EWALL-PH-03: An open label, 2-arm, Randomised phase II study to Compare the Safety and Efficacy of Ponatinib plus Chemotherapy with Imatinib plus Chemotherapy as front-line therapy for patients aged 55 years and over with Philadelphia chromosome positive (Ph+ or BCR-ABL+) Acute Lymphoblastic Leukemia (ALL)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Cardiff University

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

30 Jan 2025 → ongoing

Decision date (initial)

2025-01-30

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Funding sources

Incyte

External identifiers

EU CT number

2023-505330-95-01

EudraCT number

2018-003350-25

ClinicalTrials.gov

NCT04688983

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Therapy, Efficacy

To compare the molecular response to Ponatinib and Imatinib in combination with standard induction and consolidation chemotherapy

Secondary objectives 2

1. To compare the event free survival with Ponatinib and Imatinib in combination with standard induction and consolidation chemotherapy
2. For each endpoint comparing within the following arms: • Arm 1 – Ponatinib plus standard induction and consolidation • Arm 2 – Imatinib plus standard induction and consolidation (comparator arm) • To compare the safety and tolerability of ponatinib and imatinib in combination with induction and consolidation chemotherapy • To compare the efficacy of ponatinib and imatinib in combination with induction and consolidation chemotherapy as determined by overall survival and relapse-free survival • To determine the frequency of BCR-ABL1 tyrosine kinase domain mutations on therapy (T315I, p-loop and compound mutations) by standard molecular genetic techniques Exploratory objectives

Conditions and MedDRA coding

Blood cancer

Regulatory references

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. Male or female patients > 55 years (biological age)
2. Philadelphia chromosome- or BCR-ABL positive acute lymphoblastic leukemia
3. Not previously treated except with corticosteroids, single dose vincristine or up to three doses of cyclophosphamide (maximum cumulative dose 1g/m2) or intrathecal therapy to control meningeal leukaemia
4. No uncontrolled CNS involvement
5. WHO performance status <2
6. Normal serum levels > LLN (lower limit of normal) of potassium and magnesium, or corrected to within normal limits with supplements, prior to the first dose of study medication
7. Signed written informed consent
8. Molecular evaluation for BCR-ABL1 performed
9. Willingness of sexually active male subjects whose sexual partners are women of childbearing potential (WOCBP), to use an effective form of contraception (pearl index < 1%) during the study and at least 6 months thereafter. Effective forms of contraception are complete sexual abstinence (refraining from heterosexual intercourse during the entire period of risk associated with the study treatments), combined oral contraceptive, hormone IUCD, vaginal hormone ring, transdermal contraceptive patch, contraceptive implant or depot contraceptive injection in combination with a second method of contraception like a condom or a cervical cap/diaphragm with spermicide or surgical sterilisation (vasectomy) in male patients
10. Women of non-childbearing potential defined as sexually mature women who have undergone a hysterectomy or surgical sterilization or who have been naturally postmenopausal for at least 12 consecutive months (i.e., absence of menses in the preceding 12 consecutive months)

Exclusion criteria 15

1. Patient previously treated with tyrosine kinase inhibitors
2. Known impaired cardiac function (if uncontrolled), including any of the following: • LVEF < 40% • Complete left bundle branch block • Right bundle branch block plus left anterior hemiblock, bifascicular block • History of or presence of clinically significant ventricular or atrial tachyarrhythmias • Clinically significant resting bradycardia (< 50 beats per minute) • Congenital long QT syndrome or QTcF >470 msec on screening ECG. If QTc > 470 msec and electrolytes are not within normal ranges before ponatinib dosing, electrolytes should be corrected and then the patient rescreened for QTcF criterion. • Myocardial infarction within 12 months prior to starting study treatment • Other clinical significant heart disease (e.g. unstable angina, congestive heart failure, uncontrolled hypertension)
3. Symptomatic peripheral vascular disease
4. Any history of ischemic stroke or transient ischemic attacks (TIAs)
5. Patients with a history of another primary malignancy that is currently clinically significant or currently requires active intervention
6. Active ALL in the CNS (confirmed by CSF analysis) or testes (by clinical assessment)
7. Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing is not mandatory) or active infection with Hepatitis B or C
8. Treatment with any other investigational agent or participating in another trial within 30 days prior to entering this study
9. Inadequate hepatic functions defined as ASAT or ALAT > 2,5 times the institutional upper limit of normal or > 5 times ULN if considered due to leukemia
10. Total bilirubin > 1.5 fold the institutional upper limit unless considered to be due to organ involvement by the leukemia or to M. Gilbert/M. Meulengracht
11. Concurrent severe diseases which exclude the administration of therapy
12. Chronic pancreatitis or acute pancreatitis within 6 months of study start
13. Pregnant or lactating females
14. Patients unwilling or unable to comply with the protocol
15. Patients with history of hypersensitivity to any of the experimental treatments

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Achievement of a molecular response in treatment arms 1 and 2 defined by a BCR-ABL1/ABL1 (B/A) transcript ratio of ≤10-4 by the time point scheduled for MRD analysis after consolidation 2 (for arms 1 and 2) or within 5 months after start of study treatment, whichever is earlier.

Secondary endpoints 15

1. Event-free survival (EFS), with an event defined as failure to achieve a CR, progression, relapse or death
2. Confirmed undetectable BCR-ABL1 transcripts with an assay sensitivity of at least 10-4.5 at any time prior to maintenance therapy, after completing consolidation therapy
3. Molecular response defined by a B/A ratio ≤ 0.0003% in bone marrow
4. Time to best molecular response- this will be measured as time to event
5. Adverse event grade 3 to 5, measured at each treatment cycle
6. Discontinuation of study treatment due to an adverse event
7. Adverse events of special interest: cardiovascular and thromboembolic AE, pancreatitis, cytokine release syndrome, tumour lysis syndrome, neurologic AEs ≥ grade 3, measured at each treatment cycle
8. Early death: defined by death during the induction period from inclusion to complete remission or before day 56
9. Death in complete remission-measured as a proportion
10. Detection of a T315I or p-loop mutation
11. Detection of a compound mutation
12. Relapse - measured as a proportion
13. Premature discontinuation of ponatinib or imatinib due to toxicity
14. Relapse free survival - Relapse free survival (RFS) is calculated from the date of documented complete remission to date of relapse or death, whatever is earlier. Patients still in remission will be censored at the time of last follow-up
15. Overall survival- Overall survival (OS) is calculated from the first day of therapy to the date of death. Surviving patients will be censored at the time of last follow-up

Investigational products

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

Test 2

Comparator 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Cardiff University

Sponsor organisation

Cardiff University

Address

Neuadd Meirionnydd, Heath Park Way, Heath Heath Park Way Heath

City

Cardiff

Postcode

CF14 4YU

Country

United Kingdom

Scientific contact point

Organisation

Cardiff University

Contact name

Sarah Burns

Public contact point

Organisation

Cardiff University

Contact name

Sarah Burns

Locations

3 EU/EEA countries · 9 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

Documents 15 files

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

Application history

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