E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
|
E.1.1.1 | Medical condition in easily understood language |
Follicular lymphoma is a type of blood cancer. It is the most common of the indolent (slow-growing) non-Hodgkin's lymphomas, and the second-most-common form of non-Hodgkin's lymphomas overall. |
|
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 | PT |
E.1.2 | Classification code | 10016910 |
E.1.2 | Term | Follicle centre lymphoma, follicular grade I, II, III stage IV |
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 | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of the current study is to demonstrate the equivalent efficacy of DRL_RI and MabThera® in subjects with cluster of differentiation (CD)20-positive, low tumour burden follicular lymphoma (LTB-FL) in the first-line treatment setting, as measured by overall response rate (ORR). |
|
E.2.2 | Secondary objectives of the trial |
·To compare the progression-free survival (PFS), ORR at Week 12, overall survival (OS), and duration of response (DOR) of DRL_RI with MabThera® in subjects with CD20- positive, LTB-FL. ·To compare the safety, tolerability, and immunogenic ity of DRL_RI with MabThera® in subjects with CD20-positive, LTB-FL.
|
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Signed written informed consent.
2. Male or female subjects aged ≥18 years of age.
3. Histologically confirmed, Grade 1-3a, previously untreated, CD20-positive, LTB-FL as per Groupe D’Etude des Lymphomes Folliculaires (GELF) criteria. Subjects must have tissue available for the central pathology review, and a centrally-confirmed diagnosis prior to being randomised. Should a subject be eligible as per the central imaging review but not as per the Study Centre Review the subject will be considered eligible if confirmed both by the Investigator and the Medical Monitor. For any other disagreement in eligibility the subject will be considered ineligible.
4. Ann Arbor Stage II to IV of histological Grade 1, 2, or 3a.
5. ECOG status of 0 to 1.
6. Low tumour burden follicular lymphoma defined as: · As per central radiological assessment, nodal or extranodal mass involvement with diameter measuring <7 cm · As per central radiological assessment, involvement of <3 nodal sites with diameter measuring >3 cm · Absence of systemic symptoms or B-symptoms* (asymptomatic) *B-symptoms defined as weight loss >10% within last 6 months, recurrent or continuous night sweats, intermittent or continuous fever recorded as axillary or oral temperature >38°C for at least 3 days · As per central radiological assessment, absence of splenomegaly (defined as spleen size higher than 16 cm by computed tomography [CT] scan) · Absence of risk of vital organ compression based on clinical finding · Absence of leukemic phase (leukemic phase defined as a count >5,000/µL of circulating tumour cells) · Absence of clinically significant cytopenias (defined as a platelet count of <100,000/µL, haemoglobin <10 g/dL, or absolute neutrophil count <1,500/µL) · Absence of clinically significant serous effusion based on clinical examination and CT scan · Serum LDH not higher than the upper limit of normal (ULN) by local laboratory.
7. Subject has at least 1 measurable tumour mass in 2 dimensions as per central radiological assessment, and the mass must be: · Nodal lesion >15 mm in the longest dimension; or · Nodal lesion >10 mm to ≤15 mm in the longest dimension and >10 mm in the shortest dimension; or · Extranodal lesion with both long and short dimensions ≥10 mm.
8. Creatinine clearance ≥45 mL/min as calculated by the Cockcroft-Gault method.
9. Aspartate transaminase, alanine transaminase, alkaline phosphatase values ≤3 × ULN, total or conjugated bilirubin values ≤1.5 × ULN.
10. Life expectancy ≥3 months.
11. Able to comply with the study protocol.
12. If female subject, then subject should be non-pregnant, non-lactating. Adequate contraception or post-menopausal/non-childbearing status. Women of childbearing potential must practice effective birth control for the duration of the study and for 12 months after the last study drug dose. For this same duration, male subjects participating in the study should avoid passing the semen to female partners during sexual intercourse.
|
|
E.4 | Principal exclusion criteria |
1. Prior use of rituximab or any CD20 monoclonal antibody for any reason.
2. Any contraindication to the use of rituximab.
3. Any prior therapy for follicular lymphoma (including but not limited to chemotherapy, radiotherapy).
4. Subjects who, in the opinion of the Investigator, require additional concomitant treatment for lymphoma.
5. Evidence of histologic transformation to high grade lymphoma or diffuse large B-cell lymphoma.
6. Known Central Nervous System (CNS) involvement by lymphoma. (Note: CNS imaging is not required unless clinically indicated).
7. Subjects on chronic supra-substitutive doses (defined as doses in excess of 7.5 mg per day of prednis one or prednis one equivalent for a period longer than 3 weeks) of systemic glucocorticoids.
8. Prior malignancy, other than non-melanoma skin cancer or intraepithelial cervical neoplasia, successfully treated more than 1 year before study inclusion.
9. Subjects with any of the following: known seropositivity for or history of active viral infection with human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg) positive or hepatitis B core antibody positive, hepatitis C virus (HCV) antibody positive.
10. Subjects with active tuberculosis (TB). Subjects with evidence of latent TB or a history of TB must have completed treatment or have initiated treatment for at least 1 month before the first dose of study drug (Day 1). Tuberculosis testing (QuantiFERON®-TB Gold-in-Tube test - QFT-GIT or QuantiFERON®-TB Gold Plus) is requested only if it is required by local regulations or practice.
11. Subjects who have received a live vaccine within last 3 months of the first administration of study drug.
12. Subjects with an active uncontrolled infection requiring systemic treatment at Screening or history of documented recurrent clinically significant infection within 6 months of study inclusion (e.g., 2 or more viral, bacterial or fungal infections requiring in-patient treatment).
13. Subjects with New York Heart Association (NYHA) class III or IV congestive heart failure or relevant arrhythmia or angina based on ECG with clinical judgment.
14. Subjects with known hypersensitivity to rituximab or its excipients, or to proteins of murine or other foreign origin.
15. History or presence of a medical condition or disease that in the Investigator's opinion would place the subject at an unacceptable risk for study participation.
16. Participation in any clinical study or having taken any investigational therapy during the 2-month period immediately preceding administration of the first dose of study drug.
17. Lactating or pregnant female.
18. Women of childbearing potential who do not consent to use highly effective methods of birth control (e.g., sterilisation, or other non-hormonal forms of contraception) during treatment and for at least 12 months after the last administration of study drug. True abstinence periodic abstinence (e.g., calendar ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
19. Subject has been previously enrolled and/or randomised in this study.
20. Subject likely not to be available to complete all protocol required study visits or procedures. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is ORR, defined as the proportion of subjects in each treatment group that achieve CR, CRu or PR at Month 7 (Week 28) based on central radiology review in accordance with the response criteria for malignant lymphoma (Cheson BD et al., 1999). |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Throughout the whole study. |
|
E.5.2 | Secondary end point(s) |
· Progression-free survival defined as the time from date of randomisation to the date of documented progressive disease (PD) or death due to any cause. · Overall response rate at Week 12 based on central radiology review in accordance with published response criteria for malignant lymphoma (Cheson BD et al., 1999). · Overall survival defined as the time from date of randomisation to the date of death from any cause up to 52 weeks/End of Study (EOS). · Duration of response defined as the time from date of the first documentation of tumour response (CR, CRu or PR) to the date of first documentation of PD or to death due to any cause up to 52 weeks/EOS. · Adverse events, clinical laboratory values, vital signs, and electrocardiogram (ECG) · Anti-DRL_RI antibodies and their relationship with other outcome measures. |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Throughout the whole 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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
|
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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
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 | Yes |
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) | Yes |
E.8.2.2 | Placebo | No |
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 68 |
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 |
Belarus |
Bosnia and Herzegovina |
Bulgaria |
China |
Czech Republic |
Georgia |
Greece |
India |
Italy |
Korea, Republic of |
Poland |
Portugal |
Romania |
Russian Federation |
Serbia |
Spain |
Thailand |
Turkey |
Ukraine |
United States |
|
E.8.7 | Trial has a data monitoring committee | No |
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 | 0 |
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 | 4 |
E.8.9.2 | In all countries concerned by the trial days | 0 |