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About
This phase I trial studies the side effects and best dose of selinexor when given together with ibrutinib in treating patients with chronic lymphocytic leukemia or aggressive non-Hodgkin lymphoma that has returned after a period of improvement or does not respond to treatment. Drugs used in chemotherapy, such as selinexor, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving selinexor together with ibrutinib may be a better treatment for chronic lymphocytic leukemia or aggressive non-Hodgkin lymphoma.
Full description
PRIMARY OBJECTIVES:
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).
SECONDARY OBJECTIVES:
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.
Enrollment
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Inclusion criteria
Exclusion criteria
Patients who are concurrently receiving any other investigational agents
Patients who have received:
Patients who have underwent autologous or allogeneic stem cell transplant =< 4 weeks prior to cycle 1 day 1 or have active graft-versus-host disease are excluded
Patients unable to swallow capsules, those with uncontrolled vomiting or diarrhea or disease significantly affecting gastrointestinal function and/or inhibiting small intestine absorption such as: malabsorption syndrome, resection of the small bowel, or poorly controlled inflammatory bowel disease affecting the small intestine
Patients who are 20% below their ideal body weight
Patients must not be receiving systemic anticoagulation with warfarin; patients must be off warfarin for 30 days prior to enrollment; patients who require anticoagulation with an agent other than warfarin will not be excluded, but must be reviewed by the principal investigator prior to enrollment
As ibrutinib is extensively metabolized by cytochrome P450, family 3, subfamily A, polypeptide 4/5 (CYP3A4/5), and patients must not require continued therapy with a strong inhibitor or inducer of CYP3A4/5
Patients with active human immunodeficiency virus (HIV) or hepatitis B or C
Patients with secondary malignancy that requires active systemic therapy that will interfere with interpretation of efficacy or toxicity of selinexor; (Note: patients with basal or squamous skin carcinoma, cervical carcinoma in situ, localized breast cancer requiring hormonal therapy or localized prostate cancer (Gleason score < 5 are allowed)
Patients with active known central nervous system (CNS) involvement of CLL or lymphoma; (patients with history of CNS CLL or lymphoma now in remission are eligible for the trial)
Patients who are pregnant or breast feeding; breastfeeding should be discontinued if the mother is treated with selinexor
Patients must have recovered all toxicities from prior therapy or radiation to grade 1 or less (excluding alopecia)
Patients may not have had major surgery within 10 days of enrollment, or minor surgery within 7 days of enrollment; examples of minor surgery include dental surgery, insertion of a venous access device, skin biopsy, or aspiration of a joint; the decision about whether a surgery is major or minor can be made at the discretion of the treating physician
Patients with uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
Patients with markedly decreased visual acuity
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34 participants in 1 patient group
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Data sourced from clinicaltrials.gov
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