Clinical Trials Register

Summary
EudraCT Number:	2014-001977-15
Sponsor's Protocol Code Number:	KCP-330-009
National Competent Authority:	Greece - EOF
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2018-02-09
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Greece - EOF

A.2

EudraCT number

2014-001977-15

A.3

Full title of the trial

A Phase 2b Open-label Study of Selinexor (KPT-330) in Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL)

Φάσης 2b, ανοιχτή μελέτη του selinexor (KPT-330) σε ασθενείς με υποτροπιάζον/ανθεκτικό διάχυτο λέμφωμα από μεγάλα Β κύτταρα (DLBCL).

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A Phase 2b Open-label Study of Selinexor (KPT-330) in Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL)

A.3.2

Name or abbreviated title of the trial where available

SADAL: Selinexor Against Diffuse Aggressive Lymphoma

SADAL: Selinexor έναντι διάχυτου επιθετικού λεμφώματος

A.4.1

Sponsor's protocol code number

KCP-330-009

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT02227251

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Karyopharm Therapeutics, Inc.
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Karyopharm Therapeutics, Inc.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Karyopharm Therapeutics, Inc.
B.5.2	Functional name of contact point	Clinical Trial Information Desk
B.5.3	Address:
B.5.3.1	Street Address	85 Wells Ave
B.5.3.2	Town/ city	Newton
B.5.3.3	Post code	MA 02459
B.5.3.4	Country	United States
B.5.6	E-mail	clinicaltrials@karyopharm.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	EU/3/14/1317
D.3 Description of the IMP
D.3.1	Product name	Selinexor 20mg coated tablets
D.3.2	Product code	KPT-330
D.3.4	Pharmaceutical form	Coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Selinexor
D.3.9.1	CAS number	1393477-72-9
D.3.9.2	Current sponsor code	KPT-330
D.3.9.4	EV Substance Code	SUB168135
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	20
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

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 ORR of each arm per Lugano criteria ( Cheson 2014)

E.2.2

Secondary objectives of the trial

To be determined for each arm separately:
Duration of response (DOR)
Disease control rate (DCR)
ORR evaluated per modified Lugano criteria
To assess the safety profile of selinexor

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Written informed consent signed by the patient 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 performance status of ≤2 (Appendix 2).
4. Patients should have estimated life expectancy of >3 months at study entry.
5. Previously treated, pathologically confirmed DLBCL, NOS (whether do novo or transformed from previously diagnosed indolent lymphoma).
6. Patients must have received at least 2 but no more than 5 prior lines of systemic therapy for the treatment of their de novo or transformedDLBCL including (i) at least 1 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 1
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 2 and no more than 5 prior lines of systemic therapy, including at least 1 course of anti-CD20 antibodies, and must beapproved 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. At least 3 weeks (21 days) must have elapsed since the end of patient's most recent systemic anti-DLBCL therapy (prior to Cycle 1 Day
1). Palliative localized radiation within the therapy-free interval is
allowed. Non-chemotherapy maintenance will not be considered antiDLBCL therapy, and therefore is allowed during the therapy-free interval.
8. 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. Extranodal lesion should be considered abnormal if the long axis is >1.0 cm.
9. Female patients of child-bearing potential must have a negative serum pregnancy test at screening. Both male and female patients must agree to use highly effective methods of contraception throughout the study and for at least 90 days following the last dose of study treatment (see Section 9.5.2.1 for description of acceptable contraceptive methods). Male patients must agree not to donate sperm during the study treatment period and at least 90 days following the last dose of study treatment.
10. Adequate hematopoietic function:
a. Hemoglobin ≥10.0 g/dL within 14 days of starting therapy (patient
may receive red blood cell (RBC) transfusion within 14 days).
b. Absolute neutrophil count ≥1000 cells/mm3 (use of granulocyte growth factors prior to and during the study is acceptable).
c. Platelet count ≥100,000/mm3 within 14 days of starting therapy (use of platelet growth factors prior to and during the study is acceptable).

E.4

Principal exclusion criteria

Patients meeting any of the following exclusion criteria are not eligible to enroll in Part 2 of this study.
1. Diffuse large B-cell lymphoma with mucosa-associated lymphoid tissue (MALT) lymphoma, composite lymphoma (Hodgkin's lymphoma + NHL), DLBCL arising from CLL (Richter's transformation), or high-grade B-cell lymphoma.
2. Primary mediastinal (thymic) large B-cell lymphoma
3. Patients must not be eligible for high-dose chemotherapy with autologous stem cell transplantation rescue (Investigator must provide detailed documentation for ineligibility).
4. Known active central nervous system lymphoma or meningeal involvement. Patients with a history of CNS disease treated into remission may be enrolled.
5. Patients who have not recovered to Grade ≤1 clinically significant AEs, or to their baseline, from their most recent systemic anti-DLBCL therapy.
6. 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.
7. Major surgery within 2 weeks of first dose of study treatment.
8. Any life-threatening illness, medical condition, or organ system dysfunction which, in the Investigator's opinion, could compromise the patient's safety.
9. Uncontrolled (i.e., clinically unstable) infection requiring parenteral antibiotics, antivirals, or antifungals on Cycle 1 Day 1; however, prophylactic use of these agents is acceptable even if parenteral.
10. Patients with active hepatitis B virus (HBV), hepatitis C virus (HCV), or human immunodeficiency virus (HIV) infections. Patients with active HBV are allowed if antiviral therapy for hepatitis B has been given for >8 weeks and viral load is <100 IU/mL prior to first dose of study treatment. Patients with known history of HCV or found to be HCV antibody positive on screening, are allowed if there is documentation of
negative viral load per institutional standard. Patients with HIV who have CD4+ T cell counts ≥350 cells/μL, negative viral load per institutional standard, and no history of acquired immune deficiency syndrome (AIDS)-defining opportunistic infections in the last year are allowed.
11. Patients unable to swallow tablets, patients with malabsorption syndrome, or any other gastrointestinal disease or gastrointestinal dysfunction that could interfere with absorption of study treatment.
12. Any of the following laboratory abnormalities:
a. A circulating lymphocyte count of >50,000/μL.
b. Hepatic dysfunction: bilirubin >2.0 times the 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.
c. Severe renal dysfunction: estimated creatinine clearance of <15 mL/min, measured in 24-hour urine or calculated using the formula of Cockroft and Gault ([140-Age] x Mass (kg)/[72 x creatinine mg/dL];
multiply by 0.85 if female).
13. Female patients who are pregnant or breastfeeding.
14. Psychiatric illness or substance use that would prevent the patient from giving informed consent or being compliant with the study procedures.
15. Received strong CYP3A inhibitors ≤7 days prior to Day 1 dosing or strong CYP3A inducers ≤14 days prior to Day 1 dosing.

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 each arm (i.e., Arm A and Arm B). 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 criteria 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, or death due to disease progression, whichever occurs first.
• DCR is defined as the proportion of patients who achieve CR, PR, or SD, following randomization (i.e., ORR + SD)
• PFS is defined as the duration of time from randomization 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.
• OS is defined as the duration of time from randomization until death due to anycause. A sensitivity analysis will also be performed for OS where death will be included if it may be reasonably attributed to the patient's underlying DLBCL.
• TTP is defined as the duration of time from the date of randomization 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:
To be determined for each arm separately:
• Duration of response (DOR), defined as the duration of time from first occurrence of CR or PR until the first date that disease progression is objectively documented, or death due to disease progression, whichever occurs first. Patients without documented disease progression will be censored on the date of last disease assessment.
• Disease control rate (DCR), defined as the proportion of patients who achieve CR, PR, or SD, following randomization (i.e., ORR + SD).
• ORR evaluated per modified Lugano criteria

Secondary Safety Endpoints
To be determined for each arm separately:
• Safety endpoints include AE reports, Eastern Cooperative Oncology
Group (ECOG) performance status, vital signs, physical examinations,
concomitant medications, and laboratory safety evaluations.

E.5.2.1

Timepoint(s) of evaluation of this end point

End of study

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

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

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

Yes

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

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

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

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

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

Serbia

Austria

Belgium

Bulgaria

France

Germany

Greece

Hungary

Italy

Netherlands

Poland

Spain

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

LPLV

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

100

F.4.2.2

In the whole clinical trial

110

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

After a patient has ceased his/her participation in the study, his/her medical doctor will offer the most appropriate treatment currently available.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2018-03-16

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-02-09

P. End of Trial
P.	End of Trial Status	Ongoing

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