Clinical trial NCT05384587: Asciminib Monotherapy, With Dose Escalation, for 2nd and 1st Line Chronic Myelogenous Leukemia
Official title: A Phase II Multicenter, Open-label, Single-arm Dose Escalation Study of Asciminib Monotherapy in 2nd and 1st Line Chronic Phase - Chronic Myelogenous Leukemia (ASC2ESCALATE)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Chronic Myelogenous Leukemia - Chronic Phase
Keywords: CML
Chronic Phase
Asciminib
ASC2ESCALATE
T315I mutation
BCR-ABL
MMR
TKI
Tyrosine Kinase Inhibitor
molecular response
adult
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2022-05-20
Enrollment: 196
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: Key Inclusion Criteria:

Participants eligible for inclusion in this study must meet the following criteria: Criteria #1-5 are common to both patient cohorts (2L and 1L):

1. Signed informed consent must be obtained prior to participation in the study
2. CML-CP, no previous AP or BC
3. ≥ 18 years of age
4. ECOG performance status of 0, 1 or 2
5. 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.
6. 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
7. Treatment intolerance to 1L TKI,

   1. BCR::ABL1IS \> 0.1% at screening
   2. 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
8. Patients with newly diagnosed CML-CP (treatment with a prior TKI (imatinib, or nilotinib, or dasatinib or bosutinib) for ≤ 4 weeks is allowed)

Key Exclusion Criteria:

1. Previous treatment

   1. With 2 or more ATP-binding site TKIs (for 2L patient cohort)
   2. More than 4 weeks with 1-ATP-binding site TKIs (for 1L patient cohort)
2. Previous treatment with asciminib
3. Known presence of the T315I mutation at any time prior to study entry
4. Known second chronic phase of CML after previous progression to AP/BC
5. Previous treatment with a hematopoietic stem-cell transplantation
6. Patient planning to undergo allogeneic hematopoietic stem cell transplantation
7. 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
8. History of acute pancreatitis within 1 year of study entry or past medical history of chronic pancreatitis
9. Participation in a prior investigational study within 30 days prior to enrollment or within 5 half-lives of the investigational product, whichever is longer
10. 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
11. Pregnant or nursing (lactating) women
12. 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.
13. 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).
14. 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).
15. 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.
16. Known hypersensitivity to the study treatment.

Primary outcomes:
measure: Percentage of participants who achieve Major Molecular Response (MMR) in the 2L setting
timeFrame: Baseline up to 12 months
Secondary outcomes:
measure: Percentage of participants achieving Molecular Response 4.5 (MR4.5) at 24 and 36 months
timeFrame: Baseline, 24 and 36 months
measure: MMR Rate at visit (other than 12 month)
timeFrame: Baseline, 3, 6, 18, 24, 30 and 36 months
measure: MR2 Rate at visit
timeFrame: Baseline, 3, 6, 12, 18, 24, 30 and 36 months
measure: MR4 Rate at visit
timeFrame: Baseline, 3, 6, 12, 18, 24, 30 and 36 months
measure: MR4.5 Rate at visit
timeFrame: Baseline, 3, 6, 12, 18 and 30 months
measure: MMR Rate by visit
timeFrame: Baseline up to 3, 6, 12, 18, 24, 30 and 36 months
measure: MR2 Rate by visit
timeFrame: Baseline up to 3, 6, 12, 18, 24, 30 and 36 months
measure: MR4 Rate by visit
timeFrame: Baseline up to 3, 6, 12, 18, 24, 30 and 36 months
measure: MR4.5 Rate by visit
timeFrame: Baseline up to 3, 6, 12, 18, 24, 30 and 36 months
measure: Time to MMR
timeFrame: Baseline up to 36 months
measure: Duration of MMR
timeFrame: Baseline up to 36 months
measure: Time to Treatment Failure (TTF)
timeFrame: Baseline up to 36 months
measure: Progression Free Survival (PFS)
timeFrame: Baseline up to 36 months
measure: Overall Survival (OS)
timeFrame: Baseline up to 36 months.
measure: Number of Adverse Events and Serious Adverse Events
timeFrame: Baseline up to 36 months
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Anchorage
country: United States
facility: Alaska Oncology and Hematology
state: Alaska
city: Scottsdale
country: United States
facility: City of Hope Phoenix
state: Arizona
city: Tucson
country: United States
facility: USO Arizona Oncology
state: Arizona
city: Cerritos
country: United States
facility: Onco Inst of Hope and Innovation
state: California
city: Duarte
country: United States
facility: City of Hope National Medical
state: California
city: Fresno
country: United States
facility: UCSF Fresno Internal Medicine
state: California
city: Fullerton
country: United States
facility: Virginia K Crosson Cancer Center
state: California
city: Los Angeles
country: United States
facility: UCLA
state: California
city: Oakland
country: United States
facility: Alta Bates Summit Medical Center
state: California
city: Torrance
country: United States
facility: Lundquist Inst BioMed at Harbor
state: California
city: Boulder
country: United States
facility: Rocky Mountain Cancer Centers
state: Colorado
city: New Haven
country: United States
facility: Yale University School Of Medicine
state: Connecticut
city: Stamford
country: United States
facility: The Stamford Hospital
state: Connecticut
city: Fort Myers
country: United States
facility: Florida Cancer Specialists
state: Florida
city: Jacksonville
country: United States
facility: Baptist MD Anderson Cancer Center
state: Florida
city: Saint Petersburg
country: United States
facility: Florida Cancer Specialists-North
state: Florida
city: Stuart
country: United States
facility: Florida Cancer Specialists East
state: Florida
city: Atlanta
country: United States
facility: City Of Hope Atlanta
state: Georgia
city: Atlanta
country: United States
facility: Emory University School of Medicine Winship Cancer Institute
state: Georgia
city: Augusta
country: United States
facility: Augusta University Georgia
state: Georgia
city: Marietta
country: United States
facility: Northwest Georgia Oncology Center
state: Georgia
city: Indianapolis
country: United States
facility: Franciscan Health Indianapolis
state: Indiana
city: Indianapolis
country: United States
facility: Investigative Clinicl Rsrch of Indi
state: Indiana
city: Iowa City
country: United States
facility: Holden Comp Can Cent Quad Cities U
state: Iowa
city: Wichita
country: United States
facility: Wichita Community Clcl Onco Program
state: Kansas
city: Lexington
country: United States
facility: University of Kentucky
state: Kentucky
city: Shreveport
country: United States
facility: Louisiana State University
state: Louisiana
city: Boston
country: United States
facility: Dana Farber Cancer Center
state: Massachusetts
city: Detroit
country: United States
facility: Henry Ford Hospital
state: Michigan
city: Jackson
country: United States
facility: Jackson Onc Associates
state: Mississippi
city: Columbia
country: United States
facility: University Missouri Ellis Fischel Cancer Center
state: Missouri
city: Saint Louis
country: United States
facility: Siteman Cancer Center
state: Missouri
city: Billings
country: United States
facility: St Vincent Frontier Cancer Center
state: Montana
city: Lincoln
country: United States
facility: Nebraska Hematology Oncology P C
state: Nebraska
city: Lebanon
country: United States
facility: Dartmouth Hitchcock Medical Center
state: New Hampshire
city: Clifton
country: United States
facility: Care Access Research Clifton
state: New Jersey
city: Edison
country: United States
facility: Hackensack Meridian Health
state: New Jersey
city: Hackensack
country: United States
facility: Hackensack University Medical Ctr
state: New Jersey
city: New Brunswick
country: United States
facility: Rutgers Cancer Institute of New Jersey
state: New Jersey
city: Albuquerque
country: United States
facility: UNM
state: New Mexico
city: Lake Success
country: United States
facility: Clinical Research Alliance
state: New York
city: Mineola
country: United States
facility: NYU Langone Long Island
state: New York
city: New York
country: United States
facility: Manhattan Hematol Oncol Associates
state: New York
city: New York
country: United States
facility: Mt Sinai Medical Center
state: New York
city: Port Jefferson Station
country: United States
facility: New York Bld And Cancer Specialists
state: New York
city: Stony Brook
country: United States
facility: SUNY Stony Brook Medical Oncology
state: New York
city: Syracuse
country: United States
facility: SUNY Upstate Medical Center
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina
state: North Carolina
city: Charlotte
country: United States
facility: Novant Health Heart and Vascular Institute
state: North Carolina
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest Uni Health Sci
state: North Carolina
city: Canton
country: United States
facility: Gabrail Cancer Center
state: Ohio
city: Cincinnati
country: United States
facility: Hematology Oncology Care
state: Ohio
city: Columbus
country: United States
facility: James Cancer Hospital and Solove Research Institute Ohio State
state: Ohio
city: Portland
country: United States
facility: Oregon Health Sciences University
state: Oregon
city: Easton
country: United States
facility: Care Access Research
state: Pennsylvania
city: Philadelphia
country: United States
facility: Thomas Jefferson University
state: Pennsylvania
city: Pittsburgh
country: United States
facility: UPMC
state: Pennsylvania
city: Greenville
country: United States
facility: Bon Secours Cancer Center
state: South Carolina
city: Sioux Falls
country: United States
facility: Avera Cancer
state: South Dakota
city: Nashville
country: United States
facility: Sarah Cannon Research Institute
state: Tennessee
city: Austin
country: United States
facility: Texas Oncology P A
state: Texas
city: Dallas
country: United States
facility: Texas Oncology
state: Texas
city: Fort Worth
country: United States
facility: Ctr For Cancer And Blood Disorders
state: Texas
city: Houston
country: United States
facility: Houston Methodist Hospital
state: Texas
city: Houston
country: United States
facility: Univ of TX MD Anderson Cancer Cntr
state: Texas
city: San Antonio
country: United States
facility: Mays Cancer Center
state: Texas
city: San Antonio
country: United States
facility: Texas Oncology San Antonio
state: Texas
city: Tyler
country: United States
facility: Texas Oncology Northeast Texas
state: Texas
city: Ogden
country: United States
facility: Community Cancer Trials of Utah
state: Utah
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute
state: Utah
city: Gainesville
country: United States
facility: Virginia Cancer Specialists
state: Virginia
city: Norfolk
country: United States
facility: Virginia Oncology Associates
state: Virginia
city: Richmond
country: United States
facility: Virginia Cancer Institute
state: Virginia
city: Seattle
country: United States
facility: VA Puget Sound Health Care System
state: Washington
city: Seattle
country: United States
facility: Fred Hutch Cancer Research
state: Washington
city: Tacoma
country: United States
facility: Northwest Medical Specialties
state: Washington
city: Madison
country: United States
facility: Dean Health System
state: Wisconsin
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
Study officials:
affiliation: Novartis
name: Novartis
role: STUDY_DIRECTOR
References: