Addition of sulfalasazine to chemotherapy for the treatment of AML in the elderly

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Assistance Publique Hopitaux De Paris

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

15 Apr 2025 → ongoing

Decision date (initial)

2024-06-14

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Fondation ARC

External identifiers

EU CT number

2024-513084-38-00

EudraCT number

2022-001269-11

ClinicalTrials.gov

NCT05580861

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Pharmacokinetic, Efficacy, Therapy, Pharmacodynamic

Phase I
To assess the safety, characterize the dose-limiting toxicities (DLTs), and identify the maximal tolerated dose (MTD), and recommended phase II dose (RP2D) of the combination of Sulfasalazine (SSZ) with Idarubicin (IDA) and Cytarabine (AraC) in patients with newly diagnosed non-favorable AML.
Probability of DLT should not exceed 33% at the end of the induction cycle (EOI) of IDA-AraC + SSZ treatment (up to Day 42).
Phase II
To assess preliminarily the anti-leukemia efficacy of the combination of IDA-AraC + SSZ, mainly in phase II, in newly diagnosed non-favorable AML with reference from historical data on complete remission rate, and MRD.

Secondary objectives 4

1. To characterize the pharmacokinetics (PK) of SSZ, IDA and AraC when administered in combination, during phase I
2. To characterize the pharmacodynamics (PD) of SSZ, IDA and AraC when administered in combination, during phase I, and to confirm it during the phase II of the trial
3. To describe during the phase I of the trial the response of the leukemia to the treatment, the survival of patients up to 12 months after the EOI visit
4. To document further during the phase II of the trial the safety profile and confirm the recommended phase II dose of the IDA, AraC and SSZ combination

Conditions and MedDRA coding

Recently diagnosed non favorable Acute Myeloid Leukemias

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. Patients aged 60 years or older
2. With newly diagnosed AML (short course treatment with hydroxyurea and or steroids is acceptable). Patients with AML secondary to an antecedent Myelodysplastic Syndromes (MDS) or Myeloproliferative Neoplasms (MPN) are eligible, as those with therapy-related AML.
3. Eligible for intensive chemotherapy in the investigator’s opinion
4. Multiparameter Flow Cytometry detected at screening allowing and / or compatible with MFCM-based MRD monitoring defined according to ELN criteria (Phase II only)
5. ECOG performance status ≤2
6. AST and ALT ≤3.0 x upper the limit of normal (ULN) and 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 MDRD equation
8. Written informed consent obtained prior to any screening procedures
9. Eligible for National Health Insurance in France.

Exclusion criteria 31

1. Myeloid Sarcoma with < 20% bone marrow blasts
2. Patient who has received a vaccine injection with live-attenuated virus in the last three weeks
3. Proven central nervous system leukemic involvement
4. Favorable risk cytogenetics: t(15;17), t(8;21), inv(16) or t(16;16) or presence of PML-RARA, RUNX1-RUNX1T1 or CBFB-MYH11 fusion transcript
5. Presence of FLT3-ITD or TKD mandating treatment with midostaurin.
6. Concurrent therapy with any cytotoxic drug within 3 weeks before the first study dose. Only hydroxyurea for the control of blood counts is permitted
7. Patients planned to received CPX-351 for myelodysplasia-related changes or therapy-related AML
8. Previous treatment with sulfasalazine in the last 5 years or ongoing treatment with sulfasalazine or 5-aminosalicylic acid (5-ASA) for ulcerative colitis or inflammatory rheumatisms.
9. History of allergy SSZ, one of its metabolites (5-aminosalicylic acid, 5-ASA) or mesalazine, other sulfonylarylamines sulfonamides or salicylates, or sulfasalazine excipients
10. History of allergic reaction to idarubicin or idarubicin excipients
11. History of allergic reaction to cytarabine or cytarabine excipients
12. Known glucose 6-phosphate dehydrogenase deficiency
13. Known acute intermittent porphyria or porphyria variegata
14. Uncontrolled systemic fungal, bacterial, or viral infection (defined as ongoing signs/symptoms related to the infection without improvement despite appropriate treatment).
15. Other uncontrolled or active malignant disease within prior 12 months (excluding myelodysplastic syndrome; cutaneous basal cell carcinoma, “in-situ” carcinoma of the cervix or breast, or other local malignancy excised).
16. Known human immunodeficiency virus (HIV) infection or HIV-related malignancy
17. Clinically active hepatitis B or hepatitis C infection
18. Inability to swallow
19. Known malabsorption syndrome or other condition that may significantly impair absorption of oral study medications
20. Participation in another therapeutic interventional clinical study within 30 days of enrolment
21. Administration of any therapy considered investigational (i.e., used for non-approved indications(s) or in the context of a research investigation) within 5 drug half-lives (whichever is longer) prior to the first dose of study drug
22. Previous treatment by anthracyclines
23. Any contraindication to use anthracyclines including uncontrolled coronary disease, severe renal failure, severe hepatic failure, recent myocardial infarction, symptomatic congestive heart failure, severe cardiomyopathy, significant arrhythmia as estimated by the investigator or LVEF <53% as assessed by echocardiography or MUGA, anterior treatment by idarubicin and/or anthracyclines and anthracènediones beyond the maximum cumulative dose
24. Any contraindication to use cytarabine including degenerative and toxic encephalopathy
25. Any condition requiring treatment with digoxin
26. Any of concurrent severe and/or uncontrolled medical condition, which could compromise participation in the study
27. Females who are pregnant or breastfeeding
28. In a man whose sexual partner is a woman of childbearing potential, unwillingness or inability of the man or woman to use a highly effective contraceptive method for the entire treatment period and for at least 6 months after completion of protocol treatment. Highly effective contraception methods include: combined (estrogen and progestogen containing) hormonal methods associated with inhibition of ovulation, intra-uterine device; surgical sterilization (including bilateral tubal occlusion, partner’s vasectomy) or sexual abstinence if this is the preferred and usual lifestyle of the patient. Male patients must not freeze or donate sperm starting at screening and throughout the treatment period and 3 months after the administration of the final dose of study medication.
29. In a heterosexually active woman of childbearing potential, unwillingness or inability to use a highly effective contraceptive method (as described above) for the entire treatment period and for at least 6 months after the administration of the final dose of study medication. Women are not regarded as of childbearing potential if they are post-menopausal (at least 2 years without menses) or are surgically sterile (at least 1 month before enrollment). Female patients must not donate or retrieve, for their own use, ova from the time of screening and throughout the treatment period, and for 12 weeks after the administration of the final dose of study medication. Female patients must agree not to breastfeed from the time of screening and throughout the protocol period, and for (5 1/2 lives) days after the administration of the final dose of study medication.
30. Adults subjects to a legal protection order or unable to give their consent
31. Persons deprived of their freedom by judicial or administrative decision, person hospitalized without their consent by virtues of articles L 3212-1 and L3213-1 and who are not subject to the provisions of article L 1121

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. Phase I : Documentation during the dose escalation of dose limiting toxicity (DLT)
2. Phase I : Identification of a maximal tolerated dose (MTD) anticipated to be the recommended phase II dose (RP2D) - MTD is defined by a target DLT rate of 33%, assessed during the dose escalation phase by a continual reassessment method - RP2D is anticipated to be the MTD. However, it could be equal to one dose level lower than the MTD. It will be determined in interaction with the DSMB, insofar that this dose level is validated by PK/PD studies and efficacy preliminary data.
3. Phase II : MRD-negative Complete Response at EOI (day 28-42) per ELN 2022 Criteria

Secondary endpoints 5

1. Assessment of safety - Safety outcome measures will be assessed continuously during the study. Monitoring of ECGs and clinical laboratory values are integral to safety assessment. Adverse events (AE), treatment emergent adverse events (TEAE) and treatment-related TEAEs will be evaluated according to the NCI CTCAE version 5.0.
2. Pharmacokinetics - To assess SSZ and its metabolites, IDA (and its metabolite) and AraC. This will allow to determine a PK model for SSZ at an early and late time point and confirm the lack of interaction between SSZ and IDA or AraC.
3. Pharmacodynamics - Pharmacodynamic assays aim at demonstrating ROS induction upon SSZ exposure relative to pre-treatment levels.
4. Antileukemia activity - Response at EOI assessment (day 28-42) per ELN 2022 Criteria.
5. Antileukemia activity - Survival assessment at 12 months

Investigational products

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

Test 1

Auxiliary 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Assistance Publique Hopitaux De Paris

Sponsor organisation

Assistance Publique Hopitaux De Paris

Address

Porte 23, 1 Avenue Claude Vellefaux 1 Avenue Claude Vellefaux

City

Paris Cedex 10

Postcode

75475

Country

France

Scientific contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Raphael Itzykson

Public contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Raphael Itzykson

Locations

1 EU/EEA country · 13 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Temporary halts 1 · Art. 38 CTR

Urgent safety measures 1 · Art. 54 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 6 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