Selinexor and Ibrutinib in Treating Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia or Aggressive Non-Hodgkin Lymphoma
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|ClinicalTrials.gov Identifier: NCT02303392|
Recruitment Status : Suspended (pending amendment)
First Posted : November 27, 2014
Last Update Posted : June 4, 2020
|Condition or disease||Intervention/treatment||Phase|
|Prolymphocytic Leukemia Recurrent Adult Diffuse Large Cell Lymphoma Recurrent Mantle Cell Lymphoma Recurrent Small Lymphocytic Lymphoma Refractory Chronic Lymphocytic Leukemia||Drug: Selinexor Drug: Ibrutinib Other: Pharmacological Study Other: Laboratory Biomarker Analysis||Phase 1|
I. To determine the maximum tolerated dose for the combination of selinexor and ibrutinib in patients with relapsed or refractory chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia(SLL)/B-cell prolymphocytic leukemia (PLL) or aggressive non-Hodgkin lymphoma (NHL).
I. To characterize the safety and tolerability of the combination of selinexor and ibrutinib in patients with relapsed or refractory CLL/SLL/PLL or aggressive NHL.
II. To characterize the pharmacokinetic (PK) properties of the combination of selinexor and ibrutinib in patients with relapsed or refractory CLL/SLL/PLL or aggressive NHL.
III. To obtain preliminary evidence on efficacy of the combination of selinexor and ibrutinib in patients with relapsed or refractory CLL/SLL/PLL or aggressive NHL.
IV. To obtain preliminary evidence of response in CLL/SLL/PLL and diffuse large B-cell lymphoma (DLBCL) patients receiving the combination of selinexor and ibrutinib as related to CLL/SLL/PLL karyotype and immunoglobulin variable heavy chain (IgVH) mutational status and DLBCL subtype, respectively.
V. To evaluate the inhibition of the B-cell receptor signaling pathway in patients with relapsed or refractory CLL/SLL/PLL who receive the combination of selinexor and ibrutinib.
VI. To evaluate the change in localization of tumor suppressor and growth regulation proteins in patients with relapsed or refractory CLL/SLL/PLL following treatment with selinexor in general and as related to response.
VII. To preliminarily assess potential causes for primary and secondary resistance to selinexor and ibrutinib.
VIII. To measure intracellular levels of selinexor and metabolites in peripheral blood mononuclear cells and to identify how this relates to pharmacodynamics effects and clinical outcomes.
OUTLINE: This is a dose-escalation study of selinexor.
Patients receive ibrutinib orally (PO) on days 8-28 of course 1 and on days 1-28 on subsequent courses and selinexor PO twice daily (BID) weekly on day 1 or bi-weekly on days 1 and 3. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 4 weeks and then every 6 months thereafter.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||92 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Dose Escalation Study of Selinexor (KPT-330), a Selective Inhibitor of Nuclear Export, and Ibrutinib, a Bruton's Tyrosine Kinase Inhibitor, in Patients With Relapsed and Refractory Chronic Lymphocytic Leukemia or Aggressive Non-Hodgkin Lymphoma|
|Actual Study Start Date :||March 11, 2015|
|Estimated Primary Completion Date :||December 31, 2020|
|Estimated Study Completion Date :||December 31, 2020|
Experimental: Treatment (selinexor, ibrutinib)
Patients receive ibrutinib PO on days 8-28 of course 1 and on days 1-28 on subsequent courses and selinexor PO BID weekly on day 1 or bi-weekly on days 1 and 3. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Other: Pharmacological Study
Other Name: pharmacological studies
Other: Laboratory Biomarker Analysis
- Dose limiting toxicity assessed by Common Terminology Criteria for Adverse Events (CTCAE) version (v) 4 criteria [ Time Frame: Day 28 ]
- Incident of toxicity graded by CTCAE V4 [ Time Frame: Up to 4 years ]Toxicities will be tabulated by type and grade and displayed in summary form. In addition, the number of courses started/completed, number of patients requiring dose reductions, and the reason for going off treatment may be summarized to assess treatment tolerability.
- Clinical response defined as those with CR or PR measured by International Working Group Criteria for NHL patients and IWCLL 2008 guidelines for CLL patients [ Time Frame: Up to 4 years ]The degree of response will be summarized within each stratum and at each dose level.
- Overall response rate (ORR) [ Time Frame: Up to 4 years ]Calculated as the number of evaluable responders divided by the total number of evaluable patients. ORR will be presented for those patients treated at the maximum tolerated dose with an exact 90 % confidence interval.
- Progression free survival (PFS) [ Time Frame: Date of study enrollment to disease progression or death, whichever occurs first assessed up to 4 years ]Kaplan-Meier curves and lifetables of PFS will be generated for each stratum. The 1-year point estimates of PFS will be presented along with standard error.
- Overall Survival (OS) [ Time Frame: Date of study enrollment to death assessed up to 4 years ]Kaplan-Meier curves and lifetables of OS will be generated for each stratum. The 1-year point estimates of OS will be presented along with standard error.
- Response as related to CLL karyotype mutational status [ Time Frame: Up to 4 years ]
- Response as related to IgVH mutational status [ Time Frame: Up to 4 years ]
- Pharmacokinetic parameters [ Time Frame: Course 1 days 1 and 22 (within 10 min before swallowing capsules), at 30 minutes, 1, 2, 4, 8, and 24 hours ]Area under the curve, half-life of intervention ( t1/2), clearance, maximum concentration, time to peak concentration, steady state concentration, trough estimation, and estimate t1/2 of accumulation. Measured through blood sample collection and reported as continuous variable. Computed using non-compartmental and compartmental methods and summarized with descriptive statistics.
- Changes in markers of down modulation or inhibition of the B-cell receptor pathway [ Time Frame: Baseline to up to 4 years ]Markers of down modulation or inhibition of the B-cell receptor pathway including Bruton's tyrosine kinase (BTK) expression and phosphorylation of spleen tyrosine kinase (SYK), v-akt murine thymoma viral oncogene homolog 1 (AKT), and extracellular-signal-regulated kinase (ERK) will be assessed pretreatment and post-treatment where feasible, and reported as a continuous measure.
- Change in localization of tumor suppressor and oncogene proteins and messenger ribonucleic acids (mRNAs) [ Time Frame: Baseline to up to 4 years ]Change in localization of tumor suppressor and oncogene proteins and mRNAs, tumor protein 53 (P53), p73, B-cell lymphoma (Bcl)-2, myc proto-oncogene protein (c-myc), Bcl-6, nuclear factor-kappa B (NFκB)/I kappa B (IκB), forkhead box protein O3 alpha (FOXO3a) and FOXO1 will be measured through blood sample collection, analyzed by immunoblot, and reported as percentage of protein fragments observed in the nucleus at each time point. changes in expression will be explored graphically using boxplots and/or individual line plots, as well as analytically with repeated measures models.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02303392
|United States, Ohio|
|Arthur G. James Cancer Hospital and Solove Research Institute at Ohio State University Medical Center|
|Columbus, Ohio, United States, 43210|
|United States, Utah|
|Huntsman Cancer Institute|
|Salt Lake City, Utah, United States, 84112|
|Principal Investigator:||Jennifer Woyach, MD||Ohio State University Comprehensive Cancer Center|