A Study of Ivosidenib or Enasidenib in Combination With Induction Therapy and Consolidation Therapy, Followed by Maintenance Therapy in Patients With Newly Diagnosed Acute Myeloid Leukemia or Myedysplastic Syndrome EB2, With an IDH1 or IDH2 Mutation, Respectively, Eligible for Intensive Chemotherapy

Acute Myeloid Leukemia Clinical Trial

— HOVON150AML  

Official title:

A Phase 3, Multicenter, Double-blind, Randomized, Placebo-controlled Study of Ivosidenib or Enasidenib in Combination With Induction Therapy and Consolidation Therapy Followed by Maintenance Therapy in Patients With Newly Diagnosed Acute Myeloid Leukemia or Myelodysplastic Syndrome With Excess Blasts-2, With an IDH1 or IDH2 Mutation, Respectively, Eligible for Intensive Chemotherapy.

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03839771
• Other study ID #: HO150
• Secondary ID: 2018-000451-41
• Status: Recruiting
• Phase: Phase 3
• Start date: March 1, 2019
• Est. completion date: March 2033

Study information

• Verified date: August 2021
• Source: Stichting Hemato-Oncologie voor Volwassenen Nederland
• Contact: B.J. Wouters, Dr.
• Phone: +31 10 704 15 60
• Email: b.wouters[@]erasmusmc.nl
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

AML and MDS-EB2 are malignancies of the bone marrow. The standard treatment for these diseases is chemotherapy. Patients participating have a special type of this disease because the leukemia cells (blasts) have developed an error in the genetic material (DNA). This error is called an IDH1 mutation or an IDH2 mutation (a mutation is a change in the DNA), which leads to changes in specific substances in the leukemia cells. This trial will investigate whether the addition of the new drugs Ivosidenib (for patients with IDH1 mutation) or Enasidenib (for patients with IDH2 mutation) to the standard treatment of chemotherapy controle the disease more effectively and for a longer period.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 968
• Est. completion date: March 2033
• Est. primary completion date: March 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Age =18 years

• Newly diagnosed AML or MDS-EB2 defined according to WHO criteria, with a documented IDH1 or IDH2 gene mutation (as determined by the clinical trial assay) at a specific site (IDH1 R132, IDH2 R140, IDH2 R172). AML may be secondary to prior hematological disorders, including MDS, and/or therapy-related (in which prior disease should have been documented to have existed for at least 3 months). Patients may have had previous treatment with hypomethylating agents (HMAs) for MDS. HMAs have to be stopped at least four weeks before registration

• Patients with dual mutant FLT3 and IDH1 or IDH2 mutations may be enrolled only if, for medical or other reasons, treatment with a FLT3 inhibitor is not considered.

• Considered to be eligible for intensive chemotherapy.

• ECOG/WHO performance status = 2

• Adequate hepatic function as evidenced by:

• Serum total bilirubin = 2.5 × upper limit of normal (ULN) unless considered due to Gilbert's disease (e.g. a mutation in UGT1A1) (only for patients in IDH2 cohort), or leukemic involvement of the liver - following written approval by the (Co)Principal Investigator.

• Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) = 3.0 × ULN, unless considered due to leukemic involvement of the liver, following written approval by the Principal Investigator.

• Adequate renal function as evidenced by creatinine clearance > 40 mL/min based on the Cockroft-Gault formula for glomerular filtration rate (GFR).

• Able to understand and willing to sign an informed consent form (ICF).

• Written informed consent

Female patient must either:

o Be of nonchildbearing potential: Postmenopausal (defined as at least 1 year without any menses) prior to screening, or Documented surgically sterile or status posthysterectomy (at least 1 month prior to screening)

o Or, if of childbearing potential: Agree not to try to become pregnant during the study and for 6 months after the final study drug administration And have a negative urine or serum pregnancy test at screening And, if heterosexually active, agree to consistently use highly effective* contraception per locally accepted standards in addition to a barrier method starting at screening and throughout the study period and for 6 months after the final study drug administration.

• Highly effective forms of birth control include:

• Consistent and correct usage of established hormonal contraceptives that inhibit ovulation,

• Established intrauterine device (IUD) or intrauterine system (IUS),

• Bilateral tubal occlusion,

• Vasectomy (A vasectomy is a highly effective contraception method provided the absence of sperm has been confirmed. If not, an additional highly effective method of contraception should be used.)

• Male is sterile due to a bilateral orchiectomy.

• Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual activity during the entire period of risk associated with the study drug. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the patient.

• List is not all inclusive. Prior to enrollment, the investigator is responsible for confirming patient will utilize highly effective forms of birth control per the requirements of the CTFG Guidance document 'Recommendations related to contraception and pregnancy testing in clinical trials', September 2014 (and any updates thereof) during the protocol defined period.

• Female patient must agree not to breastfeed starting at screening and throughout the study period, and for 2 months and 1 week after the final study drug administration.

• Female patient must not donate ova starting at screening and throughout the study period, and for 6 months after the final study drug administration.

• Male patient and their female partners who are of childbearing potential must be using highly effective contraception per locally accepted standards in addition to a barrier method starting at screening and continue throughout the study period and for 4 months and 1 week after the final study drug administration

• Male patient must not donate sperm starting at screening and throughout the study period and for 4 months and 1 week after the final study drug administration.

• Subject agrees not to participate in another interventional study while on treatment

Exclusion Criteria:

• Prior chemotherapy for AML or MDS-EB2 (with the exception of HMA). Hydroxyurea is allowed for the control of peripheral leukemic blasts in patients with leukocytosis (e.g., white blood cell [WBC] counts > 30x109/L).

• Dual IDH1 and IDH2 mutations.

• Acute promyelocytic leukemia (APL) with PML-RARA or one of the other pathognomonic variant fusion genes/chromosome translocations.

• Blast crisis after chronic myeloid leukemia (CML).

• Known allergy or suspected hypersensitivity to Ivosidenib or Enasidenib and/or any exipients.

• Taking medications with narrow therapeutic windows with potential interaction with investigational medication (see Appendix I), unless the patient can be transferred to other medications prior to enrolling or unless the medications can be properly monitored during the study.

• Taking P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP) transporter-sensitive substrate medications (see Appendix J) unless the patient can be transferred to other medications within = 5 half-lives prior to administration of ivosidenib or enasidenib, or unless the medications can be properly monitored during the study.

• Breast feeding at the start of study treatment.

• Active infection, including hepatitis B or C or HIV infection that is uncontrolled at randomization. An infection controlled with an approved or closely monitored antibiotic/antiviral/antifungal treatment is allowed.

• Patients with a currently active second malignancy. Patients are not considered to have a currently active malignancy if they have completed therapy and are considered by their physician to be at < 30% risk of relapse within one year. However, patients with the following history/concurrent conditions are allowed:

• Basal or squamous cell carcinoma of the skin

• Carcinoma in situ of the cervix

• Carcinoma in situ of the breast

• Incidental histologic finding of prostate cancer

• Significant active cardiac disease within 6 months prior to the start of study treatment, including New York Heart Association (NYHA) Class III or IV congestive heart failure (appendix G); myocardial infarction, unstable angina and/or stroke; or left ventricular ejection fraction (LVEF) < 40% by ultrasound or MUGA scan obtained within 28 days prior to the start of study treatment.

• QTc interval using Fridericia's formula (QTcF) = 450 msec or other factors that increase the risk of QT prolongation or arrhythmic events (e.g., heart failure,family history of long QT interval syndrome). Prolonged QTc interval associated with bundle branch block or pacemaking is permitted with written approval of the Principal Investigator.

• Taking medications that are known to prolong the QT interval (see Appendix K), unless deemed critical and without a suitable alternative. In those cases, they may be administered, but with proper monitoring (see section 10.2, Table 13).

• Dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the ingestion or gastrointestinal absorption of orally administered drugs.

• Clinical symptoms suggestive of active central nervous system (CNS) leukemia or known CNS leukemia. Evaluation of cerebrospinal fluid (CSF) during screening is only required if there is a clinical suspicion of CNS involvement by leukemia during screening.

• A known medical history of progressive multifocal leukoencephalopathy (PML).

• Immediately life-threatening, severe complications of leukemia such as uncontrolled bleeding, pneumonia with hypoxia or shock, and/or severe disseminated intravascular coagulation

• Any other medical condition deemed by the Investigator to be likely to interfere with a patient's ability to give informed consent or participate in the study.

• Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.

Related Conditions & MeSH terms

• Acute Myeloid Leukemia
• Anemia, Refractory, with Excess of Blasts
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute
• Myelodysplastic Syndrome With Excess Blasts-2
• Myelodysplastic Syndromes
• Preleukemia
• Syndrome

Intervention

Drug:
• AG-120
250mg tablets
• Placebo for AG-120
250mg tablets
• AG-221
100mg tablets
• Placebo for AG-221
100mg tablets

Locations

Country	Name	City	State
Australia	AU-Adelaide-FLINDERS	Adelaide
Australia	AU-Adelaide-RAH	Adelaide
Australia	AU-Brisbane-PAH	Brisbane
Australia	AU-Camperdown-RPA	Camperdown
Australia	AU-Canberra-CANBERRAHOSPITAL	Canberra
Australia	AU-Douglas-TOWNSVILLE	Douglas
Australia	AU-Hobart TAS-RHOBART	Hobart
Australia	AU-Launceston TAS-LAUNCESTON	Launceston
Australia	AU-Melbourne-ALFRED	Melbourne
Australia	AU-Melbourne-AUSTIN	Melbourne
Australia	AU-Melbourne-MONASH	Melbourne
Australia	AU-Melbourne-RMELBOURNE	Melbourne
Australia	AU-Melbourne-SVHM	Melbourne
Australia	AU-Perth-FSH	Perth
Australia	AU-Perth-RPH	Perth
Australia	AU-Perth-SCGH	Perth
Australia	AU-Sydney-CONCORD	Sydney
Australia	AU-Sydney-RNSH	Sydney
Australia	AU-Sydney-SVHS	Sydney
Australia	AU-Sydney-WSAH	Sydney
Australia	AU-Waratah-CALVARYMATER	Waratah
Austria	AT-Graz-MEDUNIGRAZ	Graz
Austria	AT-Innsbruck-IMED	Innsbruck
Austria	AT-Linz-ORDENSKLINIKUM	Linz
Austria	AT-Vienna-HANUSCH	Vienna
Belgium	BE-Antwerpen-ZNASTUIVENBERG	Antwerpen
Belgium	BE-Brugge-AZBRUGGE	Brugge
Belgium	BE-Brussel-BORDET	Brussels
Belgium	BE-Brussel-UZBRUSSEL	Brussels
Belgium	BE-Bruxelles-STLUC	Brussels
Belgium	BE-Gent-UZGENT	Gent
Belgium	BE-Haine-Saint-Paul-JOLIMONT	Haine-Saint-Paul
Belgium	BE-Hasselt-VIRGAJESSE	Hasselt
Belgium	BE-Leuven-UZLEUVEN	Leuven
Belgium	BE-Liege-CHRCITADELLE	Liège
Belgium	BE-Liege-CHULIEGE	Liège
Belgium	BE-Roeselare-AZDELTA	Roeselare
Belgium	BE-Yvoir-MONTGODINNE	Yvoir
Estonia	EE-Tartu-TARTU	Tartu
Finland	FI-Helsinki-HUS	Helsinki
Finland	FI-Tampere-TAYS	Tampere
France	FR-Amiens-CHUAMIENS	Amiens
France	FR-Angers-CHUANGERS	Angers
France	FR-Argenteuil-CHARGENTEUIL	Argenteuil
France	FR-Bayonne-CHCOTEBASQUE	Bayonne
France	FR-Besançon Cedex-JEANMINJOZ	Besançon
France	FR-Bobigny-AVICENNE	Bobigny
France	FR-Chambery-CHMETROPOLESAVOIE	Chambéry
France	FR-Le Chesnay cedex-CHVERSAILLES	Chesnay
France	FR-Clamart-HIAPERCY	Clamart
France	FR-Clermont-Ferrand-ESTAING	Clermont-Ferrand
France	FR-Créteil cedex-CHUMONDOR	Créteil
France	FR-Grenoble cedex 9-CHUGRENOBLE	Grenoble cedex 9
France	FR-Lens-CHLENS	Lens
France	FR-Lille-CHULILLE	Lille
France	FR-Limoges-CHULIMOGES	Limoges
France	FR-Lyon Pierre Benite cedex-LYONSUD	Lyon
France	FR-Lyon-LEONBERARD	Lyon
France	FR-Marseille-IPC	Marseille
France	FR-Montpellier-STELOI	Montpellier
France	FR-Mulhouse-GHRMSA	Mulhouse
France	FR-Nantes-CHUNANTES	Nantes
France	FR-Nice-CAL	Nice
France	FR-Nice-LARCHET	Nice
France	FR-Orléans-CHORLEANS	Orléans
France	FR-Paris cedex 10-SAINTLOUIS	Paris
France	FR-Paris cedex 12-SAINTANTOINE	Paris
France	FR-Paris cedex 15-NECKER	Paris
France	FR-Pessac Cedex-CHUBORDEAUX	Pessac
France	FR-Poitiers-CHUPOITERS	Poitiers
France	FR-Reims-CHREIMS	Reims
France	FR-Rennes cedex 9-CHURENNES	Rennes
France	FR-Rouen cedex-BECQUEREL	Rouen
France	FR-Strasbourg cedex-HAUTEPIERRE	Strasbourg
France	FR-Toulouse-CHUTOULOUSE	Toulouse
France	FR-Tours cedex-BRETONNEAU	Tours
France	FR-Vandoeuvre Les Nancy-CHRUNANCY	Vandœuvre-lès-Nancy
France	FR-Villejuif-GUSTAVEROUSSY	Villejuif
Germany	DE-Bad Saarow-HELIOSBADSAAROW	Bad Saarow
Germany	DE-Berlin-CAMPUSBENFRANKLIN	Berlin
Germany	DE-Berlin-CAMPUSVIRCHOW	Berlin
Germany	DE-Berlin-VIVANTESNEUKOLLN	Berlin
Germany	DE-Berlin-VIVANTESURBAN	Berlin
Germany	DE-Bochum-RUB	Bochum
Germany	DE-Bonn-UNIBONN	Bonn
Germany	DE-Braunschweig-KLINIKUMBRAUNSCHWEIG	Braunschweig
Germany	DE-Bremen-KBM	Bremen
Germany	DE-Dortmund-JOHODORTMUND	Dortmund
Germany	DE-Düsseldorf-MEDUNIDUESSELDORF	Düsseldorf
Germany	DE-Essen-KEM	Essen
Germany	DE-Esslingen-KLINIKUMESSLINGEN	Esslingen
Germany	DE-Flensburg-MALTESER	Flensburg
Germany	DE-Giessen-UKGM	Gießen
Germany	DE-Goch-KKLE	Goch
Germany	DE-Hamburg-ASKLEPIOS	Hamburg
Germany	DE-Hamburg-ASKLEPIOSSTGEORG	Hamburg
Germany	DE-Hamburg-UKE	Hamburg
Germany	DE-Hamm-EVKHAMM	Hamm
Germany	DE-Hanau-KLINIKUMHANAU	Hanau
Germany	DE-Hannover-MHHANNOVER	Hannover
Germany	DE-Hannover-SILOAHKRH	Hannover
Germany	DE-Herne-MARIENHOSPITALHERNE	Herne
Germany	DE-Homburg-UNIKLINIKSAARLAND	Homburg
Germany	DE-Karlsruhe-KLINIKUMKARLSRUHE	Karlsruhe
Germany	DE-Lebach-CARITASKHLEBACH	Lebach
Germany	DE-Lemgo-KLINIKUMLIPPE	Lemgo
Germany	DE-Luedenscheid-KLINIKUMLUEDENSCHEID	Lüdenscheid
Germany	DE-Ludwigshafen-KLILU	Ludwigshafen
Germany	DE-Magdeburg-OVGU	Magdeburg
Germany	DE-Mainz-KLINKUNIMAINZ	Mainz
Germany	DE-Mainz-UNIMEDIZINMAINZ	Mainz
Germany	DE-Meschede-HOCHSAUERLAND	Meschede
Germany	DE-Minden-MUEHLENKREISKLINKEN	Minden
Germany	DE-München-IRZTUM	München
Germany	DE-München-MEDUNIMUNCHIN	München
Germany	DE-Offenburg-ORTENAUKLINIKUM	Offenburg
Germany	DE-Oldenburg-KLINIKUMOLDENBURG	Oldenburg
Germany	DE-Passau-KLINIKUMPASSAU	Passau
Germany	DE-Stuttgart-DIAKSTUTTGART	Stuttgart
Germany	DE-Stuttgart-KLINIKUMSTUTTGART	Stuttgart
Germany	DE-Traunstein-TSSOB	Traunstein
Germany	DE-Trier-MUTTERHAUS	Trier
Germany	DE-Tübingen-MEDUNITUEBINGEN	Tübingen
Germany	DE-Ulm-UNIKLINKULM	Ulm
Germany	DE-Villingen-Schwenningen-SBKVS	Villingen-Schwenningen
Germany	DE-Wuppertal-HELIOSGESUNDHEIT	Wuppertal
Ireland	IE-Cork-CUH	Cork
Ireland	IE-Dublin 8-STJAMES	Dublin
Ireland	IE-Dublin 9-BEAUMONT	Dublin
Ireland	IE-Galway-UHGALWAY	Galway
Lithuania	LT-Vilnius-SANTA	Vilnius
Luxembourg	LU-Luxembourg-CHL	Luxembourg
Netherlands	NL-Amersfoort-MEANDERMC	Amersfoort
Netherlands	NL-Amsterdam-AMC	Amsterdam
Netherlands	NL-Amsterdam-OLVG	Amsterdam
Netherlands	NL-Amsterdam-VUMC	Amsterdam
Netherlands	NL-Arnhem-RIJNSTATE	Arnhem
Netherlands	NL-Breda-AMPHIA	Breda
Netherlands	NL-Delft-RDGG	Delft
Netherlands	NL-Den Bosch-JBZ	Den Bosch
Netherlands	NL-Den Haag-HAGA	Den Haag
Netherlands	NL-Dordrecht-ASZ	Dordrecht
Netherlands	NL-Eindhoven-MAXIMAMC	Eindhoven
Netherlands	NL-Enschede-MST	Enschede
Netherlands	NL-Groningen-UMCG	Groningen
Netherlands	NL-Leeuwarden-MCL	Leeuwarden
Netherlands	NL-Leiden-LUMC	Leiden
Netherlands	NL-Maastricht-MUMC	Maastricht
Netherlands	NL-Nieuwegein-ANTONIUS	Nieuwegein
Netherlands	NL-Nijmegen-RADBOUDUMC	Nijmegen
Netherlands	NL-Rotterdam-ErasmusMC	Rotterdam
Netherlands	NL-Utrecht-UMCUTRECHT	Utrecht
Netherlands	NL-Zwolle-ISALA	Zwolle
Norway	NO-Bergen-HELSEBERGEN	Bergen
Norway	NO-Oslo-OSLOUH	Oslo
Norway	NO-Stavanger-HELSESTAVANGER	Stavanger
Norway	NO-Tromsø-NORTHNOORWEGEN	Tromsø
Norway	NO-Trondheim-STOLAV	Trondheim
Spain	ES-Barcelona-CLINICUB	Barcelona
Spain	ES-Barcelona-GERMANTRIALS	Barcelona
Spain	ES-Barcelona-ICODURANREYNALS	Barcelona
Spain	ES-Barcelona-MUTUATERRASSA	Barcelona
Spain	ES-Barcelona-PARCDESALUTMAR	Barcelona
Spain	ES-Barcelona-SANTPAU	Barcelona
Spain	ES-Barcelona-VHEBRON	Barcelona
Spain	ES-Girona-ICSTRUETA	Girona
Spain	ES-Madrid-CSGREGORIOMARANON	Madrid
Spain	ES-Palma-SSIB	Palma
Spain	ES-Tarragona-JOAN	Tarragona
Spain	ES-Valencia-MALVARROSA	Valencia
Sweden	SE-Lund-SUH	Lund
Sweden	SE-Stockholm-KAROLINSKAHUDDINGE	Stockholm
Sweden	SE-Uppsala-UPPSALAUH	Uppsala
Switzerland	CH-Basel-USB	Basel
Switzerland	CH-Bellinzona-IOSI	Bellinzona
Switzerland	CH-Bern-INSEL	Bern
Switzerland	CH-Fribourg-HFR	Fribourg
Switzerland	CH-Geneve (14)-HCUGE	Geneve
Switzerland	CH-Lausanne-CHUV	Lausanne
Switzerland	CH-Luzern-LUKS	Luzern
Switzerland	CH-St. Gallen-KSSG	Saint Gallen
Switzerland	CH-Zürich-USZ	Zürich

Sponsors (2)

Lead Sponsor	Collaborator
Stichting Hemato-Oncologie voor Volwassenen Nederland	Deutsch-Österreichische Studiengruppe Akute Myeloische Leukämie (AMLSG)

Countries where clinical trial is conducted

Australia,  Austria,  Belgium,  Estonia,  Finland,  France,  Germany,  Ireland,  Lithuania,  Luxembourg,  Netherlands,  Norway,  Spain,  Sweden,  Switzerland, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Event-free survival (EFS)	EFS is defined as the time from randomization to failure to achieve CR or CRi after remission induction, death after achieving CR or CRi or relapse after achieving CR or CRi, whichever occurs first. A patient is said to have failed to achieve CR or CRi after induction therapy, if his/her best response during or at completion of the induction treatment is less than CRi. Patients who achieved CR/CRi after remission induction and are not known to have relapsed or died will be censored at the date of last clinical assessment.	Approximately up to 60 months following first patient enrollment
Secondary	Overall survival (OS)	OS is defined as the time from date of randomization to date of death due to any cause. Patients still alive or lost to follow up will be censored at the time they were last known to be alive.	Approximately up to 84 months following first patient enrollment
Secondary	Relapse-free survival (RFS) after CR/CRi	RFS is defined as time from the date of achievement of CR/CRi until relapse or death from any cause, whichever comes first. Patients still in first CR/CRi and alive or lost to follow up will be censored at the date of last clinical assessment.	Approximately up to 60 months following first patient enrollment
Secondary	Cumulative incidence of relapse (CIR) after CR/CRi	CIR is measured from the date of achievement of CR/CRi until the date of relapse. Patients not known to have relapsed will be censored on the date of last clinical assessment. Patients who died without relapse will be counted as a competing cause of failure.	Approximately up to 60 months following first patient enrollment
Secondary	Cumulative incidence of death (CID) after CR/CRi	CID is measured from the date of achievement of CR/CRi until the date of death from any cause. Patients not known to have died will be censored on the date they were last known to be alive. Patients who experienced relapse in CR/CRi will be counted as competing cause of failure.	Approximately up to 60 months following first patient enrollment
Secondary	Complete remission without minimal residual disease (CRMRD-) rate after induction cycle 2	CRMRD- rate is defined as the percentage of patients who achieved CR or CRi with no evidence of MRD in bone marrow	Approximately up to 60 months following first patient enrollment
Secondary	Frequency and severity of adverse events according to CTCAE version 5.0	Adverse events will be evaluated using the National Cancer Institute's Common Terminology Criteria for AEs (CTCAE) version 5.0	Continuously throughout the study, starting from informed consent until 30 days following the last administration of any study drug
Secondary	CR/CRi rates after induction cycle 1 and 2	CR and CRi are determined by the Investigator based on the European LeukemiaNet (ELN2017) recommended response criteria	Approximately up to 60 months following first patient enrollment
Secondary	CR/CRi rate after remission induction (i.e., CR or CRi as best response during or at completion of induction therapy)	CR+CRi rate after remission induction is defined as the percentage of patients with best response of CR or CRi during or at completion of induction therapy	Approximately up to 60 months following first patient enrollment
Secondary	Time to hematopoietic recovery after each chemotherapy treatment cycle	Time to hematopoietic recovery is defined as the time from the start of the cycle until recovery	Approximately up to 60 months following first patient enrollment
Secondary	EQ-5D-5L visual analogue scale (VAS)	The EQ-5D-5L is a 5 item questionnaire that assesses 5 domains including mobility, self-care, usual activities, pain/discomfort and anxiety/depression plus a visual analog scale rating "health today". Each domain has 5 levels. Each level has a 1 digit number expressing the level selected for that dimension. These levels are summed up and the self-rated health is recorded on a 20 cm vertical, visual analogue scale, with endpoints labelled 'the best health you can imagine' and 'the worst health you can imagine'.	At entry, 1st day of maintenance, every 3 months during the first year of maintenance, every 6 months during the second year of maintenance until relapse or treatment discontinuation (approximately up to 84 months following first patient enrollment)
Secondary	EORTC-QLQ-C30 global health status/QoL scale.	The EORTC QLQ-C30 is a 30-item questionnaire that assesses 5 functional subdomains (physical functioning, role functioning, emotional functioning, cognitive functioning and social functioning), 1 global health status, 3 symptom subdomains (fatigue, nausea and vomiting and pain) and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level. Estimate the average of the items that contribute to the scale; this is the raw score. a higher score represents a higher ("better") level of functioning, or a higher ("worse") level of symptoms.	At entry, 1st day of maintenance, every 3 months during the first year of maintenance, every 6 months during the second year of maintenance until relapse or treatment discontinuation (approximately up to 84 months following first patient enrollment)

External Links

•   HOVON website