Gemtuzumab Chemotherapy MRD Levels; Glasdegib Post-transplant, Adult Untreated, de Novo, Fav Interm Risk AML

Sponsor

Gruppo Italiano Malattie EMatologiche dell'Adulto (Other)

Overall Status

Recruiting

CT.gov ID

NCT04168502

Collaborator

(none)

414

Enrollment

Locations

Arms

78.2

Anticipated Duration (Months)

8.6

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

MRD driven study. Addition of gemtuzumab to conventional chemotherapy to reduce MRD of patients with favorable/intermediate-risk AML. Post-consolidation assessment of MRD. Role of a post-SCT maintenance with glasdegib.

Condition or Disease	Intervention/Treatment	Phase
Acute Myeloid Leukemia	Drug: Glasdegib Drug: Gemtuzumab Ozogamicin	Phase 3

Detailed Description

Setting up a multicenter, MRD (Minimal Residual Disease)-driven study that relies on addition of gemtuzumab ozogamicin to conventional chemotherapy to reduce the pre-transplant levels of MRD of patients with favorable/intermediate-risk (according to ELN 2017) AML. Post-consolidation assessment of MRD will be exploited to establish the final risk assignment and to verify whether the delivery of a post remission therapy intensity (AuSCT, Autologous Stem Cell Transplant, vs ASCT, Allogeneic Stem Cell Transplant) of which is MRD-driven will improve the outcome in terms of anti-leukemic efficacy. Finally, the role of a post-SCT maintenance with glasdegib will be explored.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

414 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Phase 3 Study to Assess Gemtuzumab, in Combination With Standard Chemotherapy, on MRD Levels, and the Role of Glasdegib as a Post-transplant Maintenance, in Adult, 18-60 Years, With Previously Untreated de Novo Fav-interm Risk AML

Actual Study Start Date :

Sep 24, 2020

Anticipated Primary Completion Date :

Apr 1, 2023

Anticipated Study Completion Date :

Apr 1, 2027

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Experimental arm Induction: Gemtuzumab 3 mg/m2 day 1,4,7 Daunorubicin 60 mg/m2 day 1-3 Cytosine arabinoside 200 mg/m2 day 1-7 Consolidation: Gemtuzumab 3 mg/m2 day 1 Daunorubicin 50 mg/m2 day 4-6 Cytosine arabinoside 500 mg/m2 twice a day, day 1-6 Allogeneic transplantation or Autologous transplantation according to MRD level Maintenance with glasdegib 100 mg daily for one year or until toxicity/relapse	Drug: Glasdegib After randomization patients in both arms will be randomized to maintenance with glasdegib vs clinical observation Drug: Gemtuzumab Ozogamicin Both arms, before randomization, will receive induction and consolidation with Gemtuzumab ozogamicin, Daunorubicin and Cytarabine
Active Comparator: Standard arm Induction: Gemtuzumab 3 mg/m2 day 1,4,7 Daunorubicin 60 mg/m2 day 1-3 Cytosine arabinoside 200 mg/m2 day 1-7 Consolidation: Gemtuzumab 3 mg/m2 day 1 Daunorubicin 50 mg/m2 day 4-6 Cytosine arabinoside 500 mg/m2 twice a day, day 1-6 Allogeneic transplantation or Autologous transplantation according to MRD level clinical observation	Drug: Gemtuzumab Ozogamicin Both arms, before randomization, will receive induction and consolidation with Gemtuzumab ozogamicin, Daunorubicin and Cytarabine

Arm

Intervention/Treatment

Experimental: Experimental arm

Induction: Gemtuzumab 3 mg/m2 day 1,4,7 Daunorubicin 60 mg/m2 day 1-3 Cytosine arabinoside 200 mg/m2 day 1-7 Consolidation: Gemtuzumab 3 mg/m2 day 1 Daunorubicin 50 mg/m2 day 4-6 Cytosine arabinoside 500 mg/m2 twice a day, day 1-6 Allogeneic transplantation or Autologous transplantation according to MRD level Maintenance with glasdegib 100 mg daily for one year or until toxicity/relapse

Drug: Glasdegib

After randomization patients in both arms will be randomized to maintenance with glasdegib vs clinical observation

Drug: Gemtuzumab Ozogamicin

Both arms, before randomization, will receive induction and consolidation with Gemtuzumab ozogamicin, Daunorubicin and Cytarabine

Active Comparator: Standard arm

Drug: Gemtuzumab Ozogamicin

Both arms, before randomization, will receive induction and consolidation with Gemtuzumab ozogamicin, Daunorubicin and Cytarabine

Outcome Measures

Primary Outcome Measures

Activity of GO in combination with chemotherapy in terms of MRD negativity achievement [2 months]
Percentage of MRD negativity after consolidation in patients treated in induction and consolidation with GO
Efficacy of Glasdegib maintenance vs clinical observation [2,5 years]
Disease Free Survival (DFS) in patients randomized to glasdegib maintenance or clinical observation

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 60 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Signed written informed consent according to ICH/EU/GCP and national/local laws
Patients aged between 18 and 60 years
Patients previously untreated for their AML by other chemotherapeutic agents (except for no more than 7 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.

Exclusion Criteria:

Patients already treated for their AML by other chemotherapeutic agents (except for no more than 7 days HU) or radiotherapy
Acute promyelocytic leukemia
Blast crisis of chronic myeloid leukemia
FLT3-ITD/TKD positive AML
AML supervening after other myeloproliferative disease ≥ 6 months duration
AML supervening after antecedent myelodysplastic syndromes
Therapy-related AML
Other active or progressive malignant diseases.
Inadequate renal or liver function (metabolic abnormalities > 2-2.5 times the normal upper limit)
Severe heart failure requiring diuretics
Ejection fraction < 50%
Uncontrolled infections
Severe concomitant neurological or psychiatric diseases
Patients who are pregnant or adults of reproductive potential not employing an effective method of birth control. Women of childbearing potential must have a negative serum pregnancy test within 48 hours prior to administration of chemotherapy. Post-menopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential. Male and female patients must agree to employ an effective barrier method of birth control throughout the study and for at least 6 months following discontinuation of study drug.

Contacts and Locations

Locations

	Site	City	Country
1	A.O. - SS. Antonio e Biagio e Cesare Arrigo - SC Ematologia	Alessandria	Italy
2	Aou Ospedali Riuniti "Umberto I - G.M. Lancisi - G. Salesi"- Ancona - Sod Clinica Ematologica	Ancona	Italy
3	Area Vasta N. 5 Ascoli Piceno - S. Benedetto Del Tronto, Presidio Ospedaliero Av5 Osp. Gen. Prov.Le "C.G.Mazzoni" - Uoc Ematologia	Ascoli Piceno	Italy
4	AO "San Giuseppe Moscati" - UOC Ematologia con unità di trapianto	Avellino	Italy
5	AOU Consorziale Policlinico "Aldo Moro" - UO Ematologia con trapianto	Bari	Italy
6	Policlinico S. Orsola - Malpighi - UOC Ematologia	Bologna	Italy
7	Ao Sant'Anna E San Sebastiano - Caserta - Uoc Onco Ematologia	Caserta	Italy
8	U.O.C. Oncoematologia - Istituto Oncologico Veneto Irccs, Presidio Ospedaliero S. Giacomo Apostolo	Castelfranco Veneto	Italy
9	Asur Marche Area Vasta 3 - Presidio Ospedaliero Civitanova Marche - Uods Ematologia	Civitanova Marche	Italy
10	Aou Arcispedale Sant'Anna - Cona (Fe) - Uoc Ematologia E Fisiopatologia Della Coagulazione	Cona	Italy
11	Asst Di Cremona - Ospedale Di Cremona - Uo Ematologia	Cremona	Italy
12	Aou Careggi - Firenze - Sod Ematologia	Firenze	Italy
13	Asl Frosinone, Ospedale F. Spaziani - Ematologia	Frosinone	Italy
14	Irccs Aou San Martino - Genova - Uo Ematologia E Trapianti	Genova	Italy
15	Presidio Ospedaliero Nord "Santa Maria Goretti" - UOC Ematologia	Latina	Italy
16	ASL Le/1 P.O. Vito Fazzi - UO Ematologia	Lecce	Italy
17	Aulss 3 Serenissima, Ospedale Dell'Angelo - Mestre - Uo Ematologia	Mestre	Italy
18	Asst Grande Ospedale Metropolitano Niguarda - Milano - Sc Ematologia	Milano	Italy
19	Irccs Ospedale S. Raffaele - Milano - Uo Oncoematologia	Milano	Italy
20	ISTITUTO EUROPEO DI ONCOLOGIA IRCCS - MILANO - DIVISIONE DI ONCOEMATOLOGIA 176 Milano Divisione di Onco-Ematologia Istituto Europeo	Milano	Italy
21	Aou Di Modena - Sc Ematologia	Modena	Italy
22	Ao Di Rilievo Nazionale Antonio Cardarelli - Napoli - Uoc Ematologia Con Trapianto Di Midollo	Napoli	Italy
23	Aou Federico Ii - Napoli - Uoc Ematologia	Napoli	Italy
24	Aou San Luigi Gonzaga - Orbassano - Scdu Ematologia Generale E Oncoematologia	Orbassano	Italy
25	Asl Salerno, Presidio Ospedaliero Tortora Pagani - Ematologia	Pagani	Italy
26	Ao Ospedali Riuniti Villa Sofia Cervello - Palermo - Uo Ematologia Con Utmo	Palermo	Italy
27	Aou Policlinico P. Giaccone - Palermo - Uo Ematologia	Palermo	Italy
28	Fondazione Ircss Policlinico San Matteo - Pavia - Uo Ematologia	Pavia	Italy
29	Ao Di Perugia, Ospedale S. Maria Della Misericordia - Ematologia E Trapianto Midollo Osseo	Perugia	Italy
30	Ao Ospedali Riuniti Marche Nord - Ospedale San Salvatore - Pesaro - Uoc Ematologia E Centro Trapianti	Pesaro	Italy
31	Asl Pescara, Presidio Ospedaliero 'Spirito Santo' - Uoc Ematologia Clinica	Pescara	Italy
32	Asl Di Piacenza, Ospedale "Guglielmo Da Saliceto" - Ematologia E Centro Trapianti	Piacenza	Italy
33	Ausl Della Romagna, Ospedale "Santa Maria Delle Croci" - Ravenna - Ematologia	Ravenna	Italy
34	Ausl Di Reggio Emilia - Arcispedale Santa Maria Nuova, Irccs - Sc Ematologia	Reggio Emilia	Italy
35	Ausl Della Romagna, Ospedale "Infermi" - Rimini - Uo Ematologia	Rimini	Italy
36	Ao Complesso Ospedaliero San Giovanni / Addolorata - Roma - Uoc Ematologia	Roma	Italy
37	AOU Policlinico Tor Vergata- UOC Trapianto cellule staminali	Roma	Italy
38	Aou Sant'Andrea - Roma - Uoc Ematologia	Roma	Italy
39	Fondazione Policlinico Universitario Agostino Gemelli Irccs - Roma - Area Ematologica	Roma	Italy
40	Istituti Fisioterapici Ospitalieri - Ifo - Istituto Regina Elena - Roma - Uosd Ematologia	Roma	Italy
41	Policlinico Universitario Campus Bio Medico - Roma - Uoc Ematologia E Trapianto Di Cellule Staminali	Roma	Italy
42	Università Degli Studi Di Roma "Sapienza" - Dipartimento Di Medicina Traslazionale E Di Precisione - U.O.C. Ematologia	Roma	Italy
43	Ente Ecclesiastico Casa Sollievo Della Sofferenza - San Giovanni Rotondo - Ematologia	San Giovanni Rotondo	Italy
44	Aou Di Sassari - Cliniche Universitarie - Stabilimento Cliniche Di San Pietro - Uoc Ematologia	Sassari	Italy
45	Aou Città Della Salute E Della Scienza, Ospedale S. Giovanni Battista Molinette - Torino - Sc Ematologia 2	Torino	Italy
46	Unità Operativa Di Ematologia - Presidio Ospedaliero Di Treviso - Azienda Ulss N.2 Marca Trevigiana	Treviso	Italy
47	Azienda Sanitaria Universitaria Integrata Di Trieste - Sc Ematologia	Trieste	Italy
48	Asui Di Udine - Presidio Ospedaliero "Santa Maria Della Misericordia" - Clinica Ematologica	Udine	Italy