Asciminib Monotherapy, With Dose Escalation, for 2nd and 1st Line Chronic Myelogenous Leukemia

Chronic Myelogenous Leukemia - Chronic Phase Clinical Trial

— ASC2ESCALATE  

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)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05384587
• Other study ID #: CABL001AUS08
• Status: Recruiting
• Phase: Phase 2
• Start date: November 11, 2022
• Est. completion date: February 26, 2027

Study information

• Verified date: April 2024
• Source: Novartis
• Contact: Novartis Pharmaceuticals
• Phone: 1-888-669-6682
• Email: john.sabo[@]novartis.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Description:

This trial consists of three periods: screening and baseline for up to 28 days, active treatment for up to 104 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 information / eligibility

• Status: Recruiting
• Enrollment: 182
• Est. completion date: February 26, 2027
• Est. primary completion date: February 27, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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 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: loss of MMR 7. Beyond 12 months after the initiation of to 1L TKI, a. BCR-ABL1IS > 0.1% at screening b. 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 randomization 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.

Related Conditions & MeSH terms

• Chronic Myelogenous Leukemia - Chronic Phase
• Leukemia
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive
• Leukemia, Myeloid
• Leukemia, Myeloid, Chronic-Phase

Intervention

Drug:
• asciminib
Supplied in 40 mg tablets for oral use to be taken daily. Dose may be increased at 6 and 12 months based on molecular response with BCR-ABL1 Polymerase Chain Reaction testing.

Locations

Country	Name	City	State
United States	UNM	Albuquerque	New Mexico
United States	Alaska Oncology and Hematology	Anchorage	Alaska
United States	City Of Hope Atlanta	Atlanta	Georgia
United States	Emory University School of Medicine/Winship Cancer Institute	Atlanta	Georgia
United States	Augusta University Georgia .	Augusta	Georgia
United States	Texas Oncology, P.A.	Austin	Texas
United States	St Vincent Frontier Cancer Center	Billings	Montana
United States	University of Alabama at Birmingham .	Birmingham	Alabama
United States	Dana Farber Cancer Center .	Boston	Massachusetts
United States	Rocky Mountain Cancer Centers USOR	Boulder	Colorado
United States	Onco Inst of Hope and Innovation	Cerritos	California
United States	Uni of North Carolina Hospital	Chapel Hill	North Carolina
United States	Novant Health Heart and Vascular Institute .	Charlotte	North Carolina
United States	Hematology Oncology Care	Cincinnati	Ohio
United States	Care Access Research Clifton	Clifton	New Jersey
United States	University Missouri Ellis Fischel Cancer Center	Columbia	Missouri
United States	Texas Oncology TX Oncology Baylor	Dallas	Texas
United States	City of Hope National Medical	Duarte	California
United States	Duke University Medical Center .	Durham	North Carolina
United States	Hackensack Meridian Health Research	Edison	New Jersey
United States	Florida Cancer Specialists	Fort Myers	Florida
United States	Ctr For Cancer And Blood Disorders	Fort Worth	Texas
United States	UCSF Fresno Internal Medicine	Fresno	California
United States	Virginia K Crosson Cancer Center	Fullerton	California
United States	Virginia Cancer Specialists	Gainesville	Virginia
United States	Bon Secours Cancer Center	Greenville	South Carolina
United States	Hackensack University Medical Ctr	Hackensack	New Jersey
United States	Houston Methodist Hospital	Houston	Texas
United States	Univ of TX MD Anderson Cancer Cntr	Houston	Texas
United States	Franciscan Health Indianapolis	Indianapolis	Indiana
United States	Investigative Clinicl Rsrch of Indi	Indianapolis	Indiana
United States	Jackson Onc Associates	Jackson	Mississippi
United States	Baptist MD Anderson Cancer Center	Jacksonville	Florida
United States	Clinical Research Alliance Research	Lake Success	New York
United States	Dartmouth Hitchcock Medical Center	Lebanon	New Hampshire
United States	University of Kentucky	Lexington	Kentucky
United States	Nebraska Hematology-Oncology, P.C.	Lincoln	Nebraska
United States	UCLA	Los Angeles	California
United States	Northwest Georgia Oncology Center .	Marietta	Georgia
United States	Medical College of Wisconsin	Milwaukee	Wisconsin
United States	NYU Langone Long Island	Mineola	New York
United States	Rutgers Cancer Institute of New Jersey	New Brunswick	New Jersey
United States	Manhattan Hematol Oncol Associates	New York	New York
United States	Virginia Oncology Associates VOA - Lake Wright	Norfolk	Virginia
United States	Community Cancer Trials of Utah	Ogden	Utah
United States	Thomas Jefferson University	Philadelphia	Pennsylvania
United States	New York Bld And Cancer Specialists	Port Jefferson Station	New York
United States	Oregon Health Sciences University .	Portland	Oregon
United States	Siteman Cancer Center .	Saint Louis	Missouri
United States	Florida Cancer Specialists-North	Saint Petersburg	Florida
United States	Huntsman Cancer Institute .	Salt Lake City	Utah
United States	Mays Cancer Center	San Antonio	Texas
United States	Texas Oncology San Antonio TO San Antonio	San Antonio	Texas
United States	City of Hope Phoenix	Scottsdale	Arizona
United States	Fred Hutch Cancer Research	Seattle	Washington
United States	VA Puget Sound Health Care System	Seattle	Washington
United States	Louisiana State University Main Centre	Shreveport	Louisiana
United States	Avera Cancer Avera Cancer Institute	Sioux Falls	South Dakota
United States	The Stamford Hospital	Stamford	Connecticut
United States	SUNY Stony Brook Medical Oncology	Stony Brook	New York
United States	Florida Cancer Specialists East	Stuart	Florida
United States	SUNY Upstate Medical Center	Syracuse	New York
United States	Northwest Medical Specialties	Tacoma	Washington
United States	Lundquist Inst BioMed at Harbor .	Torrance	California
United States	USO Arizona Oncology	Tucson	Arizona
United States	Texas Oncology Northeast Texas	Tyler	Texas
United States	Wichita Community Clcl Onco Program Oncology	Wichita	Kansas
United States	Wake Forest Uni Health Sci Oncology	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	To investigate MR2, MR4, MR4.5 rate at visit	MR2, MR4 and MR4.5 at all scheduled data collection time points except for MR4.5 at 24 month	Baseline up to 24 months
Primary	Percentage of participants who achieve Major Molecular Response (MMR) in the 2L setting	MMR is defined as BCR-ABL1IS = 0.1%).	Baseline up to 12 months
Secondary	Percentage of participants achieving Molecular Response (MR4.5)	Molecular response (MR) will be assessed. The rate of MR4.5 where MR4.5 is 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).	Baseline up to 24 months
Secondary	Number of Adverse Events and Serious Adverse Events	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.	Baseline up to 24 months
Secondary	MMR Rate - All scheduled time points	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, h/she will still be considered as achieving MMR by that time point.	Baseline up to 3, 6, 18, and 24 months
Secondary	Time to MMR	Time to MMR is defined and calculated as date of first documented MMR - start date of study treatment +1 day.	Baseline up to 24 months
Secondary	Duration of MMR	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.	Baseline up to 24 months
Secondary	Time to Treatment Failure (TTF)	Time to treatment failure (TTF) is defined as the time from date of randomization to an event of treatment failure.	Baseline up to 24 months
Secondary	Progression Free Survival (PFS)	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.	Baseline up to 24 months
Secondary	Overall Survival (OS)	Time from the first dose of study treatment to death due to any cause during the study.	Baseline up to 24 months.
Secondary	MR2 Rate - All scheduled time points	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 MMR but then loses it before or at the visit, h/she will still be considered as achieving MR2 by that time point.	Baseline up to 3, 6, 12, 18, and 24 months
Secondary	MR4 Rate - All scheduled time points	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 MMR but then loses it before or at the visit, h/she will still be considered as achieving MR4 by that time point.	Baseline up to 3, 6, 12, 18, and 24 months
Secondary	MR4.5 Rate - All scheduled time points	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 MMR but then loses it before or at the visit, h/she will still be considered as achieving MR4.5 by that time point.	Baseline up to 3, 6, 12, and 18