A Phase 2 Study of Gemtuzumab Ozogamicin (GO)-Gilteritinib Combination in Adults with FLT3-ITD Relapse/refractory (R/R) AML

Inclusion Criteria:

• Patients aged 18 years old or more

• Confirmed diagnosis of R/R AML positive for CD33 antigen as determined locally byimmunophenotyping according to routine practice, defined as:

• AML refractory to 1 or 2 intensive chemotherapy courses or a treatment byhypomethylating agents (HMAs)

• Or AML in first hematologic relapse or progression after front-line therapy,including intensive chemotherapy or hypomethylating agents (HMAs).

• Previous treatments with FLT3 inhibitors (other than gilteritinib) are allowed

• R/R AML secondary to a prior chemotherapy or radiotherapy for another cancer (tAML) could be included.

• Presence of a FLT3-ITD mutation (allelic ratio ≥0.05 at last evaluation)* or a FLT3TKD mutation

• Patient with no contraindication to gemtuzumab ozogamicin (GO), cytarabine andgilteritinib

• ECOG performance status ≤2

• AST and ALT ≤ 2.5 x upper the limit of normal (ULN) and/or total and direct serumbilirubin ≤ 1.5 x ULN unless considered due to leukemia

• Estimated glomerular filtration rate (GFR) ≥ 50 mL/min according to the formulausually used by the investigator

• Written informed consent obtained prior to any screening procedures

• Eligible for National Health Insurance in France

Exclusion Criteria:

• Acute promyelocytic leukemia or AML with BCR-ABL1 gene fusion

• Secondary AML (sAML) defined by a history of prior myelodysplastic syndrome (MDS) ormyeloproliferative syndrome (MPN) including chronic myelomonocytic leukemia (CMML)

• Patient with contraindications to the administration of gemtuzumab ozogamicin (GO),cytarabine and gilteritinib. Refer to the SPCs of the molecules mentioned concerningthe contraindications, special warnings, precautions for use, dose modifications inthe event of toxicity, contraception and monitoring of patients and drugs prohibitedor to be used with caution.

• Proven central nervous system leukemic involvement

• Prior allogeneic HSCT within the last 6 months and/or history of acute GVHD of grade >1

• Prior treatment with gemtuzumab ozogamicin within the last 3 months preceding theinitiation of the treatment in the present clinical trial

• Uncontrolled or active malignant disease within prior 12 months (excluding cutaneousbasal cell carcinoma, "in-situ" carcinoma of the cervix or breast, or other localmalignancy excised)

• Uncontrolled or significant cardiovascular history or symptoms including:

• Prior anthracycline exposure equivalent to more than 550 mg/m2 of daunorubicin

• History of clinically relevant ventricular arrhythmias (e.g. ventriculartachycardia, ventricular fibrillation or torsade de pointes)

• History of 2° (Mobitz II) or 3° heart block (subjects with pacemakers areallowed if they have no history of clinically relevant arrhythmias with thepacemaker)

• History of uncontrolled angina pectoris or MI within 6 months

• History of NYHA Class 3 or 4 heart failure

• Left ventricular ejection fraction ≤ 50% or less than the institutional lowerlimit of normal

• History of complete left bundle branch block

• Unstable angina, New York Heart Association (NYHA) class 3 or 4 congestiveheart failure

• QTcF > or equal to 450 msec, long QT syndrome (including family history)

• Bradycardia < 50 bpm (unless subject has a pacemaker)

• Systolic BP ≥ 180 mmHg or diastolic BP ≥ 110 mmHg

• Uncontrolled systemic fungal, bacterial, or viral infection (defined as ongoingsigns/symptoms related to the infection without improvement despite appropriatetreatment)

• Active known HBV or HCV hepatitis or positive HIV serology

• Concurrent therapy with any other investigational agent or cytotoxic drug, within 28days before starting treatment. Only hydroxyurea ± dexamethasone is permitted forthe control of blood counts

• Current use or anticipated requirement for drugs that are known strong inducers ofCYP3 A4/5

• Current use or anticipated requirement for drugs that are known as strong inhibitorsor inducers of P glycoprotein (P-gp), as mentioned in the appendix 14 of theprotocol, with the exception of drugs that are considered absolutely essential forthe care of the subject

• Current use or anticipated treatment with concomitant drugs that target 5HT1R or 5HT2BR receptors or sigma non-specific receptor, as mentioned in the appendix 15 ofthe protocol, with exception of drugs that are considered absolutely essential forthe care of the subject

• Known malabsorption syndrome or other condition that may significantly impairabsorption of oral study medications

• Any of concurrent severe and/or uncontrolled medical condition, which couldcompromise participation in the study.

• Patient currently receiving one or more inadvisable or prohibited treatmentsdescribed in section 6.4.2 of the protocol.

• Females who are pregnant or breastfeeding.

• Women of childbearing potential or partners of women of childbearing potentialshould use a highly effective method of contraception during treatment and changethe duration of contraception after the last dose of the medicines of the study (GO,cytarabine and gilteritinib).

• For women of childbearing potential (WOCBP): agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception with a failurerate of < 1% per year during the treatment period and after the final dose ofstudy treatment for at least: - 7 months for GO, - 6 months for cytarabine, - 6months for gilteritinib. Women must refrain from donating eggs during this sameperiod. A woman is considered to be of childbearing potential if she ispostmenarcheal, has not reached a postmenopausal state (≥ 12 continuous monthsof amenorrhea with no identified cause other than menopause), and has notundergone surgical sterilization is permanently infertile due to surgery (i.e.removal of ovaries, fallopian tubes, and/or uterus) or another cause asdetermined by the investigator (e.g., Müllerian agenesis). The definition ofchildbearing potential may be adapted for alignment with local guidelines orregulations. Examples of contraceptive methods with a failure rate of < 1% peryear include bilateral tubal ligation, male sterilization, hormonalcontraceptives that inhibit ovulation, hormone-releasing intrauterine devices,and copper intrauterine devices. Hormonal contraceptive methods must besupplemented by a barrier method. The reliability of sexual abstinence shouldbe evaluated in relation to the duration of the clinical trial and thepreferred and usual lifestyle of the patient. Periodic abstinence (e.g.,calendar, ovulation, symptothermal, or postovulation methods) and withdrawalare not acceptable methods of contraception. If required per local guidelinesor regulations, locally recognized acceptable methods of contraception andinformation about the reliability of abstinence will be described in the localInformed Consent Form. Women of childbearing potential must have a negativeserum pregnancy test result within 7 days prior to first dose.

• For male patients: acceptance that most of the study treatments requirespecific reliable and effective contraception measures, as well as measuresrelated to sperm donation Agreement to remain abstinent (refrain fromheterosexual intercourse) or use contraception, and agreement to refrain fromdonating sperm, as defined below With a female partner of childbearingpotential who is not pregnant, men who are not surgically sterile must remainabstinent or use a condom plus an additional contraceptive method that togetherresult in a failure rate of < 1% per year during the treatment period and afterthe final dose of study treatment for at least: - 4 months for GO, - 6 monthsfor cytarabine, - 4 months for gilteritinib.

Men must refrain from donating sperm during this same period With pregnant female partners, men must remain abstinent or use a condom to avoid exposing the embryo during the treatment period and for at least: - 4 months for GO, - 6 months for cytarabine, - 4 months for gilteritinib. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception. If required per local guidelines or regulations, locally recognized acceptable methods of contraception and information about the reliability of abstinence will be described in the local Informed Consent Form.

• Adults subject to a legal protection order or unable to give their consent

• Persons deprived of their freedom by judicial or administrative decision, personshospitalized without their consent by virtue of articles L. 3212-1 and L. 3213-1 andwho are not subject to the provisions of article L. 1121-8.