Phase III Study of Induction and Consolidation Chemotherapy With Venetoclax in Patients With Newly Diagnosed AML or MDS-EB-2

Official title

A Randomized, Placebo-Controlled Phase III Study of Induction and Consolidation Chemotherapy With Venetoclax in Adult Patients With Newly Diagnosed Acute Myeloid Leukemia or Myelodysplastic Syndrome With Excess Blasts-2

Overview

A Randomized, Placebo-Controlled Phase III Study of Induction and Consolidation Chemotherapy With Venetoclax in Adult Patients With Newly Diagnosed Acute Myeloid Leukemia or Myelodysplastic Syndrome With Excess Blasts-2

Detailed description

Prospective, multicenter, double-blind, randomized, placebo-controlled phase 3 clinical study. The randomized phase of the study will be preceded by a feasibility run-in dose-escalation phase in patients with AML in which the venetoclax dose for the phase 3 part will be established.

After the feasibility run-in phase, eligible patients will be randomized to intensive chemotherapy with venetoclax or placebo. Patients will receive two cycles of induction chemotherapy; patients achieving CR or CRi after two cycles will continue with consolidation treatment according to initial randomization, and according to Cooperative Group-specific consolidation regimens or investigator choice. Patients achieving morphologic leukemia-free state (MLFS) only, may also continue consolidation treatment on protocol. Assignment to either allogeneic hematopoietic cell transplantation (HCT), conventional chemotherapy or autologous HCT will be done according to institutional standards, and based on (prognostic) disease characteristics, individual patient assessment, and established comorbidity risk scores (e.g., HCT-CI score).

Interventions

• Drug Venetoclax
  Venetoclax will be administered in Induction cycle 1, Induction cycle 2 and in the chemo consolidation therapy in addition to the standard chemotherapy
• Drug Placebo
  Placebo will be administered in Induction cycle 1, Induction cycle 2 and in the chemo consolidation therapy in addition to the standard chemotherapy
• Combination product Standard chemotherapy
  Induction cycle 1: Patients will receive cytarabine 200 mg/m2 continuous IV (days 1-7) and daunorubicin 60 mg/m2 IV (days 1-3). Induction cycle 2: Patients ≤ 60 yrs will receive cytarabine 1000 mg/m2 BID (3h IV), days 1-4, and daunorubicin 60 mg/m2 IV (days 1-3). Patients \>60 yrs will receive cytarabine 1000 mg/m2 BID (3h IV), days 1-4 without daunorubicin. Consolidation chemotherapy with intermediate doses of cytarabine. Patients ≤60 yrs will receive up to 3 cycles of IDAC (single dose 1500 m
• Other Allogeneic stem cell transplantation
  Generally, patients will proceed to allogeneic HCT upon completion of remission induction chemotherapy. It is however allowed, as per investigator's discretion, for a patient to receive 'bridging' consolidation chemotherapy in exceptional cases of delay towards transplantation. At baseline, HLA-compatible donor search must be initiated as soon as possible, first among siblings and second in the world donor bank for unrelated donors or cord blood. In order to avoid inappropriate delay in cases wh

Primary outcome measures

• Event Free Survival (EFS) [Time frame: 6 months/16 months after inclusion of last patient]
• Frequency of dose-limiting toxicities (DLTs) during the observation period (Primary safety endpoint during dose-finding phase) [Time frame: after cycle 1 (maximal day 42)]

Secondary outcome measures (12)

• Overall Survival (OS) [Time frame: 6 months/16 months/28 months after inclusion of last patient]
• CR/CRi rate [Time frame: 2 months]
• CR rate [Time frame: 2 months]
• Event Free Survival (EFS) including CRh [Time frame: 6 months/16 months after inclusion of last patient]
• Rates of complete remission without measurable residual disease (CRMRD-) after induction therapy [Time frame: 2 months]
• Relapse-free survival (RFS) in newly diagnosed AML patients [Time frame: 16 months after inclusion of last patient]
• Cumulative incidence of relapse (CIR) in newly diagnosed AML patients [Time frame: 16 months after inclusion of last patient]
• Cumulative incidence of death (CID) [Time frame: 16 months after inclusion of last patient]
• EQ-5D-5L questionnaire of the EuroQoL (EQ) group, among AML patients [Time frame: at study entry, 2 months, 3 months, 6 months]
• European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-C30) among AML patients [Time frame: at study entry, 2 months, 3 months, 6 months]
• Patient Reported Outcome Measurement Information System (PROMIS) Cancer Fatigue short form among AML patients [Time frame: at study entry, 2 months, 3 months, 6 months]
• CR/CRh rate [Time frame: 2 months]

Eligibility criteria

Inclusion criteria

• Patients with newly diagnosed acute myeloid leukemia (AML) according to the International Consensus Classification (ICC).
• Age ≥ 18 and ≤ 75 years.
• Patients considered eligible for intensive chemotherapy.
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
• Molecular analysis centrally performed in AMLSG and HOVON laboratories.
• Adequate renal function as evidenced by serum creatinine ≤ 2.0 × upper limit of norm (ULN) or creatinine clearance >40 mL/min based on the Cockcroft-Gault glomerular filtration rate (GFR).
• Adequate hepatic function as evidenced by:

• Serum total bilirubin ≤ 2.5 × ULN unless considered due to Gilbert's disease, or leukemic involvement following approval by the Principal Investigators or Trial Coordinators of the study
• Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) ≤ 3.0 × ULN, unless considered due to leukemic involvement following approval by the Principal Investigators or Trial Coordinators.
• No prior chemotherapy for AML, except hydroxyurea for up to 14 days during the diagnostic screening phase for the control of peripheral leukemic blasts in patients with leukocytosis (e.g., white blood cell \[WBC\] counts > 25x109/L); patients may have had previous treatment with erythroid stimulating agents (ESA) or hypomethylating agents (HMAs) for an antecedent phase of MDS; ESA and HMAs have to be stopped at least four weeks before start of study treatment.
• Patients must not have received a known strong or moderate CYP3A inducer 7 days before start of study treatment. Patients must have no known medical conditions requiring chronic therapy with moderate or strong CYP3A inducers.
• Female patient must either:

• Be of nonchildbearing potential:

• Postmenopausal (defined as at least 1 year without any menses)
• Documented surgically sterile (e.g. documented hysterectomy, bilateral oophorectomy, bilateral salpingectomy or congenital sterile) or status post hysterectomy (at least 1 month prior to screening)
• Or, if of childbearing potential (not surgically sterile and not postmenopausal)

• Not planning to become pregnant during the study and for 6 months after the final study drug administration
• And have a negative urine or serum pregnancy test at screening
• And, if heterosexually active, agree to consistently apply one highly effective\* method of birth control in combination to a barrier method for the duration of the study and for 27 weeks after the final study drug administration

\*Highly effective forms of birth control include

• Consistent and correct usage of established hormonal contraceptives that inhibit ovulation for at least 1 month prior to taking study drug. (hormonal contraception is only a highly effective method of birth control, if a combined \[estrogen and progestogen containing\] hormonal contraception or a progestogen-only hormonal contraception - both associated with inhibition of ovulation - is used.
• Established intrauterine device (IUD) or intrauterine system (IUS)
• Bilateral tubal occlusion
• Vasectomy - a vasectomy is highly effective contraception method provided the absence of sperm has been confirmed. If not, an additional highly effective method of contraception should be used.
• Male is sterile due to a bilateral orchiectomy.
• Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual activity during the entire period of risk associated with the study drug. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the patient.

\*List is not all inclusive. Prior to enrolment, the investigator is responsible for confirming patient will utilize highly effective forms of birth control in combination with a barrier method according to locally accepted standards during the protocol defined period.

• Female patient must agree not to breastfeed starting at screening and throughout the study period, and for 2 months and 1 week after the final study drug administration.
• Female patient must not donate ova starting at screening and throughout the study period, and for 27 weeks after the final study drug administration.
• Men must use a latex condom during any sexual contact with WOCBP, even if they have undergone a successful vasectomy and must agree to avoid to father a child (while on therapy and for 27 weeks after the final study drug administration). In addition, their female partners of childbearing potential have to use a highly effective method of birth control.
• Male patient must not donate sperm starting at screening and throughout the study period and for 27 weeks after the final study drug administration.
• Able to understand and willing to sign an informed consent form (ICF).

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

Quadruple blind

Primary purpose

Treatment

Study locations

Germany · 50 centers

• Klinikum Aschaffenburg-Alzenau gGmbH — Aschaffenburg
• HELIOS Klinikum Bad Saarow GmbH — Bad Saarow
• Charité Berlin - Campus Mitte — Berlin
• Charité Berlin - Campus Benjamin Franklin — Berlin
• Charité Berlin - Campus Virchow Klinikum — Berlin
• Vivantes am Urban — Berlin
• Vivantes Neukölln — Berlin
• Vivantes Spandau — Berlin
• … and 42 more centers

Netherlands · 20 centers

• Jeroen Bosch ziekenhuis — 's-Hertogenbosch
• Meander Medisch Centrum — Amersfoort
• Amsterdam UMC Stichting — Amsterdam
• OLVG — Amsterdam
• Rijnstate Ziekenhuis Stichting — Arnhem
• Amphia Hospital — Breda
• Reinier de Graaf Gasthuis — Delft
• Albert Schweitzer Ziekenhuis — Dordrecht
• … and 12 more centers

Austria · 6 centers

• Tirol Kliniken GmbH — Innsbruck
• Kepler Universitaetsklinikum GmbH — Linz
• Ordensklinikum Linz GmbH — Linz
• Landeskrankenhaus (LKH) Rankweil, Interne E am Landeskrankenhaus Rankweil — Rankweil
• Gemeinnuetzige Salzburger Landeskliniken Betriebsgesellschaft mbH — Salzburg
• Hanusch Krankenhaus Der Wiener Gebietskrankenkasse — Vienna

Belgium · 6 centers

• Ziekenhuis Aan De Stroom — Antwerp
• Az St-Jan Brugge-Oostende A.V. — Bruges
• Universitair Ziekenhuis Brussel — Brussels
• Katholieke Universiteit te Leuven — Leuven
• Algemeen Ziekenhuis Delta — Roeselare
• CHU UCL NAMUR - Mont Godinne — Yvoir

Norway · 4 centers

Center list to be confirmed — check the primary protocol.

Estonia · 2 centers

• North Estonia Medical Centre Foundation — Tallinn
• Tartu University Hospital — Tartu

Finland · 2 centers

• Helsinki University Central Hospital Meilahden Kolmiosairaala — Helsinki
• Tampere University Hospital — Tampere

Lithuania · 1 center

• Vilnius University Hospital Santaros Klinik — Vilnius

Identifiers

NCT: NCT04628026 · AMLSG31-19/HO501/AbbVieB18-982

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗