A Phase III Study to Compare the Efficacy, Safety, and Immunogenicity of Proposed Rituximab Biosimilar (DRL_RI) with MabThera® in Subjects with Previously Untreated Follicular Lymphoma

Phase 1

Conditions: Follicular Lymphoma
MedDRA version: 21.1Level: PTClassification code 10016910Term: Follicle centre lymphoma, follicular grade I, II, III stage IVSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Therapeutic area: Diseases [C] - Cancer [C04]

Registration Number: EUCTR2018-004223-36-IT

Lead Sponsor: Dr. Reddy's Laboratories S.A.

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Authorised-recruitment may be ongoing or finished

Sex: All

Target Recruitment: 284

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 sufficient tissue samples available for the central pathology review, ( Section 8.1.1) 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.
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.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 184
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 100

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, (including recurrence) within 5 years of screening,other than non-melanoma skin cancer or intraepithelial cervical neoplasia, which should have been 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),.
10. Subjects with positive serological test for hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb) or hepatitis C virus (HCV) antibody can only be included in the study if any of the following is fulfilled.
· Subjects with a negative HBsAg and positive total HBcAb must have a HBV deoxyribonucleic acid (DNA) level <20 IU/mL (or 112 copies/mL) by polymerase chain reaction (PCR) to participate in the study. In addition, it is required for these subjects to follow consultation with a hepatologist / relevant expert regarding initiation, monitoring, and use of HBV antiviral therapy and the subject must be willing to undergo PCR HBV DNA testing during treatment and agree to receive treatment as indicated. HBV DNA re-test will be performed as per the schedule of assessments (ref. table no. 1-1) and further as needed, at the discretion of the Investigator.
· Subjects with a positive test because of HBV vaccination may be included (i.e., HbsAg negative, anti-HBs+, HBcAb–).
· Subjects positive for HCV antibody are eligible only if the PCR test for HCV ribonucleic acid (RNA) is negative.
11. 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).If latent TB is suspected based on clinical or epidemiological grounds, it should be further investigated using the tuberculosis testing as appropriate following local practice or investigator judgment.
12. Subjects who have received a live vaccine within last 3 months of the first administration of study drug.
13. 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).
14. 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.
15. Subjects with known hypersensitivity to rituximab or its excipients, or to proteins of murine or other foreign origin.
Please refer to Protocol for the other criteria

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: 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).;Secondary Objective: ·To compare the ORR at Week 12, CR at Week 28 and duration of response (DOR), PFS and OS of DRL_RI with MabThera® in subjects with CD20- positive, LTB-FL.<br>·To compare the safety, tolerability, and immunogenic ity of DRL_RI with MabThera® in subjects with CD20-positive, LTB-FL.;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);Timepoint(s) of evaluation of this end point: Throughout the whole study.

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): · 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).<br>· Complete Response (CR) rate at Month 7 (Week 28).<br>· 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.<br>· 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.<br>· 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).<br>· Adverse events, clinical laboratory values, vital signs, and electrocardiogram (ECG)<br>· Anti-rituximab antibodies and their relationship with other outcome measures.;Timepoint(s) of evaluation of this end point: Throughout the whole study.

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