Neoplasms

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Leukemia

Leukemia, Myeloid

Leukemia, Myeloid, Acute

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Hematologic Diseases

Myeloid Leukemia

Acute Myeloid Leukemia

Acute Non Lymphoblastic Leukemia

Acute Graft Versus Host Disease

All Drugs and Chemicals

Antineoplastic Agents

Antibodies

Antibodies, Monoclonal

Venetoclax

Azacitidine

Immunoglobulins

Antimetabolites

Enzyme Inhibitors

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))

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

NP137

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

Azacitidine Injection

Anne-Sophie MICHALET, MD

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.

The dual treatment, VENETOCLAX and AZACITIDINE, is the standard of care for patients with newly diagnosed AML who are ineligible for intensive chemotherapy. However, upfront resistance as well as relapse following initial response demonstrate the need to improve this therapeutic strategy.

NP137 is a first-in-class humanized monoclonal antibody targeting specifically and selectively Netrin-1. Based on data collected from non clinical studies NP137 should act in synergy with VENETOCLAX and AZACITIDINE to reactivate and enhance the apoptotic pathway in AML cells.

The herein proposed study to assess the safety (Safety run in/ phase I part) and the preliminary efficacy signal (extension phase II part) of the NP137 when combined to AZACITIDINE AND VENETOCLAX in patients with refractory acute myeloid leukemia after 2 cycles of Azacitidine and Venetoclax.

This study will be an open-label, Phase I/II trial. the first part, consists to a safety run to assess the security and the tolerability of the drugs combination from the first 6 to 12 first patients enrolled into the study. All patients will receive a fixed dose of NP137 at the RP2D (Recommended Phase 2 Dose) determined from the First in human NP137 study(DL1) . A dose deescalation of NP137 is planned to DL-1 according to the Dose Limiting Toxicities observed during this period. The second part will be will be then conducted as a phase II using an adaptive Bayesian approach allowing to quickly stop treatment without evidence of efficacy. The clinical activity will be assessed based on ELN (European LeukemiaNet) criteria 2027 for the Acute Myeloid Leukemia.

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.

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

A Phase I/II Study to Evaluate the Safety Clinical and Biological Activity of a Humanized Monoclonal Antibody Targeting Netrin-1 (NP137) in Combination With Standard AZACITIDINE+ VENETOCLAX in Patients With Refractory Acute Myeloid Leukemia

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.

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.

Incidence of any adverse events graded according to NCI-CTCAE V5.0

Measurement of the duration of response (CR/CRi)

Best overall response, is determined by the best response designation. For subjects without documented progression or subsequent anticancer therapy, all available response designations will contribute to the BOR determination :from the date of first intake of study drug until progression or at time of initiation of a new anti-cancer treatment

Objective Response Rate after 2 cycles of study treatment defined as the proportion of participants who achieve: complete remission (CR) or complete remission with incomplete hematologic recovery (CRi) after 2 cycles of treatment (2 cycles of A+V including 4 injections of NP137)

Overall survival measured from the date of treatment start to the date of death from any cause; patients not known to have died at last follow-up are censored on the date they were last known to be alive.

Progression Free survival defined as the time from the initiation of the study treatment until first evidence of disease treatment failure : from the date of first intake of study drug until progression

Time to Treatment Failure Rate (TTF) defined as the time from the initiation of study treatment to its early discontinuation. Reasons for prematurely discontinuing treatment can include cancer progression but also adverse events, patient choice, or death.

Death in Medullary Aplasia Rate based on cytological assessment: Deaths occurring ≥7 days following completion of initial treatment while cytopenic, with an aplastic or hypoplastic bone marrow obtained within 7 days of death, without evidence of persistent leukemia.

Time to neutrophil / platelet count recovery (absolute neutrophil count (ANC) \> 1 × 109/L (defined as neutrophil recovery) and platelet count \> 100 × 109/L (defined as platelet recovery)).

Area under the concentration-time curve from time zero to the last sample with the quantifiable concentration

Area under the concentration-time curve from time zero to infinity corresponding to the definite integral of a curve that describes the variation of a drug concentration in blood plasma as a function of time (drug exposure in plasma)

Clearance: volume of plasma from which NP137 is completely removed per unit time.

Terminal elimination half-life: time required for the amount of NP137 in the body to decrease by half.

NETRIS Pharma

Centre Leon Berard

On day 1 of cycle 1, Azacitidine 75 mg/m2 will be given by injection or infusion, and will continue for 7 days. Azacitidine doses will be given in subsequent cycles for patients who do not achieve response. Venetoclax will be administered orally once daily on days 2 through 28 in cycle 1. Beginning with cycle 2, and each subsequent cycle, venetoclax will be administered Days 1 through 28.

Azacitidine will be given at dose of 75mg/m2 in Cycle 1 days 1-7; repeat in cycle 2 and 3 if no response. Starting on day 2 of cycle 1, venetoclax will be administered orally with doses increased to a target dose of 600 mg (administer 100 mg on day 2, 200 mg on day 3, 400 mg on day 4 and 600 mg on day 5), then 600 mg daily.

Azacitidine and Venetoclax

Dan Pollyea

This study is being done to determine if treatment with azacitidine and venetoclax is effective treatment for elderly patients with acute myeloid leukemia (AML) who have not received previous treatment. Azacitidine and venetoclax will be given as induction treatment followed by venetoclax maintenance treatment for patients who respond to the induction treatment.

This is a phase 2 study for elderly patients who have not received previous treatment for acute myeloid leukemia (AML). Up to 42 patients will be enrolled. All patients will be treated with azacitidine and venetoclax until a minimal residual disease (MRD) negative response is achieved. Once patients achieve a MRD negative composite response, azacitidine will be discontinued and venetoclax dose will be decreased to "maintenance" dose.

Azacitidine and Venetoclax as Induction Therapy With Venetoclax Maintenance in the Elderly With AML

Azacitidine and Venetoclax (ABT-199) as Induction Therapy With Venetoclax Maintenance in Previously Untreated Elderly Patients With Acute Myeloid Leukemia (AML)

Determine how long responses last in patients treated with azacitidine and venetoclax followed by venetoclax maintenance treatment

The number of patients who achieve an MRD negative composite response

The median number of days that have elapsed leading to an MRD negative composite response

The number of patients who survive to one year after date of study enrollment

Hematologic toxicities will be measured by incidence of febrile neutropenia, ≥ grade 2 bleeding complications and number of transfusions received

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Acute Myeloid Leukemia Treated With With NETrin Abs in Combination With [AZACITIDINE + VENETOCLAX]	NCT06150040	Acute Myeloid L...	NP137 Azacitidine Inj... Venetoclax	65 Years -	Centre Leon Berard
Acute Myeloid Leukemia Treated With With NETrin Abs in Combination With [AZACITIDINE + VENETOCLAX]	NCT06150040	Acute Myeloid L...	NP137 Azacitidine Inj... Venetoclax	65 Years -	Centre Leon Berard
Acute Myeloid Leukemia Treated With With NETrin Abs in Combination With [AZACITIDINE + VENETOCLAX]	NCT06150040	Acute Myeloid L...	NP137 Azacitidine Inj... Venetoclax	65 Years -	Centre Leon Berard
Azacitidine and Venetoclax as Induction Therapy With Venetoclax Maintenance in the Elderly With AML	NCT03466294	Acute Myeloid L...	Azacitidine and...	60 Years -	University of Colorado, Denver

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