UMIN-CTR Clinical Trial

Basic information
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
Condition	Philadelphia chromosome-positive acute lymphoblastic leukemia
Classification by specialty	Hematology and clinical oncology
Classification by malignancy	Malignancy
Genomic information	YES

Objectives
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

Assessment
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.

Base
Study type	Interventional

Study design
Basic design	Single arm
Randomization	Non-randomized
Randomization unit
Blinding	Open -no one is blinded
Control	Historical
Stratification
Dynamic allocation
Institution consideration
Blocking
Concealment

Intervention
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

Eligibility
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

Research contact person
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

Public contact
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

Sponsor
Institute	JALSG
Institute
Department

Funding Source
Organization	Ministry of Health, Labor and Welfare
Organization
Division
Category of Funding Organization	Japanese Governmental office
Nationality of Funding Organization	Japan

Other related organizations
Co-sponsor
Name of secondary funder(s)

IRB Contact (For public release)
Organization	Toyohashi Municipal Hospital
Address	50 Hachikennishi Aotake-cho, Toyohashi, Japan
Tel	0532-33-6111
Email	sugiura-isamu@toyohashi-mh.jp

Secondary IDs
Secondary IDs	NO
Study ID_1
Org. issuing International ID_1
Study ID_2
Org. issuing International ID_2
IND to MHLW

Institutions
Institutions

Other administrative information
Date of disclosure of the study information	2013 Year 11 Month 01 Day

Related information
URL releasing protocol
Publication of results	Unpublished

Result
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

Progress
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
Other related information

Management information
Registered date	2013 Year 10 Month 30 Day
Last modified on	2022 Year 01 Month 30 Day

Link to view the page
URL(English)	https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000014230