A Phase I/II Study of NMS-03592088, a FLT3, KIT and CSF1R Inhibitor, in Patients with Relapsed or Refractory AML or CMML

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Nerviano Medical Sciences S.r.l., Nerviano Medical Sciences S.r.l.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

13 Feb 2019 → 29 Aug 2024

Decision date (initial)

2023-12-19

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

External identifiers

EU CT number

2023-508655-39-00

EudraCT number

2018-002793-47

ClinicalTrials.gov

NCT03922100

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Safety, Efficacy

Phase I
• To determine the maximum tolerated dose (MTD) or maximum administered dose (MAD) and the recommended Phase II dose (RP2D) of NMS-03592088 administered orally once daily for 21 consecutive days followed by 7 days of rest in a 28 day cycle (Schedule A) or once daily for 28 consecutive days (Schedule B) in adult patients with selected hematologic malignancies who have exhausted standard treatment options or for whom standard therapy is considered unsuitable.
Phase II
• To explore the antitumor activity of NMS-03592088 in FLT3-ITD mut AML.

Conditions and MedDRA coding

Acute Myeloid Leukemia (AML) or Chronic Myelomonocytic Leukemia(CMML) relapsed or refractory

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. Patients with relapsed/refractory disease who have failed standard therapy or are unsuitable for standard treatment, with the following confirmed diagnosis: • AML as defined by the ELN recommendations
2. Patients with confirmed diagnosis of AML as defined by the 2022 ELN recommendations positive for FLT3-ITD mutation in the BM or PB as determined by central laboratory test performed at study entry. Patients with very rapidly proliferative disease who, in the opinion of the Investigator, cannot wait for the central laboratory results can be enrolled based on a local test performed at study entry. Patients with an allelic ratio ≥ 0.05 will be considered to have FLT3ITD-mutated disease. Patients positive for FLT3- D835 or I836 mutations will not be eligible.
3. Patients must have failed standard of care including venetoclax and gilteritinib based therapies (cohort 1) or standard of care (cohort 2)
4. Adult (age >= 18 years) patients
5. ECOG performance status <= 2
6. The interval from prior antitumor treatment to time of NMS-03592088 administration should be at least 2 weeks for any agents other than hydroxyurea.
7. All acute toxic effects (excluding alopecia) of any prior therapy must have resolved to NCI CTCAE version 5.0 Grade ≤ 1
8. Adequate hepatic function, as defined by serum transaminases (i.e., AST/ALT) <= 2.5 x ULN, ALP <= 2.5 x ULN and total bilirubin <= 1.5 x ULN unless abnormality considered due to Gilbert’s syndrome (FR: in which case the limit is 2 mg/dL).
9. Adequate renal function, as defined by serum creatinine  1.5 x ULN and an estimated glomerular filtration rate (eGFR) ≥ 45 mL/min as calculated by the BSA-unadjusted Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, *  (eGFR (mL/min)= eGFR (mL/min/1.73 m2 ) x [BSA (m2)/1.73] where eGFR (mL/min/1.73 m2 ) = 141 x min(Scr/κ,1)α x max(Scr/κ, 1)-1.209 x 0.993Age x 1.018 [if female] x 1.159 [if African American
10. Patients must use highly effective contraception. Female patients must be surgically sterile or be postmenopausal or must agree to the use of highly effective contraception during the period of therapy and in the following 90 (IT and ES) and 208 (FR) days after discontinuation of study treatment. Since NMS-03592088 has potential induction of CYP3A4, WOCBP must be advised that hormonal contraceptives might lose efficacy and must use alternate form of highly effective contraception. Male patients must be surgically sterile or must agree to use highly effective contraception during the period of therapy and in the following 90 (IT and ES) and 118 (FR) days after discontinuation of study treatment.
11. Capability to swallow capsules intact (without chewing, crushing, or opening)
12. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests and other study indications or procedures
13. Signed and dated IEC or IRB-approved informed consent form indicating that the patient is aware of the neoplastic nature of his/her disease and has been informed of the procedures to be followed, the investigational nature of the therapy, potential benefits, side effects, discomforts, risks and alternative treatments.

Exclusion criteria 20

1. Current enrollment in another interventional clinical study
2. Diagnosis of acute promyelocytic leukemia or BCR-ABL-positive leukaemia
3. Currently active second malignancy, except for adequately treated basal or squamous cell skin cancer and/or cone biopsied in situ carcinoma of the cervix uteri and/or superficial bladder cancer.
4. Patients with known leukemia involvement of CNS.
5. Hematopoietic stem cell transplantation (HSCT) within 3 months of treatment start and/or persistent nonhematologic toxicities of Grade ≥2 related to the transplant
6. Active acute or chronic graft versus host disease (GVHD) requiring immunosuppressive treatment
7. Patients with QTcF interval ≥ 480 milliseconds or with risk factors for torsade de pointes (e.g., uncontrolled heart failure, uncontrolled hypokalemia, history of prolonged QTc interval or family history of long QT syndrome). For patients receiving treatment with concomitant medications known to prolong the QTc interval, replacement with another treatment needs to be considered. If replacement or discontinuation is not clinically feasible, a careful risk/benefit evaluation should be performed prior to enrollment.
8. Pregnancy. All female patients with reproductive potential must have a negative pregnancy test (serum or urine) within the screening period prior to start of study drug.
9. Breast-feeding or planning to breast feed during the study or within 3 months after study treatment.
10. Known hypersensitivity to any of the components of the NMS-03592088 drug product
11. Any of the following in the previous 6 months: myocardial infarction, unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack, pulmonary embolism, deep vein thrombosis
12. Known active, life threatening or clinically significant uncontrolled systemic infection.
13. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness.
14. Active Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV) C infection.
15. Known active gastrointestinal disease (e.g., Crohn’s disease, ulcerative colitis, or short gut syndrome) or other malabsorption syndromes that would impact on drug absorption.
16. Known active gastrointestinal ulcer
17. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration or may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the patient inappropriate for entry into this study or could compromise protocol objectives in the opinion of the Investigator and/or the Sponsor.
18. Known diagnosis of myasthenia gravis
19. France specific: Concomitant anticoagulant use that is not already stabilized therapeutically
20. France specific: Subjects under legal protection or unable to express their consent; subjects deprived of liberty; subjects who are not members or not beneficiaries of a social security scheme.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Phase I • Drug related first-cycle dose limiting toxicities (DLTs) Phase II • FLT3-ITD mut AML: Composite Complete Remission (CRc) Rate, i.e. Complete Remission (CR) + Complete Remission with Incomplete Hematologic Recovery (CRi), as defined by the Investigators based on the 2022 European LeukemiaNet (ELN) recommendations

Investigational products

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

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Nerviano Medical Sciences S.r.l.

Sponsor organisation

Nerviano Medical Sciences S.r.l.

Address

Via Louis Pasteur 10

City

Nerviano

Postcode

20014

Country

Italy

Scientific contact point

Organisation

Nerviano Medical Sciences S.r.l.

Contact name

Global Clinical Development

Public contact point

Organisation

Nerviano Medical Sciences S.r.l.

Contact name

Global Clinical Development

Third parties 2

Nerviano Medical Sciences S.r.l.

Sponsor organisation

Nerviano Medical Sciences S.r.l.

Address

Via Louis Pasteur 10

City

Nerviano

Postcode

20014

Country

Italy

Locations

3 EU/EEA countries · 17 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 3 · Art. 38 CTR

Results and documents

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

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 4 files

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

Application history

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