Clinical trial NCT04607772: Study of Selinexor in Combination With Backbone Treatments or Novel Therapies In Participants With Relapsed or Refractory (RR) Diffuse Large B-Cell Lymphoma (DLBCL)
Official title: A Multicenter, Phase 1/2 Study of Selinexor in Combination With Backbone Treatments or Novel Therapies in Patients With Relapsed or Refractory (RR) Diffuse Large B-Cell Lymphoma (DLBCL)
Study type: INTERVENTIONAL
Overall status: SUSPENDED
Phase: PHASE1
PHASE2
Conditions: Relapsed or Refractory Diffuse Large B-Cell Lymphoma
Keywords: Karyopharm
Diffuse Large B-Cell Lymphoma
DLBCL
KPT-330
Selinexor
Bendamustine
Rituximab
Polatuzumab Vedotin
Gemcitabine
Oxaliplatin
Ibrutinib
Lenalidomide
Tafasitamab
Venetoclax
Lead sponsor: Karyopharm Therapeutics Inc
Sponsor class: INDUSTRY
First posted: 2020-10-29
Enrollment: 350
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: This is a Phase 1/2, multicenter, open-label study to evaluate the efficacy, and safety of various combinations with selinexor in participants with RR DLBCL. The study will be conducted in two phases: Phase 1 and 2. The Phase 1 of the study will be a standard 3 + 3 dose escalation to determine the maximal tolerated dose (MTD), recommended Phase 2 dose (RP2D) for each treatment arm, and assess the dose limiting toxicities (DLTs). The Phase 2 of the study will be a dose expansion study to assess the efficacy and safety of for RP2D selected at the end of Phase 1 of the study for each treatment arm.


Eligibility criteria: Inclusion Criteria:

1. Participants greater than or equal to (≥) 18 years of age.
2. Have pathologically confirmed relapsed/refractory (RR) DLBCL, not otherwise specified (NOS).
3. Participants with High Grade B-cell Lymphoma (HGBL) are allowed in Phase 2 only.
4. Prior lines of systemic therapy for the treatment of DLBCL:

   * For Arms A, B, C, E, F, G, H: Participants must have received at least 1 but no more than 3 prior lines of systemic therapy for the treatment of DLBCL.
   * For Arm D (S-R-GemOx) participants must have received at least 1 but not more than 2 lines of systemic therapy.
5. Positron emission tomography (PET) positive measurable disease per the Lugano Classification 2014, having at least 1 node with longest diameter (LDi) greater than (\>) 1.5 centimetres (cm) or 1 extranodal lesion with LDi \>1 cm.
6. Adequate bone marrow function at Screening.
7. Circulating lymphocytes less than or equal to (≤) 50 \* 109/L.
8. Adequate liver and kidney function.
9. Eastern Cooperative Oncology Group (ECOG) performance status of ≤2.
10. An estimated life expectancy of \>6 months at Screening.
11. Participants with primary refractory disease defined as no response or relapse within 6 months after ending first-line treatment will be allowed on study (up to 20 percentage \[%\] of enrolled participants in each Phase).
12. Male participants, and female participants of childbearing potential must agree to use highly effective methods of contraception during the duration of the study and will continue following the last dose of study treatment for the longest duration stated on the label of each of the given drugs (depending on each arm).
13. Female participants of childbearing potential must have a negative serum pregnancy test at Screening. Female participants of childbearing potential in the S-LR arm and the S-LT arm must have 2 negative pregnancy tests before Lenalidomide treatment (Non-Childbearing potential: Age \>50 years and naturally amenorrhoeic for \>1 year, or previous bilateral salpingo-oophorectomy, or hysterectomy).
14. Participants with active hepatitis B Virus (HBV) are eligible if antiviral therapy for hepatitis B has been given for \>8 weeks and viral load is \<100 international units per milliliter (IU/mL); participants with untreated hepatitis C Virus (HCV) are eligible if viral load is negative per institutional standard; participants with human immunodeficiency virus (HIV) are eligible if cluster of differentiation 4 (CD4+) T-cell counts ≥350 cells per microliter (cells/μL), viral load is negative and no history of acquired immunodeficiency syndrome (AIDS)-defining opportunistic infections in the last year.

Exclusion Criteria:

1. DLBCL with mucosa-associated lymphoid tissue (MALT) lymphoma; composite lymphoma (Hodgkin lymphoma + NHL); Gray zone lymphoma; DLBCL transformed from Chronic Lymphocytic Leukemia (Richter Syndrome); Primary mediastinal large B-cell lymphoma (PMBCL); T-cell rich large B-cell lymphoma.
2. Previous treatment with selinexor or other XPO1 inhibitors.
3. Contraindication to any drug contained in the different treatment arms.
4. Use of any standard or experimental anti-DLBCL therapy (including nonpalliative radiation, chemotherapy, immunotherapy, radio-immunotherapy, or any other anticancer therapy) \<21 days prior to Cycle 1 Day 1 (C1D1). Low dose steroids \<30 mg prednisone (or equivalent) and palliative radiotherapy are permitted.
5. Received strong cytochrome P450 3A (CYP3A) inhibitors ≤7 days prior to Day 1 dosing or strong CYP3A inducers ≤14 days prior to Day 1 dosing.
6. Any AE, by Cycle 1 Day 1 (C1D1), which has not recovered to Grade ≤1 (CTCAE, v. 5.0), or returned to baseline, related to the previous DLBCL therapy, except alopecia.
7. Major surgery \<14 days of C1D1.
8. Autologous stem cell transplant (SCT) \<100 days or allogeneic SCT \<180 days prior to C1D1 or active graft-versus-host disease after allogeneic SCT (or cannot discontinue graft versus host disease \[GVHD\] treatment or prophylaxis).
9. Prior chimeric antigen receptor T cell (CAR-T cell) infusion at any time (Phase 1 only); prior CAR-T cell infusion ≤120 days prior to C1D1 (Phase 2 only).
10. Any life-threatening illness, medical condition, or organ system dysfunction which, in the Investigator's opinion, could compromise the participant's safety, or able to comply with the study procedures.
11. Uncontrolled (i.e., clinically unstable) infection requiring parenteral antibiotics, antivirals, or antifungals within 7 days prior to first dose of study treatment; however, prophylactic use of these agents is acceptable (including parenteral).
12. Inability to swallow tablets, malabsorption syndrome, or any other GI disease or dysfunction that could interfere with absorption of study treatment.
13. Breastfeeding women or pregnant women.
14. Inability or unwillingness to sign informed consent form.
15. In the opinion of the Investigator, participants who are below their ideal body weight and would be unduly impacted by changes in their weight.
16. Known allergy to any of the drug planned to be given.

    The following are Arm Specific exclusion criteria:
17. Arm B (S-PR): Serum total bilirubin \>1.5 \* ULN, Neuropathy Grade ≥2 (CTCAE, v5.0).
18. Arm C (S-PBR): Serum total bilirubin \>1.5 \* ULN, Neuropathy Grade ≥2 (CTCAE, v5.0).
19. Arm D (S-R-GemOx): Neuropathy Grade 2≥ (CTCAE, v5.0) interstitial lung disease or pulmonary fibrosis.

Primary outcomes:
measure: Phase 1: Maximum Tolerated Dose (MTD)
timeFrame: Within the first cycle (maximum 28 days) of treatment
measure: Phase 1: Recommended Phase 2 Dose (RP2D)
timeFrame: Up to 6 cycles (up to 6 months) of treatment
measure: Phase 2: Overall Response Rate (ORR) per the Lugano Classification 2014
timeFrame: Cycle 1 Day 1 (each cycle consists of maximum 28 days) until a complete response (CR) or partial response (PR) (up to 6 months)
Secondary outcomes:
measure: Phase 1: Overall Response Rate per the Lugano Classification 2014
timeFrame: Cycle 1 Day 1 (each cycle consists of maximum 28 days) until a complete response (CR) or partial response (PR) (up to 6 months)
measure: Phase 1: Disease Control Rate (DCR) per Lugano Classification 2014
timeFrame: Cycle 1 Day 1 (each cycle consists of maximum 28 days) until a CR or PR or stable disease (SD) (up to 6 months)
measure: Phase 1: Duration of Response (DOR) per Lugano Classification 2014
timeFrame: Time from the first response of PR or CR until disease progression (up to 12 months)
measure: Phase 1: Overall Response Rate (ORR) per the Modified Lugano Classification
timeFrame: Cycle 1 Day 1 (each cycle consists of maximum 28 days) until a CR or PR (up to 6 months)
measure: Phase 1: Number of Participants With Adverse Events (AEs) by Occurrence, Nature, and Severity
timeFrame: From start of study drug administration up to 30 days after last dose of study treatment (up to 24 months)
measure: Phase 2: Overall Response Rate per the Modified Lugano Classification
timeFrame: Cycle 1 Day 1 (each cycle consists of maximum 28 days) until a complete response (CR) or partial response (PR) (up to 6 months)
measure: Phase 2: Disease Control Rate (DCR) per Lugano Classification 2014
timeFrame: Cycle 1 Day 1 (each cycle consists of maximum 28 days) until a CR or PR or stable disease (SD) (up to 6 months)
measure: Phase 2: Duration of Response (DOR) per Lugano Classification 2014
timeFrame: Time from the first response of PR or CR until disease progression or death (up to 12 months)
measure: Phase 2: Number of Participants With AEs by Occurrence, Nature, and Severity
timeFrame: From start of study drug administration up to 30 days after last dose of study treatment (up to 24 months)
Other outcomes:
Locations:
city: Tucson
country: United States
facility: University of Arizona
state: Arizona
city: Encinitas
country: United States
facility: California Cancer Associates for Research and Excellence
state: California
city: La Jolla
country: United States
facility: UC San Diego Moores Cancer Center
state: California
city: Orange
country: United States
facility: University of California Irvine
state: California
city: Aurora
country: United States
facility: US Oncology - Rocky Mountain Cancer Center
state: Colorado
city: Maywood
country: United States
facility: Loyola University Medical Center
state: Illinois
city: Des Moines
country: United States
facility: Mission Cancer + Blood
state: Iowa
city: Ann Arbor
country: United States
facility: University of Michigan Health System
state: Michigan
city: Detroit
country: United States
facility: Karmanos Cancer Institute
state: Michigan
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: Buffalo
country: United States
facility: Roswell Park Comprehensive Cancer Center
state: New York
city: Eugene
country: United States
facility: US Oncology - Oncology Associates of Oregon
state: Oregon
city: Pittsburgh
country: United States
facility: UPMC Hillman Cancer Center
state: Pennsylvania
city: Greenville
country: United States
facility: US Oncology - Prisma Health
state: South Carolina
city: Austin
country: United States
facility: US Oncology - Texas Oncology Austin Midtown
state: Texas
city: Dallas
country: United States
facility: University of Texas Southwestern
state: Texas
city: Houston
country: United States
facility: Baylor Clinic - Mcnair Center
state: Texas
city: Vancouver
country: United States
facility: US Oncology - Northwest Cancer Specialists
state: Washington
Study officials:
References: