UMIN-CTR Clinical Trial

Public title

Phase II Clinical Trial of Dasatinib Therapy Aiming for Treatment-Free Remission in Patients with Chronic Phase Chronic Myeloid Leukemia

Acronym

Dasatinib Therapy Aiming for TFR in Patients with CML-CP (D-FREE)

Scientific Title

Phase II Clinical Trial of Dasatinib Therapy Aiming for Treatment-Free Remission in Patients with Chronic Phase Chronic Myeloid Leukemia

Scientific Title:Acronym

Dasatinib Therapy Aiming for TFR in Patients with CML-CP (D-FREE)

Region

Japan

Condition

Chronic Phase Chronic Myeloid Leukemia

Classification by specialty

Hematology and clinical oncology

Classification by malignancy

Malignancy

Genomic information

YES

Narrative objectives1

Evaluate the rate of sustained treatment-free remission (TFR) with no molecular relapse and no need for resumption of dasatinib treatment by discontinuation of dasatinib treatment in patients with Ph-positive chronic myeloid leukemia-chronic phase (CML-CP) who sustained molecular response on the international scale (IS) <= 0.0032% (hereinafter referred to as "MR4.5") for 1 year with a tyrosine kinase inhibitor (TKI), dasatinib hydrate (hereinafter referred to as "dasatinib"). Also, evaluate the relationship of sustained TFR to gene polymorphism/mutation and specify gene markers to judge the advisability of discontinuing TKI treatment. Molecular relapse is defined as IS loss of <= 0.1% (hereinafter referred to as "MMR") once or IS loss of <= 0.01% (hereinafter referred to as "MR4") 2 consecutive times.

Basic objectives2

Efficacy

Basic objectives -Others

Trial characteristics_1

Trial characteristics_2

Developmental phase

Phase II

Primary outcomes

Percentage of patients in TFR who show no molecular relapse and do not need resumption of dasatinib treatment 12 months after discontinuation of dasatinib treatment

Key secondary outcomes

Percentage of patients in TFR 24, 36, and 48 months after discontinuation of dasatinib treatment.
Molecular relapse free survival 12 months after discontinuation of dasatinib treatment
Overall survival (OS) including all causes of death 12, 24, 36, and 48 months after discontinuation of dasatinib treatment
Dasatinib doses and time to MR4.5
Event free survival (EFS) during dasatinib treatment period.
Frequency and degree of TKI withdrawal syndrome after discontinuation of dasatinib treatment.

Study type

Interventional

Basic design

Single arm

Randomization

Non-randomized

Randomization unit

Blinding

Open -no one is blinded

Control

Uncontrolled

Stratification

Dynamic allocation

Institution consideration

Blocking

Concealment

No. of arms

1

Purpose of intervention

Treatment

Type of intervention

Medicine

Interventions/Control_1

Basic treatment is to take 100 mg of dasatinib, once daily, repeatedly. The maximum daily dose is 140 mg, and the dose can be increased, decreased, or treatment can be stopped at the discretion of investigators as needed. Discontinuation of dasatinib treatment in patients who sustained molecular response on the international scale (IS)<= 0.0032% (MR4.5) for 1 year by treatment with dasatinib.

Interventions/Control_2

Interventions/Control_3

Interventions/Control_4

Interventions/Control_5

Interventions/Control_6

Interventions/Control_7

Interventions/Control_8

Interventions/Control_9

Interventions/Control_10

Age-lower limit

18

years-old

<=

Age-upper limit

Not applicable

Gender

Male and Female

Key inclusion criteria

1) Patients with newly diagnosed CML-CP
2) Patients aged 18 years and over
3) Patients with ECOG performance status groups of 0 to 2
4) Patients with adequate functions of major organs (liver, kidney, and lung) (according to reference levels of each institution)
5) Patients who gave a written informed consent to participation in the trial. Minors who gave a written informed consent or one obtained from their legal representatives

Key exclusion criteria

1)Active multiple cancers
2)Pregnant women and lactating mothers
3)Women who do not intend to or cannot use appropriate contraceptives during the registration period
4)Patients with a history or complications of the following severe or uncontrollable symptoms
Myocardial infarction within the past 6 months
Angina pectoris within the past 3 months
Gastrointestinal haemorrhage within the past 3 months
Congestive cardiac failure within the past 3 months
Having plural effusion
Electrocardiogram QTc interval prolonged exceeding 450 msec at the start of treatment (baseline) (Fridericia correction)
Present or past history of pulmonary hypertension
5)Patients with a history or complications of diseases judged as inappropriate for study implementation by investigators.

Target sample size

300

Name of lead principal investigator

1st name	CHIKASHI
Middle name
Last name	YOSHIDA

Organization

National Hospital Organization Mito Medical Center

Division name

Department of Hematology

Zip code

311-3193

Address

280 Sakuranosato, Ibaraki-machi, Higashi-ibaraki-gun, Ibaraki, 311-3193, Japan

TEL

0292407711

Email

c.yoshida@mitomedical.org

Name of contact person

1st name	CHIKASHI
Middle name
Last name	YOSHIDA

Organization

National Hospital Organization Mito Medical Center

Division name

Department of Hematology

Zip code

311-3193

Address

280 Sakuranosato, Ibaraki-machi, Higashi-ibaraki-gun, Ibaraki, 311-3193, Japan

TEL

0292407711

Homepage URL

Email

c.yoshida@mitomedical.org

Institute

Kanto CML Study Group

Institute

Department

Personal name

Organization

Bristol-Myers Squibb K.K.

Organization

Division

Category of Funding Organization

Profit organization

Nationality of Funding Organization

Co-sponsor

Name of secondary funder(s)

Organization

Institutional Review Board of Nippon Medical School Foundation

Address

Tokyo Sendagi 1-1-5, Bunkyo-ku

Tel

03-5802-8115

Email

officetokutei@nms.ac.jp

Secondary IDs

YES

Study ID_1

jRCTs031180332

Org. issuing International ID_1

Japan Registry of Clinical Trails

Study ID_2

Org. issuing International ID_2

IND to MHLW

Institutions

Date of disclosure of the study information

2016

Year

05

Month

21

Day

URL releasing protocol

https://link.springer.com/article/10.1007/s12185-023-03549-3

Publication of results

Published

URL related to results and publications

https://link.springer.com/article/10.1007/s12185-023-03549-3

Number of participants that the trial has enrolled

181

Results

The study examined whether CML-CP patients (pts) treated with dasatinib (DAS) for <=3 years (yrs) and maintained MR4.5 for exactly 1 year (yr) would achieve TFR if DAS was discontinued. Of the first 21 pts who discontinued, 17 developed molecular relapse. The median duration of treatment with DAS before cessation was 18.9 months, which was shorter than previously reported. These results indicate that maintaining MR4.5 for 1 yr is not sufficient to achieve TFR in CML-CP pts treated with DAS for <= 3 yrs.

Results date posted

2023

Year

11

Month

26

Day

Results Delayed

Results Delay Reason

Date of the first journal publication of results

Baseline Characteristics

This study investigated patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP). Of the 173 patients included in the analysis, 59.0% (102 patients) were aged < 60 years and 41.0% (71 patients) were aged >= 60. The sex composition was 57.8% (100 patients) male and 42.2% (73 patients) female. Regarding risk classification, the proportions of Sokal low-, intermediate-, and high-risk groups were 45.7% (79 patients), 38.2% (66 patients), and 15.6% (27 patients), respectively. Hasford low-, intermediate-, and high-risk groups were 39.9% (69 patients), 50.9% (88 patients), and 8.7% (15 patients), respectively. EUTOS low- and high-risk groups were 89.6% (155 patients) and 10.4% (18 patients), respectively.

Participant flow

Of a total of 181 patients registered in the study, 8 patients (4 patients, found ineligible after enrollment; 4 patients, unknown) were excluded and 173 patients initiated the protocol treatment with second generation tyrosine kinase inhibitor(2G-TKI)dasatinib.
Subsequently, 60 patients transitioned to the consolidation phase[*1] and 21 patients moved to the stop phase[*2]. Of the patients who transitioned to the stop phase, 17 developed molecular relapse[*3]. The study was terminated prematurely upon the recommendation of the Efficacy and Safety Evaluation Committee in accordance with the pre-specified protocol safety monitoring criteria[*4]. Four patients were under observation during the stop phase when the entire study was terminated. The patients who developed molecular relapse entered the dasatinib retreatment phase, and all the patients regained Molecular Response[*5] (MR) 4.
*1 Patients entered this phase if they achieved MR 4.5 (defined as BCR-ABL1IS <= 0.0032% in the international criteria for determining molecular response) during the induction phase within 2 years of dasatinib treatment. In this phase, dasatinib treatment was continued at the same dose as in the induction phase.
*2 Patients entered this phase if they maintained MR4.5 during the consolidation phase for 12 months. In this phase, dasatinib treatment was discontinued.
*3 Defined as loss of major molecular response (MMR) (BCR-ABL1IS > 0.1%) or loss of MR4 (BCR-ABL1IS > 0.01% confirmed 2 consecutive times).
*4 i.e., the study should be terminated if the treatment-free remission (TFR) rate is less than 25% in the first 20 patients who have entered the stop phase
*5 Defined as BCR-ABL1IS <= 0.01%

Adverse events

In this study, National Cancer Institute Common Terminology Criteria for Adverse Events Japanese version 4.0 JCOG version (CTCAE v4.0-JCOG) grade 4 or higher hematologic toxicity and grade 3 or higher non-hematologic adverse events were collected. Grade 1 or higher TKI withdrawal syndrome during the stop phase were also collected.
Adverse events and the number of patients in the study phases were as follows. The induction phase: neutropenia 4, anemia 1, thrombocytopenia 2 (all above were grade 4), allergic reaction 3, erythroderma 1, edema 1, pleural effusion 1, nausea 1, diarrhea 3, and constipation 1 (all above were grade 3). The consolidation phase: acute coronary syndrome 1 and bone pain 1 (all above were grade 3). The retreatment phase: cerebral infarction 1 (grade 3). The stop phase: arthralgia 2 and myalgia 1 (all above were grade 1) reported as TKI withdrawal syndrome.

Outcome measures

Primary endpoint
#The proportion of patients who achieved TFR, defined as having no molecular relapse and no need for resumption of dasatinib treatment 12 months after dasatinib discontinuation, was not calculated because the study was terminated prematurely at the interim analysis and TFR was observed in only one patient at 12 months after dasatinib discontinuation. The proportion of patients with observed molecular relapse within 12 months of the study discontinuation was 17/21 (81.0%, 95% CI: 58.1 - 94.6).
The median duration of dasatinib treatment before discontinuation in the stop phase was 18.9 months (range 14.9-25.5).
Secondary endpoints
#The proportions of patients with TFR at 24, 36, and 48 months after dasatinib discontinuation were not calculated for the same reasons as in the analysis of the primary endpoint.
#Molecular relapse-free survival at 12 months after dasatinib discontinuation was 16.7%, and the median molecular relapse-free survival at 12 months was 4.0 months (95% CI: 2.4 - 5.0).
#Overall survival including all causes of death at 12, 24, 36, and 48 months after dasatinib discontinuation was not calculated because no deaths were identified after dasatinib discontinuation.
#Of 172 patients, 65 (37.6%, 95% CI: 30.3 - 45.2) achieved MR4.5. The median duration of dasatinib for achieving MR4.5 was 7.7 months (range 3.0-21.1 months).
#Dasatinib dose in relation to achievement of MR4.5: The total dasatinib dose corresponding to 50% achievement of MR4.5 by the Kaplan-Meier method was 63,600 mg (95% confidence interval [CI]: 43,500 to N.A.), but the 95% CI was wide due to the small number of patients who reached MR4.5, and the upper limit of the 95% CI could not be estimated.
#Event-free survival (EFS) during the dasatinib treatment period was estimated to be 94.9% for 1 year and 63.5% for 2 years. A large number of patients were censored due to early termination of the study.
#Tyrosine kinase inhibitor withdrawal syndrome was observed in 2 of the 21 patients who entered the stop phase. Two (9.5%) patients had grade 1 arthralgia and one (4.8%) had grade 1 myalgia, and all of them recovered.
Exploratory endpoints
#Factors associated with achievement of MR4.5 and maintenance of TFR were assessed by sex, Sokal Score, Hasford Score, EUTOS Score, age (>=60 years old, < 60 years old), and achievement of MMR[*6] at 3 months. In both univariate and multivariate analyses, achievement of MMR at 3 months was statistically and significantly related with achievement of MR 4.5. Factors associated with TFR were not assessed because TFR at 12 months after dasatinib discontinuation was observed in only one patient. Increased lymphocyte counts at 1 and 3 months after the start of dasatinib treatment were not assessed, as they increased in all patients.
*6 Defined as a BCR-ABL1 level <= 0.1% on the international scale for molecular response (BCR-ABL1IS)

Plan to share IPD

IPD sharing Plan description

Recruitment status

Main results already published

Date of protocol fixation

2016

Year

05

Month

06

Day

Date of IRB

2016

Year

03

Month

24

Day

Anticipated trial start date

2016

Year

06

Month

01

Day

Last follow-up date

2021

Year

12

Month

03

Day

Date of closure to data entry

Date trial data considered complete

Date analysis concluded

2023

Year

12

Month

03

Day

Other related information

Registered date

2016

Year

05

Month

09

Day

Last modified on

2023

Year

11

Month

26

Day

Link to view the page

Value
https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000025612