Clinical trial NCT04687761: Clinical Trial to Assess the Safety and Tolerability of the Combination of Low-dose Cytarabine or Azacitidine Plus Venetoclax and Quizartinib in Newly Diagnosed AML Patients Aged Equal or More Than 60 Years Old
Official title: A Phase I-II, Multicentre, Open Label Clinical Trial to Assess the Safety and Tolerability of the Combination of Low-dose Cytarabine or Azacitidine, Plus Venetoclax and Quizartinib in Newly Diagnosed Acute Myeloid Leukemia Patients Aged Equal or More Than 60 Years Old Ineligible for Standard Induction Chemotherapy
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE1
PHASE2
Conditions: Leukemia, Myeloid, Acute
De Novo
Age More 60yr
Keywords: Acute myeloid Leukaemia
Newly Diagnosed
Lead sponsor: PETHEMA Foundation
Sponsor class: OTHER
First posted: 2020-12-29
Enrollment: 84
Sex: ALL
Minimum age (years): 60
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Phase 1: Study treatment will start at level 1 and therapeutic level will be escalated or descalated depending on the apparition of DLT. DLT will be monitored during cycle 1 and it is defined as any grade 3-4 related extrahematological toxicity or grade 4 neutropenia not recovered on day 56 since C1D1 not attributable to persistent leukemia.

Phase I will consist of two parallel dose escalation cohorts, with consecutive assignment to each group (first patient will be assigned to AZA-based schedule, second to LDAC-based, third to AZA-based, etc).

Phase II includes two treatment arm groups (AZA-based RP2D vs. LDAC-based RP2D). Patients will be enrolled at diagnosis, within a maximum 28 days screening period, will be assessed for eligibility and therefore randomized to follow the assigned treatment arm (open label design). All screening activities will be performed after patient's informed consent form is signed. Patients will start the assigned regimen 48h maximum after randomization.
Primary purpose: TREATMENT

Brief summary: A phase I-II trial based on the combination of three drugs regimen LDAC or Azacitidine + Venetoclax + Quizartinib that in this population could be well tolerated by a sequential type administration. The first objective is to achieve rapid control of the disease, using two different schemes, one based in Azacitidine and the other in LDAC, by dose escalation in phase I of the trial. The second goal is to prevent relapse through a maintenance schedule. Phase II will study the efficacy and safety of the recommended dose for Phase II

Detailed description: The prognosis of AML in elderly patients remain very poor and without significant advances in last decades. AML is a heterogeneous disease in which many altered molecular pathways could contribute to the disease. Thus, curative approaches have been based on highly eradicating regimens using high-dose chemotherapy. However, the low rate of CRs and the high rate of deaths due to toxicity and relapses in elderly patients should stimulate the development of new regimens that overcome these therapeutic obstacles. In recent years, there are a series of new drugs under development that allow the design of sequential combination therapies in this vulnerable population. These drugs have an acceptable toxicity profile and are apparently effective in monotherapy or even in combination, being able to improve the CR rate in this population. The investigators hypothesize that the combination of two targeted drugs that have different mechanisms of action could be capable of breaking the viability of leukemic cells as well as their proliferative qualities, and therefore prolong survival. In this way, the combined action of a pro-apoptotic agent (Venetoclax) and an antiproliferative agent (Quizartinib) could produce a powerful antileukemic effect, preventing the adaptive escape mechanisms of leukemic cells. The investigators have designed a phase I-II trial based on the combination of three drugs regimen LDAC or Azacitidine + Venetoclax + Quizartinib that in this population could be well tolerated by a sequential type administration. The first objective is to achieve rapid control of the disease, using two different schemes, one based in Azacitidine and the other in LDAC, by dose escalation in phase I of the trial. The second goal is to prevent relapse through a maintenance schedule. Phase II will study the efficacy and safety of the recommended dose for Phase II.

Eligibility criteria: Inclusion Criteria:

1. Newly diagnosed AML.
2. Morphological diagnosis of AML (WHO criteria 2008).
3. Patient must be considered be ineligible for treatment with a standard cytarabine and anthracycline induction regimen due to age or co-morbidities defined by the following criteria: 3.1. ≥ 71 years of age; 3.2. ≥ 60 to 70 years of age with at least one of the following co-morbidities:

   * ECOG Performance Status of 2 or 3;
   * Cardiac history of CHF requiring treatment or Ejection Fraction ≤ 55% or chronic stable angina;
   * DLCO ≤ 65% or FEV1 ≤ 65% or significant history of chronic pulmonary obstructive;
   * Creatinine clearance ≥ 30 mL/min to \< 50 ml/min
   * Moderate hepatic impairment with total bilirubin, SGPT or SGOT \> 1.5 to ≤ 3.0 × 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 and approved by the Trial Coordinators before study enrollment (e.g, prior MDS or MPS, high-risk cytogenetics)
4. ECOG performance status ≤ 3.
5. Male subjects who are sexually active, must agree, from Study Day 1 through at least 120 days after the last dose of study drug, to practice the protocol specified contraception (see Section 0).
6. Female subjects must be either postmenopausal for at least 1 year before screening 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, 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.
7. Subject must voluntarily sign and date an informed consent, approved by an Independent Ethics Committee (IEC) 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:

1. Age \<60 years.
2. Genetic diagnosis of acute promyelocytic leukemia.
3. Treated (excluding surgery or hormone-therapy) for another malignancy within 6 months before randomization or previously diagnosed with another malignancy and have any evidence of disease which may compromise the administration of investigational treatment schedule.
4. Presence of any severe psychiatric disease or physical condition that, according to the physician´s criteria, contraindicates the inclusion of the patient into the clinical trial.
5. Serum creatinine ≥ 2.5 mg/dL or creatinine clearance \< 30 mL/min (unless it is attributable to AML activity).
6. Bilirubin, SGPT or SGOT \> 3 times the upper normal limit (unless it is attributable to AML activity).
7. WBC\> 50 x 109/L. Subject should have white blood cell count \<50 × 109/L before starting therapy. Patients who are cytoreduced with leukapheresis or with hydroxyurea may be enrolled if they meet the eligibility criteria before starting therapy.
8. Contraindications for Quizartinib or Venetoclax.
9. History of known CNS leukemia, including cerebrospinal fluid positive for AML blasts.
10. Prior treatment with any investigational drug or device within 30 days prior to Randomization (within 2 weeks for investigational or approved immunotherapy) or currently participating in other investigational procedures
11. Prior treatment with other FLT3-ITD or BCL-2 inhibitors.
12. Known uncontrolled or significant cardiovascular disease, including any of the following:

    1. Bradycardia of less than 50 beats per minute, unless the subject has a pacemaker;
    2. QTcF interval \>450 msec;
    3. Diagnosis of or suspicion of long QT syndrome (including family history of long QT syndrome);
    4. Systolic blood pressure ≥180 mmHg or diastolic blood pressure ≥110 mmHg;
    5. History of clinically relevant ventricular arrhythmias (eg, ventricular tachycardia, ventricular fibrillation, or Torsade de Pointes);
    6. History of second (Mobitz II) or third degree heart block (subjects with pacemakers are eligible if they have no history of fainting or clinically relevant arrhythmias while using the pacemaker);
    7. History of uncontrolled angina pectoris or myocardial infarction within 6 months prior to Screening;
    8. History of New York Heart Association Class 3 or 4 heart failure;
    9. Known history of left ventricular ejection fraction (LVEF) ≤45% or less than the institutional lower limit of normal;
    10. Complete left bundle branch block;
13. Prior therapy for AML (except hydroxiurea).
14. Subject enrolling into a dose-escalation cohort must not have received a known strong or moderate inducer or inhibitor of cytochrome P450 (CYP) 3A within 7 days before the first Quizartinib or Venetoclax dose. Subject enrolling into a safety expansion cohort must not have received a known strong or moderate inducer or strong inhibitor of CYP3A within 7 days before the first Quizartinib or Venetoclax dose.
15. Subject must not have consumed grapefruit, grapefruit products, Seville oranges (including marmalade-containing Seville oranges), or star fruit within 3 days before anticipated first dose of Venetoclax and must consent not to consume through the last dose of Venetoclax.
16. Active acute or chronic systemic fungal, bacterial, or viral infection not well controlled by antifungal, antibacterial or antiviral therapy at physician discretion;
17. Known active clinically relevant liver disease (eg, active hepatitis B, or active hepatitis C)
18. Known history of human immunodeficiency virus (HIV).
19. History of hypersensitivity to any excipients in the Quizartinib, Venetoclax or other study medication.
20. Non mutated FLT3-ITD subjects will be considered ineligible during the randomized Phase II after 48 non mutated FLT3-ITD subjects have been randomized.

Primary outcomes:
measure: Phase I: Recommended phase 2 dose (RP2D)
timeFrame: Approximately 6 months after first patient first visit (FPFV)
measure: Phase II: CR/Cri rate of AZA based and LDAC based
timeFrame: Aproximatey 3 years after FPFV
Secondary outcomes:
measure: CR/CRi rate
timeFrame: After cycle 1 and after cycle 4, being each cycle of 28 days
measure: Overall survival (OS)
timeFrame: Through study completion: 2 years after the last patient has been enrolled into the study, an average of 48 months.
measure: Overall hematologic and non-hematologic toxicity
timeFrame: Through study completion: 2 years after the last patient has been enrolled into the study, an average of 48 months.
measure: Event-free survival (EFS)
timeFrame: 1, 2 and 3 years.
measure: Disease-free survival (DFS)
timeFrame: 1, 2 and 3 years.
measure: Relapse-free survival (RFS)
timeFrame: 1, 2 and 3 years.
measure: Cumulative incidence of relapse
timeFrame: 1, 2 and 3 years.
measure: Impact on the quality of life assessed by EuroQoL Group EQ-5D-5L
timeFrame: At the screening, after cycle 2, after cycle 6, and after cycle 12, being each cycle of 28 days; and through study completion, an average of 48 months.
measure: Impact on the quality of life assessed by EORTC QLQ-C30
timeFrame: at the screening, after 6 cycles, after 12 cycles since start of therapy, being each cycle of 28 days; and through study completion, an average of 48 months
measure: Use of medical resources during treatment phase
timeFrame: At the end of treatment phase: after cycle 4, being each cycle of 28 days.
measure: Quality of CR
timeFrame: After cycle 1, cycle 4 and then every 3 cycles during the first 2 years after start of the therapy (each cycle of 28 days).
measure: CRh rate
timeFrame: Through study completion: 2 years after the last patient has been enrolled into the study, an average of 48 months.
measure: Early mortality
timeFrame: First 30 and 60 days
measure: CR/Cri rate of AZA based and LDAC based, in secondary AML subset
timeFrame: Through study completion: 2 years after the last patient has been enrolled into the study, an average of 48 months.
measure: CR/Cri rate of AZA based and LDAC based, in CBF subset
timeFrame: Through study completion: 2 years after the last patient has been enrolled into the study, an average of 48 months.
measure: CR/Cri rate of AZA based and LDAC based, in FLT3-ITD subset
timeFrame: Through study completion: 2 years after the last patient has been enrolled into the study, an average of 48 months.
measure: CR/Cri rate of AZA based and LDAC based, in NPM1 subset
timeFrame: Through study completion: 2 years after the last patient has been enrolled into the study, an average of 48 months.
measure: CR/Cri rate of AZA based and LDAC based, in P53 subset
timeFrame: Through study completion: 2 years after the last patient has been enrolled into the study, an average of 48 months.
measure: CR/Cri rate of AZA based and LDAC based, in IDH1/IDH2 subset
timeFrame: Through study completion: 2 years after the last patient has been enrolled into the study, an average of 48 months.
measure: MRD negativity rate in the BM
timeFrame: After cycle 1, cycle 4 and then every 3 cycles, being each cycle of 28 days.
measure: MRD negativity rate in PB
timeFrame: After cycle 1, cycle 4 and then every 3 cycles, being each cycle of 28 days.
measure: Natural Killer (NK) cell phenotypes and functions (immune recovery) analysis.
timeFrame: At screening and after first and fourth cycles of treatment, being each cycle of 28 days.
measure: Baseline and relapse molecular characterization by NGS.
timeFrame: At baseline and at through study completion due to relapse/resistance, an average of 48 months.
Other outcomes:
Locations:
city: Alcalá De Henares
country: Spain
facility: Hospital Universitario Príncipe de Asturias
city: Barcelona
country: Spain
facility: Hospital Clínic
city: Cáceres
country: Spain
facility: Hospital San Pedro de Alcántara
city: Jerez De La Frontera
country: Spain
facility: Hospital Universitario de Jerez de La Frontera
city: León
country: Spain
facility: Hospital de León (Complejo Asistencial Universitario de León)
city: Lleida
country: Spain
facility: Hospital Universitari Arnau de Vilanova de Lleida
city: Madrid
country: Spain
facility: Hospital Universitario Infanta Leonor
city: Madrid
country: Spain
facility: Hospital Universitario La Zarzuela
city: Majadahonda
country: Spain
facility: Hospital Universitario Puerta de Hierro Majadahonda
city: Manresa
country: Spain
facility: Hospital de Sant Joan de Deu (Manresa)
city: Murcia
country: Spain
facility: Hospital Clinico Universitario Virgen de La Arrixaca
city: Palma De Mallorca
country: Spain
facility: Hospital Universitari Son Espases
city: Santander
country: Spain
facility: Hospital Universitario Marques de Valdecilla
city: Terrassa
country: Spain
facility: Hospital Universitari Mutua de Terrassa
city: Valencia
country: Spain
facility: Hospital Universitario y Politécnico La Fe
Study officials:
affiliation: Hospital Universitario La Fe
name: Pau Montesinos, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital San Pedro Alcántara
name: Juan Bergua, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Fundación PETHEMA
name: Carmen López-Carrero García
role: STUDY_CHAIR
References:
citation: Dohner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Buchner T, Dombret H, Ebert BL, Fenaux P, Larson RA, Levine RL, Lo-Coco F, Naoe T, Niederwieser D, Ossenkoppele GJ, Sanz M, Sierra J, Tallman MS, Tien HF, Wei AH, Lowenberg B, Bloomfield CD. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017 Jan 26;129(4):424-447. doi: 10.1182/blood-2016-08-733196. Epub 2016 Nov 28.
citation: Juliusson G, Antunovic P, Derolf A, Lehmann S, Mollgard L, Stockelberg D, Tidefelt U, Wahlin A, Hoglund M. Age and acute myeloid leukemia: real world data on decision to treat and outcomes from the Swedish Acute Leukemia Registry. Blood. 2009 Apr 30;113(18):4179-87. doi: 10.1182/blood-2008-07-172007. Epub 2008 Nov 13.
citation: Menzin J, Lang K, Earle CC, Kerney D, Mallick R. The outcomes and costs of acute myeloid leukemia among the elderly. Arch Intern Med. 2002 Jul 22;162(14):1597-603. doi: 10.1001/archinte.162.14.1597.
citation: Fenaux P, Mufti GJ, Hellstrom-Lindberg E, Santini V, Gattermann N, Germing U, Sanz G, List AF, Gore S, Seymour JF, Dombret H, Backstrom J, Zimmerman L, McKenzie D, Beach CL, Silverman LR. Azacitidine prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count acute myeloid leukemia. J Clin Oncol. 2010 Feb 1;28(4):562-9. doi: 10.1200/JCO.2009.23.8329. Epub 2009 Dec 21.
citation: Burnett AK, Milligan D, Prentice AG, Goldstone AH, McMullin MF, Hills RK, Wheatley K. A comparison of low-dose cytarabine and hydroxyurea with or without all-trans retinoic acid for acute myeloid leukemia and high-risk myelodysplastic syndrome in patients not considered fit for intensive treatment. Cancer. 2007 Mar 15;109(6):1114-24. doi: 10.1002/cncr.22496.
citation: Cortes JE, Kantarjian H, Foran JM, Ghirdaladze D, Zodelava M, Borthakur G, Gammon G, Trone D, Armstrong RC, James J, Levis M. Phase I study of quizartinib administered daily to patients with relapsed or refractory acute myeloid leukemia irrespective of FMS-like tyrosine kinase 3-internal tandem duplication status. J Clin Oncol. 2013 Oct 10;31(29):3681-7. doi: 10.1200/JCO.2013.48.8783. Epub 2013 Sep 3.
citation: Martinelli G, Perl AE, Dombret H, et al. Effect of quizartinib (AC220) on response rates and long-term survival in elderly patients with FLT3-ITD positive or negative relapsed/refractory acute myeloid leukemia. J Clin Oncol. 2013;31 (suppl): abstr 7021
citation: Konopleva M, Contractor R, Tsao T, Samudio I, Ruvolo PP, Kitada S, Deng X, Zhai D, Shi YX, Sneed T, Verhaegen M, Soengas M, Ruvolo VR, McQueen T, Schober WD, Watt JC, Jiffar T, Ling X, Marini FC, Harris D, Dietrich M, Estrov Z, McCubrey J, May WS, Reed JC, Andreeff M. Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia. Cancer Cell. 2006 Nov;10(5):375-88. doi: 10.1016/j.ccr.2006.10.006.
citation: Tsao T, Shi Y, Kornblau S, Lu H, Konoplev S, Antony A, Ruvolo V, Qiu YH, Zhang N, Coombes KR, Andreeff M, Kojima K, Konopleva M. Concomitant inhibition of DNA methyltransferase and BCL-2 protein function synergistically induce mitochondrial apoptosis in acute myelogenous leukemia cells. Ann Hematol. 2012 Dec;91(12):1861-70. doi: 10.1007/s00277-012-1537-8. Epub 2012 Aug 15.
citation: Nakayama K, Nakayama K, Negishi I, Kuida K, Sawa H, Loh DY. Targeted disruption of Bcl-2 alpha beta in mice: occurrence of gray hair, polycystic kidney disease, and lymphocytopenia. Proc Natl Acad Sci U S A. 1994 Apr 26;91(9):3700-4. doi: 10.1073/pnas.91.9.3700.
citation: Yamamura K, Kamada S, Ito S, Nakagawa K, Ichihashi M, Tsujimoto Y. Accelerated disappearance of melanocytes in bcl-2-deficient mice. Cancer Res. 1996 Aug 1;56(15):3546-50.
citation: Lees JA, Weinberg RA. Tossing monkey wrenches into the clock: new ways of treating cancer. Proc Natl Acad Sci U S A. 1999 Apr 13;96(8):4221-3. doi: 10.1073/pnas.96.8.4221. No abstract available.
citation: Shapiro GI. Cyclin-dependent kinase pathways as targets for cancer treatment. J Clin Oncol. 2006 Apr 10;24(11):1770-83. doi: 10.1200/JCO.2005.03.7689.
citation: Schwartz GK, Shah MA. Targeting the cell cycle: a new approach to cancer therapy. J Clin Oncol. 2005 Dec 20;23(36):9408-21. doi: 10.1200/JCO.2005.01.5594.
citation: Chen YN, Sharma SK, Ramsey TM, Jiang L, Martin MS, Baker K, Adams PD, Bair KW, Kaelin WG Jr. Selective killing of transformed cells by cyclin/cyclin-dependent kinase 2 antagonists. Proc Natl Acad Sci U S A. 1999 Apr 13;96(8):4325-9. doi: 10.1073/pnas.96.8.4325.
citation: Cheson BD, Bennett JM, Kopecky KJ, Buchner T, Willman CL, Estey EH, Schiffer CA, Doehner H, Tallman MS, Lister TA, Lo-Coco F, Willemze R, Biondi A, Hiddemann W, Larson RA, Lowenberg B, Sanz MA, Head DR, Ohno R, Bloomfield CD; International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. Revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol. 2003 Dec 15;21(24):4642-9. doi: 10.1200/JCO.2003.04.036.
citation: Creutzig U, Kaspers GJ. Revised recommendations of the International Working Group for diagnosis, standardization of response criteria, treatment outcomes, and reporting standards for therapeutic trials in acute myeloid leukemia. J Clin Oncol. 2004 Aug 15;22(16):3432-3. doi: 10.1200/JCO.2004.99.116. No abstract available.
citation: European Medicines Agency. Summary of product characteristics. https://www.ema.europa.eu/documents/product-information/vidaza-epar-product-information_en.pdf. Accessed 12 December 2018
citation: CIMA- Centro de información online de medicamentos de la AEMPS - https://cima.aemps.es/cima/pdfs/es/ft/49154/FT_49154.pdf
citation: U.S. Department of Health and Human Services. National Institutes of Health. National Cancer Institute. https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf. Accessed 12 December 2018
citation: Montesinos P, Lorenzo I, Martin G, Sanz J, Perez-Sirvent ML, Martinez D, Orti G, Algarra L, Martinez J, Moscardo F, de la Rubia J, Jarque I, Sanz G, Sanz MA. Tumor lysis syndrome in patients with acute myeloid leukemia: identification of risk factors and development of a predictive model. Haematologica. 2008 Jan;93(1):67-74. doi: 10.3324/haematol.11575.
citation: Herdman M, Gudex C, Lloyd A, Janssen M, Kind P, Parkin D, Bonsel G, Badia X. Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L). Qual Life Res. 2011 Dec;20(10):1727-36. doi: 10.1007/s11136-011-9903-x. Epub 2011 Apr 9.
citation: European Organization for Research and Treatment of Cancer QLQ-C30 questionnaire (EORTC Quality of Life): https://www.eortc.org/app/uploads/sites/2/2018/08/Specimen-QLQ-C30-English.pdf.