PEVOLAM: Study to Compare Azacitidine Plus Pevonedistat Versus Azacitidine in Patients With Acute Myeloid Leukemia Not Eligible for Standard Chemotherapy

Sponsor

PETHEMA Foundation (Other)

Overall Status

Recruiting

CT.gov ID

NCT04090736

Collaborator

Millennium Pharmaceuticals, Inc. (Industry), Dynamic Science S.L. (Industry)

466

Enrollment

Locations

Arms

46.6

Anticipated Duration (Months)

6.9

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Randomized phase III, multicentre, open label clinical trial to compare pevonedistat in combination with azacytidine versus azacytidine alone, which can be considered a standard of care for patients with newly diagnosed acute myeloid leukemia not eligible for intensive chemotherapy (thus not eligible for an allogeneic hematopoietic stem cell transplant.

Condition or Disease	Intervention/Treatment	Phase
Leukemia, Myeloid, Acute	Drug: Pevonedistat Drug: Azacitidine	Phase 3

Detailed Description

Prospective, 1:1 randomized multicentre, open label, phase III clinical trial to evaluate efficacy and safety of pevonedistat in combination with azacytidine versus azacytidine in the treatment of naïve adult patients with acute myeloid leukemia who are not eligible for standard induction therapy due to age, co-morbidities or risk-factors.

Subjects will be randomized to one of the two treatment arms in a 1:1 ratio, both of which will have treatment cycles of 28 days:

Arm A: Pevonedistat (PEVO) 20 mg/m2 IV on days 1, 3, and 5 plus Azacitidine (AZA) 75 mg/m2 subcutaneous (SC) administered on a 5-on/2-off [weekend]/2-on schedule in 28-day cycles (IV AZA can be administered for any patients who have non-tolerated local reactions)
Arm B: AZA 75 mg/m2 SC on a 5-on/2-off [weekend]/2-on schedule in 28-day cycle (IV AZA can be administered for any patients who have non-tolerated local reactions)

466 subjects will be randomized in the study. Subjects will continue their study treatment until documented disease progression per Investigator assessment, unacceptable toxicity, withdrawal of consent, or the subject meets other protocol criteria for discontinuation

Study Design

Study Type:

Interventional

Anticipated Enrollment :

466 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Randomized, prospective, multicenter, open label study.Randomized, prospective, multicenter, open label study.

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Randomized Phase III, Multicentre, Open Label Clinical Trial Comparing Azacitidine Plus Pevonedistat Versus Azacitidine in Older/Unfit Patients With Newly Diagnosed Acute Myeloid Leukemia Who Are Ineligible for Standard Induction Chemotherapy

Actual Study Start Date :

Aug 13, 2019

Anticipated Primary Completion Date :

Jun 30, 2023

Anticipated Study Completion Date :

Jun 30, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm A: Pevonedistat plus Azacitidine Pevonedistat 20 mg/m2 IV on days 1, 3, and 5 plus Azacitidine 75 mg/m2 subcutaneous administered on a 5-on/2-off [weekend]/2-on schedule in 28-day cycles (intravenous Azacitidine can be administered for any patients who have non-tolerated local reactions)	Drug: Pevonedistat Pevonedistat 20 mg/m2 intravenous on days 1, 3, and 5 (28-day cycles) Drug: Azacitidine Azacitidine 75 mg/m2 subcutaneous on a 5-on/2-off [weekend]/2-on schedule (28-day cycle). Intravenous for patients who have non-tolerated local reactions
Active Comparator: Arm B: Azacitidine Azacitidine 75 mg/m2 subcutaneous on a 5-on/2-off [weekend]/2-on schedule in 28-day cycle (intravenous azacitidine can be administered for any patients who have non-tolerated local reactions)	Drug: Azacitidine Azacitidine 75 mg/m2 subcutaneous on a 5-on/2-off [weekend]/2-on schedule (28-day cycle). Intravenous for patients who have non-tolerated local reactions

Arm

Intervention/Treatment

Experimental: Arm A: Pevonedistat plus Azacitidine

Pevonedistat 20 mg/m2 IV on days 1, 3, and 5 plus Azacitidine 75 mg/m2 subcutaneous administered on a 5-on/2-off [weekend]/2-on schedule in 28-day cycles (intravenous Azacitidine can be administered for any patients who have non-tolerated local reactions)

Drug: Pevonedistat

Pevonedistat 20 mg/m2 intravenous on days 1, 3, and 5 (28-day cycles)

Drug: Azacitidine

Azacitidine 75 mg/m2 subcutaneous on a 5-on/2-off [weekend]/2-on schedule (28-day cycle). Intravenous for patients who have non-tolerated local reactions

Active Comparator: Arm B: Azacitidine

Azacitidine 75 mg/m2 subcutaneous on a 5-on/2-off [weekend]/2-on schedule in 28-day cycle (intravenous azacitidine can be administered for any patients who have non-tolerated local reactions)

Drug: Azacitidine

Azacitidine 75 mg/m2 subcutaneous on a 5-on/2-off [weekend]/2-on schedule (28-day cycle). Intravenous for patients who have non-tolerated local reactions

Outcome Measures

Primary Outcome Measures

Overall survival (OS) [through study completion, an average of 1 year]
Time from the date of randomization to the date of death.

Secondary Outcome Measures

Event-free survival (EFS) [through study completion, an average of 1 year]
Time from randomization to the date of the occurrence of any of the following events: progressive disease, failure to achieve complete response or complete remission with incomplete blood count recovery at 6 months after initiation of treatment, relapse from complete response (CR)/ incomplete complete response (CRi) or death from any cause, whichever occurs first
Composite complete remission [through study completion, an average of 1 year]
The proportion of subjects with complete response plus complete remission with incomplete blood count recovery
Overall response rate [through study completion, an average of 1 year]
The proportion of subjects with complete response plus complete remission with incomplete blood count recovery plus partial response
Cumulative incidence of relapse [through study completion, an average of 1 year]
Calculated using the competing risk method (Fine & Gray)
Health status/quality of life [through study completion, an average of 1 year]
Global health status/quality of life based on patient reported outcome EORTC Quality of life questionnaire (QLQ)-C30 and supplemental items.
Health status/quality of life [through study completion, an average of 1 year]
Global health status/quality of life based on patient reported outcome: EQ-5D-5L questionnaire.
Use of medical resources determined by the use of antibiotics [through study completion, an average of 1 year]
Compare the use of antibiotics during the study between treatment groups
Use of medical resources determined by the use of transfusions [through study completion, an average of 1 year]
Compare the use of transfusions during the study between treatment groups
Use of medical resources determined by the number of hospital admissions [through study completion, an average of 1 year]
Compare the number of hospital admissions during the study between treatment groups
Pharmacokinetic [At day 1, 3 and 5 of cycle 1, cycle 2 and cycle 3 (each cycle is 28 days)]
Plasma concentration of Pevonedistat
Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) [through study completion (an average of 1 year)]
Adverse events of Pevonedistat plus Azacitidine versus Azacitidine regimen
Quality of composite complete remission determined by the minimal residual disease determined by RT-qPCR in the NPM1+ and CBF subsets and in bone marrow by MPFC in the remaining patients [through study completion, an average of 1 year]
To evaluate the quality of composite complete remission determining the minimal residual disease in patients with complete remission and complete remission with incomplete blood count recovery
Overall survival based on somatic mutations [through study completion, an average of 1 year]
To explore relationship of somatic mutations at baseline with overall survival
Event free survival based on somatic mutations [through study completion, an average of 1 year]
To explore relationship of somatic mutations at baseline with event free survival
Overall response rate based on somatic mutations [through study completion, an average of 1 year]
To explore relationship of somatic mutations at baseline with the overall response rate
Overall survival based on cytogenetic abnormalities [through study completion, an average of 1 year]
To explore relationship of cytogenetic abnormalities at baseline with overall survival
Event free survival based on cytogenetic abnormalities [through study completion, an average of 1 year]
To explore relationship of cytogenetic abnormalities at baseline event free survival
Overall response rate based on cytogenetic abnormalities [through study completion, an average of 1 year]
To explore relationship of cytogenetic abnormalities at baseline with the overall response rate
Red blood cells transfusion transfusion Independence (no use of red blood cells transfusion for a period of at least 8 weeks) [through study completion, an average of 1 year]
To determine if PEVO + AZA increase the duration of red blood cells transfusion Independence (transfusion independence requires that the patient receive no red blood cells transfusions for a period of at least 8 weeks)
Platelet transfusion Independence (no use of platelets transfusión for a period of at least 8 weeks) [through study completion, an average of 1 year]
To determine if PEVO + AZA increase the duration of platelets transfusion Independence (transfusion independence requires that the patient receive no platelets transfusions for a period of at least 8 weeks)
Biomarkers (CBF) predictive of PEVO activity [through study completion, an average of 1 year]
To assess biomarkers (CBF) predictive of PEVO activity evaluated by the overall response rate and minimal residual disease
Biomarkers (FLT3-ITD) predictive of PEVO activity [through study completion, an average of 1 year]
To assess biomarkers (FLT3-ITD) predictive of PEVO activity evaluated by the overall response rate and minimal residual disease
Biomarkers (NPM1) predictive of PEVO activity [through study completion, an average of 1 year]
To assess biomarkers (NPM1) predictive of PEVO activity evaluated by the overall response rate and minimal residual disease
Biomarkers (P53) predictive of PEVO activity [through study completion, an average of 1 year]
To assess biomarkers (P53) predictive of PEVO activity evaluated by the overall response rate and minimal residual disease
Biomarkers (IDH1/IDH2 ) predictive of PEVO activity [through study completion, an average of 1 year]
To assess biomarkers (IDH1/IDH2) predictive of PEVO activity evaluated by the overall response rate and minimal residual disease

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Male or female patients 18 years or older
Morphological diagnosis of Acute Myeloid Leukemia (AML) (WHO criteria 2008)
Subject must have an Eastern Cooperative Oncology Group (ECOG) Performance status (PS) of 0 to 3 (ECOG 0-2 for patients greater than or equal to 75 years old).
Newly diagnosed AML
Patient must be considered be ineligible for treatment with a standard Ara-C and anthracycline induction regimen due to age or co-morbidities defined by one of the following:
≥ 75 years of age
Or ≥ 18 to 74 years of age with at least one of the following:

ECOG Performance Status of 2 or 3;
Cardiac history of cardiac heart failure requiring treatment or Ejection Fraction ≤ 50% or chronic stable angina;
Diffusing Capacity of the Lung for Carbon Monoxide (DLCO) ≤ 65% or Forced Expiratory Volume in 1 second (FEV1) ≤ 65% or significant history of chronic pulmonary obstructive disease;
Glomerular filtration rate (GFR) ≥ 30 mL/min to < 50 ml/min or levels of creatinine between the upper limit of the normal range (ULN) and 2.5 mg/dL (≤ 250 μmol/l).
Hepatic impairment with total bilirubin > 1.5 to ≤ 3 × ULN or with alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) > 2.5×ULN to ≤ 5×ULN
Non active/controlled prior neoplastic disease
Any other patient´s comorbidity or disease condition that the physician judges to be incompatible with intensive chemotherapy must be reviewed, documented, and approved by the Sponsor before study enrollment).

Clinical laboratory values within the following parameters (repeat within 3 days before the first dose of study drug if laboratory values used for randomization were obtained more than 3 days before the first dose of study drug):

Total bilirubin ≤ 1.5 × ULN except in patients with Gilbert's syndrome or ≤ 3 × ULN if elevation is attributed to underlying leukemia. Patients with Gilbert's syndrome may enroll with direct bilirubin ≤3 × ULN of the direct bilirubin. Elevated indirect bilirubin due to posttransfusion hemolysis is allowed.
ALT and AST ≤ 2.5×ULN or ≤ 5×ULN if elevation is attributed to underlying leukemia.
Adequate renal function as demonstrated by a creatinine clearance ≥ 30 mL/min (calculated by the Cockcroft Gault formula, (see Appendix 5).
Albumin >2.7 g/dL.

Subject has a white blood cell count <50 × 109/L. Patients who are cytoreduced with leukapheresis or with hydroxyurea may be enrolled if they meet the eligibility criteria before starting therapy.
Female subjects must be either postmenopausal for at least 1 year before screening (see Appendix 12 for definition) OR permanently surgical sterile (bilateral oophorectomy, bilateral salpingectomy or hysterectomy) OR Women of Childbearing Potential (WOCBP) must agree to practice 1 highly effective method and 1 additional effective (barrier) method of contraception (see Appendix 11), at the same time, from the time of signing the informed consent through 4 months after the last dose of study drug (female and male condoms should not be used together), or Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, postovulation methods] withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception). Female subjects of childbearing potential must have negative results for pregnancy test performed and must not be lactating and breastfeeding.
Male subjects even if surgically sterilized (i.e., status post vasectomy), who are sexually active, must agree, from Study Day 1 through at least 4 months after the last dose of study drug, to practice effective barrier contraception during the entire study treatment period and through 4 months after the last dose of study drug (female and male condoms should not be used together), or agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, postovulation methods for the female partner] withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception.)
Subject must voluntarily sign and date an informed consent, approved by an Independent Ethics Committee (IEC)/Institutional Review Board (IRB), prior to the initiation of any screening or study specific procedures, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.

Exclusion Criteria:

Previous treatment for myelodysplastic síndrome (MDS) or Chronic Myelomonocytic Leukemia (CMML) or myeloproliferative neoplasms (MPN), with chemotherapy or other antineoplastic agents including HMAs (up to 2 cycles of Hypomethylating agents (HMA) such as decitabine or azacitidine. Previous treatment is permitted with hydroxyurea and with lenalidomide, except that lenalidomide may not be given within 8 weeks before the first dose of study drug.
Subject has history MPN with BCR-ABL1 translocation and AML with BCR-ABL1 translocation.
Genetic diagnosis of acute promyelocytic leukemia.
Eligible for intensive chemotherapy and/or allogeneic stem cell transplantation.

The reason a patient is not eligible for intensive chemotherapy and/or allogeneic stem cell transplantation is described in the inclusion criteria section
The reason a patient is not eligible for intensive chemotherapy must be documented in the electronic case report form (eCRF).

Patients with either clinical evidence of or history of central nervous system involvement by AML.
Diagnosed or treated for another malignancy within 1 year before randomization or previously diagnosed with another malignancy and have any evidence of residual disease which may compromise the administration of AZA or AZA+PEVO.
Psychological,social, or geographic factors that otherwise preclude the patient from giving informed consent, following the protocol, or potentially hamper compliance with study treatment and follow-up.
Subject has a white blood cell count > 50 × 109/L.
Contraindications for PEVO or AZA.
Known hypersensitivity to pevonedistat or its excipients.
Female patients who intend to donate eggs (ova) during the course of this study or for 4 months after receiving their last dose of study drug(s).
Female patients who are both lactating and breastfeeding or have a positive serum pregnancy test during the screening period or a positive urine pregnancy test on Day 1 before first dose of study drug.
Male patients who intend to donate sperm or father a child during the course of this study or for 4 months after receiving their last dose of study drug(s).
Subject is known to be positive for HIV (HIV testing is not required for eligibility assessment). Known HIV positive patients who meet the following criteria will be considered eligible:

Cluster of differentiation 4 (CD4) count > 350 cells/mm3
Undetectable viral load
Maintained on modern therapeutic regimens utilizing non-cytochrome P450 (CYP)-interactive agents
No history of AIDS-defining opportunistic infections

Subject is known to be positive for hepatitis B or C infection, with the exception of those with an undetectable viral load within 3 months (Hepatitis B or C testing is not required for eligibility assessment).
Known hepatic cirrhosis or severe preexisting hepatic impairment.
Patients with the following will be excluded: uncontrolled intercurrent illness including, but not limited to known cardiopulmonary disease defined as unstable angina, clinically significant arrhythmia, congestive heart failure (New York Heart Association Class III or IV; see Appendix 7), and/or ST elevation myocardial infarction within 6 months before first dose, or severe symptomatic pulmonary hypertension requiring pharmacologic therapy, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. As an example, well-controlled atrial fibrillation would not be an exclusion whereas uncontrolled atrial fibrillation would be an exclusion. Patients with medical comorbidities that will preclude safety evaluation of the combination should not be enrolled.
Subject has chronic respiratory disease that requires continuous oxygen, or significant history of renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, hepatic, cardiovascular disease, any other medical condition that in the opinion of the investigator would adversely affect his/her participating in this study.
Treatment with strong Cytochrome P450, family 3, subfamily A (CYP3A) inducers (see Appendix 8) within 14 days before the first dose of pevonedistat.
Patients with uncontrolled coagulopathy or bleeding disorder.
High blood pressure which cannot be controlled by standard treatments
Prolonged rate corrected QT (QTc) interval ≥ 500 msec, calculated according to institutional guidelines.
As infection is a common feature of AML, patients with active infection are permitted to enroll provided that the infection is under control and no signs of systemic inflammatory response beyond low grade fever that makes patient clinically unstable in the opinion of the investigator. Patients with uncontrolled infection shall not be enrolled until infection is treated and brought under control.
Patients who have received an investigational agent (for any indication) within 5 half-lives of the agent and until toxicity from this has resolved to grade 1 or less; if the half-life of the agent is unknown, patients must wait 4 weeks prior to first dose of study treatment.
Systemic antineoplastic therapy for malignant conditions other than myeloid neoplasms within 14 days before the first dose of any study drug.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Hospital de Coimbra	Coimbra		Portugal
2	IPO Lisboa	Lisboa		Portugal
3	IPO Porto	Porto		Portugal
4	Complejo Hospitalario Universitario de Santiago	Santiago De Compostela	A Coruña	Spain	15706
5	Hospital Txagorritxu	Vitoria	Alava	Spain	01009
6	Hospital Universitario Central de Asturias	Oviedo	Asturias	Spain	33006
7	ICO Badalona- Hospital Universitari Germans Trias i Pujol	Badalona	Barcelona	Spain	08916
8	ICO Hospitalet- Hospital Duran i Reynals	Hospitalet del Llobregat	Barcelona	Spain	08908
9	Hospital Universitario Donostia	San Sebastián	Guipuzcoa	Spain
10	Complejo Hospitalario de Jaén	Jaén	Jaen	Spain	23007
11	Complejo Hospitalario Universitario de Gran Canaria Dr. Negrín	Las Palmas De Gran Canaria	Las Palmas	Spain	35020
12	Hospital Universitario Quirón Madrid	Pozuelo De Alarcón	Madrid	Spain	28223
13	Hospital Universitario Infanta Sofía	San Sebastián De Los Reyes	Madrid	Spain	28702
14	Hospital Regional Universitario de Málaga	Málaga	Malaga	Spain	29010
15	Hospital Universitario Virgen de la Victoria	Málaga	Malaga	Spain	29010
16	Hospital General Universitario Santa Lucía	Cartagena	Murcia	Spain	30200
17	Complejo Hospitalario Universitario de Vigo	Vigo	Pontevedra	Spain	36312
18	Hospital Universitario de Canarias	La Laguna	Santa Cruz De Tenerife	Spain
19	Hospital Universitario Virgen del Rocío	Sevilla	Sevila	Spain	41013
20	Hospital General Nuestra Señora del Prado	Talavera De La Reina	Toledo	Spain	45600
21	Hospital Universitario de Cruces	Baracaldo	Vizcaya	Spain	48903
22	Hospital Universitario de Basurto	Bilbao	Vizcaya	Spain	48013
23	Hospital Universitario de Galdakao	Galdakao	Vizcaya	Spain	48960
24	Complejo Hospitalario Universitario A Coruña	A Coruña		Spain	15006
25	Complejo Hospitalario Universitario de Albacete	Albacete		Spain	02006
26	Hospital General Universitario de Alicante	Alicante		Spain	03010
27	Complejo Hospitalario Torrecárdenas	Almería		Spain	04004
28	Hospital Dr. José Molina Orosa	Arrecife		Spain
29	Hospital San Agustin	Avilés		Spain
30	Hospital Universitario de Badajoz	Badajoz		Spain
31	Hospital de Barbastro	Barbastro		Spain
32	Hospital del Mar	Barcelona		Spain
33	Hospital Vithas Xanit Internacional	Benalmádena		Spain
34	Hospital Universitario de Burgos	Burgos		Spain	09006
35	Hospital Universitario Puerta del Mar	Cadiz		Spain	11009
36	Hospital General Universitario de Castellón	Castelló		Spain
37	Complejo Hospitalario de Cáceres	Cáceres		Spain	10003
38	Complejo Hospitalario Regional Reina Sofía	Córdoba		Spain	14004
39	Hospital General Universitario de Elche	Elche		Spain
40	ICO Girona- Hospital Universitari Dr Josep Trueta	Gerona		Spain	17007
41	Hospital Universitario Virgen de las Nieves	Granada		Spain	18014
42	Hospital Universitario de Guadalajara	Guadalajara		Spain
43	Hospital Universitario Juan Ramón Jiménez	Huelva		Spain	21005
44	Hospital San Jorge	Huesca		Spain
45	Complejo Hospitalario Lucus Augusti	Lugo		Spain
46	Hospital Universitario Ramón y Cajal	Madrid		Spain	28034
47	Hospital Clínico San Carlos	Madrid		Spain	28040
48	Hospital Universitario Fundación Jiménez Díaz	Madrid		Spain	28040
49	Hospital Universitario 12 de Octubre	Madrid		Spain	28041
50	Hospital Universitario Madrid Norte Sanchinarro	Madrid		Spain	28050
51	Hospital General Universitario Morales Meseguer	Murcia		Spain	30008
52	Hospital Quirón de Málaga	Málaga		Spain
53	Complexo Hospitalario Universitario de Ourense	Ourense		Spain	32005
54	Hospital Son Llàtzer	Palma de Mallorca		Spain
55	Complexo Hospitalario de Pontevedra	Pontevedra		Spain	36071
56	Hospital Universitario de Salamanca	Salamanca		Spain	37007
57	Complejo Hospitalario Universitario Nuestra Señora de la Candelaria	Santa Cruz De Tenerife		Spain	38010
58	Hospital General de Segovia	Segovia		Spain
59	Hospital de Valme	Sevilla		Spain
60	Hospital Universitari Joan XXIII	Tarragona		Spain	43005
61	Hospital Virgen de la Salud	Toledo		Spain
62	Hospital Clínico Universitario de Valencia	Valencia		Spain	46010
63	Hospital Universitario Dr. Peset Aleixandre	Valencia		Spain	46017
64	Hospital Universitari i Politecnic La Fe	Valencia		Spain	46026,
65	Hospital Clínico Universitario de Valladolid	Valladolid		Spain	47003
66	Hospital Clínico Universitario Lozano Blesa	Zaragoza		Spain	50009
67	Hospital Universitario Miguel Servet	Zaragoza		Spain	50009
68	Complejo Asistencial de Ávila	Ávila		Spain