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Lymphoma, Follicular

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Follicular Lymphoma

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Rituximab

Immunomodulating Agents

Antineoplastic Agents, Immunological

Immunologic Factors

Dose of 375mg/m2 body surface area (BSA) i.v. on Days 1, 8, 15, and 22

SAIT101

MabThera®

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.

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.

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

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).

Pharmacokinetic endpoint: maximum plasma concentration (Cmax, µg/ml ) after the first dose (Week 1) and the fourth dose (week 4) (Cmax,w1, Cmax,w4).

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).

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).

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.

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.

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.

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.

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.

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.

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.

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)

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.

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.

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.

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.

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.

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.

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.

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.

Archigen Biotech Limited

All AEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA) v22.1. If an AE changed from non-SAE to be an SAE, it was treated as a new event and was counted as 2 events in the AE summary. A treatment-emergent AE (TEAE) was defined as any AE with an onset date on or after the date of the first dose of study treatment until Week 28, or the End of Study (EOS) visit, if earlier.

SAIT101: Dose of 375 mg/m2 body surface area (BSA) intravenous on Weeks 1, 2, 3, and 4.

MabThera: Dose of 375 mg/m2 body surface area (BSA) intravenous on Weeks 1, 2, 3, and 4.

MabThera

MabThera: Dose of 375 mg/m2 body surface area (BSA) intravenous on Weeks 1, 2, 3 and 4.

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Hungary

Czechia

United States

United Kingdom

Spain

South Korea

Turkey

Italy

Mexico

South Africa

Australia

Chile

France

Germany

Ukraine

Thailand

Serbia

Panama

India

Georgia

Guatemala

Belarus

Croatia

Egypt

Philippines

Region of Enrollment

Height (cm)

Weight at baseline (kg)

Body Mass Index (kg/m^2)

Body Surface Area (m^2)

Disease duration was derived from initial disease diagnosis date to the date of informed consent. Note that initial disease diagnosis can be confirmed by biopsy after informed consent.

Disease Duration (Years)

Females of childbearing potential

The ECOG score is used in the evaluation of cancer patients and can help with prognosis and management of the malignant condition because performance status is highly correlated with survival. A higher ECOG rating score generally equates to a worst outcome. ECOG scores 0 and 1 are defined as:

ECOG Score 0: Asymptomatic (Fully active, able to carry on all pre-disease activities without restriction);

ECOG Score 1: Symptomatic but completely ambulatory (Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature.

Eastern Co-operative Oncology Group (ECOG) performance status

Antidrug Antibody (ADA) Status at Baseline

Ann Arbor staging is the staging system for lymphomas, both in Hodgkin's lymphoma and non-Hodgkin lymphoma.

Stage I indicates that the cancer is located in a single region.

Stage II indicates that the cancer is located in two separate regions, an affected lymph node or lymphatic organ and a second affected area.

Stage III indicates that the cancer has spread to both sides of the diaphragm.

Stage IV indicates diffuse or disseminated involvement of one or more extralymphatic organs.

Ann Arbor Staging

Ann Arbor staging is the staging system for lymphomas, both in Hodgkin's lymphoma (formerly designated Hodgkin's disease) and non-Hodgkin lymphoma (abbreviated NHL). It was initially developed for Hodgkin's, but has some use in NHL. It has roughly the same function as TNM staging in solid tumors

Ann Arbor Clinical Stage (CS) as obtained by doctor's examination and tests, An Arbor Pathological Stage (PS) as obtained by exploratory laparotomy with splenectomy.

Type of Ann Arbor Staging

Follicular Lymphoma International Prognostic Index (FLIPI) score of 0 to 1 is considered "low risk" with a 10 year overall survival of 70%. A score of 2 is considered "intermediate risk" with a 10 year overall survival of 50%. Finally, a score of ≥ 3 is considered "high risk" with a 10 year overall survival of 35%.

Risk Groups According to Follicular Lymphoma International Prognostic Index (FLIP-2) Score

Medical Director

Adjusted Difference Rate (%) in Overall Response Rate (ORR) of SAIT101 versus MabThera at Week 28.

SAIT101: Dose of 375 mg/m2 body surface area (BSA) intravenous on Weeks 1, 2, 3 and 4,

Overall Response Rate (ORR) at Week 28

Adjusted Difference Rate of Overall Response Rate (ORR) of SAIT101 versus MabThera at Week 12.

Overall Response Rate (ORR) at Week 12

CR at Week 12

CR at Week 28

Complete Response (CR) at Weeks 12 and 28

PR at Week 12

PR at Week 28

Partial Response (PR) at Weeks 12 and 28

SD at Week 12

SD at Week 28

Stable Disease (SD) at Weeks 12 and 28

PD at Week 12

PD at Week 28

Progressive Disease (PD) at 12 and 28 Weeks

Time to Event (TTE) Hazard Ratio (HR) of SAIT101:MabThera. The TTE is defined as the time from the date of randomization to the date when an event occurs; an event is disease progression as assessed by Investigator, death due to any cause, or the start of new treatment, whichever comes first.

Time to Event (TTE)

Statistical Comparison: geometric least square (GLS) Mean Ratio (90% Confidence Interval (CI)) (%) of SAIT101 versus MabThera Area Under the Concentration time Curve Day 0 to Week 1 (AUC0-168,w1) (h×µg/mL). The statistical comparison of the loge-transformed primary parameters between treatments is based on an analysis of variance model with fixed effect for treatment.

Statistical Comparison: geometric least square (GLS) Mean Ratio (90% Confidence Interval (CI)) %) of SAIT101 versus MabThera Area Under the Concentration time Cure Day 0 to Week 4 (AUC0-168,w4) (h×µg/mL). The statistical comparison of the loge-transformed primary parameters between treatments is based on an analysis of variance model with fixed effect for treatment.

AUC0-168, week 1

AUC0-168, week 4

Truncated Area Under the Concentration-time Curve (AUC) Over the First and Fourth Dosing Intervals (AUC0 168,w1, AUC0-168,w4).

Statistical Comparison: geometric least square (GLS) Mean Ratio (90% CI) (%) of SAIT101 versus MabThera maximum plasma concentration at Week 1 (Cmax,w1) (h×µg/mL). The statistical comparison of the loge-transformed primary parameters between treatments is based on an analysis of variance model with fixed effect for treatment.

Statistical Comparison: geometric least square (GLS) Mean Ratio (90% CI) (%) of SAIT101 versus MabThera maximum plasma concentration at Week 4 (Cmax,w1) (h×µg/mL). The statistical comparison of the loge-transformed primary parameters between treatments is based on an analysis of variance model with fixed effect for treatment

Cmax, week 1

Cmax, week 4

Maximum Concentration (Cmax) After the First Dose and the Fourth Dose (Cmax,w1, Cmax,w4).

Accumulation Ratio for AUC0-168 Obtained From the Fourth Dose Versus the First Dose (RAUC).

Accumulation Ratio for the Maximum Plasma Concentration (Cmax) From the Fourth Dose Versus the First Dose (RCmax).

Statistical Comparison: geometric least square (GLS) Mean Ratio (90% CI) (%) of SAIT101 versus MabThera trough plasma concentration at the end of the dosing period (Day 29) (Ctrough,d29) (µg/mL) . The statistical comparison of the log-transformed primary parameters between treatments is based on an analysis of variance model with fixed effect for treatment

Ctrough Day 8

Ctrough Day 15

Ctrough Day 22

Ctrough Day 29

Trough Concentrations on Days 1, 8, 15, 22, and 29 (Ctrough).

Week 1 Mean Change from Baseline

Week 2 Mean Change from Baseline

Week 3 Mean Change from Baseline

Week 4 Mean Change from Baseline

Week 5 Mean Change from Baseline

Week 12 Mean Change from Baseline

Week 20 Mean Change from Baseline

Week 28 Mean Change from Baseline

Observed Change From Baseline CD19+ B-Lymphocyte Cluster of Differentiation 19 (CD-19+ B-Cell) Counts up to Week 28

Week 1 % Change from Baseline

Week 2 % Change from Baseline

Week 3 % Change from Baseline

Week 4 % Change from Baseline

Week 5 % Change from Baseline

Week 12 % Change from Baseline

Week 20 % Change from Baseline

Week 28 % Change from Baseline

Percent Change From Baseline CD19+ B-Lymphocyte Cluster of Differentiation 19 (CD-19+ B-Cell) Counts up to Week 28

AUEC0-168,w1 (cells*day/µL)

AUEC0-168,w2 (cells*day/µL)

AUEC0-168,w3 (cells*day/µL)

AUEC0-168,w4 (cells*day/µL)

AUEC0-w12 (cells*day/µL)

AUEC0-w28 (cells*day/µL)

Area Under the Curve Change From Baseline B-lymphocyte Cluster of Differentiation 19 (CD19+ B-cell) Count Time Curve (AUEC) Over the Dosing Interval

Statistical Comparison of CD19+ B-cell Pharmacodynamic Parameters (Pharmacodynamic Analysis Set). Area under the pharmacodynamic time effect curve from baseline (Time 0) to Week 1 (AUEC0-168,w1), normalized (cells/µL). The statistical comparison of the between treatments is based on an analysis of covariance (ANOVA) model with fixed effect for treatment and a covariate for baseline value.

Statistical Comparison of CD19+ B-cell Pharmacodynamic Parameters (Pharmacodynamic Analysis Set). Area under the pharmacodynamic time effect curve from baseline (Time 0) to Week 2 (AUEC0-168,w2), normalized (cells/µL). The statistical comparison of the between treatments is based on an analysis of covariance (ANOVA) model with fixed effect for treatment and a covariate for baseline value.

Statistical Comparison of CD19+ B-cell Pharmacodynamic Parameters (Pharmacodynamic Analysis Set). Area under the pharmacodynamic time effect curve from baseline (Time 0) to Week 3 (AUEC0-168,w3), normalized (cells/µL). The statistical comparison of the between treatments is based on an analysis of covariance (ANOVA) model with fixed effect for treatment and a covariate for baseline value.

Statistical Comparison of CD19+ B-cell Pharmacodynamic Parameters (Pharmacodynamic Analysis Set). Area under the pharmacodynamic time effect curve from baseline (Time 0) to Week 4 (AUEC0-168,w4), normalized (cells/µL). The statistical comparison of the between treatments is based on an analysis of covariance (ANOVA) model with fixed effect for treatment and a covariate for baseline value.

Statistical Comparison of CD19+ B-cell Pharmacodynamic Parameters (Pharmacodynamic Analysis Set). Area under the pharmacodynamic time effect curve from baseline (Time 0) to Week 12 (AUEC0-168,w12), normalized (cells/µL). The statistical comparison of the between treatments is based on an analysis of covariance (ANOVA) model with fixed effect for treatment and a covariate for baseline value.

Statistical Comparison of CD19+ B-cell Pharmacodynamic Parameters (Pharmacodynamic Analysis Set). Area under the pharmacodynamic time effect curve from baseline (Time 0) to Week 28 (AUEC0-168,w28), normalized (cells/µL). The statistical comparison of the between treatments is based on an analysis of covariance (ANOVA) model with fixed effect for treatment and a covariate for baseline value.

AUEC0-168,w1, normalized (cells/µL)

AUEC0-168,w2, normalized (cells/µL)

AUEC0-168,w3, normalized (cells/µL)

AUEC0-168,w4, normalized (cells/µL)

AUEC0-w12, normalized (cells/µL)

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

Spots Global Cancer Trial Database for low tumor burden follicular lymphoma (ltbfl)