UMIN-CTR Clinical Trial

Public title

Phase II study of dasatinib (DA) in combination with chemotherapy and allogeneic stem cell transplantation (SCT) for newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia by Japan Acute Leukemia Study Group (JALSG Ph+ALL213)

Acronym

Phase II study of DA in combination with chemotherapy and allogeneic SCT for newly diagnosed Ph+ALL (JALSG Ph+ALL213)

Scientific Title

Phase II study of dasatinib (DA) in combination with chemotherapy and allogeneic stem cell transplantation (SCT) for newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia by Japan Acute Leukemia Study Group (JALSG Ph+ALL213)

Scientific Title:Acronym

Phase II study of DA in combination with chemotherapy and allogeneic SCT for newly diagnosed Ph+ALL (JALSG Ph+ALL213)

Region

Japan

Condition

Philadelphia chromosome-positive acute lymphoblastic leukemia

Classification by specialty

Hematology and clinical oncology

Classification by malignancy

Malignancy

Genomic information

YES

Narrative objectives1

To evaluate the efficacy and safety of DA in combination with chemotherapy and allogeneic SCT for patients with newly diagnosed Philadelphia-chromosome positive acute lymphophblastic leukemia

Basic objectives2

Safety,Efficacy

Basic objectives -Others

Trial characteristics_1

Exploratory

Trial characteristics_2

Explanatory

Developmental phase

Phase II

Primary outcomes

3-year event-free survival

Key secondary outcomes

Key secondary endpoints are;
1. The proportion of complete hematological remission (CHR) after induction.
2. The proportion of complete molecular remission (CMR) at the following points.
(1) after intensive consolidation
(2) pre- and day30, day100 post- SCT.
3. 3-, and 5-year OS, EFS, RFS.
4. Prognostic significance of CMR at the following points.
(1) after intensive consolidation, (2) pre-SCT, (3) day30 of post-SCT, (4) day100 of post-SCT
5. The efficacy of hematopoietic SCT; day100, 1-year OS, RFS, relapse rate, non-relapse mortality.
6. Prognostic significance of additional cytogenetic abnormalities
7. The proportion of therapy related mortality
8. Analysis of early death in induction and intensive consolidation therapy.
9. The frequency of adverse events in each steps of treatment.
10. Safety of hematopoietic SCT; frequency of graft failure, acute and chronic GVHD.

Study type

Interventional

Basic design

Single arm

Randomization

Non-randomized

Randomization unit

Blinding

Open -no one is blinded

Control

Historical

Stratification

Dynamic allocation

Institution consideration

Blocking

Concealment

No. of arms

1

Purpose of intervention

Diagnosis

Type of intervention

Medicine

Interventions/Control_1

After the 7-day PSL therapy, during which positivity of BCR-ABL fusion transcript must be proved, 4-week DA is given with 3-week PSL to achieve CHR. Then 4-week DA is given following 4 drugs (VCR,CPM,DNR,PSL) combination to aim at CMR. C1 (HDMTX/ AraC+DA) and C2 (VCR,DNR,CPM +DA) consolidation are repeated up to 4 cycles. Patient who has an adequate donor proceed to allogeneic SCT during the consolidation. Patient who has no adequate donor proceed to 12 courses of 4-week DA-based maintenance therapy.

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

15

years-old

<=

Age-upper limit

65

years-old

>

Gender

Male and Female

Key inclusion criteria

1. Acute lymphoblastic leukemia.
2. BCR/ABL positive.
3. aged >= 15 years and < 64 years.
4. Patients must not be previously treated except PSL in the prephase PSL therapy.
5. ECOG performance status of 0, 1, 2 or 3.
6. Patients must have adequate cardiac, hepatic, renal, and pulmonary functions.
7. Voluntary written consent must be given before enrollment.

Key exclusion criteria

1. Heart insufficiency.
2. Pulmonary fibrosis, interstitial pneumonitis.
3. Uncontrollable diabetes mellitus.
4. Grade 4 infection.
5. HIV antibody positive.
6. HBs antigen positive.
7. Concurrent disease which may exaggerate adverse events by dasatinib.
1) Pleural effusion, ascites, or other fluid retention..
2) Congenital bleeding diathesis.
3) Diseases requiring anticoagulant or anti-platelet agents.
4) Acquired bleeding diathesis..
8. Psychiatric illness.
9. Active another malignancy.
10. Female patients who are breast feeding or pregnant.
11. Patients who, in the judgment of the investigator, would be inappropriate for entry into this study.

Target sample size

77

Name of lead principal investigator

1st name	Isamu
Middle name
Last name	Sugiura

Organization

Toyohashi Municipal Hospital

Division name

Division of Hematology/Oncology

Zip code

441-8570

Address

50 Hachiken-Nishi, Aotake-Cho, Toyohashi

TEL

0532-33-6111

Email

sugiura-isamu@toyohashi-mh.jp

Name of contact person

1st name	Isamu
Middle name
Last name	Sugiura

Organization

Toyohashi Municipal Hospital

Division name

Division of Hematology/Oncology

Zip code

441-8570

Address

50 Hachiken-Nishi, Aotake-Cho, Toyohashi

TEL

0532-33-6111

Homepage URL

http://www.jalsg.jp

Email

sugiura-isamu@toyohashi-mh.jp

Institute

JALSG

Institute

Department

Personal name

Organization

Ministry of Health, Labor and Welfare

Organization

Division

Category of Funding Organization

Japanese Governmental office

Nationality of Funding Organization

Japan

Co-sponsor

Name of secondary funder(s)

Organization

Toyohashi Municipal Hospital

Address

50 Hachikennishi Aotake-cho, Toyohashi, Japan

Tel

0532-33-6111

Email

sugiura-isamu@toyohashi-mh.jp

Secondary IDs

NO

Study ID_1

Org. issuing International ID_1

Study ID_2

Org. issuing International ID_2

IND to MHLW

Institutions

Date of disclosure of the study information

2013

Year

11

Month

01

Day

URL releasing protocol

Publication of results

Unpublished

URL related to results and publications

https://doi.org/10.1182/bloodadvances.2021004607

Number of participants that the trial has enrolled

81

Results

DA-based two-step induction in which DA was introduced instead of IM to enhance efficacy and two-step induction to minimize toxicity showed improved survival significantly in terms of the primary endpoint of 3Y-EFS. Toxicity was minimized. No one died of chemotherapy-related toxicity. However, 16% of patients died of transplanted-related toxicity. 3Y-EFS and OS for the evaluable patients were 66% and 82%, Those of patients who underwent alloHSCT in CR1 were 72% and 88%, respectively

Results date posted

2022

Year

01

Month

30

Day

Results Delayed

Delay expected

Results Delay Reason

The results have not been published yet.

Date of the first journal publication of results

2022

Year

01

Month

25

Day

Baseline Characteristics

Median age 45 (16-64)　years
　Gender, male/female, n(%)
37 (47.4)/41(52.6)
　ECOG PS, 0/1 44 (56.4)/29 (37.2)
2/3 4 ( 5.1)/ 1 ( 1.3)
BCR-ABL1 type, n(%)
　major 17 (21.8)
　minor 56 (71.8)
　major+minor 5 ( 6.4)
Copy no. of BCR-ABL1(x105) med. (range)
all case 3.9 (0.21-34.0)
　major 2.7 (0.86- 4.9)
minor 4.2 (0.21-34.0)
Cytogenetics, n (%)
t(9;21) only 18/77 (23.4)
additional abnormality
50/77 (64.9)

Participant flow

Eighty-one patients were enrolled from 46 hospitals between 1 November 2013 and 12 April 2016. Of them, 78 patients were eligible. All of them achieved complete hematological remission after induction. Fifty-eight patients, whose CRR was 75.9%, underwent allogeneic hematopoietic stem cell transplantation (HSCT) and 6 completed the protocol chemotherapy only. Fourteen patients withdrew the study. Follow up of the study was ended on 1 July 2019 to evaluate the primary end point.

Adverse events

Chemotherapy-related mortality was not reported during chemotherapy. Major toxicities were neutropenia and related infectious complications, such as febrile neutropenia and sepsis. Grade 4 neutropenia were noted 51.3%, 93.5%, 98.6% and 34.9% in IND, IC, C1-1, and C2-1, which caused grade 3 febrile neutropenia 6.4%, 15.6%, 69.0%, and 7.0%, respectively. Grade4 FN were reported 2.8% in C1-1. Grade 4 sepsis was reported 1.3%, 6.5%, 8.5%, and 0.0%. Grade 4 other non-hematological were 1.3%-1.4%. As DA related toxicities, grade 3 liver dysfunction were reported 12.8%, 3.9%, and 12.7%, in IND, IC, and C1-1, respectively. One patient developed severe allergic reactions. Six (10.3%) patients died in remission due to transplant-related toxicity. Grade1/2 bleeding was reported 5 and 2 patients in IN and C1-1, respectively. Three of 5 bleeding in IN were complicated with grade3/4 DIC. Grade1/2 pleural effusion was reported 2, 1, and 1 patient in IN, IC, and C1-1.

Outcome measures

Primary Endpoint:
At the median follow-up of 4 years(2.5-5.4), the 3Y-EFS was 66.2% (90%CI, 56.4%-74.2%). The lower level of 90% CI was 56.4%, which exceeded the threshold of 45%. Thus, the treatment in this trial was determined to be effective.

Plan to share IPD

none

IPD sharing Plan description

none

Recruitment status

Completed

Date of protocol fixation

2013

Year

09

Month

04

Day

Date of IRB

2013

Year

09

Month

19

Day

Anticipated trial start date

2013

Year

11

Month

01

Day

Last follow-up date

2019

Year

07

Month

01

Day

Date of closure to data entry

Date trial data considered complete

Date analysis concluded

Other related information

Registered date

2013

Year

10

Month

30

Day

Last modified on

2022

Year

01

Month

30

Day

Link to view the page

Value
https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000014230