A Phase II Study of Selinexor Plus Cytarabine and Idarubicin in Patients With Relapsed/Refractory Acute Myeloid Leukemia (AML)

Study Overview
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Brief Summary
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Acute Myeloid Leukemia (AML) is currently treated with chemotherapy by combining several drugs with different ways of inhibiting the cell growth. In this trial, standard chemotherapeutics that have proven their effectiveness for years, Ara-C and Idarubicin, will be combined with a new drug called Selinexor. Selinexor inhibits the growth of cancer cells by keeping certain proteins in the nucleus which control the cell growth.

Official Title
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An Investigator-Initiated Study To Evaluate Ara-C and Idarubicin in Combination With the Selective Inhibitor Of Nuclear Export (SINE) Selinexor (KPT-330) in Patients With Relapsed Or Refractory AML

Conditions
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Acute Myeloid Leukemia (Relapsed/Refractory)

Intervention / Treatment
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* Drug: Selinexor
* Drug: Idarubicin
* Drug: Cytarabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Cytological or histological diagnosis of AML with the exception of promyelocytic leukemia (AML M3) Patients must have relapsed/refractory disease (relapse after stem cell transplantation is permitted) as defined as: patients with <PR after first cycle of induction chemotherapy, or patients with <CR(i) after second cycle of induction chemotherapy, or patients who relapse after conventional chemotherapy or patients who have undergone a single stem cell transplantation and who have relapse of their AML. Men and women aged ≥18 years and eligible for standard dose of chemotherapy (7+3); A period of at least 3 weeks needs to have elapsed since last treatment (with the exception of hydroxyurea) before participating in this study. Hydroxyurea induction therapy to reduce peripheral blast counts is permitted prior to initiation of treatment on protocol. Treatment may begin in <3 weeks from last treatment if deemed in the best interest of the patient after discussion with the PI of the study; ECOG performance status ≤ 2 Serum biochemical values with the following limits unless considered due to leukemia: creatinine ≤2 mg/dl; total bilirubin ≤2x ULN, unless increase is due to hemolysis or congenital disorder; transaminases (SGPT or SGOT) ≤2.5x ULN. Ability to swallow and retain oral medication; Ability to understand and provide signed informed consent; Cardiac ejection fraction must be >/=50% (by echocardiography). Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures. Exclusion Criteria: Treatment with any investigational agent within four weeks. Cumulative anthracycline dose (daunorubicin or equivalent) >360 mg/m^2 HIV infection Presence of any medical or psychiatric condition which may limit full compliance with the study, including but not limited to: Presence of CNS leukemia Unresolved toxicity from previous anti-cancer therapy or incomplete recovery from surgery. For patients after SCT as part of prior treatment: Necessity of immunosuppressive drugs GvHD > grade 1 Any of the following within the 12 months prior to study drug administration: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack, pulmonary embolism, deep vein thrombosis, or other thromboembolic event. Ongoing cardiac dysrhythmias of NCI CTCAE >/= Grade 2. Other severe acute or chronic medical or psychiatric condition, or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, and in the judgment of the investigator would make the patient inappropriate for entry into this study. Clinically significant bleeding within 1 month

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: In the initial protocol, 25 patients are included in the clinical trial on the schedule described as cohort 1. After an amendment 15 further patients are included on the schedule described as cohort 2.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1 / Selinexor 40 mg/m^2 in combination with cytarabine and idarubicin<br>All enrolled patients are treated with cytarabine at a dose of 100 mg/m² continuous infusion (day 1-7) and idarubicin at a dose of 10 mg/m^2 iv (day 1,3,5) every 4 weeks and selinexor for up to 2 induction cycles. If a second cycle is applied idarubicin is only given on day 1 and 3. Selinexor is administered at a dose of 40 mg/m^2 twice weekly orally starting on day 2 (total of 8 doses per induction cycle). | Drug: Selinexor<br>* Patients receive Selinexor as specified in arm/group description (8 doses of 40 mg/m^2 or 6 doses of 60 mg per induction cycle).<br>* Other names: KPT-330;Drug: Idarubicin<br>* Infusion, iv, 10 mg/m^2, on days 1,3,5 in cycle 1, on days 1,3 in cycle 2<br>Drug: Cytarabine<br>* Continuous infusion day 1 to 7, 100 mg/m^2, iv,<br>* Other names: Ara-C;|
| Experimental: Cohort 2 / Selinexor 60 mg flat dose in combination with cytarabine and idarubicin<br>All enrolled patients are treated with cytarabine at a dose of 100 mg/m^2 continuous infusion (day 1-7) and idarubicin at a dose of 10 mg/m^2 iv (day 1,3,5) every 4 weeks and selinexor for up to 2 induction cycles. If a second cycle is applied idarubicin is only given on day 1 and 3. Selinexor is administered at a flat dose of 60 mg twice weekly orally in weeks 1-3 of a 4-week cycle starting on day 2 (total of 6 doses per induction cycle). | Drug: Selinexor<br>* Patients receive Selinexor as specified in arm/group description (8 doses of 40 mg/m^2 or 6 doses of 60 mg per induction cycle).<br>* Other names: KPT-330;Drug: Idarubicin<br>* Infusion, iv, 10 mg/m^2, on days 1,3,5 in cycle 1, on days 1,3 in cycle 2<br>Drug: Cytarabine<br>* Continuous infusion day 1 to 7, 100 mg/m^2, iv,<br>* Other names: Ara-C;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With CR/CRi = Overall Reponse Rate | Efficacy of selinexor in combination with standard chemotherapy in patients with relapsed/refractory AML by determination of rate of complete response (CR) or morphologic complete response with incomplete blood count recovery (CRi), as defined by the recommendations on diagnosis and management of AML in adults from an international expert panel, on behalf of the European LeukemiaNet: CR: Absolute Neutrophil count (ANC) >1.0x10^9/L, Platelet count >100x10^9/L, Bone marrow blasts <5%, no Auer rods, no evidence of extramedullary disease. CRi: Same as CR, but ANC may be <1.0x10^9/L and/or Platelet count <100x10^9/L. Patients with morphologic leukemia free-state (MLFS) were included in the group of responders. MLFS: Bone marrow blasts <5%, no Auer rods, no evidence of extramedullary disease. The best response after Selinexor treatment was analyzed, thus the best response after the induction cycle(s). | 1-2 induction cycles (4 - 8 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Partial Remission (PR) = Rate of PR | Efficacy of selinexor in combination with standard chemotherapy in patients with relapsed/refractory AML by determination of rate of partial remission(PR) as defined by the recommendations on diagnosis and management of AML in adults from an international expert panel, on behalf of the European LeukemiaNet: PR: Absolute Neutrophil count (ANC) >1.0x10^9/L, Platelet count >100x10^9/L, at least a 50% decrease in the percentage of marrow aspirate blasts to 5-25%, or marrow blasts <5% with persistent Auer rods. The best response after Selinexor treatment was analyzed, thus the best response after the induction cycle(s). | 1-2 induction cycles (4 - 8 weeks) | 
| Percentage of Patients Transplanted After Induction Therapy (Stem Cell Transplantation) | Percentage of patients being transplanted after induction therapy (stem cell transplantation) | 1-2 induction cycles (4 - 8 weeks) | 
| Early Death Rate | Early death was defined as death before the end of the first induction cycle. | 1 induction cycle (4 weeks) | 
| Overall Survival | Overall survival (OS) was calculated from the date of informed consent to the date of death. Patients still alive at the end of follow-up were censored at the last date of follow-up. | Time from registration to event, max 2 years | 
| Relapse-Free Survival | Relapse-free survival (RFS) was calculated from the date of CR/CRi until death or relapse, whichever occurred first. Patients were censored on the date of the last follow-up if they were alive without relapse. | Time from registration to event, max 2 years | 
| Event-Free Survival | Event-free survival (EFS) was calculated from the time of informed consent until death, not achieving CR/CRi or relapse after CR/CRi. | Time from registration to event, max 2 years | 
| Progression-Free Survival | Progression-free survival (PFS) was calculated from the time of informed consent to the date of recurrence or death, whichever occurred first. Patients were censored at the date of the last follow-up visit if they were alive without relapse. Disease progression was defined as presence of >50% increase in bone marrow blasts to a level of at least 50% and/or a doubling of the percentage of peripheral blood blasts to a level of at least 50%. | Time from registration to event, max 2 years |