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

Lymphoma, Follicular Clinical Trial

— RAMO-2  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02809053
• Other study ID #: AGB002
• Status: Completed
• Phase: Phase 3
• Start date: January 18, 2017
• Est. completion date: January 10, 2020

Study information

• Verified date: September 2020
• Source: Archigen Biotech Limited
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 315
• Est. completion date: January 10, 2020
• Est. primary completion date: July 17, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Lymphoma
• Lymphoma, Follicular

Intervention

Biological:
• SAIT101
Dose of 375mg/m2 body surface area (BSA) i.v. on Days 1, 8, 15, and 22
• MabThera®
Dose of 375mg/m2 body surface area (BSA) i.v. on Days 1, 8, 15, and 22

Locations

Country	Name	City	State
Australia	Research Site	Canberra	Australian Capital Territory
Chile	Research site	Temuco	Araucania
Czechia	Research site	Hradec Kralove
Czechia	Reasearch site	Praha
Czechia	Research site	Praha
France	Research site	Libourne Cedex	Gironde
France	Research site	Poitiers	Vienne
Germany	Research site	Hamburg
Hungary	Research site	Budapest
Italy	Research site	San Giovanni Rotondo	Foggia
Italy	Research site	Terni
Korea, Republic of	Research site	Busan
Korea, Republic of	Research site	Seoul
Korea, Republic of	Research site	Seoul
Mexico	Research site	Mexico City	Distrito Federal
South Africa	Research site	Pretoria	Gauteng
Spain	Research site	Cádiz
Spain	Research site	L'Hospitalet de Llobregat	Barcelona
Spain	Research site	Madrid
Turkey	Research site	Ankara
Turkey	Research site	Istanbul
Turkey	Research site	Mersin
Turkey	Research site	Samsun
United Kingdom	Research site	Norwich	Norfolk
United States	Research site	Whittier	California

Sponsors (1)

Lead Sponsor	Collaborator
Archigen Biotech Limited

Countries where clinical trial is conducted

United States,  Australia,  Chile,  Czechia,  France,  Germany,  Hungary,  Italy,  Korea, Republic of,  Mexico,  South Africa,  Spain,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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
Other	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
Other	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
Other	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
Other	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
Other	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.
Other	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.
Other	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.
Other	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.
Other	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.
Other	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.
Other	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
Other	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
Primary	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	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
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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