A multicentre, randomized trial in adults with de novo Philadelphia-Chromosome positive acute lymphoblastic leukemia to assess the efficacy of ponatinib versus imatinib in combination with low-intensity chemotherapy, to compare end of therapy with indication for SCT versus TKI, blinatumomab and chemotherapy in optimal responders and to evaluate blinatumomab in suboptimal responders (GMALL-EVOLVE)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Goethe University Frankfurt

Participant type

Patients

Age range

18-64 years

Gender

Male and Female

Therapeutic area

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

Trial duration

13 Jul 2023 → ongoing

Decision date (initial)

2024-11-08

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

External identifiers

EU CT number

2024-517966-40-00

EudraCT number

2022-000760-21

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy

To prove non-inferiority in the overall survival (OS) of patients (pts) with Ph+ ALL and molecular CR treated with tyrosinkinase inhibitor (TKI), chemotherapy (chemo) alternating with Blinatumomab (Blina) (TKI-Chemo-Blina) versus end of therapy (EOT) with indication for SCT

Secondary objectives 1

1. To compare the rate of molecular complete remission after induction and first consolidation with chemotherapy and Ponatinib versus Imatinib

Conditions and MedDRA coding

Acute lymphoblastic leukemia (ALL), de novo, Ph/BCR::ABL1 positive (Ph+)

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 1

1. Male or female patients >= 18 years, <=65 years, Philadelphia chromosome or BCR::ABL1 positive ALL, Not previously treated except with corticosteroids ≤ 7 days, standard GMALL prephase with dexamethasone and cyclophosphamide including intrathecal therapy, hydroxyurea, a single dose vincristine or other cytostatic drugs and start of standard induction for Ph-positive ALL (1 dose vincristine, 1 dose of Rituximab, 2 doses dexamethasone and up to 5 days Imatinib), ECOG performance status ≤2, Signed written inform consent, Molecular evaluation for BCR::ABL1 performed, Negative pregnancy test in women of childbearing potential, Woman of childbearing potential willing to use 2 highly effective methods of contraception while receiving study treatment and for an additional 3 months after the last dose of study treatment (Pearl-Index <1%). Male who has a female partner of childbearing potential willing to use 2 highly effective forms of contraception while receiving study treatment and for at least an additional 3 months after the last dose of study treatment (Pearl-Index <1%). Effective Contraception is defined as: o abstinence o a hormonal contraceptive method (birth control pills, intrauterine spiral, vaginal ring, contraceptive patches, depot implants or injections) in combination with barrier methods (condoms, cervical cap, diaphragm with spermicides) o Vasectomy in patients or male partners Women of childbearing potential are defined as mature women without hysterectomie or surgical sterilization or women without menopause. Menopause means without without menstruation for natural reasons for one year, 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, Serum lipase ≤ 1.5 x ULN. For serum lipase > ULN - ≤ 1.5 x ULN, value must be considered not clinically significant and not associated with risk factors for acute pancreatitis, Normal QTcF interval ≤450 ms for males and ≤470 ms for females, Signed and dated written informed consent is available, Participation in the registry of the German Multicenter Study Group for Adult ALL (GMALL)

Exclusion criteria 1

1. History of malignancy other than ALL diagnosed within 5 years (yrs) prior to start of protocol-specified therapy with defined exceptions: o Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease o Adequately treated cervical carcinoma in situ without evidence of disease o Adequately treated breast ductal carcinoma in situ without evidence of disease o Prostatic intraepithelial neoplasia without evidence of prostate cancer, Contraindications against the use of Imatinib, Ponatinib, chemotherapy or Blinatumomab, Patient previously treated with tyrosine kinase inhibitors, Nursing women, Known impaired cardiac function, including any of the following: o LVEF < 40% o Complete left bundle branch block o Right bundle branch block plus left anterior hemiblock, bifascicular block o History of or presence of clinically significant ventricular or atrial tachyarrhythmias o Clinically significant resting bradycardia (< 50 beats per minute) o Congenital long QT syndrome or QTcF >470 msec for females and >450 msec for males on screening ECG. If QTc > 470 msec for females and > 450 msec for males and electrolytes are not within normal ranges before ponatinib dosing, electrolytes should be corrected and then the patient rescreened for QTcF crite- rion. o Myocardial infarction within 12 months prior to starting study treatment o Other clinically significant heart disease (e.g. unstable angina, congestive heart failure, uncontrolled hypertension), Symptomatic peripheral vascular disease, Any history of ischemic stroke or transient ischemic attacks (TIAs), Uncontrolled hypertriglyceridaemia, History or presence of clinically relevant CNS pathology such as epilepsy, childhood or adult seizure, paresis, cerebrovascular ischemia/haemorrhage, severe brain injuries, aphasia, stroke, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, psychosis (with exception of CNS leukemia that is well controlled with intrathecal therapy), History or active relevant autoimmune disease, Known hypersensitivity to immunoglobulins or to any other component of the study drug formulation, Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing is not man- datory) or active infection with Hepatitis B or C, History of pancreatitis within 6 months previous to start of treatment within the trial, Treatment with any other investigational agent or participating in another trial within 30 days prior to entering this study, Inadequate hepatic functions defined as ASAT or ALAT > 2,5 times the institutional upper limit of noral or > 5 times ULN if considered due to leukemia, 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, Concurrent severe diseases which exclude the administration of therapy e.g. severe, uncontrolled acute or chronic infections, Inability to understand and/or unwillingness to sign a written informed consent

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Probability of overall survival at 2,3 and 4 years from randomization I in patients with mo- lecular remission after consolidation 1 comparing a combination treatment of TKI, Blina- tumomab and chemotherapy versus EOT with indication for SCT

Secondary endpoints 1

1. Rate of molecular complete remission at week 11 after consolidation with chemotherapy in combination with Ponatinb versus Imatinib

Investigational products

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

Test 2

Comparator 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Goethe University Frankfurt

Sponsor organisation

Goethe University Frankfurt

Address

Theodor-Stern-Kai 7

City

Frankfurt Am Main

Postcode

60590

Country

Germany

Scientific contact point

Organisation

Goethe University Frankfurt

Contact name

GMALL Studienzentrale

Public contact point

Organisation

Goethe University Frankfurt

Contact name

GMALL Studienzentrale

Locations

1 EU/EEA country · 89 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 22 files

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

Application history

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