STUDY AGORA-1 / ALFA 2100: Phase 2 on the combinaison of Gemtuzumab Ozogamicin witk gilteritinib in adult patients with acute myeloid leukemia (AML) with a relapsed or refractory FLT3 mutation.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Centre Antoine Lacassagne

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

8 Aug 2024 → ongoing

Decision date (initial)

2024-08-08

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Astellas Pharma Europe Ltd · Pfizer

External identifiers

EU CT number

2023-504176-25-00

EudraCT number

2021-001813-35

ClinicalTrials.gov

NCT05199051

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Dose response, Efficacy

Stage 1 - Safety of the addition of gilteritinib to the AGORA treatment platform

The primary objective of the first stage is to evaluate the safety of combining gilteritinib with the GO-cytarabine AGORA platform in patients with FLT3-ITD and/or FLT3-TKD mutated R/R AML, through occurrence of dose-limiting toxicity (DLT).

Stage 2 - Event-free survival (EFS)

The primary objective of the second extension stage is to evaluate the efficacy of combining gilteritinib with the GO-cytarabine AGORA platform in patients with FLT3-ITD and/or FLT3-TKD mutated R/R AML through event-free survival (EFS).

Secondary objectives 8

1. Response rates to the study treatment
2. Early mortality rates, at day-30
3. Incidence of subsequent allogeneic HSCT, overall and in responding patients specifically
4. Duration of response (DOR), relapse-free survival (RFS) and overall survival (OS)
5. Subgroup analyses, defined by patient, disease and treatment related factors
6. Safety (AEs, SAEs, TEAEs and incidence of sinusoidal obstruction syndrome) (SOS))
7. Patient-reported outcomes (PROs)
8. Sensitivity analyses

Conditions and MedDRA coding

Acute Myeloid Leukemia

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

1. Patients aged 18 years old or more
2. Confirmed diagnosis of R/R AML positive for CD33 antigen as determined locally by immunophenotyping according to routine practice, defined as: - AML refractory to 1 or 2 intensive chemotherapy courses or a treatment by hypomethylating agents (HMAs) - Or AML in first hematologic relapse or progression after front-line therapy, including intensive chemotherapy or hypomethylating agents (HMAs). - Previous treatments with FLT3 inhibitors (other than gilteritinib) are allowed - R/R AML secondary to a prior chemotherapy or radiotherapy for another cancer (tAML) could be included.
3. Presence of a FLT3-ITD mutation (allelic ratio ≥0.05 at last evaluation)* or a FLT3 TKD mutation
4. Patient with no contraindication to gemtuzumab ozogamicin (GO), cytarabine and gilteritinib
5. ECOG performance status ≤2
6. AST and ALT ≤ 2.5 x upper the limit of normal (ULN) and/or total and direct serum bilirubin ≤ 1.5 x ULN unless considered due to leukemia
7. Estimated glomerular filtration rate (GFR) ≥ 50 mL/min according to the formula usually used by the investigator

Exclusion criteria 18

1. Acute promyelocytic leukemia or AML with BCR-ABL1 gene fusion
2. Secondary AML (sAML) defined by a history of prior myelodysplastic syndrome (MDS) or myeloproliferative syndrome (MPN) including chronic myelomonocytic leukemia (CMML)
3. Patient ineligible for an intensive chemotherapy.
4. Patient with contraindications to the administration of gemtuzumab ozogamicin (GO), cytarabine and gilteritinib. Refer to the SPCs of the molecules mentioned concerning the contraindications, special warnings, precautions for use, dose modifications in the event of toxicity, contraception and monitoring of patients and drugs prohibited or to be used with caution.
5. Proven central nervous system leukemic involvement
6. Prior allogeneic HSCT within the last 6 months and/or history of acute GVHD of grade >1
7. Prior treatment with gemtuzumab ozogamicin within the last 3 months preceding the initiation of the treatment in the present clinical trial
8. Uncontrolled or active malignant disease within prior 12 months (excluding cutaneous basal cell carcinoma, “in-situ” carcinoma of the cervix or breast, or other local malignancy excised)
9. Uncontrolled or significant cardiovascular history or symptoms
10. Uncontrolled systemic fungal, bacterial, or viral infection (defined as ongoing signs/symptoms related to the infection without improvement despite appropriate treatment)
11. Active known HBV or HCV hepatitis or positive HIV serology
12. Concurrent therapy with any other investigational agent or cytotoxic drug, within 28 days before starting treatment. Only hydroxyurea ± dexamethasone is permitted for the control of blood counts
13. Current use or anticipated requirement for drugs that are known strong inducers of CYP3 A4/5
14. Current use or anticipated requirement for drugs that are known as strong inhibitors or inducers of P glycoprotein (P-gp), as mentioned in the appendix 14 of the protocol, with the exception of drugs that are considered absolutely essential for the care of the subject
15. Current use or anticipated treatment with concomitant drugs that target 5HT1R or 5HT2BR receptors or sigma non-specific receptor, as mentioned in the appendix 15 of the protocol, with exception of drugs that are considered absolutely essential for the care of the subject
16. Known malabsorption syndrome or other condition that may significantly impair absorption of oral study medications
17. Any of concurrent severe and/or uncontrolled medical condition, which could compromise participation in the study
18. Patient currently receiving one or more inadvisable or prohibited treatments described in section 6.4.2 of the protocol.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Stage 1 of the study: assessment of safety of the addition of gilteritinib to the AGORA treatment platform Safety of combining gilteritinib with the GO-cytarabine AGORA platform in patients with FLT3-ITD and/or FLT3-TKD mutated R/R AML will be assessed through the identification of dose-limiting toxicities (DLTs) if any.
2. Stage 2 of the study: assessment of efficacy of gilteritinib-combined to GO/cytarabine AGORA platform through EFS. The definition of EFS will be adapted to the current real-life setting, including the increasing number of experimental options. Actually, the decision to switch toward another therapy may be influenced by other events than hematologic relapse, like suboptimal tolerance or MRD monitoring or simply availability of new promising options.

Secondary endpoints 7

1. Response rate, including CR, CRi and CRh*; the overall response rate (ORR) being defined as CR/CRi/CRh rates *: CRi, CR with incomplete hematologic recovery, meaning CR with platelet count <100,000/µL or absolute neutrophil count <1000/µL; CRh, CR with partial hematologic recovery, meaning CR not fulfilling CR or CRi criteria but with platelet count >50,000/µL AND absolute neutrophil count >500/µL.
2. Early mortality rates, at day-30
3. Incidence of subsequent allogeneic HSCT, overall and in responding patients specifically
4. Duration of response (DOR), relapse-free survival (RFS) and overall survival (OS)
5. Subgroup analyses:  Subgroups defined by a patient related factor: age (<65 vs ≥65y),  Subgroups defined by disease related factors: cytogenetics, mutation profiles (including NPM1 and FLT3-ITD), ELN-risk classification 2022  Subgroups defined by treatment related factor by the performance of a subsequent allogeneic HSCT
6. Safety through the occurrence of (AEs), serious adverse events (SAEs), and treatment emergent adverse events (TEAEs)
7. Patient reported outcome

Investigational products

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

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Centre Antoine Lacassagne

Sponsor organisation

Centre Antoine Lacassagne

Address

33 Avenue De Valombrose

City

Nice Cedex 2

Postcode

06189

Country

France

Scientific contact point

Organisation

Centre Antoine Lacassagne

Contact name

Juliette LAMBERT

Public contact point

Organisation

Centre Antoine Lacassagne

Contact name

Juliette LAMBERT

Locations

1 EU/EEA country · 31 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

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