| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Follicular Lymphoma (FL), advanced disease in need of therapy |
| Follikulaarinen lymfooma |
|
| E.1.1.1 | Medical condition in easily understood language |
This trial is targeting patients with advanced follicular lymphoma in need
of therapy. These patients could avoid an eventually unnecessary and
toxic chemotherapy treatment. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
| MedDRA Classification |
| 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 |
The objective of this trial is to study the activity and the safety of the 1st
line treatment with Ibrutinib in combination with Rituximab for patients
with advanced follicular lymphoma in need of therapy. |
|
| E.2.2 | Secondary objectives of the trial | |
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Histologically confirmed FL CD20+; grade 1, 2, 3a; stage III+IV;
stage II not suitable for radiotherapy; all FLIPI
6.1.3 Tumor specimens (slides or block) available for pathological review
6.1.4 In need of systemic therapy (at least one of the following
indications must be fulfilled):
Symptomatic disease
Bulky disease (≥ 6 cm)
Steady, clinically significant progression over at least 6 months of any
tumor lesion
B-symptoms (weight loss > 10% in 6 months, drenching night sweats,
fever > 38°C not due to infection)
Anemia (hemoglobin < 100 g/L) or thrombocytopenia (platelets 50-
100 x 109/L) due to lymphoma
6.1.5 At least one two-dimensionally measurable lesion with a longest
diameter (LDi) ≥ 15 mm or a measurable extranodal lesion with a LDi >
10 mm in contrast-enhanced 18F-FDG PET/CT* scan
6.1.6 At least one FDG-avid tumor lesion in contrast-enhanced 18F-FDG
PET/CT* scan
6.1.7 Age 18-85 years
6.1.8 WHO performance status 0-2
6.1.9 Adequate bone marrow function:
Absolute neutrophil count (ANC) > 1.0 x 109/L independent of growth
factor support
Platelets ≥ 100 x 109/L or ≥ 50 x 109/L if bone marrow involvement
independent of transfusion support in either situation
6.1.10 Adequate hepatic function:
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST)
≤ 3 x upper limit of normal (ULN)
Total bilirubin ≤ 1.5 x ULN unless bilirubin rise is due to Gilbert's
syndrome or of non-hepatic origin
6.1.11 Adequate renal function:
Serum creatinine ≤ 2 x ULN and corrected calculated creatinine
clearance ≥ 40 mL/min/1.73m2.
6.1.12 Women of childbearing potential have a negative serum (betahuman
chorionic gonadotropin [-hCG]) or urine pregnancy test at
Screening.
6.1.13 Women of childbearing potential and men who are sexually active
must be practicing a highly effective method of birth control during and
after the study consistent with local regulations regarding the use of
birth control methods for subjects participating in clinical trials. Men
must agree to not donate sperm during and after the study. For females
and males, these restrictions apply for 12 months after the last dose of
study drug.
6.1.14 Patient compliance and geographic proximity allow proper
staging and follow-up. |
|
| E.4 | Principal exclusion criteria |
6.2.1 Tumor bulk requiring fast response
6.2.2 Known central nervous system lymphoma
6.2.3 Previous systemic FL therapies
6.2.4 Major surgery 4 weeks prior to randomization
6.2.5 Previous or concomitant malignancy diagnosed within 3 years with
the exception of adequately treated cervical carcinoma in situ or
localized non-melanoma skin cancer
6.2.6 History of stroke or intracranial hemorrhage within 6 months prior
to randomization
6.2.7 Clinically significant cardiovascular diseases such as uncontrolled
or symptomatic arrhythmias, congestive heart failure, or myocardial
infarction within 6 months of screening, or any Class 3 (moderate) or
Class 4 (severe) cardiac disease as defined by the New York Heart
Association Functional Classification
6.2.8 Known history of human immunodeficiency virus (HIV) or active
Hepatitis C Virus or active Hepatitis B Virus infection or any uncontrolled
active systemic infection requiring intravenous (i.v.) antibiotics
6.2.9 Concomitant diseases that require anticoagulation with warfarin or
equivalent vitamin K antagonists (eg. phenprocoumon), factor Xa
inhibitors (e.g. rivaroxaban, apixaban), direct thrombin inhibitors (e.g.
dabigatran) or platelet inhibitors/antiplatelet agents
6.2.10 Concomitant diseases that require treatment with strong or
moderate CYP3A inhibitors, including St. John's wort (see
http://medicine.iupui.edu and also chapter 9)
6.2.11 Any concomitant drugs contraindicated for use with the trial
drugs according to the approved product information or known
hypersensitivity to the trial drugs Ibrutinib/Placebo and Rituximab or to
any of their components (including placebo)
6.2.12 Concurrent treatment with other experimental drugs or other
anticancer therapy, treatment in a clinical trial within 30 days prior to
trial entry
6.2.13 Vaccinated with live, attenuated vaccines 4 weeks prior to
randomization
6.2.14 Any life-threatening illness, medical condition, or organ system
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dysfunction which, in the Investigator's opinion, could compromise the
subject's safety, interfere with the absorption or metabolism of Ibrutinib
capsules, or put the study outcomes at undue risk
6.2.15 Psychiatric disorder precluding understanding information of trial
related topics, giving informed consent or interfering with compliance
for oral drug intake
6.2.16 Women who are pregnant or breastfeeding
6.2.17 Patients regularly taking corticosteroids during the last 4 weeks,
unless administered at a dose equivalent to Prednisone ≤ 15 mg/day for
indications other than lymphoma or lymphoma-related symptoms |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Complete Response (CR) at 24 months determined by PET/CT scan by
the IRR panel
Any assessment within a window of week 102 to week 118 (inclusive)
will be considered as the 24 months response assessment for
determining the CR status. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Secondary endpoints:
CR at 30 months determined by PET/CT scan by the IRR panel
MRD evaluation
Overall response (OR) at 24 weeks
Duration of complete response (DUR)
Progression-free survival (PFS)
Event-free survival (EFS)
Time to next anti-lymphoma therapy (TTNT)
Overall survival (OS)
Adverse Events (AEs)
Exploratory endpoints |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
CR: at 30 months
MRD evaluation: baseline and week 106
Overall response (OR): at 24 weeks
Duration of complete response: at 12 or 24 weeks or thereafter
Progression-free survival (PFS): at 12 or 24 weeks or thereafter
Event-free survival (EFS): 12, 24 or 52 weeks
Time to next anti-lymphoma therapy (TTNT): at 12 or 24 weeks or
thereafter
Overall survival (OS) from randomization until death.
Adverse events (AEs) throughout treatment phase
Exploratory endpoints |
|
| 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 | No |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| 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 | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 32 |
| 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 |
| Denmark |
| Finland |
| Italy |
| Norway |
| Sweden |
| Switzerland |
|
| 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
|
End of trial is defined as "last visit of the last subject undergoing the
trial"
Last patient, last treatment (planned) Q4 2019
Last patient, last visit (planned) Q4 2029
All patients will be followed-up for 10 years after the first Rituximab
administration. Afterwards, in the following 10 years, information on
survival, disease status and further treatment may be collected upon
request of SAKK without scheduled trial visits. Overall collection of
patient data may last 20 years. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 20 |
| 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 | 20 |
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