A phase III, multi-center, open-label, randomized study of oral asciminib versus Investigator selected Tyrosine Kinase Inhibitor (TKI) in adult patients with newly diagnosed Philadelphia Chromosome Positive Chronic Myelogenous Leukemia in Chronic Phase
A study of oral asciminib versus other TKIs in adult patients with newly diagnosed Ph+ CML-CP
Kazuyuki Suzuki
Novartis Pharma. K.K.
Toranomon Hills Mori Tower 23-1, Toranomon 1-chome Minato-ku, Tokyo 105-6333, Japan
+81-120-003-293
rinshoshiken.toroku2@novartis.com
Kazuyuki Suzuki
Novartis Pharma. K.K.
Toranomon Hills Mori Tower 23-1, Toranomon 1-chome Minato-ku, Tokyo 105-6333, Japan
+81-120-003-293
rinshoshiken.toroku2@novartis.com
Not Recruiting
Jan. 05, 2022
Dec. 28, 2021
36
Interventional
randomized controlled trial
open(masking not used)
active control
parallel assignment
treatment purpose
Participants eligible for inclusion in this study must meet all of the following criteria:
1. Male or female patients >= 18 years of age.
2. Patients with CML-CP within 3 months of diagnosis.
3. Diagnosis of CML-CP with cytogenetic confirmation of Philadelphia chromosome of (9;22) translocations (presence of BCR-ABL1 in a review of a minimum 20 metaphases is required).
Documented chronic phase CML will meet all the below criteria:
- < 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.
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0, or 1.
5. 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 (ClCr) >= 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
6. Patients must have the following laboratory values >= lower limit of normal (LLN) 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 ClCr* >= 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 ClCr* >= 90 mL/min)
- Magnesium (magnesium increase of up to 3.0 mg/dL or 1.23 mmol/L if associated with ClCr* >= 90 mL/min)
- For patients with mild to moderate renal impairment (ClCr* >= 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. ClCr* as calculated using Cockcroft-Gault formula
7. Signed informed consent must be obtained prior to any study related screening procedures being performed.
8. 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.
Participants meeting any of the following criteria are not eligible for inclusion in this study:
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. Treatment with imatinib for =<2 weeks is allowed, but no other treatment with tyrosine kinase inhibitors prior to study entry is permitted.
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 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 msec (male patients), >=460 msec (female patients) on the average of three serial baseline ECG (using the QTcF formula) as determined by central reading. If QTcF >= 450 msec 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.
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 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. A patient having positive HBV-DNA should not be enrolled in the study.
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 drug (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. If local regulations deviate from the contraception methods listed below to prevent pregnancy, local regulations apply and will be described in the ICF.
i. Pregnant or nursing (lactating) women
ii. 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. For asciminib, this period of time is 3 days. Patients taking investigator-selected TKI should be willing to follow contraception requirements in the locally-applicable prescribing information for the TKI received in the study. Highly effective contraception methods include:
- Total abstinence (when this is in line with the preferred and usual lifestyle of the participant. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
- Female sterilization (have had surgical bilateral oophorectomy (with or without hysterectomy) total hysterectomy or bilateral tubal ligation at least six weeks before taking study treatment). In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment.
- Male partner's sterilization (at least 6 months prior to screening): the vasectomized male partner should be the sole partner for that participant.
- Use of oral, injected or implanted hormonal methods of contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS) or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception. In case of use of oral contraception women should have been stable on the same pill for a minimum of 3 months before taking study treatment.
- Women are considered post-menopausal if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms). Women are considered not of child bearing potential if they are post-menopausal or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy or bilateral tubal ligation at least six weeks before taking study medication. In the case of oophorectomy alone, women are considered post-menopausal and not of child bearing potential only when the reproductive status of the woman has been confirmed by follow up hormone level assessment.
iii. Sexually active males taking investigator-selected TKI should be willing to follow contraception requirements in the locally-applicable prescribing information for the TKI received in the study.
18age old over
No limit
Both
newly diagnosed Ph+ CML-CP
Arm1: Asciminib 80 mg QD under fasting conditions
Arm2: Investigator selected TKI that will include one of the below treatments as per the pre-randomized selection of TKI (imatinib or the 2G TKI (nilotinib or dasatinib or bosutinib)) .
-Imatinib 400 mg QD administered with food
-Nilotinib 300 mg BID administered under fasting conditions
-Dasatinib 100 mg QD administered with or without meal
-Bosutinib 400 mg QD administered with food
To compare the efficacy of asciminib versus Investigator selected TKI with respect to the proportion of patients that are in Major Molecular Response (MMR) at Week 48.
To compare the efficacy of asciminib versus Investigator selected TKI, within the stratum of patients with imatinib as the pre-randomization selected TKI, with respect to the proportion of patients that are in MMR at Week 48
Novartis Pharma. K.K.
Institutional Review Board of Yamagata Univesity Hospital
2-2-2 Iida-nishi, Yamagata-city, Yamagata
+81-23-628-5840
m-suto@med.id.yamagata-u.ac.jp
Approval
Yes
Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent expert panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.
This trial data is currently available according to the process described on www.clinicalstudydatarequest.com.
