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Dasatinib Combined With Chemotherapy in Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia

Primary Purpose

Acute,Leukemia, Lymphoid

Status

Completed

Phase

Phase 2

Locations

China

Study Type

Interventional

Intervention

Dasatinib

prednisone

cyclophosphamide

daunorubicin

vincristine

cytarabine

mercaptopurine

methotrexate

dexamethasone

mitoxantrone

etoposide

allogeneic hematopoietic stem cell transplantation

autologous hematopoietic stem cell transplantation

About this trial

This is an interventional treatment trial for Acute,Leukemia, Lymphoid focused on measuring Acute, Leukemia, Lymphoid, Philadelphia chromosome, dasatinib

Eligibility Criteria

18 Years - 55 Years (Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Patients aged 18 to 60 years with De novo Philadelphia chromosome positive (Philadelphia chromosome positive or BCR/ABL transcript positive) acute lymphoblastic leukemia.
Eastern Cooperative Oncology Group (ECOG) Performance status 2.
Adequate end organ function as defined by: Total bilirubin ≤ 1.5 x upper limit of normal（ULN）; serum glutamic-oxaloacetic transaminase(SGOT) and serum glutamic pyruvic transaminase(SGPT) ≤ 2.5 x ULN; Creatinine ≤ 1.5 x ULN; Serum amylase and lipase ≤ 1.5 x ULN; Alkaline phosphatase ≤ 2.5 x ULN unless considered tumor related; Patients must have adequate cardiac function (ejection fraction ≥ 45 % on Multiple Gated Acquisition (MUGA) scan).
Patients must have the following laboratory values (≥ lower limit of normal (LLN) or corrected to within normal limits with supplements prior to the first dose of study medication.): Potassium ≥ LLN; Magnesium ≥ LLN; Phosphorus ≥ LLN
Patients should sign informed consent form.

Exclusion Criteria:

Impaired cardiac function:
Long QT syndrome or a known family history of long QT syndrome; clinically significant resting brachycardia (<50 beats per minute); ejection fraction < 45 % on MUGA scan. QTc interval > 450 msec on baseline ECG (using the QTcF formula). If QTcF interval>450 msec and electrolytes are not within normal ranges, electrolytes should be corrected and then the patient re-screened for QTc. Myocardial infarction within 12 months prior to starting study; other clinically significant heart disease (e.g. unstable angina, congestive heart failure or uncontrolled hypertension, uncontrolled arrhythmias).
Patients who are currently receiving treatment with any medications that have the potential to prolong the QT interval and the treatment cannot be either discontinued or switched to a different medication prior to starting study drug.
Other concurrent severe and/or uncontrolled medical conditions:
Patients with another primary malignant disease, except those that do not currently require treatment; acute or chronic liver, pancreatic or severe renal disease; another severe and/or life-threatening medical disease.
Patients who are: (a) pregnant, (b) breast feeding, (c) of childbearing potential without a negative pregnancy test prior to baseline and (d) male or female of childbearing potential unwilling to use contraceptive precautions throughout the trial (post-menopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential).
Who is known human deficiency virus (HIV) positive.
Use of any other investigational agent in the last 30 days.

Sites / Locations

Institute of Hematology & Blood Diseases Hospital

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Arm A

Arm Description

Dasatinib 100 mg per day will be given orally along with combination chemotherapy starting day 8 of induction chemotherapy. Dasatinib will be given continuously (if it's tolerable) for 2 years since achievement of complete remission (CR) as part of consolidation chemotherapy and maintenance therapy.Patients can receive allogeneic hematopoietic stem cell transplantation (HSCT),or patients who keep BCR/ABL negative can receive autologous HSCT whenever possible during their first CR. Otherwise, they will finish the consolidation chemotherapy.

Outcomes

Primary Outcome Measures

Overall survival (OS)

Secondary Outcome Measures

Disease-free survival (DFS)

The complete remission (CR) rate

The molecular CR rate

The plasma level of dasatinib in the regimen

The Cerebrospinal fluid level of dasatinib in the regimen

Number of adverse event of combined treatment

Grade of adverse event of combined treatment

Full Information

NCT ID

NCT02523976

First Posted

August 5, 2015

Last Updated

August 2, 2022

Sponsor

Institute of Hematology & Blood Diseases Hospital, China

1. Study Identification

Unique Protocol Identification Number

NCT02523976

Brief Title

Dasatinib Combined With Chemotherapy in Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia

Official Title

Dasatinib Plus Multi-agent Chemotherapy for New Diagnosed Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia

Study Type

Interventional

2. Study Status

Record Verification Date

August 2022

Overall Recruitment Status

Completed

Study Start Date

August 1, 2015 (undefined)

Primary Completion Date

December 31, 2021 (Actual)

Study Completion Date

December 31, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Institute of Hematology & Blood Diseases Hospital, China

4. Oversight

Data Monitoring Committee

5. Study Description

Brief Summary

In this single-center, open-label, no control,prospective clinical trial, a total of 30 Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) patients will be enrolled. Dasatinib 100 mg per day will be given orally along with combination chemotherapy starting day 8 of induction chemotherapy. Dasatinib will be given continuously (if it's tolerable) for 2 years since achievement of complete remission (CR) as part of consolidation chemotherapy and maintenance therapy.Patients can receive allogeneic hematopoietic stem cell transplantation (HSCT) or autologous HSCT whenever possible during their first CR. Otherwise, they will finish the consolidation chemotherapy. The purpose of current study is to determine the clinical efficacy and tolerability of combination therapy of Dasatinib with multi-agent chemotherapy in newly-diagnosed Ph+ ALL.

Detailed Description

In this single-center, open-label, Phase II study, nonrandomized,no control,prospective clinical trial,a total of 30 Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) patients will be enrolled.Patients will be diagnosed according to morphologic,immunologic, cytogenetic and molecular(MICM) criteria, including bone marrow morphology, immunophenotype, cytogenetic and molecular genetic (BCR/ABL gene, qualitative and quantitative analysis) examination. Dasatinib 100 mg per day will be given orally along with combination chemotherapy starting day 8 of induction chemotherapy. Dasatinib will be given continuously (if it's tolerable) for 2 years since achievement of complete remission (CR) as part of consolidation chemotherapy and maintenance therapy.Patients can receive allogeneic hematopoietic stem cell transplantation (HSCT),or patients who keep BCR/ABL negative can receive autologous HSCT whenever possible during their first CR. Otherwise, they will finish the consolidation chemotherapy. Total duration of follow-up will be 2 year after last enrollment. Pre-treatment evaluation will include complete blood count (CBC) with reticulocyte count, chemistry, electrolytes, coagulation, hepatitis profile, chest X-ray.Evaluation during treatment will include: CBC every two days during myelosuppression, chemistry, electrolytes, coagulation before each cycles of chemotherapy. Quantitative PCR (RQ-PCR) for Bcr-Abl will be done from bone marrow mononuclear cells at diagnosis, at CR, and before each cycles of consolidation chemotherapy,then every 3 months during maintenance therapy. For patients who undergo allogeneic HSCT, quantitative PCR for Bcr-Abl will be done from bone marrow mononuclear cells at the initiation of conditioning, and then every 3 months. PCR will be done in IS standardized lab. Side effects of combination therapy will be monitored and described according to Common Toxicity Criteria, version 4.0 (National Cancer Institute, USA). The purpose of current study is to determine the clinical efficacy and tolerability of combination therapy of Dasatinib with multi-agent chemotherapy in newly-diagnosed Ph+ ALL.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Acute,Leukemia, Lymphoid

Keywords

Acute, Leukemia, Lymphoid, Philadelphia chromosome, dasatinib

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

30 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Arm A

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Dasatinib

Intervention Description

Second-generation tyrosine kinase inhibitor

Intervention Type

Drug

Intervention Name(s)

prednisone

Intervention Type

Drug

Intervention Name(s)

cyclophosphamide

Intervention Type

Drug

Intervention Name(s)

daunorubicin

Intervention Type

Drug

Intervention Name(s)

vincristine

Intervention Type

Drug

Intervention Name(s)

cytarabine

Intervention Type

Drug

Intervention Name(s)

mercaptopurine

Intervention Type

Drug

Intervention Name(s)

methotrexate

Intervention Type

Drug

Intervention Name(s)

dexamethasone

Intervention Type

Drug

Intervention Name(s)

mitoxantrone

Intervention Type

Drug

Intervention Name(s)

etoposide

Intervention Type

Procedure

Intervention Name(s)

allogeneic hematopoietic stem cell transplantation

Intervention Type

Procedure

Intervention Name(s)

autologous hematopoietic stem cell transplantation

Primary Outcome Measure Information:

Title

Overall survival (OS)

Time Frame

From date of diagnosis until the date of death from any cause, assessed up to 60 months.

Secondary Outcome Measure Information:

Title

Disease-free survival (DFS)

Time Frame

From the date of complete remission(CR) until the date of documented relapse,assessed up to 60 months.

Title

The complete remission (CR) rate

Time Frame

Participants will be followed for the duration of the treatment, an expected average of 6 months.

Title

The molecular CR rate

Time Frame

Participants will be followed for the duration of the treatment, an expected average of 24 months.

Title

The plasma level of dasatinib in the regimen

Time Frame

Up to 3 months.

Title

The Cerebrospinal fluid level of dasatinib in the regimen

Time Frame

Up to 6 months.

Title

Number of adverse event of combined treatment

Time Frame

Participants will be followed for the duration of the treatment, an expected average of 24 months.

Title

Grade of adverse event of combined treatment

Time Frame

Participants will be followed for the duration of the treatment, an expected average of 24 months.

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

55 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Patients aged 18 to 60 years with De novo Philadelphia chromosome positive (Philadelphia chromosome positive or BCR/ABL transcript positive) acute lymphoblastic leukemia. Eastern Cooperative Oncology Group (ECOG) Performance status 2. Adequate end organ function as defined by: Total bilirubin ≤ 1.5 x upper limit of normal（ULN）; serum glutamic-oxaloacetic transaminase(SGOT) and serum glutamic pyruvic transaminase(SGPT) ≤ 2.5 x ULN; Creatinine ≤ 1.5 x ULN; Serum amylase and lipase ≤ 1.5 x ULN; Alkaline phosphatase ≤ 2.5 x ULN unless considered tumor related; Patients must have adequate cardiac function (ejection fraction ≥ 45 % on Multiple Gated Acquisition (MUGA) scan). Patients must have the following laboratory values (≥ lower limit of normal (LLN) or corrected to within normal limits with supplements prior to the first dose of study medication.): Potassium ≥ LLN; Magnesium ≥ LLN; Phosphorus ≥ LLN Patients should sign informed consent form. Exclusion Criteria: Impaired cardiac function: Long QT syndrome or a known family history of long QT syndrome; clinically significant resting brachycardia (<50 beats per minute); ejection fraction < 45 % on MUGA scan. QTc interval > 450 msec on baseline ECG (using the QTcF formula). If QTcF interval>450 msec and electrolytes are not within normal ranges, electrolytes should be corrected and then the patient re-screened for QTc. Myocardial infarction within 12 months prior to starting study; other clinically significant heart disease (e.g. unstable angina, congestive heart failure or uncontrolled hypertension, uncontrolled arrhythmias). Patients who are currently receiving treatment with any medications that have the potential to prolong the QT interval and the treatment cannot be either discontinued or switched to a different medication prior to starting study drug. Other concurrent severe and/or uncontrolled medical conditions: Patients with another primary malignant disease, except those that do not currently require treatment; acute or chronic liver, pancreatic or severe renal disease; another severe and/or life-threatening medical disease. Patients who are: (a) pregnant, (b) breast feeding, (c) of childbearing potential without a negative pregnancy test prior to baseline and (d) male or female of childbearing potential unwilling to use contraceptive precautions throughout the trial (post-menopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential). Who is known human deficiency virus (HIV) positive. Use of any other investigational agent in the last 30 days.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Jianxiang Wang, Dr.

Organizational Affiliation

Institute of Hematology & Blood Diseases Hospital, China

Official's Role

Principal Investigator

Facility Information:

Facility Name

Institute of Hematology & Blood Diseases Hospital

City

Tianjin

State/Province

Tianjin

ZIP/Postal Code

300020

Country

China

12. IPD Sharing Statement

Citations:

PubMed Identifier

34120773

Citation

Gong X, Li L, Wei H, Liu B, Zhou C, Zhang G, Liu K, Lin D, Gong B, Wei S, Li Y, Mi Y, Wang Y, Wang J. A Higher Dose of Dasatinib May Increase the Possibility of Crossing the Blood-brain Barrier in the Treatment of Patients With Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia. Clin Ther. 2021 Jul;43(7):1265-1271.e1. doi: 10.1016/j.clinthera.2021.05.009. Epub 2021 Jun 10.

Results Reference

derived

PubMed Identifier

33858040

Citation

Zhang GJ, Gong XY, Qiu SW, Zhou CL, Liu KQ, Lin D, Liu BC, Wei H, Wei SN, Li Y, Gu RX, Gong BF, Liu YT, Fang QY, Mi YC, Wang Y, Wang JX. [Dasatinib combined with multi-agent chemotherapy regimen in newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia: a prospective study from a single center]. Zhonghua Xue Ye Xue Za Zhi. 2021 Feb 14;42(2):109-115. doi: 10.3760/cma.j.issn.0253-2727.2021.02.004. Chinese.

Results Reference

derived

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Dasatinib Combined With Chemotherapy in Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia

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