International multicenter, open-label clinical trial for the treatment of acute myeloid leukemia in children and adolescents

Overview

Sponsor-declared trial summary

Key facts

Sponsor

GPOH gGmbH

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

6 Dec 2022 → ongoing

Decision date (initial)

2023-10-02

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

German Cancer Aid

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy

Group A: To determine if the event-free-survival of patients with de-novo AML other than APL can be improved with the therapeutic use of CPX-351
Group B: To determine the initial efficacy of Gemtuzumab-Ozogamicin when added to standard chemotherapy backbone in children with relapsed or refractory AML (CBF-AML will receive standard therapy: IDA-FLA)
Group C: To compare GVRDS in patients treated with Treosulfan-based conditioning regimen compared with those treated with BuCyMel. GVRDS is a composite endpoint. Events included in the composite
endpoint GVRDS are:
▪ Acute GvHD grade 3-4 (G)
▪ Chronic GvHD (moderate and severe) (G)
▪ VOD Grad 3 or 4 (V)
▪ Clinical or Molecular Relapse (R)
▪ Death from any cause (D)
▪ Diagnosis of a second malignant neoplasm (S)
All Groups: To collect samples for biological and toxicity studies

Secondary objectives 21

1. All Groups: To establish a diagnostic and logistic network to obtain an individual characterization of AML based on morphology, immunophenotype, type I and type II mutations, signal pathway activation, and monitoring of MRD and/or treatment response for individualized stratification to targeted therapy within a short timeframe.
2. Group A: To improve the EFS through cytogenetic-, molecular genetic- and MRDbased risk classification
3. Group A: To validate the risk stratification algorithm, defined by the collaborating study groups
4. Group A: To compare the OS probability in the 2 randomization arms
5. Group A: To compare the EFS probability in the 2 randomization arms
6. Group A: To compare the CR rate (after the 2 inductions) between the 2 randomization arms
7. Group A: To compare treatment-related mortality between the 2 randomization arms
8. Group A: To identify the molecular relapse after intensive chemotherapy through MRD monitoring in peripheral blood (up to month 18 from diagnosis)
9. Group B: To determine the clinical outcome in Group B in comparison to the historical control, defined as refractory disease, complete remission rate after second reinduction courses, cumulative incidence of relapse, eventfree survival and overall survival
10. Group B:To evaluate the incidence of treatment-related mortality and toxicity of GO according to the CTCAE 5.0 when added to the standard chemotherapy backbone, in terms of mucosal toxicity, bone marrow (BM) aplasia, liver toxicity with special respect to the development of VOD, also called SOS, short- and long-term cardiotoxicity and other adverse reactions, as compared to patients treated with standard chemotherapy backbone only.
11. Group B:To identify additional prognostic factors in pediatric relapsed AML, other than early treatment response, cytogenetic/molecular lesions, and duration of first complete remission
12. Group B:To describe MRD trajectories after 1st and 2nd induction (either by flow or by molecular genetic); in case of delayed HSCT, a 3rd MRD measurement will be performed before HSCT
13. Group C: To evaluate the treatment-related toxicities for various organ systems (CTCAE v5 grade 3-5)
14. Group C:To evaluate the neutrophil and platelet engraftment
15. Group C:To evaluate the Donor chimerism d30/d100
16. Group C: To evaluate the 100-day Grade 2-4 Acute GvHD
17. Group C: To evaluate the 3-year Chronic GvHD
18. Group C: To evaluate the 3-year Non-Relapse Mortality (NRM)
19. Group C: To evaluate 3-year Relapse rate (DFS)
20. Group C: To evaluate the 3-year Overall survival (OS)
21. Group C: To evaluate the 3-year Event-free survival (EFS)

Conditions and MedDRA coding

Acute Myeloid Leukemia

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. All Groups: Understand and voluntarily provide written permission of parental/legal representative(s) to the ICF prior to conducting any study related assessments/procedures, also concerning data and biomaterial transfer according to ICH/GCP and national/local regulations
2. All Groups: Able to adhere to the study visit schedule and other protocol requirements
3. All Groups: Negative serum pregnancy tests for females of child-bearing potential within 10 days prior to treatment
4. Group A: Diagnosis of de-novo AML (according to WHO classification 2016)
5. Group A: Acute leukemia of ambiguous lineage (MPAL; according to WHO classification 2016: acute undifferentiated leukemia (AUL, bilineal leukemia; biphenotypic leukemia, dominant myelogenous; lineage switch)
6. Group A: Children and adolescents < 18 years of age at start of initial chemotherapy
7. Group A: Acceptance that vaccination with live vaccines is not possible while participating in the trial
8. Group B: Patients with first relapsed (including relapse after SCT) or primary refractory AML
9. Group B: Children and adolescents < 18 years of age at start of initial chemotherapy and < 21 years of age at start of this relapsed AML treatment
10. Group C: Patients with AML and indication for first allogenic HSCT
11. Group C: Age at time of inclusion from 1 month (28 days) to less than 18 years at diagnosis; up to 21 years at time of HSCT
12. Group C: Criteria for allogeneic HSCT: o in AML complete remission (CR) o available MSD, MFD or MUD; matched is defined as at least 9/10 after 4 digit typing for HLA-A, B, C, DRB1, DQB1 loci

Exclusion criteria 28

1. All Groups: Existing syndromes which exclude treatment including Fanconi anemia or other chromosomal instability syndromes
2. All Groups: Patients with trisomy 21 and ML-DS and/or transient myeloproliferative syndrome
3. All Groups: Patients with an acute promyelocytic leukemia (APL), AML with t(15;17)
4. All Groups: Treatment-related or secondary AML
5. All Groups: Symptomatic cardiac dysfunction (CTCAE 5.0 Grade 3 or 4)
6. All Groups: Any other organ dysfunction (CTCAE 5.0 Grade 4) that will interfere with the administration of the therapy according to this protocol
7. All Groups: Evidence of uncontrolled invasive fungal infection or other severe systemic infection requiring treatment doses of systemic/parenteral therapy including known active viral infection with human immunodeficiency virus (HIV) or Hepatitis Type B and C
8. All Groups: Participation in another clinical trial with an intervention interfering with the aims of this trial
9. All Groups: Pregnant or breast-feeding patients
10. All Groups: Female and male subjects with child-bearing potential who avoid using highly effective contraconceptive measure(ment)s
11. All Groups: Hypersensitivity to the active substance or other excipients contained in the investigational medical product listed in the summary of product characteristics (SmPC) or Investigators Brochure (IB)
12. Group A: Previous therapy with cytostatic medicines of more than 14 days and other than specified in protocol as allowed prephase
13. Group A: Diagnosed Wilson’s Disease
14. Group B: Fractional Shortening at echocardiography below 29%
15. Group B: A Karnofsky performance status < 40% (children ≥ 16 years) or a Lansky performance status of < 40% (children < 16 years) before start of the first course
16. Group B: Impaired liver function: Bilirubin > 3 times upper normal limit; transaminases > 3 times upper normal limit
17. Group B: History of VOD
18. Group B: Renal impairment with creatinine < 30 ml/min
19. Group B: Decompensated haemolytic anaemia
20. Group C: A Karnofsky performance status < 60% (children ≥ 16 years) or a Lansky performance status of < 60% (children < 16 years) before start of the Group treatment
21. Group C: Treatment with cytotoxic drugs within 10 days prior to planned study drug administration
22. Group C: Impaired liver function: Bilirubin ≥ 3 times upper normal limit; transaminases ≥ 5 times upper normal limit
23. Group C: Renal impairment with creatinine < 30 ml/min
24. Group C: Cardiac insufficiency requiring treatment; LVEF ≤ 35% (for patients with history of cardiac disease or anthracycline exposure)
25. Group C: Impaired pulmonary function: PO2 ≤ 70 mm Hg or DLCO ≤ 60%
26. Group C: Requirement of supplementary continuous oxygen
27. Group C: Symptomatic involvement of CNS: leukemic infiltration not cleared by prior intrathecal chemotherapy and/or cranial radiotherapy
28. Group C: Other disease, comorbidity or condition that would severely limit life expectancy

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. Group A1-A3: The primary endpoint is Event Free Survival (EFS)
2. Group B: The primary endpoint is Overall Survival (OS). OS is defined as the time from inclusion to death from any cause. Survivors will be censored at the date of the last follow-up evaluation
3. Group C: A composite endpoint will be used as primary endpoint. Graft-versus host disease, VOD, Relapse Free Survival (GVRDS) is defined as the time from randomization to first failure event.

Secondary endpoints 17

1. Group A, C: Overall survival (OS)
2. Group B, C: Event Free Survival (EFS)
3. All Groups: Cumulative incidence of Relapse (CIR)
4. All Groups: Non-relapse mortality (NRM)
5. Group A: Primary induction failures
6. Group A: Risk-Group after Induction 2 Disease-free survival (DFS)
7. Group A: Blast at Ind1
8. Group A: MRD-level at Ind1
9. Group A: MRD-level at Ind2
10. Group A-C: Adverse Events
11. Group A-C: Early death Complete remission (CR)
12. Group A-C: CNS infestation (CICNS)
13. Group C: Graft failure
14. Group C: Engraftment
15. Group C: aGvHD
16. Group C: cGvHD
17. Group C: VOD Grade 3/4

Investigational products

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

Test 15

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

GPOH gGmbH

Sponsor organisation

GPOH gGmbH

Address

Holsterhauser Platz 2, Holsterhausen Holsterhausen

City

Essen

Postcode

45147

Country

Germany

Scientific contact point

Organisation

Gpoh Gemeinnützige GmbH

Contact name

Dirk Reinhardt

Public contact point

Organisation

Gpoh Gemeinnützige GmbH

Contact name

Katharina Waack-Buchholz

Third parties 4

Locations

6 EU/EEA countries · 110 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 150 files

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

Application history

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