Asciminib Monotherapy, With Dose Escalation, for 2nd and 1st Line Chronic Myelogenous Leukemia
- Conditions
- Chronic Myelogenous Leukemia - Chronic Phase
- Interventions
- Registration Number
- NCT05384587
- Lead Sponsor
- Novartis Pharmaceuticals
- Brief Summary
This will be a multicenter Phase II open-label study of asciminib in CML-CP patients who have been previously treated with one prior ATP- binding site TKI with discontinuation due to treatment failure, warning or intolerance. (2L patient cohort). In addition, newly diagnosed CML-CP patients who may have received up to 4 weeks of prior TKI are included in a separate 1L patient cohort.
- Detailed Description
This trial consists of three periods: screening and baseline for up to 28 days, active treatment for up to 156 weeks and a safety follow up period for 30 days.
Ninety-two (92) 2L patients with CML-CP without T315I mutation who had 1 prior ATP-binding site TKI discontinued due to treatment failure, warning or intolerance will be considered for the current study. Patients will be tested at screening for the T315I mutation and excluded if the mutation is found.
To gain additional insights into the effect of asciminib in the 1L setting, an additional cohort of newly diagnosed CML-CP patients will be enrolled in the study. Based on the number of participating sites, it is approximated that between 60 and 90 patients could be enrolled. Enrollment of the 1L cohort will be stopped when a maximum of 90 patients have been enrolled or when approximately 60 patients have been enrolled and the 2L cohort is fully recruited, whichever comes first.
Informed consent will be obtained before any procedures are performed for the study including eligibility assessments.
All eligible patients will be initially treated with asciminib at 80 mg QD. At 6 months of study treatment, patients who have achieved BCR-ABL1IS ≤1% will continue on the same dose whereas those who have not will increase dose to 200mg QD.
At 12 months of study treatment, patients will be evaluated for the primary endpoint of the study (MMR at 12 month in 2L patient cohort) and will pursue one of the following:
* Continue on the current dose of asciminib if MMR is achieved
* Increase dose to 200 mg QD if on 80 mg QD dosing and MMR is not achieved
* Increase dose to 200 mg BID if on 200 mg QD dosing and MMR is not achieved
* Take the patient off the study and switch to Investigator's agent of choice if MMR is not achieved and it is in the interest of the patient based on investigator's clinical judgment of prospect treatment benefit.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 196
Participants eligible for inclusion in this study must meet the following criteria: Criteria #1-5 are common to both patient cohorts (2L and 1L):
-
Signed informed consent must be obtained prior to participation in the study
-
CML-CP, no previous AP or BC
-
≥ 18 years of age
-
ECOG performance status of 0, 1 or 2
-
Adequate end organ function within 14 days before the first dose of asciminib treatment.
Patients with mild to moderate renal and hepatic impairment are eligible if:
- Total bilirubin ≤ 3.0 x ULN without AST/ALT increase
- Aspartate transaminase (AST) ≤ 5.0 x ULN
- Alanine transaminase (ALT) ≤ 5.0 x ULN
- Serum lipase ≤ 1.5 x ULN. For serum lipase > ULN and ≤ 1.5 x ULN, value should be considered not clinically significant and not associated with risk factors for acute pancreatitis
- Alkaline phosphatase ≤ 2.5 x ULN
- Creatinine clearance ≥ 30 mL/min as calculated using Cockcroft- Gault formula
Criteria #6 and 7 are specific to the 2L patient cohort. These are meant to be either/or. It is not required to have both criteria satisfied.
-
Warning or failure (according to 2020 ELN Recommendations; Hochhaus et al) to 1L TKI therapy at the time of screening
a. Warning is defined as: i. Six months after the initiation of treatment: BCR::ABL1IS >1-10% ii. Twelve months after the initiation of treatment: BCR::ABL1IS >0.1-1% b. Treatment failure/resistance to 1L TKI is defined as: i. BCR::ABL1IS >10% if 1L treatment duration between 6 and 12 months ii. BCR::ABL1IS >1% if 1L treatment longer than 12 months treatment iii. Beyond 12 months after initiation of treatment: loss of MMR
-
Treatment intolerance to 1L TKI,
- BCR::ABL1IS > 0.1% at screening
- Intolerance is defined as:
i. Non-hematologic intolerance: Patients with grade 3 or 4 toxicity while on therapy, or with persistent grade 2 toxicity, unresponsive to optimal management, including dose adjustments (unless dose reduction is not considered in the best interest of the patient if response is already suboptimal) ii. Hematologic intolerance: Patients with grade 3 or 4 toxicity (absolute neutrophil count [ANC] or platelets) while on therapy that is recurrent after dose reduction to the lowest doses recommended by manufacturer
Criteria #8 is specific to the 1L patient cohort
-
Patients with newly diagnosed CML-CP (treatment with a prior TKI (imatinib, or nilotinib, or dasatinib or bosutinib) for ≤ 4 weeks is allowed)
Key
-
Previous treatment
- With 2 or more ATP-binding site TKIs (for 2L patient cohort)
- More than 4 weeks with 1-ATP-binding site TKIs (for 1L patient cohort)
-
Previous treatment with asciminib
-
Known presence of the T315I mutation at any time prior to study entry
-
Known second chronic phase of CML after previous progression to AP/BC
-
Previous treatment with a hematopoietic stem-cell transplantation
-
Patient planning to undergo allogeneic hematopoietic stem cell transplantation
-
Cardiac or cardiac repolarization abnormality, including any 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)
- QTcF at screening ≥450 msec (male patients), ≥450 msec (female patients)
- 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
-
History of acute pancreatitis within 1 year of study entry or past medical history of chronic pancreatitis
-
Participation in a prior investigational study within 30 days prior to enrollment or within 5 half-lives of the investigational product, whichever is longer
-
Treatment with medications that meet one of the following criteria is not allowed and should be switched to an alternative at least one week prior to the start of treatment with study treatment:
- Strong inducers of CYP3A for patients on the dose of 80 mg QD and 200mg QD
- Strong inducers and inhibitors of CYP3A for patients on the dose of 200 mg BID
-
Pregnant or nursing (lactating) women
-
Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception. Highly effective contraception for women should be maintained throughout the study and for at least 7 days after the last dose.
-
Sexually active males unwilling to use a condom during intercourse while taking study treatment and for 7 days after stopping study (only for patients treated with asciminib).
-
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).
-
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.
-
Known hypersensitivity to the study treatment.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Asciminib asciminib 80 mg initial oral dose taken once a day with possible dose escalation
- Primary Outcome Measures
Name Time Method Percentage of participants who achieve Major Molecular Response (MMR) in the 2L setting Baseline up to 12 months MMR is defined as BCR::ABL1IS ≤ 0.1%. A patient will be counted as having achieved MMR at 12 month if he/she meets the MMR criterion at 12 month.
- Secondary Outcome Measures
Name Time Method Percentage of participants achieving Molecular Response 4.5 (MR4.5) at 24 and 36 months Baseline, 24 and 36 months Percentage of participants who achieve MR4.5 (defined as a ≥ 4.5 log reduction in BCR::ABL1 transcripts compared to the standardized baseline equivalent to ≤ 0.0032% BCR::ABL1/ABL % by international scale as measured by real time Polymerase Chain Reaction \[PCR\]) at the specified visits, i.e., if a patient achieves an MR4.5 but then loses it before or at the visit, he/she will be considered as non-responder for MR4.5 at that time point.
MMR Rate at visit (other than 12 month) Baseline, 3, 6, 18, 24, 30 and 36 months Percentage of participants who achieve MMR (defined as BCR::ABL1IS ≤ 0.1%) at the specified visit, i.e., if a patient achieves an MMR earlier but then loses it at the visit, he/she will be considered as non-responder for MMR at the specified visit
MR2 Rate at visit Baseline, 3, 6, 12, 18, 24, 30 and 36 months Percentage of participants who achieve MR2 (defined as a ≥ 2 log reduction in BCR::ABL1 transcripts) at the specified visit, i.e., if a patient achieves an MR2 earlier but then loses it at the visit, he/she will be considered as non-responder for MR2 at the specified visit
MR4 Rate at visit Baseline, 3, 6, 12, 18, 24, 30 and 36 months Percentage of participants who achieve MR4 (defined as a ≥ 4 log reduction in BCR::ABL1 transcripts) at the specified visit, i.e if a patient achieves an MR4 earlier, but then loses it at the visit, he/she will be considered as non-responder for MR4 at the specified visit
MR4.5 Rate at visit Baseline, 3, 6, 12, 18 and 30 months Percentage of participants who achieve MR4.5 (defined as a ≥ 4.5 log reduction in BCR::ABL1 transcripts) at the specified visit, i.e if a patient achieves an MR4.5 earlier, but then loses it at the visit, he/she will be considered as non-responder for MR4.5 at the specified visit
MMR Rate by visit Baseline up to 3, 6, 12, 18, 24, 30 and 36 months Percentage of participants who achieve MMR at or before the specified visit, i.e., if a patient achieves an MMR but then loses it before or at the visit, he/she will still be considered as achieving MMR by that time point.
MR2 Rate by visit Baseline up to 3, 6, 12, 18, 24, 30 and 36 months Percentage of participants who achieve MR2 (defined as a ≥ 2 log reduction in BCR::ABL1 transcripts) at or before the specified visit, i.e., if a patient achieves an MR2 but then loses it before or at the visit, he/she will still be considered as achieving MR2 by that time point.
MR4 Rate by visit Baseline up to 3, 6, 12, 18, 24, 30 and 36 months Percentage of participants who achieve MR4 (defined as a ≥ 4 log reduction in BCR::ABL1 transcripts) at or before the specified visit, i.e., if a patient achieves an MR4 but then loses it before or at the visit, he/she will still be considered as achieving MR4 by that time point.
MR4.5 Rate by visit Baseline up to 3, 6, 12, 18, 24, 30 and 36 months Percentage of participants who achieve MR4.5 (defined as a ≥ 4.5 log reduction in BCR::ABL1 transcripts) at or before the specified visit, i.e., if a patient achieves an MR4.5 but then loses it before or at the visit, he/she will still be considered as achieving MR4.5 by that time point.
Time to MMR Baseline up to 36 months Time to MMR is defined and calculated as date of first documented MMR - start date of study treatment +1 day.
Duration of MMR Baseline up to 36 months Duration of MMR is defined as the time from the date of first documented MMR to the earliest date of loss of MMR, progression to Accelerated Phase (AP) or Blast Crisis (BC), or CML-related death.
Time to Treatment Failure (TTF) Baseline up to 36 months Time to treatment failure (TTF) is defined as the time from date of randomization to an event of treatment failure.
Progression Free Survival (PFS) Baseline up to 36 months Time from the first dose of study treatment to the earliest occurrence of documented progression to Accelerated Phase (AP) or Blast Crisis (BC) or the date of death from any cause, before the end of the treatment phase.
Overall Survival (OS) Baseline up to 36 months. Time from the first dose of study treatment to death due to any cause during the study.
Number of Adverse Events and Serious Adverse Events Baseline up to 36 months Clinically significant findings for vitals, laboratory values and electrocardiogram (ECG) will be reported as adverse events and or serious adverse events as determined by the investigator.
Trial Locations
- Locations (80)
University of Alabama at Birmingham
🇺🇸Birmingham, Alabama, United States
Lundquist Inst BioMed at Harbor
🇺🇸Torrance, California, United States
Rocky Mountain Cancer Centers
🇺🇸Boulder, Colorado, United States
Yale University School Of Medicine
🇺🇸New Haven, Connecticut, United States
Augusta University Georgia
🇺🇸Augusta, Georgia, United States
Dana Farber Cancer Center
🇺🇸Boston, Massachusetts, United States
Northwest Georgia Oncology Center
🇺🇸Marietta, Georgia, United States
Holden Comp Can Cent Quad Cities U
🇺🇸Iowa City, Iowa, United States
Wichita Community Clcl Onco Program
🇺🇸Wichita, Kansas, United States
Louisiana State University
🇺🇸Shreveport, Louisiana, United States
Siteman Cancer Center
🇺🇸Saint Louis, Missouri, United States
Hackensack Meridian Health
🇺🇸Edison, New Jersey, United States
Clinical Research Alliance
🇺🇸Lake Success, New York, United States
University of North Carolina
🇺🇸Chapel Hill, North Carolina, United States
Novant Health Heart and Vascular Institute
🇺🇸Charlotte, North Carolina, United States
Duke University Medical Center
🇺🇸Durham, North Carolina, United States
Wake Forest Uni Health Sci
🇺🇸Winston-Salem, North Carolina, United States
Gabrail Cancer Center
🇺🇸Canton, Ohio, United States
James Cancer Hospital and Solove Research Institute Ohio State
🇺🇸Columbus, Ohio, United States
Oregon Health Sciences University
🇺🇸Portland, Oregon, United States
Avera Cancer
🇺🇸Sioux Falls, South Dakota, United States
Sarah Cannon Research Institute
🇺🇸Nashville, Tennessee, United States
Texas Oncology
🇺🇸Dallas, Texas, United States
Virginia Oncology Associates
🇺🇸Norfolk, Virginia, United States
Texas Oncology San Antonio
🇺🇸San Antonio, Texas, United States
Huntsman Cancer Institute
🇺🇸Salt Lake City, Utah, United States
Alaska Oncology and Hematology
🇺🇸Anchorage, Alaska, United States
City of Hope Phoenix
🇺🇸Scottsdale, Arizona, United States
USO Arizona Oncology
🇺🇸Tucson, Arizona, United States
Onco Inst of Hope and Innovation
🇺🇸Cerritos, California, United States
City of Hope National Medical
🇺🇸Duarte, California, United States
UCSF Fresno Internal Medicine
🇺🇸Fresno, California, United States
Virginia K Crosson Cancer Center
🇺🇸Fullerton, California, United States
UCLA
🇺🇸Los Angeles, California, United States
Alta Bates Summit Medical Center
🇺🇸Oakland, California, United States
The Stamford Hospital
🇺🇸Stamford, Connecticut, United States
Florida Cancer Specialists
🇺🇸Fort Myers, Florida, United States
Baptist MD Anderson Cancer Center
🇺🇸Jacksonville, Florida, United States
Florida Cancer Specialists-North
🇺🇸Saint Petersburg, Florida, United States
Florida Cancer Specialists East
🇺🇸Stuart, Florida, United States
City Of Hope Atlanta
🇺🇸Atlanta, Georgia, United States
Emory University School of Medicine Winship Cancer Institute
🇺🇸Atlanta, Georgia, United States
Henry Ford Hospital
🇺🇸Detroit, Michigan, United States
Franciscan Health Indianapolis
🇺🇸Indianapolis, Indiana, United States
Investigative Clinicl Rsrch of Indi
🇺🇸Indianapolis, Indiana, United States
University of Kentucky
🇺🇸Lexington, Kentucky, United States
Jackson Onc Associates
🇺🇸Jackson, Mississippi, United States
University Missouri Ellis Fischel Cancer Center
🇺🇸Columbia, Missouri, United States
St Vincent Frontier Cancer Center
🇺🇸Billings, Montana, United States
Nebraska Hematology Oncology P C
🇺🇸Lincoln, Nebraska, United States
Dartmouth Hitchcock Medical Center
🇺🇸Lebanon, New Hampshire, United States
Care Access Research Clifton
🇺🇸Clifton, New Jersey, United States
Hackensack University Medical Ctr
🇺🇸Hackensack, New Jersey, United States
Rutgers Cancer Institute of New Jersey
🇺🇸New Brunswick, New Jersey, United States
UNM
🇺🇸Albuquerque, New Mexico, United States
NYU Langone Long Island
🇺🇸Mineola, New York, United States
Manhattan Hematol Oncol Associates
🇺🇸New York, New York, United States
Mt Sinai Medical Center
🇺🇸New York, New York, United States
New York Bld And Cancer Specialists
🇺🇸Port Jefferson Station, New York, United States
SUNY Stony Brook Medical Oncology
🇺🇸Stony Brook, New York, United States
SUNY Upstate Medical Center
🇺🇸Syracuse, New York, United States
Hematology Oncology Care
🇺🇸Cincinnati, Ohio, United States
Care Access Research
🇺🇸Easton, Pennsylvania, United States
Thomas Jefferson University
🇺🇸Philadelphia, Pennsylvania, United States
UPMC
🇺🇸Pittsburgh, Pennsylvania, United States
Bon Secours Cancer Center
🇺🇸Greenville, South Carolina, United States
Texas Oncology P A
🇺🇸Austin, Texas, United States
Ctr For Cancer And Blood Disorders
🇺🇸Fort Worth, Texas, United States
Houston Methodist Hospital
🇺🇸Houston, Texas, United States
Univ of TX MD Anderson Cancer Cntr
🇺🇸Houston, Texas, United States
Mays Cancer Center
🇺🇸San Antonio, Texas, United States
Texas Oncology Northeast Texas
🇺🇸Tyler, Texas, United States
Community Cancer Trials of Utah
🇺🇸Ogden, Utah, United States
Virginia Cancer Specialists
🇺🇸Gainesville, Virginia, United States
Virginia Cancer Institute
🇺🇸Richmond, Virginia, United States
VA Puget Sound Health Care System
🇺🇸Seattle, Washington, United States
Fred Hutch Cancer Research
🇺🇸Seattle, Washington, United States
Northwest Medical Specialties
🇺🇸Tacoma, Washington, United States
Dean Health System
🇺🇸Madison, Wisconsin, United States
Medical College of Wisconsin
🇺🇸Milwaukee, Wisconsin, United States