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.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
1
IV infusion, 14mg/kg or 9mg/kg, every 2 weeks
Subcutaneous injection, 75 mg/m², on cycle Days 1-7 (28-days cycle)
Orally, 70 mg, every day on Days 1-28
Centre Léon Bérard
Lyon, France
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.
Time frame: 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.
Time frame: 16 weeks
Adverse events
Incidence of any adverse events graded according to NCI-CTCAE V5.0
Time frame: 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
Measurement of the duration of response (CR/CRi)
Time frame: 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)
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
Time frame: Every 28 days, up to 1 year
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Objective Response Rate
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)
Time frame: 8 weeks
Overall survival
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.
Time frame: Until up to 1 year follow-up of the last patient enrolled
Progression Free survival
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 frame: Every 28 days, up to 1 year follow-up of the last patient enrolled
Treatment Failure
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.
Time frame: Continuously, up to 1 year follow-up of the last patient enrolled
Death in Medullary Aplasia
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 frame: Every 28 days, up to 1 year follow-up of the last patient enrolled
Neutrophil / platelet count recovery
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)).
Time frame: Continuously, up to 1 year follow-up of the last patient enrolled
Pharmacokinetic parameter: Cmax
Plasma peak concentration
Time frame: Cycle 1 day 1, pre-dose; cycle 1 day 1, 3hours post-dose; cycle 1 day 2; cycle 1 day 7 or day 8; cycle 1 day 15, pre-dose; cycle 7 day 1, pre-dose; if Grade ≥3 infusion-related reaction and at the end of treatment visit (each cycle is 28 days)
Pharmacokinetic parameter: tmax
Time to reach the peak concentration
Time frame: Cycle 1 day 1, pre-dose; cycle 1 day 1, 3hours post-dose; cycle 1 day 2; cycle 1 day 7 or day 8; cycle 1 day 15, pre-dose; cycle 7 day 1, pre-dose; if Grade ≥3 infusion-related reaction and at the end of treatment visit (each cycle is 28 days)
Pharmacokinetic parameter: AUCt (Area under the concentration-time)
Area under the concentration-time curve from time zero to the last sample with the quantifiable concentration
Time frame: Cycle 1 day 1, pre-dose; cycle 1 day 1, 3hours post-dose; cycle 1 day 2; cycle 1 day 7 or day 8; cycle 1 day 15, pre-dose; cycle 7 day 1, pre-dose; if Grade ≥3 infusion-related reaction and at the end of treatment visit (each cycle is 28 days)
Pharmacokinetic parameter: AUC∞ (Area under the concentration-time)
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)
Time frame: Cycle 1 day 1, pre-dose; cycle 1 day 1, 3hours post-dose; cycle 1 day 2; cycle 1 day 7 or day 8; cycle 1 day 15, pre-dose; cycle 7 day 1, pre-dose; if Grade ≥3 infusion-related reaction and at the end of treatment visit (each cycle is 28 days)
Pharmacokinetic parameter: CL (Clearance)
Clearance: volume of plasma from which NP137 is completely removed per unit time.
Time frame: Cycle 1 day 1, pre-dose; cycle 1 day 1, 3hours post-dose; cycle 1 day 2; cycle 1 day 7 or day 8; cycle 1 day 15, pre-dose; cycle 7 day 1, pre-dose; if Grade ≥3 infusion-related reaction and at the end of treatment visit (each cycle is 28 days)
Pharmacokinetic parameter: t1/2
Terminal elimination half-life: time required for the amount of NP137 in the body to decrease by half.
Time frame: Cycle 1 day 1, pre-dose; cycle 1 day 1, 3hours post-dose; cycle 1 day 2; cycle 1 day 7 or day 8; cycle 1 day 15, pre-dose; cycle 7 day 1, pre-dose; if Grade ≥3 infusion-related reaction and at the end of treatment visit (each cycle is 28 days)