after stopping study medication.
16. Known hypersensitivity to the study treatment.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Time to discontinuation of study treatment due to adverse event (TTDAE). TTDAE is defined as the time from the date of first dose of study treatment to the date of discontinuation of study treatment due to adverse event (AE).

Secondary endpoints 3

1. Secondary endpoint on efficacy: •MMR at and by all scheduled time points •MR4.0 and MR4.5 at and by all scheduled time points •Complete Hematological Response at and by all scheduled time points •BCR::ABL1 ≤1% at and by all scheduled time points •Duration of MMR, MR4.0, MR4.5 •Time to first MMR, first MR4.0, first MR4.5 •Time to treatment failure •Event Free Survival •Progression free survival •Overall survival •TTD due to selected reasons
2. Secondary endpoint on PRO: Change from baseline in overall scores and individual scales of the EORTC QLQ-C30, EORTC QLQ-CML24.
3. Secondary endpoint on safety: Type, frequency and severity of adverse events, dose modification due to adverse event, changes in laboratory values that fall outside the pre-determined ranges and clinically notable ECG changes, and other safety data (vital signs, physical examination).

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Comparator 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Novartis Pharma AG

Sponsor organisation

Novartis Pharma AG

Address

Lichtstrasse 35

City

Basel

Postcode

4056

Country

Switzerland

Scientific contact point

Organisation

Novartis Pharma AG

Contact name

Novartis Pharma Arzneimittel GmbH

Public contact point

Organisation

Novartis Pharma AG

Contact name

Novartis Pharma Arzneimittel GmbH

Third parties 20

Locations

10 EU/EEA countries · 78 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 79 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

7 submissions — initial application plus substantial / non-substantial modifications