A Precision Medicine Trial for Patients With Relapsed or Refractory T Cell ALL

Official title

A Precision Medicine Randomized Trial for Patients With Relapsed or Refractory T-cell Acute Lymphoblastic Leukemian Based on a Functional Approach

Overview

To evaluate the benefit of a precision medicine based strategy (targeted therapeutic options (TTOs)) for patients with relapsed/refractory T-cell acute lymphoblastic leukemia (T-ALL) (in terms of composite remission).

Interventions

• Drug Venetoclax + Tofacitinib
  Cycle 1: Venetoclax, 100 mg/d PO day1; 200 mg/d day2; 300 mg/d day3 and 400 mg/day thereafter (100 mg/day in case of concomitant administration of azoles) Tofacitinib, 10 mg BID PO started from day 5 Cycle 2 and 3 (4, 5 and 6 if applicable): Venetoclax, 400 mg/day PO (100 mg/day in case of concomitant administration of azoles) Tofacitinib, 10 mg BID PO
• Drug Venetoclax+ Everoliumus +Enrylaze
  Cycle 1: Venetoclax, 100 mg/d PO day1; 200 mg/d day2; 300 mg/d day3 and 400 mg/day thereafter (100 mg/day in case of concomitant administration of azoles) Everolimus, 5 mg/day orally continuously. Everolimus must be administered at least 6 hours after venetoclax. Enrylaze 25 mg/m2 intravenously at day1, 3, 5, 7 (half dose for patients \>50 years) Cycle 2 and 3 (4, 5 and 6 if applicable): Venetoclax, 400 mg/day PO (100 mg/day in case of concomitant administration of azoles) Everolimus, 5 mg
• Drug Venetoclax + 5 Azacitidine
  Cycle 1: Venetoclax, 100 mg/day PO day1; 200 mg/d day2; 300 mg/d day3 and 400 mg/day thereafter (100 mg/d in case of concomitant administration of azoles) 5-azacytidine, 75 mg/m² sub cut QD started from day5 to day10 Cycle 2 and 3 (4, 5 and 6 if applicable): Venetoclax, PO 400 mg/day (100 mg/day in case of concomitant administration of azoles) 5-azacytidine, 75 mg/m² sub cut QD started from day1 to day7

Primary outcome measures

• Remission rate [Time frame: 3 months]

Eligibility criteria

Inclusion criteria

• Patients aged 15y or more (under 18y only for France)
• Signed informed consent for patients aged ≥ 18 years and signed informed consent from both parents for patients aged between ≥ 15 years and < 18 years (only for France).
• Patients with T-cell acute lymphoblastic leukemia in first or second relapse or in the refractory phase.

• Patients with first relapses are eligible if relapse occurred within 24 months post complete remission achievement and if nelarabine is not considered as appropriate salvage therapy.
• Patients with second and all subsequent relapses are eligible.
• Refractory patients are defined as patients not responding after at least 2 lines of chemotherapy (induction + salvage).
• Patients with relapses post-transplant and post CART-cells treatments are eligible.
• Blast cells in blood and/or bone marrow to allow the shipment to one of the 3 reference laboratories in France, Spain and The Netherlands or An informative biological assessment already performed within 10 days prior to inclusion in one of the three reference laboratories in France, Spain or The Netherlands with at least one targeted therapeutic option validated (TTO1, venetoclax + tofacitinib; TTO2, venetoclax+ everolimus + enrylaze; TTO3, venetoclax + 5-azacytidine) by one of the three National Validation Committees.
• Adequate ECOG score (0-3).
• Patients must be affiliated to a National Health systems (see country-based specificity).
• Patients must not have a contra-indication for venetoclax, tofacitinib, everolimus, glutaminolytic agents (enrylaze) or 5-azacytidine.
• Willingness of women of child-bearing potential (WOCBP) or of male patients whose sexual partners are WOCBP to use an effective form of contraception during the study and at least 6 months thereafter.

Exclusion criteria

• Patients in palliative care.
• Patients with late relapses after the first complete remission (> 24 months post complete remission).
• Patients with extramedullary only relapses or with clinically symptomatic central nervous system (CNS) involvement.
• Pregnant or lactating women.
• Participation in another clinical trial with an investigative drug at the time of study enrolment.
• Individuals with another active uncontrolled malignancy.
• Known active HBV-, HCV and HIV related diseases.
• Patient under curatorship or deprived of liberty (except for minors).
• Patients with contra-indication to chemotherapy except if considered related to the ALL:

• ASAT (SGOT) and/or ALAT (SGPT) > 5 x ULN
• Total bilirubin ≥ 2.5 x ULN
• Estimated glomerular filtration rate (GFR) < 50 mL/mn using the MDRD equation

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

France · 53 centers

• Centre Hospitalier du Pays d'Aix — Aix-en-Provence
• CHU Amiens Picardie — Amiens
• Chu Angers — Angers
• CH Victor Dupouy — Argenteuil
• Centre Hospitalier d'Avignon — Avignon
• CH cote basque — Bayonne
• CHU Besancon — Besançon
• Hopital Avicenne — Bobigny
• … and 45 more centers

Spain · 10 centers

• Insitut Catala d'Oncologia Badalona — Barcelona
• Vall D'Hebron University Hospital — Barcelona
• Hospital General Universitario Gregorio Marnon — Madrid
• Hospital Universitario Virgen de la Victoria — Málaga
• Hopital Gerneral Universitario Morales Meseguar — Murcia
• Hospital Universitario de Salamanca — Salamanca
• Hematologist at Hospital Universitario Donostia — San Sebastián
• Hospital Universitario Marques de Valdecilla — Santander
• … and 2 more centers

Czechia · 2 centers

• University Hospital Brno — Brno
• Czech medical chamber — Prague

Netherlands · 2 centers

• Erasmus Medical Center — Rotterdam
• University Medical Center Utrecht — Utrecht

Germany · 1 center

• Universtatsklinikum Frankfurt Med. Klinik II — Frankfurt

Poland · 1 center

• Wroclaw Medical University — Wroclaw

Identifiers

NCT: NCT07522801 · P23/15_All Target · 2024-516570-30-00

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗