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

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ClinicalTrials.gov Identifier: NCT04640779
Recruitment Status : Recruiting
First Posted : November 23, 2020
Last Update Posted : February 11, 2021
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Mayo Clinic

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
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 Drug: Choline Salicylate Drug: Selinexor Phase 1

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 39 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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)
Actual Study Start Date : February 8, 2021
Estimated Primary Completion Date : December 15, 2023
Estimated Study Completion Date : December 15, 2024


Arm Intervention/treatment
Experimental: Treatment (selinexor, choline salicylate)
Patients 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.
Drug: Choline Salicylate
Given PO

Drug: Selinexor
Given PO
Other Names:
  • ATG-010
  • CRM1 Nuclear Export Inhibitor KPT-330
  • KPT-330
  • Selective Inhibitor of Nuclear Export KPT-330
  • SINE KPT-330
  • Xpovio




Primary Outcome Measures :
  1. 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 ]
    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 :
  1. Incidence of adverse events [ Time Frame: At the end of each cycle (each cycle is 28 days) up to 12 cycles ]
    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.

  2. Overall response rate [ Time Frame: At the end of each cycle (each cycle is 28 days) up to 12 cycles ]
    Response will be evaluated using all cycles of treatment. Exact binomial 95% confidence intervals for the true response rate will be calculated.

  3. Clinical benefit rate [ Time Frame: At the end of each cycle (each cycle is 28 days) up to 12 cycles ]
    Response will be evaluated using all cycles of treatment. Exact binomial 95% confidence intervals for the true response rate will be calculated.

  4. Duration of response [ Time Frame: At the end of each cycle (each cycle is 28 days) up to 12 cycles ]
    The distribution of duration of response will be estimated using the method of Kaplan-Meier.


Other Outcome Measures:
  1. CRM1 expression [ Time Frame: At the end of each cycle (each cycle is 28 days) up to 12 cycles ]
    Will determine if the CRM1 expression grade, assessed via immunohistochemistry and reported as grade 1 (low), grade 2 (moderate) and grade 3 (high), in malignant cells correlates with overall response rate after treatment with selinexor.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

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): NCT04640779


Locations
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United States, Minnesota
Mayo Clinic in Rochester Recruiting
Rochester, Minnesota, United States, 55905
Contact: Clinical Trials Referral Office    855-776-0015    mayocliniccancerstudies@mayo.edu   
Principal Investigator: Jonas Paludo, M.D.         
Sponsors and Collaborators
Mayo Clinic
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Jonas Paludo Mayo Clinic in Rochester
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Responsible Party: Mayo Clinic
ClinicalTrials.gov Identifier: NCT04640779    
Other Study ID Numbers: LS1981
NCI-2020-09704 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
LS1981 ( Other Identifier: Mayo Clinic in Rochester )
P30CA015083 ( U.S. NIH Grant/Contract )
P50CA15083 ( Other Grant/Funding Number: Mayo Clinic in Rochester )
First Posted: November 23, 2020    Key Record Dates
Last Update Posted: February 11, 2021
Last Verified: February 2021

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Lymphoma
Lymphoma, Non-Hodgkin
Lymphoma, B-Cell
Lymphoma, Mantle-Cell
Lymphoma, Large B-Cell, Diffuse
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Salicylates
Choline
Lipotropic Agents
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Gastrointestinal Agents
Lipid Regulating Agents
Nootropic Agents
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Inflammatory Agents
Antirheumatic Agents
Cyclooxygenase Inhibitors
Enzyme Inhibitors