A Randomized, Double-blind, Multi-center, Multi-national Trial to Evaluate the Efficacy, Safety, and Immunogenicity of SAIT101 Versus Rituximab as a First-line Immunotherapy Treatment in Patients With Low Tumor Burden Follicular Lymphoma (RAMO-2)

This is a Randomized, Double-blind, Multi-center, Multi-national Trial to Evaluate the statistical equivalence of efficacy, safety and immunogenicity of SAIT101 Versus Rituximab as a First-line Immunotherapy Treatment in asymptomatic patients with Low Tumor Burden Follicular Lymphoma.

Study Overview

• Status: Completed
• Conditions: Lymphoma, Follicular
• Intervention / Treatment: Biological: SAIT101; Biological: MabThera®

Detailed Description

This is a Randomized, Double-blind, Multi-center, Multi-national Trial to Evaluate the statistical equivalence of efficacy, safety and immunogenicity of SAIT101 Versus Rituximab as a First-line Immunotherapy Treatment in asymptomatic patients with Low Tumor Burden Follicular Lymphoma. Patients will be randomized in a 1:1 ratio to receive study drug once a week for 4 weeks, and will then be followed up for up to 52 weeks after the first dose. Randomization will be stratified by inclusion in the PK/PD sub-population and Follicular lymphoma international prognostic index 2 (FLIPI-2) score.

Visits are scheduled at Weeks 1, 2, 3, and 4 (study drug infusion visits), and then at Weeks 5, 12, 20, 28, 36, and 52 (i.e., End of Study [EOS]). Efficacy response assessments will be performed at Weeks 12 and 28, while safety assessments will continue until end of Study (EOS).

The primary objectives is to compare the efficacy of SAIT101 with rituximab licensed in the European Union (hereafter designated MabThera®, brand name in EU) when administered as a first-line immunotherapy in patients with low tumor burden follicular lymphoma (LTBFL) and the secondary objectives is to evaluate SAIT101 versus MabThera® with respect to safety and tolerability, immunogenicity and Pharmacokinetics (PK)/Pharmacodynamics (PD) in a sub-population of patients.

• Study Type: Interventional
• Enrollment (Actual): 315
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Australian Capital Territory
    • Canberra, Australian Capital Territory, Australia, 2605
      • Research Site
• Chile
  • Araucania
    • Temuco, Araucania, Chile, 4810469
      • Research Site
• Czechia
  • Hradec Kralove, Czechia, 500 05
    • Research Site
  • Praha, Czechia, 128 08
    • Research Site
  • Praha, Czechia, 15000
    • Reasearch Site
• France
  • Gironde
    • Libourne Cedex, Gironde, France, 33505
      • Research Site
  • Vienne
    • Poitiers, Vienne, France, 86021
      • Research Site
• Germany
  • Hamburg, Germany, 22081
    • Research Site
• Hungary
  • Budapest, Hungary, 1083
    • Research Site
• Italy
  • Terni, Italy, 05100
    • Research Site
  • Foggia
    • San Giovanni Rotondo, Foggia, Italy, 71013
      • Research Site
• Korea, Republic of
  • Busan, Korea, Republic of, 49241
    • Research Site
  • Seoul, Korea, Republic of, 03080
    • Research Site
  • Seoul, Korea, Republic of, 01757
    • Research Site
• Mexico
  • Distrito Federal
    • Mexico City, Distrito Federal, Mexico, 03720
      • Research Site
• South Africa
  • Gauteng
    • Pretoria, Gauteng, South Africa, 0181
      • Research Site
• Spain
  • Cádiz, Spain, 11009
    • Research Site
  • Madrid, Spain, 28040
    • Research Site
  • Barcelona
    • L'Hospitalet de Llobregat, Barcelona, Spain, 08907
      • Research Site
• Turkey
  • Ankara, Turkey, 06340
    • Research Site
  • Istanbul, Turkey, 34098
    • Research Site
  • Mersin, Turkey, 33343
    • Research Site
  • Samsun, Turkey, 55139
    • Research Site
• United Kingdom
  • Norfolk
    • Norwich, Norfolk, United Kingdom, NR4 7UY
      • Research Site
• United States
  • California
    • Whittier, California, United States, 90603
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Patients with histologically-confirmed Low Tumor Burden Follicular Lymphoma, without B symptoms, Ann Arbor stage II to Non-Hodgkin's Lymphoma (NHL) (CD20+ Follicular Lymphoma of Grades 1, 2, or 3a)

2. Low tumor burden according to The Groupe d'Etude des Lymphomes Folliculaires (GELF) criteria defined as:

   • Normal serum lactate dehydrogenase (LDH)
   • No mass ≥7 cm.
   • Less than 3 nodal sites, each with diameter >3 cm
   • No systemic or B symptoms (fever >38°C for 3 consecutive days; recurrent, drenching night sweats; unintentional weight loss exceeding 10% body weight in the last 6 months.
   • No splenomegaly ≥16 cm by CT scan.
   • No risk of vital organ compression.
   • No pleural or peritoneal serous effusion.
   • No leukemic phase >5,000/µL circulating tumor cells.
   • No cytopenias (defined as platelets <100,000/mm3, hemoglobin <10 g/dL, or absolute neutrophil count <1,500/mm3).
3. Patients not previously treated for their FL, including any previous treatment for FL under clinical trials except localized radiation therapy for previous limited stage disease.

Exclusion Criteria:

1. Previous treatment with any chemotherapy and/or rituximab or other monoclonal antibody.
2. Prior radiotherapy completed <28 days before study enrollment.
3. Anticipated need for concomitant administration of any other experimental drug, or a concomitant chemotherapy, anticancer hormonal therapy, radiotherapy, or immunotherapy during study participation.
4. Concomitant disease which requires continuous therapy with corticosteroids at doses equivalent to prednisolone >20 mg/day.
5. Transformation to high-grade lymphoma secondary to previously untreated low-grade lymphoma.
6. Prior or concomitant malignancies within 5 years prior to screening, with the exceptions of non-melanoma skin cancer, adequately treated carcinoma in situ of the cervix, adequately treated breast cancer in situ, and localized prostate cancer stage T1c, provided that the patient underwent curative treatment and remains relapse free.
7. Patients with a body surface area >3.0 m2.
8. Major surgery (excluding lymph node biopsy) within 28 days prior to randomization.
9. Primary or secondary immunodeficiency (history of, or currently active), including known history of human immunodeficiency virus (HIV) infection or positive test at screening.
10. Acute, severe infection (e.g., sepsis and opportunistic infections), or active, chronic or persistent infection that might worsen with immunosuppressive treatment (e.g., herpes zoster).
11. Positive serological test for hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb) or hepatitis C serology.
12. Confirmed current active tuberculosis (TB)
13. Central nervous system (CNS) or meningeal involvement, or cord compression by the lymphoma; history of CNS lymphoma
14. History of a severe allergic reaction or anaphylactic reaction to a biological agent or history of hypersensitivity to any component of the trial drug (e.g., hypersensitivity or allergy to murine products).
15. Patients who have significant cardiac disease, including but not limited to history of congestive heart failure (New York Heart Association Class III/IV; see Appendix 7), unstable angina, or uncontrolled cardiac arrhythmia.
16. Uncontrolled or severe hypertension, or cerebrovascular disease.
17. Serious underlying medical conditions that, per the Investigator's discretion, could impair the ability of the patient to participate in the trial
18. Any other co-existing medical or psychological condition(s) that will preclude participation in the study or compromise ability to give informed consent and/or comply with study procedures.
19. Treatment with any investigational medicinal product (IMP) within 4 weeks prior to initiation of 1st infusion of study drug, or treatment with a drug that has not received regulatory approval for any indication within 4 weeks or a minimum of 5 half-lives, whichever is longer, of the 1st infusion of study drug.
20. Receipt of a live/attenuated vaccine within 6 weeks prior to the screening visit.
21. Females who are pregnant, breastfeeding, or planning a pregnancy during the treatment period or within 12 months after the last infusion of study drug.
22. Patients who are investigational site staff members directly involved in the conduct of the trial, and their family members, site staff members otherwise supervised by the investigator, or patients who are Archigen employees directly involved in the conduct of the trial.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: MabThera®	Biological: MabThera®; Dose of 375mg/m2 body surface area (BSA) i.v. on Days 1, 8, 15, and 22; Other Names: Rituximab
Experimental: SAIT101	Biological: SAIT101; Dose of 375mg/m2 body surface area (BSA) i.v. on Days 1, 8, 15, and 22

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate (ORR) at Week 28	Overall Response Rate (ORR) (Complete Response [CR] + Partial Response [PR]) at Week 28, as defined by International Working Group (IWG) criteria 2007. Tumour assessments were assessed by central imaging review per International Working Group (IWG) Criteria 2007. The 95% CI for overall response rate (ORR) was calculated using the Exact method and combined using the Rubin's rule when multiple imputation was applicable.	Baseline (Day 0) to Week 28.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate (ORR) at Week 12	Overall Response Rate (ORR) = Complete Response (CR) + Partial Response (PR). Tumour assessments were assessed by central imaging review per the International Working Group (IWG) Criteria 2007. The 95% CI for overall response rate (ORR) was calculated using the Exact method and combined using the Rubin's rule when multiple imputation was applicable.	Baseline (Day 0) to Week 12
Complete Response (CR) at Weeks 12 and 28	Efficacy Endpoint: Complete Response (CR) at Weeks 12 and 28. Tumour assessments were assessed by central imaging review per International Working Group (IWG) Criteria 2007.	Baseline (Day 0) to Week 12 and Week 28.
Partial Response (PR) at Weeks 12 and 28	Efficacy Endpoint: Partial Response (PR) at Weeks 12 and 28. Tumour assessments were assessed by central imaging review per International Working Group (IWG) Criteria 2007.	Baseline (Day 0) to Week 12 and Week 28.
Stable Disease (SD) at Weeks 12 and 28	Efficacy endpoint: number of participants with Stable Disease (SD) at Weeks 12 and 28. Tumour assessments were assessed by central imaging review per International Working Group (IWG) Criteria 2007.	Baseline (Day 0) to Week 12 and Week 28.
Progressive Disease (PD) at 12 and 28 Weeks	Efficacy endpoint: number of participants with Progressive Disease (PD) at 12 and 28 Weeks. Tumour assessments were assessed by central imaging review per International Working Group (IWG) Criteria 2007.	Baseline (Week 0)to Week 12 and Week 28.
Time to Event (TTE)	Time to Event (TTE) is defined as the time of randomisation to the date when an event occurred for a maximum follow-up period of 32 weeks from baseline; an event is disease progression, death due to any cause, or the start of new treatment for follicular lymphoma, whichever comes first.	Baseline (Day 0) to time of event or up to a maximum of 32 weeks, whichever is sooner

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Truncated Area Under the Concentration-time Curve (AUC) Over the First and Fourth Dosing Intervals (AUC0 168,w1, AUC0-168,w4).	Pharmacokinetic endpoint: truncated area under the concentration-time curve (AUC) over the first (Day 1) and fourth (Day 22) dosing intervals (AUC0 168,w1, AUC0-168,w4).	Baseline (Day 0) to dosing on Week 1 and Week 4
Maximum Concentration (Cmax) After the First Dose and the Fourth Dose (Cmax,w1, Cmax,w4).	Pharmacokinetic endpoint: maximum plasma concentration (Cmax, µg/ml ) after the first dose (Week 1) and the fourth dose (week 4) (Cmax,w1, Cmax,w4).	Baseline (Day 0) to dosing on Week 1 and Week 4
Accumulation Ratio for AUC0-168 Obtained From the Fourth Dose Versus the First Dose (RAUC).	Pharmacokinetic endpoint: accumulation ratio for the Area Under the Concentration Time Cure 0 to 168 hours (AUC0-168) obtained from the fourth dose (Week 4) versus the first dose (Week 1) (RAUC). Accumulation ratio, calculated for AUC0-168 as (AUC0 168,w4/AUC0 168,w1).	Baseline (Day 0) to dosing on Week 1 and Week 4
Accumulation Ratio for the Maximum Plasma Concentration (Cmax) From the Fourth Dose Versus the First Dose (RCmax).	Pharmacokinetic endpoint: accumulation ratio for maximum plasma (Cmax) ratio from the fourth dose on Week 4 versus the first dose of treatment on Week 1 (RCmax). Accumulation ratio, calculated for Cmax as (Cmax,w4/Cmax,w1).	Baseline (Day 0) to dosing on Week 1 and Week 4
Trough Concentrations on Days 1, 8, 15, 22, and 29 (Ctrough).	Pharmacokinetic endpoint: trough plasma concentration (Ctrough) during the dosing phase on Days 1, 8, 15, 22, and 29. Concentrations at predose on Days 8, 15, and 22 (µg/mL) and the time equivalent to the predose on Day 29, obtained directly from the observed concentration versus time data.	Baseline (Day 0) to Days 1, 8, 15, 22 and 29
Observed Change From Baseline CD19+ B-Lymphocyte Cluster of Differentiation 19 (CD-19+ B-Cell) Counts up to Week 28	Pharmacodynamic Endpoint: Arithmetic mean observed change from baseline of B-lymphocyte antigen cluster of differentiation 19 (CD-19+ B-cell) counts (cells/μL) up to Week 28 by treatment.	Baseline (Day 1) to Weeks 1, 2, 3, 4, 5, 12, 20 and 28.
Percent Change From Baseline CD19+ B-Lymphocyte Cluster of Differentiation 19 (CD-19+ B-Cell) Counts up to Week 28	Pharmacodynamic Endpoint: percent change from baseline of B-lymphocyte antigen cluster of differentiation 19 (CD-19+ B-cell) counts (cells/μL) up to Week 28 by treatment.	Baseline (Day 1) to Weeks 1, 2, 3, 4, 5, 12, 20 and 28.
Area Under the Curve Change From Baseline B-lymphocyte Cluster of Differentiation 19 (CD19+ B-cell) Count Time Curve (AUEC) Over the Dosing Interval	Pharmacodynamic Endpoint: Area under the change from baseline CD19+ B-cell count time curve (AUEC) over the first dosing interval on week 1 from time 0 to the time prior to the second dose (AUEC0 168,w1), AUEC over the second dosing interval on week 2 from time 0 to the time prior to the third dose (AUEC0-168,w2), AUEC over the third dosing interval on week 3 from time 0 to the time prior to the fourth dose (AUEC0-168,w3), AUEC over the fourth dosing interval on week 4 from time 0 to 168 hours post dose (AUEC0-168,w4), AUEC from time 0 on week 1 to the time point on week 12 (AUEC0-w12), AUEC from time 0 on week 1 to the time point on week 28 (AUEC0 w28) for the change from baseline CD19+ B-cell count data.	Baseline (Day 0) to Week 1, 2, 3, 4 12 and 28.
Normalized Area Under the Curve Change From Baseline B-lymphocyte Cluster of Differentiation 19 (CD19+ B-cell) Count Time Curve (AUEC) Over the Dosing Interval	Pharmacodynamic Endpoint: Area under the change from baseline CD19+ B-cell count time curve (AUEC) over the first dosing interval on week 1 from time 0 to the time prior to the second dose (AUEC0 168,w1), AUEC over the second dosing interval on week 2 from time 0 to the time prior to the third dose (AUEC0-168,w2), AUEC over the third dosing interval on week 3 from time 0 to the time prior to the fourth dose (AUEC0-168,w3), AUEC over the fourth dosing interval on week 4 from time 0 to 168 hours post dose (AUEC0-168,w4), AUEC from time 0 on week 1 to the time point on week 12 (AUEC0-w12), AUEC from time 0 on week 1 to the time point on week 28 (AUEC0 w28) for the change from baseline CD19+ B-cell count data. The time-normalized AUEC parameters presented were calculated by dividing the respective AUEC by the time interval used to calculate the AUEC.	Baseline (Day 0) to Week 1, 2, 3, 4 12 and 28.
Incidence of Antidrug Antibodies (ADA) and Neutralising Antibody (NAb) by Visit	Immunogenicity endpoint: incidence of antidrug antibodies (ADA) and Neutralising Antibody (NAb). Immunogenicity sampling was performed pre-dose at Day 1, weeks 2, 3 and 4 and at any time during the visits at weeks 5, 12, 20 and 28.	Pre-dose on Day 1 to Weeks 5, 12, 20 and 28.
Observed Change From Baseline for Immunoglobulins G and M by Scheduled Time	Exploratory pharmacodynamic endpoint: Mean (SD) Change from Baseline of Immunoglobulin (IgG) and immunoglobulin M (IgM) (mg/dL) by Scheduled Time for Each Treatment (Safety Analysis Set). Samples for IgG and IgM assessment were collected at Baseline and Weeks 1, 2, 3, 4, 5, 12, 20 and 28.	Baseline to Weeks 1, 2, 3, 4, 5, 12, 20 and 28.
Exploratory Analyses of Tumor Response and Time to Event	Exploratory Efficacy Endpoint: Analyses of Tumor Response and Time to Event, as Determined by the Combined International Working Group (IWG) Criteria 2014, Lugano Classification and IWG Criteria 2007 (Central Assessment) (Full Analysis Set)	Baseline (Day 0) to Week 28
Subgroups and Treatment Interactions of Overall Response Rate (ORR) by Region, Age, Gender and Anti-Drug Antibody (ADA) Status at Week 28.	Exploratory Efficacy Endpoint: Overall Response Rate (ORR) at Week 28 by Region, Age, Gender and Anti-Drug antibody (ADA) status. ADA status through Week 28 is 'Positive' if 'Positive' at any time point, and 'Negative' if 'Negative' at all time points. The 95% CI (confidence interval) for overall response rate (ORR) was calculated using the Exact method. The results presented in this table are based on the non-responder imputed data.	Baseline (Day 0) to Week 28

Collaborators and Investigators

• Sponsor: Archigen Biotech Limited

Study record dates

Study Major Dates

• Study Start (Actual): January 18, 2017
• Primary Completion (Actual): July 17, 2019
• Study Completion (Actual): January 10, 2020

Study Registration Dates

• First Submitted: June 20, 2016
• First Submitted That Met QC Criteria: June 20, 2016
• First Posted (Estimate): June 22, 2016

Study Record Updates

• Last Update Posted (Actual): October 8, 2020
• Last Update Submitted That Met QC Criteria: September 14, 2020
• Last Verified: September 1, 2020

More Information

Terms related to this study

• Keywords: low tumor burden follicular lymphoma (LTBFL)
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Lymphoma; Lymphoma, Follicular; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Rituximab
• Other Study ID Numbers: AGB002

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No