Acute Myeloid Leukemia Treated With With NETrin Abs in Combination With [AZACITIDINE + VENETOCLAX]

NCT06150040 | Terminated Phase 1 DMC

• 2 other identifiers: ET23-026EU number
• Study Type: interventional
• Target: 1
• Locations: 1 country
• Sites: 1

Brief Summary

The aim of this study is to investigate the safety and the clinical activities of NP137 when combined with Azacitidine and Venetoclax in patients with refractory acute myeloid leukemia after 2 cycles of Azacitidine and Venetoclax.

Conditions

Acute Myeloid Leukemia Refractory

Keywords

Acute Myeloid Leukemia; Unfit to intensive chemotherapy; NP137; Netrin-1; monoclonal antibody; Azacitidine and Venetoclax; Refractory to azacitidine and venetoclax

Outcome Measures

Primary Outcomes (2)

• Safety run in part : Incidence of Dose Limiting Toxicities (DLT)

  To assess the safety of the proposed therapeutic combination \[NP137 + AZACITIDINE VENETOCLAX\] according to the incidence of Dose Limiting Toxicities (DLT) as defined per protocol.

  4 weeks

• Phase II part : Objective Response Rate (ORR)

  To investigate the clinical activity of the proposed therapeutic combination \[NP137 + AZACITIDINE + VENETOCLAX\] through the Objective Response Rate (ORR) over the 4 cycles of AZACITIDNE +VENETOCLAX+ NP137 administration. ORR will be defined as the proportion of patients with a complete remission (CR) or complete remission with incomplete hematologic recovery (CRi), as best overall response over the 4 cycles of the study combination.

  16 weeks

Secondary Outcomes (15)

• Adverse events

  from the date of first intake of study drug until to 90 days after study drug discontinuation, (at least up to 12 months for the last patient in)

• Duration of response

  from the time of first documented response until the first progression or death, (at least up to 12 months for the last patient in)

• Best overall response (BOR)

  Every 28 days, up to 1 year

• Objective Response Rate

  8 weeks

• Overall survival

  Until up to 1 year follow-up of the last patient enrolled

Study Arms (1)

Refractory Acute Myeloid Leukemia

EXPERIMENTAL

Patients who meet primary refractory disease definition according to ELN criteria after 2 cycles of standard \[AZACITIDINE +VENETOCLAX\] (i.e: patients who have failed to have a complete remission (with complete (CR) or incomplete hematologic recovery (CRi))

Drug: NP137; Drug: Azacitidine Injection; Drug: Venetoclax

Interventions

NP137 DRUG

IV infusion, 14mg/kg or 9mg/kg, every 2 weeks

Refractory Acute Myeloid Leukemia

Azacitidine Injection DRUG

Subcutaneous injection, 75 mg/m², on cycle Days 1-7 (28-days cycle)

Refractory Acute Myeloid Leukemia

Venetoclax DRUG

Orally, 70 mg, every day on Days 1-28

Refractory Acute Myeloid Leukemia

Eligibility Criteria

• Age: 65 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Older Adult (65+)

You may qualify if:

• I1. Adult is ≥ 65 years of age at the time of signing the ICF (Inform Consent Form)
• I2. Histologically confirmed acute myeloid leukemia (AML) as defined by the 2022 World Health Organization (WHO) Classification.
• I3. Patient previously untreated for AML (except with the first 2 cycles of his/her current A+V treatment) and who is considered as ineligible for induction regimen and intensive chemotherapy due to age and other comorbidity that the physician judges to be incompatible with such treatment:
• OR Patient with expected poor prognosis under intensive /induction chemotherapy (e.g. with complex karyotype) OR "No-go" patients according ALFA decision tool (\[e.i: patient with Adverse cytogenetics ≥1 of the following: mKRAS, mTP53)
• Note : Patients with favourable-risk cytogenetics with intensive chemotherapy are not eligible, such as:
• t(8;21)(q22;q22.1); RUNX1-RUNX1T1
• inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11
• Mutated NPM1 without FLT3-ITD or with FLT3-ITDlow†
• Biallelic mutated CEBPA
• I4. Patients under treatment by A+V treatment as standard first line treatment for AML with no CR nor CRi after 2 cycles of AZACITIDINE +VENETOCLAX.
• I5. Patient must be, in the judgment of the investigator, an appropriate candidate for an experimental therapy i.e. with no available other standard treatment or options except palliative care.
• I6. Participant must have a life expectancy of at least 12 weeks.
• I7. Participants has with Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 are eligible to the safety run-in part whatever their age. Then for the expansion part, patient with ECOG PS (Performance Status) of 0 to 2 for subject ≥ 75 years OR of 0 to 3 for subject ≥ 65 to 74 years of age are eligible.
• I8. Demonstrate adequate cardiac function:
• QTc (corrected QT interval) ≤470ms

You may not qualify if:

• Creatinine clearance Calculated creatinine clearance ≥30 mL/min determined by the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) formula OR via urine collection for 24-hour creatinine clearance or serum creatinine ≤ 2 upper limit of normal (ULN)
• Bilirubin Total bilirubin \< 2 × the upper limit of normal (ULN) If total bilirubin ≥ 2 ULN, Direct Bilirubin must be \< 2 x ULN unless considered due to leukemic organ involvement(\< 5 ULN) and with the following Exception: Patients with known Gilbert disease who have serum bilirubin level ≤ 3 ULN may be enrolled.
• SGOT (serum glutamate oxaloacetate transaminase) (AST) and SGPT (serum glutamate pyruvate transaminase) (ALT) ≤ 3 x ULN unless considered due to leukemic organ involvement (\< 5 ULN)
• I10. Patient has no evidence of spontaneous tumor lysis syndrome (TLS) before NP137 introduction.
• I11. Female subjects must be either:
• Postmenopausal; defined no menses for ≥ 12 months without an alternative medical cause; OR
• Permanently surgically sterile (bilateral oophorectomy, bilateral salpingectomy or hysterectomy)
• I12. Non-sterile male subjects must use contraceptive methods with partner(s) prior to beginning study drug administration and continuing up to 3.5 months \[106 days\] after the last dose of NP137. Male subjects must agree to refrain from sperm donation from initial study drug administration during this same period.
• I13. Patient must understand, sign, and date the written voluntary informed consent form prior to any protocol-specific procedures.
• I14. Patient must be able and willing to comply with study visits and procedures as per protocol.
• I15. Patients must be covered by a medical insurance
• E1. Patient who is eligible for any curative therapy including but not limited to induction / intensive chemotherapies, CAR-T cell therapy and agrees to receive this therapy.
• E2. Patient previously treated for AML with a hypomethylating agent and/or other chemotherapeutic agents either conventional or experimental for AML before NP137 introduction.
• E3. Patient who has acute promyelocytic leukemia.
• E4. Patient who experienced:

Sponsors & Collaborators

• Centre Leon Berard: lead
• NETRIS Pharma: collaborator

Study Sites (1)

Centre Léon Bérard

Lyon, 69008, France

Location

MeSH Terms

Conditions

Leukemia, Myeloid, Acute

Interventions

netrin-1 inhibitor NP137; Azacitidine; venetoclax

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: The therapeutic combinations NP137 + \[AZACITIDINE+VENETOCLAX\] will be administered on the first 6 patients enrolled in the study at Dose Level (14 mg/kg). According to safety rules based on the dose limiting toxicities occurence, a dose reduction of NP137 at Dose Level -1 (9 mg/kg) will be assessed in 6 additional patients. After the safety run in part, study will be opened with 35 patients (including patients from the safety run in) at DL or DL-1.

Study Record Dates

• First Submitted: November 10, 2023
• First Posted: November 29, 2023
• Study Start: September 11, 2024
• Primary Completion: February 18, 2025
• Study Completion: February 18, 2025
• Last Updated: February 20, 2025

Record last verified: 2025-02

Locations

FR (1)