Asciminib as Initial Therapy for Patients With Chronic Myeloid Leukemia in Chronic Phase

Sponsor

Augusta University (Other)

Overall Status

Recruiting

CT.gov ID

NCT05143840

Collaborator

H. Jean Khoury Cure CML Consortium (Other)

Enrollment

Locations

Arm

57.4

Anticipated Duration (Months)

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This study is a multicenter Phase 2, non-randomized, open-label single-group frontline study administering asciminib in patients with newly diagnosed Chronic Myeloid Leukemia-Chronic Phase (CML-CP). The aim of this study is to evaluate the efficacy and safety of asciminib in newly diagnosed CML-CP. Patients will receive asciminib orally twice daily. Response is determined by PCR (polymerase chain reaction) blood test during the study. Patients who have not achieved a response after 24 months of single agent asciminib will be offered the addition of nilotinib. Nilotinib will be started at 300 mg BID in addition to asciminib if indicated. Patients will discontinue study treatment if they experience disease progression, or unacceptable toxicity.

Condition or Disease	Intervention/Treatment	Phase
Chronic Myeloid Leukemia, Chronic Phase Adult CML Leukemia, Myeloid Leukemia,Myeloid, Chronic	Drug: Asciminib Drug: Ascimininb + Nilotinib	Phase 2

Detailed Description

Asciminib is a potent allosteric inhibitor of BCR-ABL1 oncogene that confers resistance to tyrosine kinase inhibitors (TKIs). Asciminib has potential to combine with TKIs to prevent the emergence of BCR-ABL1 mutations, increasing the depth of molecular response in CML-CP patients. Anticipated enrollment is 50 subjects across sites.

Primary Objective:

To estimate the proportion of patients with previously untreated CML-CP attaining deep molecular response (PCR blood test).

Secondary Objectives:

To estimate the proportion of patients achieving molecular response at specific time points
To estimate the time to molecular response
To evaluate the duration of hematologic and molecular response to asciminib
To define the time to progression and overall survival for patients with CML in early CP treated with asciminib
To evaluate the safety profile of asciminib in patients with CML-CP
To evaluate the development of ABL mutations for patients with CML in early CP treated with asciminib
To analyze differences in response rates and in prognosis within different risk groups and patient characteristics
To evaluate patient-reported outcomes in patients with CML receiving asciminib
To investigate treatment-free remission after at least 2 years of sustained deep molecular remission for patients receiving single agent asciminib

Exploratory objectives:

To evaluate the safety and efficacy of concomitant use of nilotinib with asciminib in patients who have not achieved MR4.5.
To evaluate the rate of successful treatment discontinuation for patients using the combination of asciminib and nilotinib
Evaluate the role of Digital droplet PCR (ddPCR) in predicting TFR
Evaluating the correlation between the gene expression signature of patients and the chances of achieving MMR and DMR
Evaluate whether B, NK and T cells DNA mutation and RNA expression are relevant and whether they can predict response in patients with CML using single cell analysis.

Subjects must meet all inclusion criteria and none of the exclusion criteria of the study. No enrollment waivers will be granted. After successful screening, subjects will be enrolled and treatment will start within 7 days of enrollment. Eligible subjects will begin asciminib on cycle 1 day 1 of the trial. After 2 years, subjects will be offered the addition of taking nilotinib with asciminib if a molecular response is not met (PCR blood test).

Duration of each participant is expected to take approximately 5 years.

Regimen Description Study Drug Dose Route Schedule Cycle Length Asciminib 40 mg Oral Twice a day (BID) 4 weeks (28 days) Nilotinib 300 mg* Oral Twice a day (BID) 4 weeks (28 days)

*Nilotinib will be taken if indicated at a maximum dose of 300mg BID

Dose levels and dose modifications of the study drugs will be made per protocol.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

8 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Intervention Model Description:

Single group frontline asciminibSingle group frontline asciminib

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Asciminib as Initial Therapy for Patients With Chronic Myeloid Leukemia in Chronic Phase

Actual Study Start Date :

Apr 22, 2022

Anticipated Primary Completion Date :

Feb 1, 2025

Anticipated Study Completion Date :

Feb 1, 2027

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Asciminib Asciminib 40mg taken orally twice a day starting cycle 1 day 1 for up to 24 months.	Drug: Asciminib Potent tyrosine kinase inhibitor that displays anti-tumor activity by specifically targeting the ABL myristate-binding pocket (STAMP). Other Names: ABL001 Drug: Ascimininb + Nilotinib For subjects that do not achieve MR4.5 (molecular response) after 24 months of single-agent asciminib will be offered the addition of nilotinib 300mg, twice daily, with the goal of attaining MR4.5.

Arm

Intervention/Treatment

Experimental: Asciminib

Asciminib 40mg taken orally twice a day starting cycle 1 day 1 for up to 24 months.

Drug: Asciminib

Potent tyrosine kinase inhibitor that displays anti-tumor activity by specifically targeting the ABL myristate-binding pocket (STAMP).

Other Names:

ABL001

Drug: Ascimininb + Nilotinib

For subjects that do not achieve MR4.5 (molecular response) after 24 months of single-agent asciminib will be offered the addition of nilotinib 300mg, twice daily, with the goal of attaining MR4.5.

Outcome Measures

Primary Outcome Measures

Primary Outcome Measure 1: Deep Molecular Response [24 months]
This measure is the number of subjects in deep molecular response (DMR) defined as breakpoint cluster region ABL proto-oncogene 1 (BCR-ABL1) <0.0032% International Standard (IS) by real-time quantitative polymerase chain reaction (RT-PCR).

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Age ≥18 years old
Willing and able to give informed consent
Newly diagnosed with CML in chronic phase within 6 months from confirmed diagnosis and have either the b3a2 (e14a2) or b2a2 (e13a2) variants that give rise to the p210 BCR-ABL protein. Subtype classification whether b3a2 (e14a2) or b2a2 (e13a2) is not required for study eligibility.
Minimal prior CML therapy including a TKI for less than 30 days.
ECOG performance status 0-2 (appendix 1)
Adequate organ function:
AST and ALT < 3 times the institutional upper limit of normal
Creatinine < 1.5 times the institutional upper limit of normal
Total bilirubin < 1.5 times the institutional upper limit of normal or < 3.0 x the institutional upper limit of normal with Gilbert Syndrome (unless direct bilirubin is within normal limits)
Female patients must meet one of the following:
Postmenopausal for at least one year before the screening visit,
Surgically sterile
If they are of childbearing potential, agree to practice two effective methods of contraception from the time of signing of the informed consent form through 90 days after the last dose of study drug,
Must also adhere to the guidelines of any treatment-specific pregnancy prevention program, if applicable
Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, postovulation methods] and withdrawal are not acceptable contraception methods.)
Male patients, even if surgically sterilized (i.e., status post vasectomy), must agree to one of the following:
Practice effective barrier contraception during the entire study treatment period and through 90 days after the last study drug dose
Must also adhere to the guidelines of any treatment-specific pregnancy prevention program, if applicable
Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, postovulation methods] and withdrawal are not acceptable methods of contraception.)

Exclusion Criteria:

Patients with accelerated or blast phase CML (refer to appendix 4)
Active second malignancy requiring active treatment
History of recent (within 12 months) acute pancreatitis or chronic pancreatitis
Subjects who have previously received treatment with asciminib.
Subjects with PLT count < 50,000 mm3 or ANC of < 500 mm3 or Hemoglobin < 8 g/dL
Lipase > institutional upper limit of normal
Pregnant or lactating
Taking a strong inhibitors or inducers of CYP3A4 or CYP3A4 substrates with narrow therapeutic index (refer to appendix 6) at time of enrollment
Unable to comply with lab appointment schedule and PRO assessments
Another investigational drug within 4 weeks of enrollment
Any serious medical or psychiatric illness that could, in the investigator's opinion, interfere with the completion of treatment according to this protocol
Patient has undergone a prior allogeneic stem cell transplant
Screening 12-lead ECG showing a baseline corrected QT interval >480msec (patients with a pacemaker will still be eligible with QTc>500msec)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Georgia Cancer Center at Augusta University	Augusta	Georgia	United States	30912
2	Froedtert Hospital & the Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53226