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

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

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02249091

Enrollment

Registered

2014-09-25

Start date

2014-09-30

Completion date

2018-07-31

Last updated

2021-08-25

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Acute Myeloid Leukemia (Relapsed/Refractory)

Brief summary

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.

Interventions

DRUGSelinexor

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).

DRUGIdarubicin

Infusion, iv, 10 mg/m\^2, on days 1,3,5 in cycle 1, on days 1,3 in cycle 2

DRUGCytarabine

Continuous infusion day 1 to 7, 100 mg/m\^2, iv,

Study design

Allocation

NON_RANDOMIZED

Intervention model

SEQUENTIAL

Primary purpose

TREATMENT

Masking

NONE

Intervention 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.

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

1. Cytological or histological diagnosis of AML with the exception of promyelocytic leukemia (AML M3) 2. Patients must have relapsed/refractory disease (relapse after stem cell transplantation is permitted) as defined as: 1. patients with \<PR after first cycle of induction chemotherapy, or 2. patients with \<CR(i) after second cycle of induction chemotherapy, or 3. patients who relapse after conventional chemotherapy or 4. patients who have undergone a single stem cell transplantation and who have relapse of their AML. 3. Men and women aged ≥18 years and eligible for standard dose of chemotherapy (7+3); 4. 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; 5. ECOG performance status ≤ 2 6. 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. 7. Ability to swallow and retain oral medication; 8. Ability to understand and provide signed informed consent; 9. Cardiac ejection fraction must be \>/=50% (by echocardiography). 10. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures.

Exclusion criteria

1. Treatment with any investigational agent within four weeks. 2. Cumulative anthracycline dose (daunorubicin or equivalent) \>360 mg/m\^2 3. HIV infection 4. Presence of any medical or psychiatric condition which may limit full compliance with the study, including but not limited to: 5. Presence of CNS leukemia 6. Unresolved toxicity from previous anti-cancer therapy or incomplete recovery from surgery. 7. For patients after SCT as part of prior treatment: 1. Necessity of immunosuppressive drugs 2. GvHD \> grade 1 8. 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. 9. Ongoing cardiac dysrhythmias of NCI CTCAE \>/= Grade 2. 10. 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. 11. Clinically significant bleeding within 1 month

Design outcomes

Primary

Measure	Time frame	Description
Number of Participants With CR/CRi = Overall Reponse Rate	1-2 induction cycles (4 - 8 weeks)	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).

Secondary

Measure	Time frame	Description
Percentage of Patients Transplanted After Induction Therapy (Stem Cell Transplantation)	1-2 induction cycles (4 - 8 weeks)	Percentage of patients being transplanted after induction therapy (stem cell transplantation)
Early Death Rate	1 induction cycle (4 weeks)	Early death was defined as death before the end of the first induction cycle.
Overall Survival	Time from registration to event, max 2 years	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.
Number of Participants With Partial Remission (PR) = Rate of PR	1-2 induction cycles (4 - 8 weeks)	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).
Event-Free Survival	Time from registration to event, max 2 years	Event-free survival (EFS) was calculated from the time of informed consent until death, not achieving CR/CRi or relapse after CR/CRi.
Progression-Free Survival	Time from registration to event, max 2 years	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%.
Relapse-Free Survival	Time from registration to event, max 2 years	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.

Countries

Germany

Participant flow

Recruitment details

43 patients were registered in the clinical trial at 3 sites. One patient was a screening failure. Of the remaining 42 patients, the first 27 patients were treated in cohort 1 (Selinexor dosed by Body Surface Area \[BSA\] 40 mg/m\^2 per dose) and the other 15 patients were treated in cohort 2 (flat dose of Selinexor of 60 mg per dose).

Participants by arm

Arm	Count
Cohort 1 / Selinexor 40 mg/m^2 in Combination With Cytarabine and Idarubicin Induction cycle: All enrolled patients were treated with selinexor, cytarabine and idarubicin as follows: Selinexor: 40 mg/m\^2 twice weekly orally starting on day 2 (total of 8 doses per 4-week induction cycle). Idarubcin: i.v. infusion, 10 mg/m\^2, on days 1,3,5 in cycle 1 Cytarabine: continuous i.v. infusion day 1-7, 100 mg/m\^2 Up to two induction cycles were administered. If a second cycle was applied idarubicin was only given on days 1 and 3.	27
Cohort 2 / Selinexor 60 mg Flat Dose in Combination With Cytarabine and Idarubicin Induction cycle: All enrolled patients were treated with selinexor, cytarabine and idarubicin as follows: Selinexor: 60 mg flat dose twice weekly orally during weeks 1-3 of a 4-week cycle (day 2, 4, 9, 11, 16, 18; total of 6 doses per 4-week induction cycle). Idarubcin: i.v. infusion, 10 mg/m\^2, on days 1,3,5 in cycle 1. Cytarabine: continuous i.v. infusion day 1-7, 100 mg/m\^2 Up to two induction cycles were administered. If a second cycle was applied idarubicin was only given on days 1 and 3.	15
Total	42

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Adverse Event	1	0
Overall Study	CR with subsequent donor lymphocyte infusion	1	0
Overall Study	Death	3	4
Overall Study	Lack of Efficacy	8	3
Overall Study	Ongoing bone marrow aplasia, periph. pancytopenia	0	1
Overall Study	Physician Decision	4	1
Overall Study	Refractory AML	1	1
Overall Study	Stable disease with following SCT	0	1
Overall Study	Withdrawal by Subject	2	2

Baseline characteristics

Characteristic	Total	Cohort 1 / Selinexor 40 mg/m^2 in Combination With Cytarabine and Idarubicin	Cohort 2 / Selinexor 60 mg Flat Dose in Combination With Cytarabine and Idarubicin
Age, Continuous	55.6 years STANDARD_DEVIATION 14.62	54.0 years STANDARD_DEVIATION 15.18	58.5 years STANDARD_DEVIATION 13.55
Leukemia diagnosis De Novo Acute Myeloid Leukemia (AML)	31 Participants	19 Participants	12 Participants
Leukemia diagnosis Secondary AML	9 Participants	6 Participants	3 Participants
Leukemia diagnosis Therapy-induced AML	2 Participants	2 Participants	0 Participants
Prior stem cell transplantation (SCT)	17 Participants	10 Participants	7 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	1 Participants	0 Participants	1 Participants
Race (NIH/OMB) Black or African American	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	41 Participants	27 Participants	14 Participants
Region of Enrollment Germany	42 participants	27 participants	15 participants
Sex: Female, Male Female	17 Participants	11 Participants	6 Participants
Sex: Female, Male Male	25 Participants	16 Participants	9 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	16 / 27	9 / 15
other Total, other adverse events	27 / 27	15 / 15
serious Total, serious adverse events	12 / 27	8 / 15

Outcome results

Primary

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).

Time frame: 1-2 induction cycles (4 - 8 weeks)