CPX-351 versus intensive chemotherapy in patients with de novo intermediate or adverse risk AML stratified by genomics

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Centre Hospitalier Universitaire De Nice

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

15 Sep 2022 → ongoing

Decision date (initial)

2022-07-18

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Funding sources

Jazz Pharmaceuticals

External identifiers

EU CT number

2022-500295-60-00

ClinicalTrials.gov

NCT05260528

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Therapy, Efficacy

To demonstrate an improvement in the proportion of patients achieving deep remission (Complete Remission (CR)/ Complete Remission with incomplete hematologic recovery (CRi)) with a standardized flow based MRD threshold < 10-3 in the bone marrow aspirate using the LAIP/Dfn method after the first course of treatment induction in the experimental arm (induction by CPX-351) and in the control arm (induction by 3+7, idarubicine and cytarabine).

Secondary objectives 5

1. Secondary MRD objectives: o To compare the proportion of patients achieving as best response a CR/CRi with a flow based MRD threshold < 10-3 in the bone marrow aspirate using the LAIP/Dfn method in the experimental arm (induction by CPX-351) and in the control arm (conventional intensive chemotherapy), regardless of the number of treatment courses administered before to achieve this level of response. o To compare between stratified randomization arms the flow-based MRD quantified in the bone marrow according to both the LAIP/DfN method and the LSC method at D1 of (or the day before) the third cycle of treatment (consolidation 1 or 2 according the need for second induction course) and 28-42 days after the last cycle of consolidation or before allogeneic-HSCT, if any. Results will enable to distinguish: - Complete MRD flow response LAIP-/LSC- (LAIP/DfN <10-3 and LSC <10-4) - Partial MRD flow response LAIP+/LSC- or LAIP-/LSC+ - Refractory MRD LAIP+/LSC+ o To compare between the bone marrow and the peripheral blood the results of flow-based MRD quantified according to both LAIP/DfN method and the LSC methods at D1 of (or the day before) the first cycle of consolidation, the second cycle of consolidation and 28-42 days after the last cycle of consolidation or before allogeneic-HSCT, if any. o To compare between the randomization arms the results of NGS-based MRD at D1 of (or the day before) the first cycle of consolidation (or of salvage therapy), at D1 of the second cycle of consolidation (or first cycle of consolidation after a successful salvage therapy), and 28-42 days after the last cycle of consolidation or before allogeneic-HSCT, if any.
2. Clinical objectives: To compare between both randomization arms (CPX-351and conventional intensive chemotherapy) and between strata : o Overall response rate, and CR and CRi rates o Cumulative incidence of allogeneic HSCT o Early mortality at D30, D60, D100 o Overall Survival (with and without censoring at allogeneic HSCT) o Relapse-Free Survival (with and without censoring at allo-HSCT) o Event-Free Survival (with and without censoring at allo-HSCT) o Cumulative Incidence of Relapse (with and without censoring at allo-HSCT) o Hematological and non-hematological toxicity profile and safety using the NCI- common toxicity criteria (CTCAE) version 5.0 of November 2017 o Duration of hospitalization during induction and consolidation cycles
3. Genomics: oTo compare between both randomization arms (CPX-351 and conventional intensive chemotherapy) and between strata: Changes of the genomic landscape with the treatment o Association between the somatic mutations (documented with their allele frequency) associated with AML and OS, RFS
4. Quality-of-Life: Self assessment by patients
5. Exploratory objectives: To compare between the randomization arms and starta: o The secondary-type mutational profile at screening as determined by Lindsley et al (1) o Centralized functional flow cytometry assays at baseline carried on peripheral blood or bone marrow aspirate including:  P-gp activity at baseline (multidrug resistance [MDR] phenotype)  Mitochondrial priming and BCL-2 dependence at baseline (optionally, if adequate biological material) o Flow MRD  Changes of the phenotype of LSC and hematopoietic progenitors before, during, after the treatment in order to identify a potential correlation with drug resistance Comparison between classical conventional analysis of MRD flow and unsupervised strategy of MRD flow

Conditions and MedDRA coding

Acute Myeloid Leukemia

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. De novo AML
2. No MRC-defining cytogenetic lesion
3. No t(15;17), t(8;21), inv(16) or t(16;16)
4. No NPM1 gene mutation
5. No FLT3 mutated AML (FLT3 ITD or TKD)
6. Not previously treated except for short course hydroxyurea in patients presenting with high WBC count and/or tumor symptoms,
7. Age above or equal to 50 years
8. Performance status below or equal to 2 (ECOG grading),

Exclusion criteria 5

1. Prior history of documented MDS, MPN or MDS/MPN, tAML
2. Prior history of radiation therapy or chemotherapy for a solid tumor or lymphoma (exceptions to be considered: local radiotherapy for prostate cancer)
3. Patient has active and uncontrolled infection.
4. Patient has uncontrolled intercurrent illness or circumstances that could limit compliance with the study, including but not limited to the following: symptomatic congestive heart failure, unstable angina pectoris, uncontrolled cardiac arrhythmia, pancreatitis, or psychiatric or social conditions that may interfere with patient compliance.
5. Patient is currently participating or has participated in a study with an investigational compound or device within 30 days of initial dosing with study drug.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. To compare the proportion of patients achieving a CR/CRi with a flow based MRD < 10-3 in the bone marrow aspirate using the LAIP/DfN method after the first course of induction therapy, at D1 of (or the day before) the first consolidation cycle in the experimental arm (induction by CPX-351) and in the control arm (induction by 3+7, idarubicine and cytarabine).

Secondary endpoints 10

1. To compare the proportion of patients achieving as best response a CR/CRi with a flow based MRD threshold < 10-3 in the bone marrow aspirate using the LAIP/Dfn method in the experimental arm (induction by CPX-351) and in the control arm (conventional intensive chemotherapy), regardless of the number of treatment courses administered before to achieve this level of response.
2. To compare between stratified randomization arms the flow-based MRD quantified in the bone marrow according to both the LAIP/DfN method and the LSC method at D1 of (or the day before) the third cycle of treatment (consolidation 1 or 2 according the need for second induction course), and 28-42 days after the last cycle of consolidation or before allogeneic-HSCT, if any.
3. To compare between the bone marrow and the peripheral blood the results of flow-based MRD quantified according to both LAIP/DfN method and the LSC methods at D1 of (or the day before) the first cycle of consolidation, the second cycle of consolidation (or first cycle of consolidation after a successful salvage therapy), and 28-42 days after the last cycle of consolidation or before allogeneic-HSCT, if any.
4. To compare between the randomization arms and between strata the results of NGS-based MRD at D1 of (or the day before) the first cycle of consolidation (or of salvage therapy), at D1 of the second cycle of consolidation (or first cycle of consolidation after a successful salvage therapy), and 28-42 days after the last cycle of consolidation or before allogeneic-HSCT, if any.
5. - Overall response rate, and rate of CR (complete remission), CRi (complete remission with incomplete hematologic recovery) as defined in 2017 ELN recommendations - Cumulative incidence of allogeneic HSCT - Early mortality at D30, D60, D100 after the randomization - Overall Survival (with and without censoring at allo-HSCT)
6. - Relapse-Free Survival (with and without censoring at allo-HSCT) - Event-Free Survival (with and without censoring at allo-HSCT) - Cumulative Incidence of Relapse (with and without censoring at allo-HSCT) - Hematological and non-hematological toxicity profile and safety using the NCI- common toxicity criteria (CTCAE) version 5.0 of November 2017 - Duration of hospitalization related to each cycle of treatment (induction and consolidation).
7. Genomic correlations: To compare between both randomization arms (CPX-351 and conventional intensive chemotherapy) and between strata: o Changes of the genomic landscape with the treatment o Association between the AML somatic mutations (documented with their allele frequency) and OS and RFS
8. Quality of life reported by the patient according to the EORTC QLQ-C30 questionnaire
9. o Secondary-type mutational profile at screening as determined by Lindsley et al o Centralized functional flow cytometry assays at baseline be carried on peripheral blood or bone marrow aspirate at the THEMA Lab (Hopital Saint-Louis), including o P-gp activity at baseline (multidrug resistance [MDR] phenotype) o Mitochondrial priming and BCL-2 dependence (optionally, if adequate biological material)
10. Flow MRD o Changes of the phenotype of LSC and hematopoietic progenitors before, during, after the treatment in order to identify a potential correlation with drug resistance o Comparaison between classical conventional analysis of MRD flow and unsupervised strategy of MRD flow

Investigational products

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

Test 1

Comparator 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Centre Hospitalier Universitaire De Nice

Sponsor organisation

Centre Hospitalier Universitaire De Nice

Address

4 Avenue Reine Victoria

City

Nice

Postcode

06000

Country

France

Scientific contact point

Organisation

Centre Hospitalier Universitaire De Nice

Contact name

Thomas CLUZEAU

Public contact point

Organisation

Centre Hospitalier Universitaire De Nice

Contact name

Valérie FOUSSAT

Third parties 3

Locations

1 EU/EEA country · 35 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 11 files

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

Application history

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