E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Relapsed/Refractory DLBCL |
|
E.1.1.1 | Medical condition in easily understood language |
Relapsed/Refractory DLBCL |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | HLT |
E.1.2 | Classification code | 10012819 |
E.1.2 | Term | Diffuse large B-cell lymphomas |
E.1.2 | System Organ Class | 100000004851 |
|
E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the efficacy of selinexor 60 mg in comparison to a minimally effective lower threshold level of overall response rate (ORR) of 15% in patients with relapsed/refractory DLBCL. |
|
E.2.2 | Secondary objectives of the trial |
• To determine duration of response (DOR)
• To determine the disease control rate (DCR)
• To assess the safety profile of selinexor |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
The study population under evaluation will consist of male and female
patients aged 18 years or older. To be included in this study, a patient
must meet all the following criteria:
1. Written informed consent in accordance with federal, local, and
institutional guidelines. The patient must provide informed consent
prior to the first screening procedure.
2. Age ≥18 years
3. Eastern Cooperative Oncology Group (ECOG) performance status of
≤2 (Appendix 2)
4. Patients should have estimated life expectancy of >3 months at
study entry
5. Previously treated, pathologically confirmed de novo DLBCL, or
DLBCL transformed from previously diagnosed indolent lymphoma
(e.g., follicular lymphoma)
6. Patients must have received at least 2 but no more than 5 previous
systemic regimens for the treatment of their de novo or transformed
DLBCL including (i) at least one course of anthracycline-based
chemotherapy (unless absolutely contraindicated due to cardiac
dysfunction, in which case other active agents such as etoposide,
bendamustine or gemcitabine must have been given) and (ii) at least
one course of anti-CD20 immunotherapy (e.g., rituximab), unless
contraindicated due to severe toxicity. Patients who were considered
ineligible for standard multi-agent immunochemotherapy must have
received at least two and no more than five prior treatment regimens
including at least one course of anti-CD20 antibodies and must be
approved by the Medical Monitor. Prior stem cell transplantation is
allowed; induction, consolidation, stem cell collection, preparative
regimen and transplantation ± maintenance are considered a single
line of therapy
7. For patients whose most recent systemic anti-DLBCL therapy
induced a PR or CR, at least 60 days must have elapsed since the end of
that therapy. For all other patients, at least 14 weeks (98 days) must
have elapsed since the end of their most recent systemic anti DLBCL
therapy. Palliative localized radiation within the therapy-free interval is
allowed. Non chemotherapy maintenance will not be considered anti
DLBCL therapy, and therefore is allowed during the therapy-free
interval.
8. Documented clinical or radiographic evidence of progressive DLBCL
prior to dosing.
9. Patients must have measurable disease per the revised criteria for
response assessment of lymphoma (Cheson
2014). Lymph nodes should be considered abnormal if the long axis is
>1.5 cm, regardless of the short axis. If a lymph node has a long axis
of
1.1 to 1.5 cm, it should only be considered abnormal if its short axis is
>1.0. Lymph nodes ≤ 1.0 by ≤ 1.0 will not be considered abnormal for
relapse or progressive disease.
10. Female patients of child-bearing potential must have a negative
serum pregnancy test at screening and agree to use reliable methods of
contraception for three months after their last dose of medication. Male
patients must use a reliable method of contraception if sexually active
with a female of child-bearing potential. For both male and female
patients, effective methods of contraception must be used throughout
the study and for three months following the last dose (see Section
13.5.2.1 Permitted Concomitant Medication – Prevention of Pregnancy
for description of acceptable contraceptive methods). |
|
E.4 | Principal exclusion criteria |
Patients meeting any of the following exclusion criteria are not eligible
to enroll in this study.
1. Patients who are pregnant or lactating
2. DLBCL with mucosa-associated lymphoid tissue [MALT] lymphoma,
composite lymphoma (HL+NHL), or DLBCL transformed from diseases other than indolent NHL.
3. Primary mediastinal (thymic) large B-cell lymphoma (PMBL)
4. Patients must not be eligible for high-dose chemotherapy with autologous stem cell transplantation rescue (investigator must provide detailed documentation for ineligibility)
5. Known central nervous system (CNS) lymphoma or meningeal involvement
6. For patients whose most recent systematic anti-DLBCL therapy
induced a PR or CR: Radiation, chemotherapy, immunotherapy, radioimmunotherapy or any other anticancer therapy other than glucocorticoids < 60 days prior to Cycle 1 Day 1.
7. For patients whose most recent systemic anti-DLBCL therapy did not
induce a PR or CR: Radiation, chemotherapy, immunotherapy, radioimmunotherapy, or any other anticancer therapy other than glucocorticoids < 14 weeks prior to Cycle 1 Day 1
8. Patients who have not recovered to Grade ≤ 1 clinically significant AEs, or to their baseline, from their most recent systemic anti DLBCL therapy
9. Patients with active graft-versus-host disease after allogeneic stem cell transplantation. At least 4 months must have elapsed since completion of allogeneic stem cell transplantation
10. Major surgery within 2 weeks of first dose of study treatment
11. Any life-threatening illness, medical condition or organ system dysfunction which, in the investigator's opinion, could compromise the patient's safety
12. Unstable cardiovascular function:
• Symptomatic ischemia, or
• Uncontrolled clinically significant conduction abnormalities (i.e.,
ventricular tachycardia on anti-arrhythmia are excluded; 1st degree AV
block or asymptomatic LAFB/RBBB will not be excluded), or
• Congestive heart failure (CHF) of NYHA Class ≥3, or
• Myocardial infarction (MI) within 3 months
13. Uncontrolled (i.e., clinically unstable) infection requiring parenteral antibiotics, antivirals, or antifungals within one week prior to first dose; however, prophylactic use of these agents is acceptable even if parenteral
14. Active Hepatitis B or Hepatitis C infection
15. Known human immunodeficiency virus (HIV) infection (HIV testing is not required as part of this study)
16. Patients unable to swallow tablets, patients with malabsorption syndrome, or any other GI disease or GI dysfunction that could interfere with absorption of study treatment
17. Any of the following laboratory abnormalities:
• Absolute neutrophil count (ANC) <1000 cells/mm3 or platelet count
<75,000/mm3 during screening and on C1D1. Use of granulocytestimulating
factors and platelet growth factors prior to and during the study is acceptable.
• A circulating lymphocyte count of >50,000/ul
• Hepatic dysfunction: bilirubin >2.0 times the upper limit of normal
(ULN) (except patients with Gilbert's syndrome: total bilirubin of > 3 x
ULN) and alanine aminotransferase (ALT) and aspartate
aminotransferase (AST) >2.5 times ULN. In patients with known liver
involvement of their DLBCL, AST and ALT >5 x ULN.
• Severe renal dysfunction: estimated creatinine clearance of < 30
mL/min, measured in 24 hour urine or calculated using the formula of
Cockroft and Gault [(140-Age) • Mass (kg)/(72 • creatinine mg/dL);
multiply by 0.85 if female]
• Hematopoietic dysfunction: hemoglobin < 10.0 g/dL within 14 days
of and including Cycle 1 Day 1 and/or patients receiving red blood cell
(RBC) transfusion within 14 days of and including Cycle 1 Day 1
18. Patients with a body surface area (BSA) < 1.4 m2 as calculated per
Dubois 1916 or Mosteller 1987
19. Psychiatric illness or substance use that would prevent the patient from giving informed consent or being compliant with the study procedures.
20. Persons who have been committed to an institution by official or judicial order
21. Patients with dependency on the sponsor, investigator or study site. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Objective disease response assessment will be made according to the
revised criteria for response assessment of lymphoma (Cheson, 2014).
The data used for primary statistical analysis will be provided by the
central imaging laboratory.
The primary endpoint of ORR will be assessed as the ORR of selinexor
60 mg compared to a minimally effective lower threshold level of ORR
of 15%.
● The ORR is defined as the proportion of patients who achieve either
CR or PR.
● Progression is defined as the first occurrence of PD per the revised
response criteria. Clinical disease progression in the absence of formal
criteria for PD should be radiographically confirmed whenever possible
and must be comprehensively documented by the treating physician.
Patients who have clinical disease progression in the absence of formal
cirteria for PD or radiographical confirmation will be censored at the
time of last non-PD adequate response assessment.
● DOR is defined as the duration of time from first occurrence of CR or
PR until the first date that disease progression is objectively
documented
●DCR is defined as the proportion of patients who achieve CR, PR, or
SD for a minimum of 4 weeks, following randomization/enrollment
(i.e., ORR + SD)
● PFS is defined as the duration of time from
randomization/enrollment until progression or death due to any cause.
A sensitivity analysis will also be performed for PFS where death will
be included if it may be reasonably attributed to the patient's
underlying DLBCL.
●Each patient's TTP on selinexor compared with the TTP of his/her
most recent prior therapy. TTP is defined as the duration of time from
the date of randomization/enrollment until the date of progression. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Disease response will be assessed by the revised criteria for response assessment of lymphoma (Cheson, 2014; Appendix 1) in patients on Cycle 3 Day 1 (+/−1 week) and then every 8 weeks +/− 1 week (i.e., Day 1 of odd numbered cycles) until disease progression is confirmed by the central imaging laboratory. There is no maximum treatment duration. |
|
E.5.2 | Secondary end point(s) |
Secondary Efficacy Endpoints
• DOR, defined as the duration of time from first occurrence of CR or PR until the first date that recurrence of disease progression is objectively documented, for each dose level
• Safety endpoints include AE reports, ECOG performance status, vital signs, physical examinations, ECGs, ophthalmic examinations, concomitant medications and laboratory safety evaluations.
• DCR, defined as the proportion of patients who achieve CR, PR, or SD for a minimum of 4 weeks following start of therapy, compared for High-Sel and Low-Sel regimens
|
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 52 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Austria |
Belgium |
Bulgaria |
Canada |
France |
Germany |
Hungary |
Israel |
Italy |
Netherlands |
Poland |
Serbia |
Spain |
United Kingdom |
United States |
|
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 10 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 10 |
E.8.9.2 | In all countries concerned by the trial days | 0 |