A Phase II Study of Dasatinib in Children and Adolescents with Newly Diagnosed Chronic Phase CML or With Ph+ Leukemias Resistant or Intolerant to Imatinib.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Bristol Myers Squibb International Corporation

Participant type

Pediatric, Patients

Age range

0-17 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

27 Apr 2009 → 27 Jan 2025

Decision date (initial)

2024-05-24

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

External identifiers

EU CT number

2024-510784-36-00

EudraCT number

2008-002260-33

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

1. The major cytogenetic response (MCyR) rate to dasatinib therapy in children and adolescents with CP-CML subjects who prove resistant to or intolerant to imatinib.

2. The complete hematologic response (CHR) rate in children and adolescents with Ph+ ALL, AP-CML and BP-CML, who are resistant, intolerant to, or relapse after prior imatinib therapy.

Secondary objectives 3

1. To assess the safety and tolerability of dasatinib in children and adolescents treated with dasatinib for relapsed or refractory Ph+ leukemias
2. To evaluate additional measures of efficacy in children and adolescents with relapsed or refractory Ph+ leukemias treated on a given regimen of dasatinib including: – best cytogenetic rates and hematological response rates – time to response and duration of response – disease free survival (DFS) – progression-free survival (PFS) and overall survival (OS) – rates of complete (CMR) and major (MMR) molecular response
3. To describe the spectrum of the BCR-ABL mutations at baseline, at progression or end of treatment, and to explore the role of mutations as predictors of response

Conditions and MedDRA coding

Children and Adolescents with Newly Diagnosed Chronic Phase CML or with Ph+ Leukemias Resistant to or Intolerant to Imatinib

Regulatory references

EMA paediatric investigation plan (PIP)

EMEA-000567-PIP01-09

Plan to share IPD

Yes

IPD plan description

BMS will provide access to individual anonymized participant data upon request from qualified researchers, and subject to certain criteria. Additional information regarding Bristol Myer Squibb’s data sharing policy and process can be found at: https://www.bms.com/researchers-and-partners/clinical-trials-and-research/disclosure-commitment.html

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 3

1. Signed Written Informed Consent
2. Age and Sex a) Men and women, age 1 to 18 years. Women of childbearing potential (WOCBP) who are sexually active or plan to become sexually active must use two methods of contraception starting at the time of enrollment to the study, during the entire treatment period of the study and for 1 month after the last dose of investigational product to minimize the risk of pregnancy. At least one of the two methods selected must be regarded as a highly effective method of contraception as listed in the protocol section 4.2.1
3. Target Population a) Diagnosis: i) Cohort #1: Subjects must have Ph+ CML in CP (< 15% blasts in peripheral blood and bone marrow, < 20% basophils in peripheral blood, < 30% blasts + promyelocytes in peripheral blood and bone marrow, ≥ 100 X 109 platelets/L unless secondary to recent treatment, No extramedullary involvement other than liver and/or spleen, Ph+ (with 9:22 translocation) demonstrated by bone marrow cytogenetics) ii) Cohort #2: Subjects must have Ph+ ALL or Ph+ AP- or Ph+ BP-CML: (1) Ph+ ALL have to be in first or subsequent relapse or fail to achieve a complete hematological remission. (2) Ph+ AP-CML must meet at least one of the following criteria: (a) ≥ 15% but < 30% blasts in peripheral blood or bone marrow (b) ≥ 30% blasts + promyelocytes in peripheral blood and in bone marrow (c) ≥ 20% basophils in peripheral blood or bone marrow (d) < 100 X 109/L platelets unrelated to therapy (3) Ph+ BP-CML has to meet either of the following criteria: (a) ≥ 30% blasts in peripheral blood or bone marrow (b) Presence of extramedullary blastic disease other than lymph nodes, liver or spleen iii) Cohort #3: Subjects must have been newly diagnosed with Ph+ CML in CP (< 15% blasts in peripheral blood and bone marrow, < 20% basophils in peripheral blood, < 30% blasts + promyelocytes in peripheral blood and bone marrow , ≥ 100 X 109 platelets/L unless thrombocytopenia secondary to recent treatment, No extramedullary involvement other than liver and/or spleen, Ph+ (with 9:22 translocation) by bone marrow cytogenetics) b) Subjects in Cohort #1 or Cohort #2 have to be proven resistant or intolerant to imatinib: i) Intolerance Definition: occurrence of any toxicity grade ≥ 3 considered at least possibly related to imatinib and that led to discontinuation of previous imatinib therapy. ii) For Cohort #1, resistance to imatinib must meet at least one of the following criteria: (a) Failure to achieve, or loss of, CHR after ≥ 3 months of imatinib at a daily dose of 260 mg/m2 or greater. (b) Failure to achieve MCyR after ≥ 6 months of imatinib therapy at a daily dose of 260 mg/m2 or greater. (c) Failure to achieve CCyR after ≥ 12 months of imatinib therapy at a daily dose of 260 mg/m2 or greater. (d) Absolute increase of ≥ 30% of the percentage of Ph+ metaphases, confirmed at 2 - 4 weeks, after prior MCyR to imatinib at a daily dose of 260 mg/m2 or greater. iii) For Cohort #2, resistance to imatinib must meet at least one of the following criteria: (a) Failure to achieve CHR while on imatinib after a ≥ 4-week treatment or a ≥ 50% increase in peripheral blood blasts over a 2-week period (b) Subjects who achieved a CHR subsequently no longer meet the criteria consistently over a consecutive 2-week period while receiving imatinib (c) Absolute increase of ≥ 30% of the percentage of Ph+ metaphases, confirmed at ≥ 6 week interval, after prior MCyR to imatinib. (d) For subjects with Ph+ ALL, first or subsequent relapse [≥ 25% bone marrow blasts] or failure to achieve remission after prior imatinib exposure. c) *Lansky or Karnofsky scale > 50 d) *Life expectancy ≥ 12 weeks e) *Subjects must have recovered to baseline or Grade 1 (NCI CTCAE, version 3.0) from the toxicities (except alopecia) resulting from recent therapies, including chemotherapy, hormonal therapy, immunotherapy, biological therapy or investigational product and radiation therapy. f) *Serum Na, HCO3, PO4 and Ca levels ≤ grade 1 and adequate hepatic and renal function defined as AST, ALT, bilirubin and creatinine ≤ Grade 2 (NCI CTCAE, Version 3.0).

Exclusion criteria 5

1. ) Sex and Reproductive Status a) WOCBP who are unwilling or unable to use a highly effective method to avoid pregnancy for the entire study period and for up to 1 month after the last dose of investigational product. b) Women who are pregnant or breastfeeding or likely to become pregnant c) Women with a positive pregnancy test on enrollment or prior to investigational product administration. d) Sexually active fertile men not using effective birth control if their partners are WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for up to 4 weeks after the last dose of investigational product.
2. 2) Target Disease Exceptions a) Subjects for whom potentially-curative therapy is available, including hematopoietic stem-cell transplantation (HSCT) at the time when subject is assessed for enrollment b) Subjects with isolated central nervous system disease are excluded from study. Subjects with CNS-1 (no detectable blast cells in a sample of cerebrospinal fluid), CNS-2 (< 5 leukemic blast cells in a sample with < 10 erythrocytes per cubic millimeter) and CNS-3 disease (> 5 leukemic blasts per cubic millimeter in a sample with < 10 erythrocytes per cubic millimeter) are eligible for study, 28 provided this is a combined relapse which also involves the bone marrow in addition to CNS and they are asymptomatic (no convulsions or other neurological symptoms). c) Isolated extramedullary disease, with < 5% blasts in bone marrow
3. ) Medical History and Concurrent Diseases a) Any serious uncontrolled medical disorder that would impair the XML File Identifier: z6kdvfPhIIlyNDn6+JcpAPdG1JU= Page 25/41 ability of the subject to receive protocol therapy, including: i) Ongoing uncontrolled infection ii) Clinically-significant disorder of platelet function (e.g. von Willebrand's disease) or ongoing gastrointestinal bleeding iii) Clinically-significant cardiovascular disease, congenital long QT syndrome, history of ventricular arrhythmias or heart block, or prolonged QTc interval > 450 ms (Fridericia correction) on baseline electrocardiogram iv) Subjects diagnosed with the T315I mutation (mutation testing prior to inclusion is highly recommended but is not mandatory at sites without BCR-ABL testing available). v) Subjects who have experienced hypersensitivity to dasatinib or to any of the excipients. Inactive ingredients in dasatinib tablets include: lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl cellulose, and magnesium stearate. The tablet coating consists of hypromellose, titanium dioxide, and polyethylene glycol. vi) Subjects with hereditary problems of galactose intolerance or Lapp lactase deficiency or glucose-galactose malabsorption. vii) Uncorrected hypokalemia or hypomagnesemia. b) Expected non-compliance to protocol schedule or unable to have regular followup due to psychological, social, familial or geographic reasons
4. 4) Prohibited Treatments and/or Therapies a) Prior therapy with dasatinib. b) Any investigational agent or any other anti-cancer agent within 14 days prior to treatment start. i) Imatinib mesylate may be continued up to 7 days before treatment start, or, in the presence of rising peripheral blast cells, imatinib may be continued up to 2 days before treatment start. ii) If required for control of peripheral blast cells or WBCs, 6- mercaptopurine or 6-thioguanine may be given up to 2 days before treatment start and corticosteroids or hydroxyurea can be given during the period immediately prior to treatment start and during the first month of study therapy, these agents will be discontinued (or tapered in the case of corticosteroids) as soon as possible. c) Subjects requiring ongoing medications which may: i) Have a known risk of causing QTc prolongation - see Section 5.5.1.2 ii) Irreversibly inhibit platelet function, or anticoagulants - see Section 5.5.1.3 (Does not apply to low-dose heparin for prophylaxis or to heparin flushes for i.v. lines)
5. 5) Other Exclusion Criteria a) Prisoners or subjects who are involuntarily incarcerated b) Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Cohort #1: Major Cytogenetic Response (MCyR) rate, defined as the proportion of all treated subjects who achieve a complete or partial cytogenetic response on study.
2. Cohort #2: Complete Hematologic Response (CHR) rate, defined as the proportion of all treated subjects who achieve a confirmed CHR on study.

Secondary endpoints 3

1. Cohort #1: CHR rates
2. Cohort #2: MCyR rates
3. For all Cohorts: – Rates of best cytogenetic response – Time to Major Cytogenetic Response (McyR) and duration of and McyR – Time to Complete Hematologic Response (CHR) and duration of CHR – Progression-free Survival (PFS) and Disease free survival (DFS) – Overall Survival – Rates of major and complete molecular response

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Bristol Myers Squibb International Corporation

Sponsor organisation

Bristol Myers Squibb International Corporation

Address

Terhulpsesteenweg 185

City

Watermaal-Bosvoorde

Postcode

1170

Country

Belgium

Scientific contact point

Organisation

Bristol Myers Squibb International Corporation

Contact name

GSM-CT

Public contact point

Organisation

Bristol Myers Squibb International Corporation

Contact name

GSM-CT

Third parties 5

Locations

2 EU/EEA countries · 2 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 9 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications