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A randomized phase II multicenter study with a safety run-in to assess the tolerability and efficacy of the addition of oral selinexor (KPT-330) to standard induction chemotherapy in AML and high risk myelodysplasia (MDS) (IPSS-R > 4.5) in patients aged >66 years .


- candidate number24493
- NTR NumberNTR5902
- ISRCTNISRCTN no longer applicable
- Date ISRCTN created
- date ISRCTN requested
- Date Registered NTR15-jun-2016
- Secondary IDsHO103SEL 2014-001876-75
- Public TitleA randomized phase II multicenter study with a safety run-in to assess the tolerability and efficacy of the addition of oral selinexor (KPT-330) to standard induction chemotherapy in AML and high risk myelodysplasia (MDS) (IPSS-R > 4.5) in patients aged >66 years .
- Scientific TitleA randomized phase II multicenter study with a safety run-in to assess the tolerability and efficacy of the addition of oral selinexor (KPT-330) to standard induction chemotherapy in AML and high risk myelodysplasia (MDS) (IPSS-R > 4.5) in patients aged ‘έ 66 years .
- ACRONYMHOVON 103 AML Selinexor
- hypothesisTo assess the tolerability and efficacy of the addition of oral selinexor to standard induction therapy.
- Healt Condition(s) or Problem(s) studiedAcute Myeloid Leukemia (AML), Myelodysplasia
- Inclusion criteria• Patients eligible for standard chemotherapy.
• Patients 66 years and older
• Patients with:
o a diagnosis of AML and related precursor neoplasms according to WHO 2008 classification (excluding acute promyelocytic leukemia) including secondary AML (after an antecedent hematological disease (e.g. MDS) and therapy-related AML, or
o acute leukemia’s of ambiguous lineage according to WHO 2008 or
o a diagnosis of refractory anemia with excess of blasts (MDS) and IPSS-R > 4.5
• Adequate renal and hepatic functions unless clearly disease related as indicated by the following laboratory values:
o Serum creatinine ≤1.0 mg/dL (≤88.7 μmol/L); if serum creatinine >1.0 mg/dL (>88.7 μmol/L), then the estimated glomerular filtration rate (GFR) must be >60 mL/min/1.73 m2 as calculated by the Modification of Diet in Renal Disease equation where the Predicted GFR (ml/min/1.73 m2) = 186 x (Serum Creatinine in mg/dL)-1.154 x (age in years)-0.203 x (0.742 if patient is female) x (1.212 if patient is black) NOTE: if serum creatinine is measured in μmol/L, recalculate it in mg/dL according to the equation: 1 mg/dL = 88.7 μmol/L and use the above mentioned formula.
o Serum bilirubin ≤ 2.5 x upper limit of normal (ULN)
o Aspartate transaminase (AST) ≤ 2.5 x ULN
o Alanine transaminase (ALT) ≤ 2.5 x ULN
o Alkaline phosphatase ≤ 2.5 x ULN
• WHO performance status 0, 1 or 2
• Written informed consent.
• Male and female patients must use an effective contraceptive method if relevant during the study and for a minimum of 6 months after study treatment.
- Exclusion criteria• Acute promyelocytic leukemia
• Patients previously treated for AML (any antileukemic therapy including investigational agents), a short treatment period (< 2 weeks) with Hydroxyurea is allowed
• Concurrent history of active malignancy in the two past years prior to diagnosis except for:
o Basal and squamous cell carcinoma of the skin
o in situ carcinoma of the cervix
• Blast crisis of chronic myeloid leukemia
• Concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled diabetes, infection, hypertension, pulmonary disease etcetera)
• Cardiac dysfunction as defined by:
o Myocardial infarction within the last 6 months of study entry, or
o Reduced left ventricular function with an ejection fraction < 50% ad measured by MUG scan or echocardiogram or
o Unstable angina or
o New York Heart Association (NYHA) grade II or greater congestive heart failure (see Appendix I) or
o Unstable cardiac arrthythmias
• Patients with a history of non-compliance to medical regimens or who are considered unreliable with respect to compliance
• Patients with any serious concomitant medical condition which could, in the opinion of the investigator, compromise participation in the study.
• Patients who have senile dementia, mental impairment or any other psychiatric disorder that prohibits the patient from understanding and giving informed consent.
• Current concomitant chemotherapy, radiation therapy, or immunotherapy other than as specified in the protocol.
• Any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and follow-up schedule
- mec approval receivedyes
- multicenter trialyes
- randomisedyes
- masking/blindingNone
- controlActive
- groupParallel
- Type2 or more arms, randomized
- Studytypeintervention
- planned startdate 1-jul-2016
- planned closingdate1-okt-2023
- Target number of participants230
- Interventions1. Arm A: Cycle I: Dauno/Cytarabine, cycle II: Cytarabine;
2. Arm C: Cycle I: Dauno/Cytarabine/Selinexor, cycle II: Cytarabine/Selinexor.
- Primary outcome• Incidence of DLT (part A)
• The effect of selinexor on the CR rate (part B of study)
- Secondary outcome• Overall survival (time from registration till the death of the patient.)
• Event free survival (i.e., time from registration to induction failure (i.e. no CR on induction), death or relapse whichever occurs first)
• Disease free survival (time from CR on protocol treatment until relapse or death, whichever comes first)
• Prognostic value of molecular markers and gene expression profiles of the leukemia assessed at diagnosis
• Prognostic value of minimal residual disease (MRD) measurements following therapy by standardized sampling of marrow/blood
- TimepointsClinical and laboratory evaluations:
1. At entry;
2. After each induction cycle;
3. During Follow Up, every 6 months.
- Trial web sitewww.hovon.nl
- statusopen: patient inclusion
- CONTACT FOR PUBLIC QUERIESProf. Dr. G.J. Ossenkoppele
- CONTACT for SCIENTIFIC QUERIESProf. Dr. G.J. Ossenkoppele
- Sponsor/Initiator HOVON Data Center
- Funding
(Source(s) of Monetary or Material Support)
KWF Kankerbestrijding, HOVON, Karyopharm Therapeutics
- PublicationsN/A
- Brief summaryRandomized phase II study.

Primary objectives:
For part A of the study (if applicable):
1. To assess the safety and tolerability of selinexor added to standard induction chemotherapy for AML (frequency and severity of toxicities and the durations of neutropenia and thrombocytopenia) and select the feasible dose level for part B
2. To assess in a randomized comparison the effect of selinexor on the CR rate.
For part B:
1. To assess the safety and tolerability of selinexor added to standard induction chemotherapy for AML (frequency and severity of toxicities and the durations of neutropenia and thrombocytopenia) as regards the selected dose level of selinexor
2. To assess in a randomized comparison the effect of selinexor on the CR rate.

Secondary objectives:
For part B:
1. To determine the efficacy profile (event free survival (EFS) disease free survival (DFS) and overall survival (OS)) associated with the two therapy regimens.
2. To measure MRD by immunophenotyping in relation to clinical response parameters.
3. To identify potential biomarkers predictive of response, EFS, DFS and OS by exploratory genomic analysis (microarray, gene mutations)

Patient population:
Patients with AML or high risk MDS with IPSS-R > 4.5, previously untreated, age ≥ 66 yrs.

Study design:
This is a prospective, open label, multicenter study that is conducted in the frame of a masterprotocol with multiple parallel randomized phase II studies. The scheme of this design consists of one arm with the standard treatment for AML as compared to various arms with experimental treatments.
Patients in this study are treated with standard induction chemotherapy with or without selinexor. During part A of the study the feasibility of combining selinexor with DNR/Cytarabine will be evaluated and the dose of selinexor will be selected. Decisions regarding dose escalation, continuation with starting dose level or stopping, are based on the incidence of DLT (dose limiting toxicity: death within 31 days of start cycle I and before start cycle II).
During part B of the study that will be conducted with the selected dose of selinexor, the CR rate (primary endpoint) and secondary endpoints (EFS, DFS, OS, as well as MRD and genomic profiling) will be assessed.

Duration of treatment:
Expected duration of 2 cycles of induction chemotherapy with or without selinexor including evaluation is about 3 months.
- Main changes (audit trail)
- RECORD15-jun-2016 - 12-apr-2017


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