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

NCT02416908 | Completed Phase 1 Results DMC FDA Drug

• 1 other identifier: 201505084
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Acute Myeloid Leukemia

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (7)

• Time to Platelet Engraftment

  56 days

• Time to Neutrophil Engraftment

  Up to 2 years

• Event-free Survival

  Up to 2 years (median follow-up of 307 days)

• Duration of Remission

  Up to 2 years

• Relapse-free Survival

  Median follow-up of 307 days

Study Arms (3)

Phase I Schedule A (selinexor)

EXPERIMENTAL

* 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; Drug: Cladribine; Drug: G-CSF; Drug: Cytarabine; Procedure: Bone marrow biopsy

Phase I Schedule B (selinexor)

EXPERIMENTAL

* 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; Drug: Cladribine; Drug: G-CSF; Drug: Cytarabine; Procedure: Bone marrow biopsy

Phase II (selinexor)

EXPERIMENTAL

* 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; Drug: Cladribine; Drug: G-CSF; Drug: Cytarabine; Procedure: Bone marrow biopsy

Interventions

Selinexor DRUG

Also known as: KPT-330

Phase I Schedule A (selinexor); Phase I Schedule B (selinexor); Phase II (selinexor)

Cladribine DRUG

Also known as: Leustatin®, 2-CdA, 2-Chloro-2'-deoxyadenosine, CdA, Chlorodeoxyadenosine

Phase I Schedule A (selinexor); Phase I Schedule B (selinexor); Phase II (selinexor)

G-CSF DRUG

Also known as: Plerixafor, Mozobil®

Phase I Schedule A (selinexor); Phase I Schedule B (selinexor); Phase II (selinexor)

Cytarabine DRUG

Also known as: Cytosar-U ®, 1-β-Arabinofuranosylcytosine, Cytosine arabinoside, Ara-C

Phase I Schedule A (selinexor); Phase I Schedule B (selinexor); Phase II (selinexor)

Bone marrow biopsy PROCEDURE

Also known as: Bone marrow aspirate

Phase I Schedule A (selinexor); Phase I Schedule B (selinexor); Phase II (selinexor)

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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).

You may not qualify if:

• 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.

Sponsors & Collaborators

• Washington University School of Medicine: lead
• Karyopharm Therapeutics Inc: collaborator

Study Sites (1)

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

Related Links

• Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

MeSH Terms

Conditions

Leukemia, Myeloid, Acute

Interventions

selinexor; Cladribine; Granulocyte Colony-Stimulating Factor; plerixafor; Cytarabine

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

2-Chloroadenosine; Adenosine; Purine Nucleosides; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Deoxyadenosines; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides; Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Arabinonucleosides

Results Point of Contact

• Title: Geoffrey Uy, M.D.
• Organization: Washington University School of Medicine

guy@wustl.edu

314-747-8439

Study Officials

• Geoffrey Uy, M.D.

  Washington University School of Medicine

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 30, 2015
• First Posted: April 15, 2015
• Study Start: June 16, 2015
• Primary Completion: June 21, 2019
• Study Completion: June 21, 2019
• Last Updated: March 13, 2020
• Results First Posted: March 13, 2020

Record last verified: 2020-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)