Study of CLAG + Selinexor in Relapsed or Refractory Acute Myeloid Leukemia

Study Overview
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Brief Summary
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Selinexor has shown single-agent activity in a current phase I study enrolling patients with relapsed/refractory AML with durable complete remissions (CR), complete remissions with incomplete hematologic recovery (CRi), partial remissions (PR), and stable disease (SD) observed. Furthermore, common toxicities included nausea, fatigue, and anorexia and were manageable with supportive care agents. Additionally, CLAG chemotherapy has proven activity in relapsed and refractory AML, and has been shown to be a relatively well tolerated regimen without significant non-hematologic toxicity. Given the established role of CLAG chemotherapy, the single agent activity of selinexor, and their non-overlapping toxicities, the investigators propose a phase I/II open label study of selinexor in combination with CLAG for the treatment of patients with relapsed/refractory AML.

Official Title
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An Investigator Sponsored Phase I/II Study of CLAG + Selinexor in Relapsed or Refractory Acute Myeloid Leukemia

Conditions
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Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: Selinexor
* Drug: Cladribine
* Drug: G-CSF
* Drug: Cytarabine
* Procedure: Bone marrow biopsy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed AML (defined using WHO criteria) with one of the following: Primary refractory disease following ≤ 2 cycles of induction chemotherapy, or First relapse with no prior unsuccessful salvage chemotherapy, or Relapsed or refractory to hypomethylating agent, defined as a lack of response, disease progression, loss of response, or intolerance as deemed by the study investigator Age between 18 and 70 years old. ECOG performance status ≤ 3 Adequate organ function as defined below: AST(SGOT), ALT(SGPT), total bilirubin ≤ 2 x IULN except when in the opinion of treating physician is due to direct involvement of leukemia (eg. hepatic infiltration or biliary obstruction due to leukemia) or Gilbert's disease Creatinine clearance >50 ml/min, calculated using the formula of Cockroft and Gault: (140-Age) x Mass (kg) / (72 x Creatinine mg/dL); multiply by 0.85 if female. Left ventricular ejection fraction of ≥ 40% by MUGA scan or echocardiogram To ensure that no patient will receive a dose of selinexor >70mg/m^2, body surface area (BSA) calculated by Dubois method must be >1.43 m^2 Patients should not become pregnant or father a baby while on this study because the drugs in this study can affect an unborn baby. Women should not breastfeed a baby while on this study. It is important patients understand the need to use birth control while on this study. It is not anticipated that female patients enrolling in this study will be able to conceive. However, in the rare event that this is possible, female patients of child-bearing potential must agree to use dual methods of contraception and have a negative serum pregnancy test at screening, and male patients must use an effective barrier method of contraception if sexually active with a female of child-bearing potential. Acceptable methods of contraception are condoms with contraceptive foam, oral, implantable or injectable contraceptives, contraceptive patch, intrauterine device, diaphragm with spermicidal gel, or a sexual partner who is surgically sterilized or post-menopausal. For both male and female patients, effective methods of contraception must be used throughout the study and for three months following the last dose. Ability to understand and willingness to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable). Exclusion Criteria: Acute promyelocytic leukemia (AML with t(15;17)(q22;q11) and variants). Previous treatment with CLAG or other chemotherapy regimen containing both cladribine and cytarabine. Colony stimulating factors within 2 weeks of study. Active graft versus host disease (GVHD) after allogeneic stem cell transplantation. At least 2 months must have elapsed since completion of an allogeneic stem cell transplantation. Less than 2 weeks from the completion of any previous cytotoxic chemotherapy (with the exception of hydroxyurea). Concurrent active malignancy under treatment except prostate or breast cancer undergoing treatment with hormonal therapy. Treatment with any investigational agent within three weeks prior to first dose in this study. Active CNS involvement with leukemia. Unstable cardiovascular function: symptomatic ischemia, or uncontrolled clinically significant conduction abnormalities (i.e. ventricular tachycardia on antiarrhythmics are excluded and 1st degree AV block or asymptomatic LAFB/RBBB will not be excluded), or congestive heart failure (CHF) of NYHA class ≥3, or myocardial infarction (MI) within 3 months A history of allergic reactions attributed to compounds of similar chemical or biologic composition to KPT-330 or other agents used in the study. Uncontrolled infection requiring parenteral antibiotics, antivirals, or antifungals within one week prior to first dose. Infections controlled on concurrent anti-microbial agents are acceptable, and anti-microbial prophylaxis per institutional guidelines is acceptable. Any medical condition which, in the investigator's opinion, could compromise the patient's safety. Pregnant and/or breastfeeding. Patient must have a negative urine pregnancy test within 5 days of study entry. Unable to swallow tablets, or diagnosed malabsorption syndrome, or any other disease significantly affecting gastrointestinal function. Known active hepatitis B virus (HBV) or C virus (HCV) infection; or known to be positive for HCV ribonucleic acid (RNA) or HBsAg (HBV surface antigen). Known human immunodeficiency virus (HIV) infection. Serious psychiatric or medical conditions that could interfere with treatment.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase I Schedule A (selinexor)<br>Selinexor will be dosed on Days 1, 5, 10, and 12 of the 28-day cycle. All doses will be 60 mg each PO. Single agent selinexor maintenance may be given at 60 mg on Days 1, 8, 15, and 22 (4 doses per 28 day cycle). Cladribine will be given 5 mg/m^2/day IV once daily on Days 4-8. G-CSF will be given 300 mcg SC once daily on Days 3-8. Cytarabine will be given 2000 mg/m^2/day IV once daily on Days 4-8. Bone marrow biopsy will be performed at baseline, Day 3, at time of hematopoietic recovery, and as clinically indicated to assess treatment response. | Drug: Selinexor<br> <br> * Other names: KPT-330;Drug: Cladribine<br> <br> * Other names: Chlorodeoxyadenosine;Drug: G-CSF<br> <br> * Other names: Mozobil®;Drug: Cytarabine<br> <br> * Other names: Ara-C;Procedure: Bone marrow biopsy<br> <br> * Other names: Bone marrow aspirate;|
| Experimental: Phase I Schedule B (selinexor)<br>Selinexor will be dosed on Days 1, 5, 10, 12, 17, and 19 of the 28-day cycle. All doses will be 60 mg each PO. Single agent selinexor maintenance may be given at 60 mg on Days 1, 8, 15, and 22 (4 doses per 28 day cycle). Cladribine will be given 5 mg/m^2/day IV once daily on Days 4-8. G-CSF will be given 300 mcg SC once daily on Days 3-8. Cytarabine will be given 2000 mg/m^2/day IV once daily on Days 4-8. Bone marrow biopsy will be performed at baseline, Day 3, at time of hematopoietic recovery, and as clinically indicated to assess treatment response. | Drug: Selinexor<br> <br> * Other names: KPT-330;Drug: Cladribine<br> <br> * Other names: Chlorodeoxyadenosine;Drug: G-CSF<br> <br> * Other names: Mozobil®;Drug: Cytarabine<br> <br> * Other names: Ara-C;Procedure: Bone marrow biopsy<br> <br> * Other names: Bone marrow aspirate;|
| Experimental: Phase II (selinexor)<br>Selinexor will be given at the schedule as determined in Phase 1. Single agent selinexor maintenance may be given at 60 mg on Days 1, 8, 15, and 22 (4 doses per 28 day cycle). Cladribine will be given 5 mg/m^2/day IV once daily on Days 4-8. G-CSF will be given 300 mcg SC once daily on Days 3-8. Cytarabine will be given 2000 mg/m^2/day IV once daily on Days 4-8. Bone marrow biopsy will be performed at baseline, Day 3, at time of hematopoietic recovery, and as clinically indicated to assess treatment response. | Drug: Selinexor<br> <br> * Other names: KPT-330;Drug: Cladribine<br> <br> * Other names: Chlorodeoxyadenosine;Drug: G-CSF<br> <br> * Other names: Mozobil®;Drug: Cytarabine<br> <br> * Other names: Ara-C;Procedure: Bone marrow biopsy<br> <br> * Other names: Bone marrow aspirate;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability of Treatment as Measured by Incidence of Grade 3-4 Adverse Events Occurring in >5% of Participants | -All adverse events will be classified using the descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) v4.0 | From start of treatment until 30 days following last day of study treatment or until the start of a subsequent treatment for AML, whichever came first (41 days) | 
| Complete Remission Rate (CR + CRi) | Morphologic complete remission (CR): neutrophil count > 1.0 x 109 /L, platelet count ≥ 100 x 109/L, < 5% bone marrow blasts by morphologic review, no Auer rods, no evidence of extramedullary disease. (No requirements for marrow cellularity, hemoglobin concentration). Morphologic complete remission with incomplete blood count recovery (CRi): same as CR but ANC may be <1000/mcl or platelet count <100,000/mcl Participants in the phase I portion of the study, treated at the MTD will count towards the phase II accrual goal for evaluation of the primary endpoint. | Median follow-up of 34 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Platelet Engraftment | -Time to platelet engraftment: Defined as the date of the first dose of study drug to the date that the platelet count is >100,000/mm^3 in the absence of platelet transfusions. | 56 days | 
| Time to Neutrophil Engraftment | -Time to neutrophil engraftment: Defined as the date of the first dose of study drug to the date that the absolute neutrophil count is >1,000/mm3 | Up to 2 years | 
| Event-free Survival | Event-free survival (EFS): Defined as the interval from the date of first dose of study drug to date of treatment failure including progressive disease, recurrence, or discontinuation for any reason (including toxicity, patient preference, initiation of new treatment without documented progression, or death due to any cause). | Up to 2 years (median follow-up of 307 days) | 
| Duration of Remission | -Duration of remission (DOR): Defined as the interval from the date complete remission is documented to the date of recurrence. | Up to 2 years | 
| Relapse-free Survival | Relapse-free survival (RFS): For patients achieving a complete remission, defined as the interval from the date of first documentation of a leukemia free state to date of recurrence or death due to any cause. | Median follow-up of 307 days | 
| Overall Survival | Overall survival (OS): Defined as the date of first dose of study drug to the date of death from any cause. OS will be evaluated at 3 month intervals for at least 12 months and up to a maximum of 2 years. | Up to 2 years (median follow-up of 307 days) | 
| Number of Participants Who Were Able to Undergo Hematopoietic Stem Cell Transplantation | Allogeneic stem cell transplant utilization: the number of patients proceeding to allogeneic transplant within 2 months following end of study without any additional salvage therapy following study treatment. | Up to 2 years (median follow-up of 307 days) |