| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Initial and Refractory/Relapsed Richters Transformation (RT) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Richters Transformation (RT) |
|
| 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 | 18.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10058728 |
| E.1.2 | Term | Richter's syndrome |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 determine the Overall Response Rate (ORR) including Partial Response (PR) and Complete Response (CR), as well as the Duration of Response (DOR). |
|
| E.2.2 | Secondary objectives of the trial |
- To determine the Disease Control Rate (DCR = CR + PR + SD), as well as duration of DCR.
- To determine Progression Free Survival (PFS).
- To compare PFS on selinexor versus the patients PFS(s) on prior therapy(s) for RT, if applicable.
- To determine Overall Survival (OS) from diagnosis and from initiation of selinexor.
- To further evaluate toxicity of selinexor in this patient population.
- To assess Quality of Life using 1) FACT-Lym Questionnaire and 2) the EQ-5D-5L Health Questionnaire . |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Ability to understand and the willingness to sign a written informed consent document.
2. Richter’s transformation, arising in the setting of prior CLL, documented by histologically confirmed lymphoma, including large B-cell and immunoblastic variants.
3. All patients must have received at least one prior regimen for CLL, including cytotoxic chemotherapy, anti-CD20 monoclonal antibodies, a BTK inhibitor, or a PI3K inhibitor. Patients may have received high dose chemotherapy/autologous stem cell transplant (HDT/ASCT) or allogeneic hematopoietic stem cell transplant (allo SCT).
4. One or more measurable (> 1.5 cm in longest dimension) disease sites on CT (preferably PET/CT) or, if CT is contraindicated, MRI (preferably PET/MRI) scans.
5. Objective documented evidence of disease progression at study entry.
• For patients newly diagnosed with RT, this includes histologic evidence of transformation to RT (on Screening, patients must have radiographic evidence consistent with RT).
• For patients previously diagnosed with RT who have progressed after at least one prior therapy for RT, this includes radiographic and/or definitive clinical evidence of clinical progression.
6. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2 (Oken 1982)
7. Baseline platelet count ≥ 30,000/mm3 (allowing platelet transfusion and/or growth factors to reach this criteria) and absolute neutrophil count ≥ 500/mm3 (growth factors are allowed).
8. Patients who are hepatitis B PCR negative who have a recent (< 6 month) history of IVIG therapy are eligible. Patients on IVIG who are core antibody positive but PCR negative are not mandated to take anti-viral prophylaxis.
9. Adequate hepatic function: bilirubin ≤ 2 times the upper limit of normal (ULN) (except patients with Gilbert’s syndrome [hereditary indirect hyperbilirubinemia] who must have a total bilirubin of ≤ 3 x ULN) AST and ALT < 2.5 times ULN (except patients with liver involvement of their RT who must have an AST and ALT ≤ 5 x ULN).
10. Adequate renal function: estimated creatinine clearance of ≥ 30 mL/min, calculated using the Cockroft and Gault formula (140-Age) • Mass (kg)/(72 • creatinine mg/dL); multiply by 0.85 if female (Cockroft 1976).
11. Female of childbearing potential must have a negative serum β-hCG pregnancy test result within 3 days prior to first study dose. Female patients who are surgically sterilized or who are > 45 years old and have not experienced menses for > 2 years may have β Hcg pregnancy test waived. Female patients of child-bearing potential must agree to use dual methods of contraception if sexually active and have a negative serum pregnancy test at Screening. Male patients must agree to use an effective barrier method of contraception if sexually active with a female of child-bearing potential. Acceptable methods of contraception are condoms with contraceptive foam; oral, implantable or injectable contraceptives; contraceptive patch; intrauterine device; diaphragm with spermicidal gel; or a sexual partner who is surgically sterilized or post-menopausal. Total (true) abstinence (when this is in line with the preferred and usual lifestyle of the patient), is an acceptable method of contraception. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post ovulation methods) and withdrawal are not acceptable methods of contraception. For both male and female patients, effective methods of contraception must be used throughout the study and for three months following the last dose
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|
| E.4 | Principal exclusion criteria |
1. Patients who are pregnant or lactating
2. Radiation, chemotherapy, or immunotherapy or any other anticancer therapy ≤ 2 weeks prior to Cycle 1 Day 1, except ibrutinib which may be continued until one day prior to initiation of selinexor; radio-immunotherapy 4 weeks prior to Cycle 1 Day 1. Patients must have recovered to Grade ≤ 1 from clinically significant adverse effects.
3. Prolymphocytic transformation
4. Less than 1 month since completion of autologous stem cell transplantation or less than 3 months since completion of allogeneic stem cell transplantation
5. Major surgery within four weeks of Cycle 1 Day 1
6. Unstable cardiovascular function:
• symptomatic ischemia, or
• uncontrolled clinically significant conduction abnormalities (i.e., ventricular tachycardia on antiarrhythmic agents are excluded and 1st degree atrioventricular block or asymptomatic left anterior fascicular block/right bundle branch block will not be excluded), or
• congestive heart failure of NYHA Class ≥ 3, or
• myocardial infarction within 3 months
7. Uncontrolled systemic infection requiring parenteral antibiotics, antivirals, or antifungals within one week prior to first dose. Systemic infections controlled on concurrent anti-microbial agents and anti-microbial prophylaxis per institutional guidelines are acceptable, even if parenteral.
8. Presence of central nervous system (CNS) leukemia or lymphoma. Patients with active CNS malignancy. Asymptomatic small lesions are not considered active. Treated lesions may be considered inactive if they are stable for at least 3 months. Patient with malignant cells in their cerebrospinal fluid (CSF) without CNS symptoms may be included.
9. Known active hepatitis B virus (HBV) or C virus (HCV) infection; or known to be positive for HCV ribonucleic acid (RNA); patients with stable human immunodeficiency virus (HIV) on anti-retroviral therapy are acceptable. Patients with surface antigen (HBsAg) or hepatitis B PCR positivity will be excluded.
10. Impairment of gastrointestinal (GI) function or GI disease that could interfere with the absorption of selinexor, including obstructed GI tract and uncontrolled vomiting or diarrhea.
11. Inability or unwillingness to take supportive medications such as anti-nausea and anti-anorexia agents as recommended by the NCCN Clinical Practice Guidelines® (Appendix 3 and Appendix 4).
12. Serious psychiatric or medical conditions that could interfere with treatment.
13. Participation in an investigational anti-cancer study within 2 weeks prior to Cycle 1 Day 1.
14. Concurrent therapy with approved or investigational anticancer therapeutic.
15. Body surface area (BSA) <1.3 m2.
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is Overall Response Rate (ORR) (as defined by the IWG Criteria) achieved by RT patients treated with single-agent selinexor. Supportive data will be provided by the duration of ORR (DOR). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The primary endpoint is overall response rate (ORR) achieved on or after Day 1 of Cycle 3, or at any 2nd cycle thereafter, by RT patients who have been treated with at least one dose of single-agent selixenor. |
|
| E.5.2 | Secondary end point(s) |
The secondary endpoints include the determination of the following:
- DCR, including supportive data provided by duration of DCR
- Progression Free Survival (PFS)
- PFS on selinexor versus the patients PFS(s) on prior therapy(s) for RT, if applicable
- Overall Survival (OS), including OS from diagnosis and from initiation of selinexor
- Further evaluation of toxicity of selinexor in this patient population
- Assessment of Quality of Life using 1) the FACT-Lym Questionnaire and 2) the EQ 5D-5L Health Questionnaire |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Secondary end points will be evaluated at end of study. |
|
| 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 | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| 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 | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 38 |
| 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 |
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| 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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