Protocolli di ricerca attivi

AOU Città della Salute di Torino - Leucemia Acuta Mieloide

DSP-5336-101

Studio di fase 1/2, in aperto, di incremento della dose, di espansione della dose di DSP-5336 in pazienti adulti affetti da leucemia acuta con e senza riarrangiamento del gene della leucemia a linea cellulare mista (MLL) o mutazione del gene della nucleofosmina 1 (NPM1)

Patologia: Pazienti adulti con leucemie acute che abbiano già ricevuto la terapia standard, ma la cui leucemia si sia ripresentata. Altri requisiti per la partecipazione includono la presenza di cambiamenti o mutazioni a carico di uno o più geni (per esempio, riarrangiamento di MLL o mutazione di NPM1)

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Inclusion Criteria

For patients in the Phase 1 dose-escalation portion of the study:

1. Have a confirmed diagnosis of refractory or relapsed AML, ALL, or acute leukemia of ambiguous lineage according to World Health Organization (WHO) 2022 classification, as determined by pathology review at the treating institution, and who failed available standard therapies known to be active for their AML, ALL, or acute leukemia of ambiguous lineage.* Participants must have a documented KMT2A (MLL) fusion or NPM1 mutation, which includes those with coexisting FLT3 genomic alterations and/or IDH1/2 mutation, and those who are candidates for stem cell transplantation must have been offered this therapeutic option.

a. Refractory is defined as: patient did not achieve complete remission (CR) or complete remission with incomplete hematologic recovery (CRi), defined by the 2017 European LeukemiaNet (ELN) guideline under initial intensive therapy, or did not achieve CR, CRi, morphologic leukemia-free state (MLFS) or partial remission (PR) after an initial sufficient time course of treatment with hypomethylating agents (HMA) or low-dose cytarabine

(LDAC), with “sufficient time course” defined as at least 4 cycles of HMA or LDAC therapy, or at least 2 cycles of combination therapy (ie, HMA or LDAC in combination with venetoclax or glasdegib) (Hartmut et al 2017)

b. Relapse is defined as: relapse diagnosed by bone marrow assessment or by the appearance of peripheral blasts after the achievement of CR or CRi, defined by 2017 ELN guideline, with or without consolidation or maintenance, and with or without HSCT

*Examples of standard therapies include, but are not limited to: high dose cytarabine with/without anthracycline, FLAG (fludarabine, cytarabine, idarubicin, G-CSF), or targeted therapy based on the defining genetic anomaly or cell surface marker as follows: AML with IDH1 mutation: ivosidenib or olutasidenib, AML with IDH2 mutation: enasidenib, AML with FLT3 mutation: gilteritinib, AML with CD33+: gemtuzumab ozogamicin, ALL with

CD22+: inotuzumab ozogamicin, ALL with CD19+: blinatumomab, and ALL Phi+: ponatinib

For patients in the Phase 2 dose-expansion portion of the study:

2. Have a confirmed diagnosis of refractory or relapsed AML according to WHO 2022 classification, as determined by pathology review at the treating institution, and who failed available standard therapies known to be active for their AML. Participants who are candidates for stem cell transplantation must have been offered this therapeutic option. See Criterion 1 for definitions of refractory and relapsed.

3. Have documented KMT2A (MLL)-fusion or NPM1 mutation, which includes those with coexisting FLT3 genomic alterations and/or IDH1/2 mutations

For all patients:

4. Be ≥18 years of age

5. Have an Eastern Cooperative Oncology Group (ECOG) performance status ≤2

6. White blood cell (WBC) count must be below 30,000/μL at the time of enrollment and prior to starting study treatment (Hydroxyurea will be allowed prior to enrollment and during study treatment)

7. Have any prior treatment-related toxicities resolved to ≤Grade 1 prior to enrollment, with the exception of ≤Grade 2 alopecia or neuropathy

8. Have adequate renal and hepatic function at Screening as determined by:

a. Clearance of creatinine (CLcr) level ≥50 ml/min, assessed by the Cockcroft-Gault formula

b. Total bilirubin ≤1.5 times the upper limit of normal (ULN) (or ≤2.0 times ULN for patients with known Gilbert’s syndrome)

c. Aspartate aminotransferase (AST) ≤3.0 times ULN

d. Alanine aminotransferase (ALT) ≤3.0 times ULN

9. Be willing to attend study visits as required by the protocol

10. Have an estimated life expectancy ≥3 months, based on the investigator’s assessment

11. Have a negative serum or urine pregnancy test, if female patient of childbearing potential. Females of childbearing/child-producing potential are defined as women who have (1) experienced menarche and have not undergone sterilization procedures (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy), or (2) have not experienced menopause (defined as having amenorrhea continuously for more than 12 months that is not

determined to be drug induced, or who are taking hormone replacement therapy with serum follicle stimulating hormone >35 mIU/mL).

12. Must agree to use a combination of 2 or more different contraception methods (oral contraceptives/ implantable hormonal contraceptives*, and a barrier method*) or use prevention of pregnancy measures (ie, agreement to

refrain completely from heterosexual intercourse) during the study and for 6 months (for females and males alike) after the last dose of study drug, if male or female patient of child-producing potential

*For sites in Japan only: Implantable hormonal contraceptives, a diaphragm with spermicide, cervical cap with spermicide and contraceptive sponge (spermicide is already in the contraceptive sponge) included in the barrier contraceptive method are not approved and cannot be used in Japan.

13. Have AML/ALL material (eg, bone marrow or peripheral blood) suitable for genomic analysis (eg, MLLr or NPM1 mutations) of AML or ALL genetic alterations

Exclusion Criteria

1. [Criterion removed with protocol amendment]

2. Have a histologic diagnosis of acute promyelocytic leukemia

3. [Criterion removed with protocol amendment]

4. Underwent HSCT or chimeric antigen receptor cell (CAR-T) therapy or other modified T-cell therapy within 60 days prior to the first dose of DSP-5336

5. Received a donor lymphocyte infusion within 28 days prior to the first dose of DSP 5336, or receiving immunosuppressive therapy post-HSCT at the time of Screening, or with clinically active GVHD or GVHD requiring active medical intervention other than the use of topical steroids for ongoing cutaneous GVHD

6. Received antineoplastic agents (except hormonal therapies as adjuvant maintenance for breast or prostate cancers if a patient is taking before starting study treatment, and hydroxyurea given for controlling blast cells) within

14 days prior to the first dose of DSP-5336

7. Received systemic calcineurin inhibitors within 4 weeks prior to the first dose of DSP 5336

8. Received immunotherapy, including tumor vaccines and checkpoint inhibitors, within 42 days or 5 half-lives, whichever is shortest, prior to the first dose of DSP-5336

9. Have been on other investigational treatment within the previous 4 weeks prior to the first dose of DSP-5336

10. Had major surgery within 28 days prior to the first dose of DSP-5336

11. Have active central nervous system leukemia

12. [Criterion removed with protocol amendment]

13. Have abnormal ECGs at screening that are clinically significant, such as QT prolongation (QTc >450 msec for males and >470 msec for females, with QTc corrected according to Fridericia’s formula [QTcF])

14. Have a left ventricular ejection fraction (LVEF) <50%, as determined by ECHO

15. Have a history of Torsades de Pointes

16. In the opinion of the treating investigator, have any concurrent conditions that could pose an undue medical hazard or interfere with interpretation of study results; these conditions include, but are not limited to: clinically significant non-healing or healing wounds; concurrent congestive heart failure (New York Heart Association Functional Classification Class III or IV; see Section 21.7); concurrent unstable angina; concurrent cardiac arrhythmia requiring treatment (excluding asymptomatic atrial fibrillation); recent (within the prior 6 months) myocardial infarction; acute coronary syndrome within the previous 6 months; significant pulmonary disease (shortness of

breath at rest or on mild exertion), eg, due to concurrent severe obstructive pulmonary disease, concurrent hypertension not controlled with concomitant medication, or diabetes mellitus with more than 2 episodes of ketoacidosis in the prior 6 months

17. Have a known detectable viral load for human immunodeficiency virus or hepatitis C, or evidence of a hepatitis B surface antigen, all being indicative of active infection For sites in Japan only: Hepatitis B core (HBc) antibody or hepatitis B surface (HBs) antibody test should be performed if HBsAg is negative. If HBc antibody or HBs antibody test is positive, HBV DNA quantification test should be performed to confirm that HBV DNA is negative.

18. Have an active, uncontrolled, bacterial, viral, or fungal infection requiring systemic therapy

19. [Criterion removed with protocol amendment]

20. [Criterion removed with protocol amendment]

21. [Criterion removed with protocol amendment]

22. Have known severe dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the ingestion or gastrointestinal absorption of drugs administered orally, including the inability to swallow oral medication

23. Have a cognitive, psychologic, or psychosocial impediment that would impair the ability of the patient to receive therapy according to the protocol, or adversely affect the ability of the patient to comply with the informed consent process, protocol, or protocol-required visits and procedures

24. Receive concurrent sensitive substrates with a narrow safety window or strong inhibitors or inducers of CYP3A4/5, including specifically: ketoconazole, itraconazole, and isavuconazole. Other antifungals that are used as standard of care to prevent or treat infections are permitted

Note: If a patient is on one of the excluded azole class antifungals and can be switched to a permitted azole 7 or more days prior to study (≥7 days for ketoconazole and itraconazole, ≥21 days for isavuconazole), that patient could be allowed on study (Arm B) with approval of the medical monitor

25. Are pregnant or breastfeeding or planning to become pregnant

Note: Patients who are breastfeeding may be enrolled if they interrupt breastfeeding prior to the first dose of any study drugs and do not feed the baby with breast milk expressed after receiving the first dose of any study drugs. Breastfeeding should not be resumed for at least 6 months after the last dose of study drug.

26. Have any history or complication of interstitial lung disease (for sites in Japan only) and, for clinical sites operating under the European Medicines Agencies, a history of Grade ≥ 2 drug-induced interstitial lung disease or Grade ≥ 2 non-infectious pneumonitis within 6 months of starting study treatment

27. Have a known intolerance or hypersensitivity reaction to components of investigational medicinal product

GIMEMA AML1819

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Linea: I LINEA fase III

Terapia: SCHEMA 3+7+GENTUZUMAB OZOGAMICIN, valutazione MRD e allocazione a autologo o allogenico a seconda della MRD

Principali criteri di inclusione/esclusione:

LAM a rischio favorevole- intermedio
età 10-60 anni
FLT3 negativi

GIMEMA AML1919 (AMELIORATE)

Linea: I LINEA fase III

Terapia: schema 3+7+midostaurina . Valutazione al G4 della clearence blasti con randomizzazione a alte dosi di citarabina se scarsa clearence

Principali criteri di inslusione/esclusione:

LAM FLT 3 ITD o TKD positive
età 18-65 anni

GIMEMA AML 2420 (ENABLE)

Linea: I LINEA fase III

Terapia: decitabina+ venetoclax

Principali criteri di inclusione/esclusione: LAM secondaria a malattia mieloproliferativa

Leggi tutto: AOU Città della Salute di Torino - Leucemia Acuta Mieloide

AOU Città della Salute di Torino - Sindromi mielodisplastiche

GIMEMA ACROBAT

Prospective randomized study on the feasibility of allogeneic stem cell transplantation in higher-riskmyelodysplastic syndromes, performed upfront or preceded by azacitidine or conventional chemotherapy, according to the BM-blast proportion Patologia:patients aged 18-70 years, diagnosed with high-risk MDS, according to IPSS (Int-2/high) or IPSS-R (intermediate to very-high), previously untreated, judged transplant-eligible by the treating physician

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Criteri di inclusione
1. Pazienti con MDS di nuova diagnosi ad alto rischio, inclusi IPSS Intermediate-2 e alto, e IPSS-R da intermedio a molto alto
2. Età 18-70 anni
3. Precedentemente non trattato per HR-MDS
4. HSCT – idoneo
5. Aspettativa di vita ≥3 mesi;
6. Consenso informato scritto firmato secondo ICH/EU/GCP e le leggi locali nazionali
7. Eastern Cooperative Oncology Group Performance Status Grade di 0-2

Criteri di esclusione
1. Leucemia mieloide acuta con >20% di blasti nel midollo osseo o nel sangue periferico (PB);
2. tumore maligno concomitante diagnosticato negli ultimi 12 mesi (ad eccezione del basalioma cutaneo);
3. grave insufficienza renale, cardiaca, epatica o polmonare;
4. donne incinte o in allattamento o potenzialmente fertili (sia maschi che femmine), che non abbiano acconsentito evitare una gravidanza durante il periodo di prova; Le donne in età fertile e gli uomini devono essere d'accordo utilizzare un metodo contraccettivo efficace durante e fino a 3 mesi dopo il trattamento con azacitidina.
5. Infezione da HIV; infezioni attive e non controllate da HCV o HBV o cirrosi epatica;
6. malattie neurologiche o psichiatriche clinicamente rilevanti;
7. ipersensibilità (conosciuta o sospetta) all'AZA;
8. Trattamenti precedenti:
a) precedenti farmaci sperimentali (entro 30 giorni);
b) radioterapia, chemioterapia o terapia citotossica per condizioni non MDS tra le precedenti 6 mesi;
c) fattori di crescita (EPO, G-CSF o GM-CSF) nei 21 giorni precedenti;
d) ormoni androgeni nei 14 giorni precedenti;
e) precedente trapianto o terapia citotossica, inclusa azacitidina, AZA o chemioterapia, somministrati per trattare le
MDS

SELECT –MDS (Syros)

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Linea: I LINEA fase III

Terapia: Random azacitidina+ tamibarotene vs azacitidina

Principali criteri di inclusione/esclusione:
MDS risk INT –H-VH
Blasti > 5%
RARA+ ( valutazione centralizzata)

GIMEMA MDS0519 (ACROBAT)

Linea: I LINEA fase III

Terapia: Pre allogenico se bl <10% azacitidina vs BSC .Se bl > 10% azavitidina vs chemioterapia

Principali criteri di inclusione/esclusione: Pazienti candidati a trapianto allogenico di midollo

Leggi tutto: AOU Città della Salute di Torino - Sindromi mielodisplastiche

AOU Alessandria - Leucemia Acuta Mieloide

GIMEMA AML1819

Phase III study to assess the impact of gemtuzumab ozogamicin, in combination with standard chemotherapy, on the levels of minimal residual disease, in adult patients, aged 18-60 years, with previously untreated, de novo, favorable-intermediate-risk acute myeloid leukemia

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Trattamento: gemtuzumab ozogamicin,

Sindromi target: acute myeloid leukemia

Principali Criteri Inclusione:

Patients aged between 18 and 60 years.
Patients previously untreated for their AML by other chemotherapeutic agents (except for no more than 14 days HU) or radiotherapy.
Unequivocal diagnosis of de novo AML according to WHO diagnostic criteria (at least 20% blasts in the bone marrow), other than acute promyelocytic leukemia, documented by bone marrow aspiration (or biopsy in case of dry tap) (not supervening after other myeloproliferative disease or myelodysplastic syndromes of ≥ 6 months duration).
Patients with favorable-intermediate AML according to ELN 2017 (except for FLT3-ITD/TKD positive AML).
WHO performance status 0-3.
Adequate renal (serum creatinine ≤ 2 x the institutional ULN) and liver (total serum bilirubin ≤ 2 x ULN; serum ALT and AST ≤ 2.5 x ULN) function, unless considered due to organ leukemic involvement.
Left Ventricular Ejection Fraction (LVEF) ≥ 50%, as determined by echocardiogram
Absence of severe concomitant neurological or psychiatric diseases and congestive heart failure or active uncontrolled infection.
Absence of any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and the follow-up schedule.

Principali Criteri Esclusione:

2. Acute promyelocytic leukemia

3. Blast crisis of chronic myeloid leukemia

4. FLT3-ITD/TKD positive AML

5. AML supervening after other myeloproliferative disease

6. AML supervening after antecedent myelodysplastic syndromes ≥ 6 months duration

7. Therapy-related AML

8. Other active or progressive malignant diseases.

GIMEMA AML1919

A Phase 3, prospective, randomized multi-center intervention trial of early intensification in AML patients bearing FLT3 mutations based on peripheral blast clearance. A MYNERVA-GIMEMA study (AMELIORATE)

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Trattamento: 3+7+midostaurina

Sindromi target: Acute myeloid leukemia

Principali Criteri Inclusione:

1. Patients with de novo AML, untreated, newly diagnosed, according to WHO 2016 criteria

2. Presence of a mutation of FLT3 gene, either ITD and/or TKD

3. Adequate availability of diagnostic biologic material for full cytological, cytogenetic, genetic and immunophenotypic disease characterization according to ELN criteria.

4. Presence of morphologically identifiable blasts on peripheral blood at diagnosis

5. Presence of a Leukemia-associated aberrant immune-phenotype (LAIP) as assessed by MFC

(multiparametric flow cytometry) at diagnosis

6. Age between 18 and 65 years, included

7. ECOG performance status 0-2 or disease-related reversible ECOG 3 score following adequate supportive care.

Principali Criteri Esclusione:

1. Diagnosis of acute promyelocytic leukemia

2. Diagnosis of AML with t(8;21)(q22:q22)/RUNX1-RUNX1T1 and t(16;16)(p13:q22) or inversion of chromosome 16 (16)(p13q22)/CBFB-MYH11; in case of suspicion of CBF-related AML due to morphological and/or immunophenotypic features, specific FISH or molecular testing is strongly recommended

3. Left ventricular ejection fraction < 45% (by echocardiogram or MUGA)

7. QTc >470 msec on screening ECG (Fridericia’s formula)

8. A history of cancer that is not in remission phase following surgery and/or chemotherapy and/or radiotherapy with life expectancy < 1 year.

Leggi tutto: AOU Alessandria - Leucemia Acuta Mieloide

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