Clinical Trials /

Low-Dose Selinexor and Choline Salicylate for the Treatment of Patients With Residual, Relapsed or Refractory Non-Hodgkin Lymphoma

NCT04640779

Description:

This phase Ib trial evaluates the side effects and best dose of choline salicylate given together with a low dose of selinexor in treating patients with diffuse large B cell lymphoma or mantle cell lymphoma that has cancer cells remaining after attempts to remove the cancer have been made (residual), has come back (relapsed) or does not respond to treatment (refractory). Anti-inflammatory drugs, such as choline salicylate lower the body's immune response and are used with other drugs in the treatment of some types of cancer. Selinexor may stop the growth of cancer cells by blocking a protein called CRM1 that is needed for cell growth. help doctors learn more about selinexor and choline salicylate as a treatment for lymphoma. This trial may help doctors learn more about selinexor and choline salicylate as a treatment for lymphoma.

Related Conditions:
  • Diffuse Large B-Cell Lymphoma
  • Mantle Cell Lymphoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Low-Dose Selinexor and Choline Salicylate for the Treatment of Patients With Residual, Relapsed or Refractory Non-Hodgkin Lymphoma
  • Official Title: Phase Ib Trial of Low-Dose Selinexor (KPT-330) in Combination With Choline Salicylate (CS) for the Treatment of Patients With Residual/Relapsed/Refractory Non-Hodgkin Lymphoma (NHL)

Clinical Trial IDs

  • ORG STUDY ID: LS1981
  • SECONDARY ID: NCI-2020-09704
  • SECONDARY ID: LS1981
  • SECONDARY ID: P30CA015083
  • SECONDARY ID: P50CA15083
  • NCT ID: NCT04640779

Conditions

  • Recurrent Diffuse Large B-Cell Lymphoma
  • Recurrent Mantle Cell Lymphoma
  • Recurrent Non-Hodgkin Lymphoma
  • Refractory Diffuse Large B-Cell Lymphoma
  • Refractory Mantle Cell Lymphoma
  • Refractory Non-Hodgkin Lymphoma

Interventions

DrugSynonymsArms
Choline SalicylateTreatment (selinexor, choline salicylate)
SelinexorATG-010, CRM1 Nuclear Export Inhibitor KPT-330, KPT-330, Selective Inhibitor of Nuclear Export KPT-330, SINE KPT-330, XpovioTreatment (selinexor, choline salicylate)

Purpose

This phase Ib trial evaluates the side effects and best dose of choline salicylate given together with a low dose of selinexor in treating patients with diffuse large B cell lymphoma or mantle cell lymphoma that has cancer cells remaining after attempts to remove the cancer have been made (residual), has come back (relapsed) or does not respond to treatment (refractory). Anti-inflammatory drugs, such as choline salicylate lower the body's immune response and are used with other drugs in the treatment of some types of cancer. Selinexor may stop the growth of cancer cells by blocking a protein called CRM1 that is needed for cell growth. help doctors learn more about selinexor and choline salicylate as a treatment for lymphoma. This trial may help doctors learn more about selinexor and choline salicylate as a treatment for lymphoma.

Detailed Description

      PRIMARY OBJECTIVE:

      I. To evaluate the maximum tolerated dose (MTD) of choline salicylate (CS) that can be
      combined with selinexor twice weekly in patients with relapsed/refractory diffuse large B
      cell lymphoma (DLBCL) or mantle cell lymphoma (MCL).

      SECONDARY OBJECTIVE:

      I. To evaluate the response (overall response rate [ORR], clinical benefit rate [CBR] and
      duration of response [DOR]) of selinexor and CS in patients with relapsed/refractory DLBCL or
      MCL.

      CORRELATIVE RESEARCH OBJECTIVE:

      I. To determine if CRM1 expression in malignant lymphoma cells from patients treated on this
      study have a predictive role.

      OUTLINE: This is a dose-escalation study.

      Patients receive selinexor orally (PO) twice a week (BIW) on days 1, 3, 8, 10, 15, 17, 22,
      and 24, and choline salicylate PO three times daily (TID) on days 1-28. Patients undergoing
      pharmacokinetic analysis receive choline salicylate beginning on day 3 of cycle 1 (D3C1) and
      beginning on day 1 of subsequent cycles. Treatment repeats every 28 days for up to 6 cycles
      in the absence of disease progression or unacceptable toxicity. Patents who achieve >= stable
      disease continue treatment for an additional 6 cycles (maximum of 12 cycles) at the
      discretion of the treating physician and patient.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (selinexor, choline salicylate)ExperimentalPatients receive selinexor PO BIW on days 1, 3, 8, 10, 15, 17, 22, and 24, and choline salicylate PO TID on days 1-28. Patients undergoing pharmacokinetic analysis receive choline salicylate beginning on D3C1 and beginning on day 1 of subsequent cycles. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patents who achieve >= stable disease continue treatment for an additional 6 cycles (maximum of 12 cycles) at the discretion of the treating physician and patient.
  • Choline Salicylate
  • Selinexor

Eligibility Criteria

        Inclusion Criteria:

          -  Biopsy-proven relapsed and/or refractory DLBCL or MCL. Relapsed is defined as a
             relapse that occurred after having a response to the last therapy that lasted > 26
             weeks. Refractory is no response (stable disease or progressive disease while on
             therapy) or relapse within 6 months. Previous biopsies < 26 weeks prior to
             registration will be acceptable. Refractoriness to autologous stem cell transplant
             will be defined as disease progression within 52 weeks following transplant.

          -  Measurable or assessable disease: Measurable disease is defined as measurable by
             computed tomography (CT) (dedicated CT or the CT portion of a positron emission
             tomography [PET]/CT) or magnetic resonance imaging [MRI]: To be considered measurable,
             there must be at least one lesion that has a single diameter of >= 1.5 cm. NOTE: Skin
             lesions can be used if the area is >= 1.5cm in at least one diameter and photographed
             with a ruler. Patients with assessable disease by PET/CT are also eligible as long as
             the assessable disease is biopsy proven lymphoma

          -  Patients must have previously been treated with at least 2 lines of therapy

          -  Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 1, or 2

          -  Absolute neutrophil count (ANC) >= 1,000/mm^3 (obtained =< 21 days prior to
             registration)

          -  Platelet count >= 100,000/mm^3 (obtained =< 21 days prior to registration)

          -  Hemoglobin >= 8.5 g/dL (may be transfused to reach criteria) (obtained =< 21 days
             prior to registration)

          -  Total bilirubin < 2 x upper limit of normal (ULN) (or total bilirubin =< 3.0 x ULN
             with direct bilirubin =< 1.5 x ULN in patients with well-documented Gilbert's
             Syndrome) (obtained =< 21 days prior to registration)

          -  Aspartate transaminase (AST) =< 2.5 x ULN and alanine aminotransferase (ALT) =< 2.5 x
             ULN (obtained =< 21 days prior to registration)

          -  Calculated creatinine clearance must be >= 35 ml/min using the Cockcroft Gault formula
             (obtained =< 21 days prior to registration)

          -  Negative pregnancy test done =< 7 days prior to registration, for women of
             childbearing potential only

          -  Female of childbearing potential (FCBP*) must commit to take highly effective
             contraceptive precautions** without interruption during the study and continue for at
             least 12 weeks after the last dose of selinexor and CS. FCBP must refrain from
             breastfeeding and donating oocytes during the course of the study. Males must use an
             effective barrier method of contraception without interruption during the study and
             continue for at least 12 weeks after the last dose of selinexor and CS. They must
             refrain from donating sperm during the study participation.

               -  *FCBP defined as sexually mature women who have not undergone bilateral tubal
                  ligation, bilateral oophorectomy, or hysterectomy; or who have not been
                  postmenopausal (i.e., who have not menstruated at all) for at least 1 year

                    -  Highly effective forms of birth control are methods that achieve a failure
                       rate of less than 1% per year when used consistently and correctly. Highly
                       effective forms of birth control include: hormonal contraceptives (oral,
                       injectable, patch, and intrauterine devices), male partner sterilization, or
                       total abstinence from heterosexual intercourse, when this is the preferred
                       and usual lifestyle of the patient NOTE: The double-barrier method (e.g.,
                       synthetic condoms, diaphragm, or cervical cap with spermicidal foam, cream,
                       or gel), periodic abstinence (such as calendar, symptothermal,
                       post-ovulation), withdrawal (coitus interruptus), lactational amenorrhea
                       method, and spermicide-only are not acceptable as highly effective methods
                       of contraception

          -  Provide written informed consent

          -  Willing to return to enrolling institution for follow-up (during the Active Monitoring
             Phase of the study)

          -  Willingness to provide mandatory blood specimens per protocol for Pharmacokinetics
             (PKs) and banking, and mandatory tissue samples for correlative research. NOTE: If an
             institution is not able to provide the tissue, it does not cause the patient to be
             ineligible; however, the collection of these tissues is strongly recommended

        Exclusion Criteria:

          -  Any of the following because this study involves an investigational agent whose
             genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are
             unknown:

               -  Pregnant women

               -  Nursing women

          -  Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment
             of the investigator, would make the patient inappropriate for entry into this study or
             interfere significantly with the proper assessment of safety and toxicity of the
             prescribed regimens

          -  Patients known to have active hepatitis B, or C infection, or known to be positive for
             hepatitis C virus (HCV) ribonucleic acid (RNA) or hepatitis B surface antigen (HBsAg)
             (hepatitis B virus [HBV] surface antigen). Patients known to be human immunodeficiency
             virus (HIV) positive, except those with CD4+ T-cell (CD4+) counts >= 350 cells/uL and
             on an established antiretroviral therapy (ART) for at least twelve weeks and have an
             HIV viral load less than 400 copies/mL prior to enrollment

          -  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

          -  Life expectancy of < 6 months

          -  Active gastrointestinal (GI) dysfunction interfering with the ability to swallow
             tablets, or any GI dysfunction that could interfere with absorption of study treatment

          -  Known intolerance to or contraindications for choline salicylate therapy. Patients
             with known allergy to acetylsalicylic acid (ASA) are not eligible

          -  Prior exposure to a selective inhibitors of nuclear export (SINE) compound, including
             selinexor

          -  Receiving any other investigational agent which would be considered as a treatment for
             the primary neoplasm

          -  Active second malignancy requiring treatment that would interfere with the assessment
             of the response of the lymphoma to this protocol therapy. Patients with treated
             malignancies on hormonal therapy (for example breast or prostate cancer) are eligible

          -  History of myocardial infarction =< 6 months, or congestive heart failure requiring
             use of ongoing maintenance therapy for life-threatening ventricular arrhythmias

          -  Radiation, chemotherapy, or immunotherapy or any other anticancer therapy =< 2 weeks
             prior to registration. NOTE: Exception: patients on ibrutinib or corticosteroids (any
             dose) may continue therapy up until the new regimen has started at investigator
             discretion. Corticosteroids can be tapered to lowest possible dose after start of
             treatment at investigator discretion

          -  Active graft versus (vs.) host disease (after allogeneic stem cell transplantation) at
             registration

          -  Major surgery (including bowel resection) =< 3 weeks prior to registration

          -  Must not be currently eligible or have declined high-dose therapy with autologous stem
             cell transplantation rescue or chimeric antigen receptor (CAR)-T cell therapy

          -  Primary mediastinal (thymic) large B-cell lymphoma (PMBL)

          -  Known active central nervous system (CNS) lymphoma. Patients with previous CNS
             involvement can enroll if the CNS component is inactive

          -  Patients who are on active anticoagulant therapy with direct oral anticoagulants
             (DOACs), aspirin or warfarin are not eligible due to potential bleeding. EXCEPTIONS:
             Patients who are on aspirin (81 mg) for primary prevention of cardiovascular disease
             can enroll, but the ASA needs to be held while on this protocol therapy
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose of the combination of low-dose selinexor with choline salicylate
Time Frame:At the end of each cycle (each cycle is 28 days) up to 12 cycles
Safety Issue:
Description:Defined as the dose level below the lowest dose that induces dose-limiting toxicity in at least one-third of patients (at least 2 of a maximum of 6 new patients).

Secondary Outcome Measures

Measure:Incidence of adverse events
Time Frame:At the end of each cycle (each cycle is 28 days) up to 12 cycles
Safety Issue:
Description:The maximum grade for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed to determine patterns (overall and by dose level). Additionally, the relationship of the adverse event(s) to the study treatment will be taken into consideration.
Measure:Overall response rate
Time Frame:At the end of each cycle (each cycle is 28 days) up to 12 cycles
Safety Issue:
Description:Response will be evaluated using all cycles of treatment. Exact binomial 95% confidence intervals for the true response rate will be calculated.
Measure:Clinical benefit rate
Time Frame:At the end of each cycle (each cycle is 28 days) up to 12 cycles
Safety Issue:
Description:Response will be evaluated using all cycles of treatment. Exact binomial 95% confidence intervals for the true response rate will be calculated.
Measure:Duration of response
Time Frame:At the end of each cycle (each cycle is 28 days) up to 12 cycles
Safety Issue:
Description:The distribution of duration of response will be estimated using the method of Kaplan-Meier.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Mayo Clinic

Last Updated

November 23, 2020