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non-intensive treatment: venetoclax plus azacitidine

standard of care treatment: intensive chemotherapy plus gemtuzumab ozogamicin

Induction cycle 1:

100 mg venetoclax p.o. on day 1; 200 mg venetoclax p.o. on day 2; 400 mg venetoclax p.o. on days 3-28; 75 mg/m\^2 azacitidine s.c. on days 1-7

Induction cycles 2-3:

400 mg venetoclax p.o. on days 1-28; 75 mg/m\^2 azacitidine s.c. on days 1-7

Postremission cycles 1-9:

400 mg venetoclax p.o. on days 1-28; 75 mg/m\^2 azacitidine s.c. on days 1-7

Venetoclax plus Azacitidine

Induction cycle 1:

200 mg/m\^2 cytarabine cont inf i.v. on days 1-7; 60 mg/m\^2 daunorubicin i.v. on days 3-5; 3 mg/m\^2 (max 1 vial) gemtuzumab ozogamicin i.v. on days 1+4+7

Induction cycle 2 (patients not in remission, moderate or non-responders):

3000/1000 mg/m\^2 cytarabine i.v. BID on days 1-3; 10 mg/m\^2 mitoxantrone i.v. on days 3-5

Postremission cycles 1-3:

3000/1000 mg/m\^2 cytarabine i.v. BID on days 1-3

standard of care chemotherapy plus gemtuzumab ozogamicin

Manja Reimann, Dr.

Frank Fiebig

Maher Hanoun, PD Dr.

Edgar Jost, Prof.

Christoph Schmid, Prof.

Mathias Hänel, Prof.

Christoph Röllig, Prof.

Stefan Krause, Prof.

Björn Steffen, Dr.

Christine Dierks, Prof.

Tim Sauer, Dr.

Lars Fransecky, Dr.

Klaus Metzeler, Prof.

Nadine Müller, Dr.

Andreas Neubauer, Prof.

Christoph Schliemann, Prof.

Kerstin Schäfer-Eckart, Dr.

Nadia Maguire

Martin Kaufmann, Dr.

This phase II clinical trial evaluates the efficacy and tolerability of the non-intensive treatment with venetoclax and the hypomethylating agent azacitidine as compared to the standard of care chemotherapy plus gemtuzumab ozogamicin in newly diagnosed NPM1 mutated AML patients fit for intensive chemotherapy.

AML is a heterogeneous disease of malignant early myeloid cells with a poor prognosis. Currently the only potentially curative treatment for patients with AML is intensive induction chemotherapy with 7 days of standard-dose cytarabine plus 3 days of an anthracyclin (7+3) followed either by several courses of consolidation chemotherapy with high-dose cytarabine or by allogeneic stem cell transplantation as standard of care (SOC). Complete remission (CR) is achieved in 60-80% of younger patients (aged 16-60 years) and in around 50% of older patients aged ≥ 60 years by this induction chemotherapy. However, this induction chemotherapy is toxic, due to prolonged myelosuppression with resulting infectious complications and organ toxicity with severe nausea, mucositis, colitis and cardiotoxicity. Each cycle of this intensive chemotherapy usually results in prolonged hospitalization of the patients and requires extensive supportive care with blood products and anti-infective agents. In addition, patients treated with intensive induction chemotherapy are at increased risk for several serious long-term side effects including cardiac and neurological sequelae, infertility and secondary cancers. The high toxicity burden in general and cardiovascular toxicity specifically consistently increase total costs in intensive induction and consolidation chemotherapy. From this perspective there is a need for therapies with lower toxicity and better efficacy.

Due to the high risk of early mortality, older patients and those with severe pre-existing conditions are typically treated with non-intensive chemotherapy with either low-dose cytarabine (LDAC) or a hypomethylating agent (HMA) either azacitidine or decitabine.While these treatments offer at best modest efficacy with CR rates of only 10%-30% and median overall survival of 6-12 months, combinations with the B-cell lymphoma-2 inhibitor venetoclax have been shown to produce CR rates between 50-75% in patients not eligible for intensive chemotherapy. The best response of venetoclax-based regimens with response rates up to 93% and two-year overall survival of 75% has been found among others in the large group of AML patients with mutations in the NPM1 gene. Standard intensive treatment in NPM1 mutated AML patients without adverse risk features usually consisting of standard of care chemotherapy plus gemtuzumab ozogamicin (GO) induces CR rates around 85%, and leads to a 5-year overall survival of around 40% - 50%.The rate and durability of response to venetoclax-based combinations in single arm studies with NPM1 mutated AML patients compared favourably with outcomes from intensive chemotherapy. A retrospective analysis in elderly AML patients with NPM1 mutation found remission rates of 73% in the entire cohort and 96 % in patients \> 65 years. The venetoclax-based combination with the HMA azacitidine is generally well tolerated and has a better safety profile than intensive chemotherapy.

Based on these available clinical data it is postulated that non-intensive treatment with venetoclax plus azacitidine in NPM1 mutated fit AML patients may be equivalent or superior to the standard intensive treatment in terms of remission rates, relapse-free survival, treatment related mortality and health-related quality of life. This randomised controlled phase II trial (VINCENT) is to evaluate the efficacy and tolerability of the non-intensive treatment with venetolcax and azacitidine (Ven+Aza arm) in a wide age-range of newly diagnosed NPM1 mutated AML patients fit for intensive chemotherapy in comparison to standard of care chemotherapy plus GO (SOC arm).

Venetoclax Plus Azacitidine Versus Intensive Chemotherapy for Fit Patients With Newly Diagnosed NPM1 Mutated AML

Venetoclax Plus Azacitidine Versus Standard Intensive Chemotherapy for Patients With Newly Diagnosed Acute Myeloid Leukemia (AML) and NPM1 Mutations Eligible for Intensive Treatment

* Failure to achieve a CR/CRi/CRh after a maximum of two induction cycles in the control arm (SOC) or three induction cycles in the investigational arm (VEN+AZA), i.e. primary induction failure
* Hematologic relapse after previous CR/CRi/CRh
* Molecular failure, defined as either

  * Molecular progression, defined as confirmed ≥ 1 log10 increase of NPM1 MRD level in any two samples in a patient without prior MRD negativity or
  * Molecular relapse after previous MRD negativity, defined as confirmed ≥ 1 log10 between two consecutive positive samples in a patient who was previously tested as MRD negative
* Death

cumulative occurence of CTCAE grade 3 and grade 4 adverse events

CR/CRi/CRh rate is defined as the proportion of patients, who achieved a CR or CRi or CRh during study participation.

Proportion of patients with absence of detectable NPM1 mutant transcripts or with detectable NPM1 mutant transcripts who do not meet any of the definitions of molceular failure during study participation.

Proportion of patients with detectable NPM1 mutant transcripts present after four cycles of treatment with less than a 4 log10 reduction from baseline.

Proportion of patients, who achieved a CR or CRi or CRh with NPM1-mutant transcripts/ABL1 transcripts \<0.01% during study participation.

Early mortality is defined as death from any reason within 14, 30 and 60 days from day 1 of induction treatment.

Relapse-free survival is defined as the time interval from date of first CR/CRi/CRh until either morphologic or molecular relapse or death in remission.

Overall survival is defined as time interval from date of randomization until death from any cause.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Venetoclax Plus Azacitidine Versus Intensive Chemotherapy for Fit Patients With Newly Diagnosed NPM1 Mutated AML	NCT05904106	Acute Myeloid L...	Venetoclax plus... standard of car...	18 Years - 70 Years	Technische Universität Dresden
Venetoclax Plus Azacitidine Versus Intensive Chemotherapy for Fit Patients With Newly Diagnosed NPM1 Mutated AML	NCT05904106	Acute Myeloid L...	Venetoclax plus... standard of car...	18 Years - 70 Years	Technische Universität Dresden

Spots Global Cancer Trial Database for standard of care chemotherapy plus gemtuzumab ozogamicin