A Study to Assess Safety and Efficacy of CHO-H01 in Subjects With Refractory or Relapsed Non-Hodgkin's Lymphoma

Study Overview
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Brief Summary
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This is a 2-part study. Part 1/Phase 1 of the study will be conducted to determine the safety and tolerability of CHO-H01 in subjects with relapsed/refractory CD20+ non-Hodgkin's lymphoma. It will also determine maximum tolerated dose (MTD) and recommended phase II dose (RP2D). Part 2/Phase 2 will assess the anticancer activity and safety of CHO-H01 in subjects with relapsed/refractory CD20+ non-Hodgkin's lymphoma.

Detailed Description
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Phase I FIH study includes subjects with relapsed/refractory CD20 + non-Hodgkin's lymphoma, who may benefit from treatment with CHO-H01. In Phase I of the study, the first 2 cohorts will follow a 2-step modified accelerated titration dose escalation design and subsequent cohorts will follow a standard 3+3 dose escalation design. The investigational medicinal product, CHO-H01, will be administered via IV infusion once weekly for 4 weeks in Cycle 1 and then once only (on Day 1) in each subsequent 21-day cycle until disease progression or for up to 6 cycles (19 weeks) of treatment. Once the MTD/RP2D has been confirmed, Phase IIa of the study will be initiated. The purpose of Phase IIa is to assess anticancer activity and safety in 2 cohorts of subjects with either aggressive B-cell lymphoma (DLBCL-NOS) or indolent (follicular) B-cell lymphoma, until intolerable toxicity or disease progression, withdrawal, or death occurs.

Official Title
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A Phase I/IIa, Open-label, Multicenter Study of the Safety and Efficacy of CHO-H01 as a Single Agent to Subjects With Refractory or Relapsed Non-Hodgkin's Lymphoma

Conditions
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Non-Hodgkin Lymphoma

Intervention / Treatment
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* Biological: CHO-H01


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Life expectancy of >12 weeks. Body mass index of 18 to 32 kg/m2. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. Phase I: Have histologically (laboratory test) confirmed CD20 + non-Hodgkin's lymphoma according to the World Health Organization's 2016 classification: Low grade lymphoma: follicular lymphoma (Grades 1-3a), marginal zone lymphoma, small lymphocytic lymphoma; Other lymphoma: DLBCL (NOS: to include germinal center B-cell-like [GCB] and activated B-cell-like [ABC]), follicular lymphoma Grade 3b, mantel cell lymphoma; primary mediastinal large B-cell lymphoma. Phase IIa: Histologically confirmed CD20 + non-Hodgkin's lymphoma according to the World Health Organization's 2016 classification,15 only: Follicular lymphoma: Grades 1-3a; DLBCL (NOS: to include germinal center B-cell-like [GCB] and activated B cell-like [ABC]). Have at least one measurable lesion that is at least 1.5 cm in its largest dimension. Off treatment for 30 days from last anti-CD20 infusion until planned administration of CHO-H01. If no original sample is available, is willing and able to provide an adequate tumor biopsy sample at Screening. Have adequate cardiac function: without clinically significant and/or uncontrolled heart disease. Must be sterile, or have a monogamous partner who is surgically sterile, or at least 2 years postmenopausal, or be committed to use an acceptable form of birth control for the duration of the study (male), and for the duration of the study and for 3 months following the last CHO-H01 administration (female). Exclusion Criteria: Must not have a history of egg allergy or allergic reactions to any component of CHO-H01. Must not have any known or current illnesses (such as autoimmune disease, unless well controlled or resolved), infection, or other condition that could limit study compliance or interfere with assessments. Subjects who have received anti-programmed death-ligand 1 (PD-L1), programmed cell death 1 (PD-1), or cytotoxic T-lymphocyte associated protein 4 (CTLA-4) therapy. Subjects who have completed an autologous stem cell transplant within 100 days prior to CHO-H01 therapy or an allogeneic stem cell transplant. Subjects with known hepatitis B surface antigen (HBsAg) seropositive or known or suspected active hepatitis C infection with detectable viral load. Subjects with known human immunodeficiency virus (HIV) infection Subjects who have had radiation therapy, major surgical procedure or live vaccinations within 28 days prior to CHO-H01 administration. Subjects with a history of type I hypersensitivity or anaphylactic reactions to murine proteins or to previous infusions of CD20 monoclonal antibodies. Subjects who have received (or are receiving) systemic corticosteroids: At a daily dose higher than 15 mg prednisone or equivalent within 14 days prior to the first administration of CHO-H01; Topical, inhaled, nasal, and ophthalmic steroids are allowed. Inadequate bone marrow, hepatic or renal function. Subjects with a history of seizure disorder. Subjects who are pregnant or breast feeding.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Interventional Model Description: 3+3 sequential cohort design
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CHO-H01<br>Subjects will receive CHO-H01. | Biological: CHO-H01<br>* Subjects will be administered intravenous (IV) infusion of CHO-H01, once a week for 4 weeks (Cycle 1- 28-Day cycle), and then once (on Day 1) in each subsequent 21-day cycle until disease progression (or a total of 6 cycles [19 weeks] of study).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of subjects with adverse events (AE) (Phase I and Phase IIa) | To assess the safety and tolerability of CHO-H01 in subjects with relapsed/refractory CD20 + non-Hodgkin's lymphoma in Phase 1 and of the DLBCL-NOS and follicular subtypes in Phase IIa of the study. | From Screening (Day -28 to Day 1) up to final follow-up visit (30 days after the last administration of CHO-H01 in Cycle 6) [approximately 16 months] | 
| Number of subjects with dose-limiting toxicities (Phase I) | All AEs and toxicities are evaluated based on the National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE) Version 5.0. The 5 general grades are Grade 1: Mild, Grade 2: Moderate, Grade 3: Severe, Grade 4: Life-threatening or disabling, and Grade 5: Death (outcome of AE). | Cycle 1 (duration of Cycle 1 is 28 days) | 
| Objective Response Rate (Phase IIa) | Objective response rate (ORR) is the proportion of subjects with a best overall response of complete response (CR) or partial response (PR). ORR will be measured based on Modified (not using PET imaging) Lugano Revised Criteria for Response assessment. | Cycle 3 Day 1 Up to End of treatment (EOT) or Final Follow-up Visit (30 days after the last administration of CHO-H01 in Cycle 6) [approximately 16 months] | 
| Best overall response (Phase IIa) | The best overall response (CR, PR, stable disease [SD], or progressive disease [PD]) is defined as the best response across all time points. | Cycle 3 Day 1 Up to End of treatment (EOT) or Final Follow-up Visit (30 days after the last administration of CHO-H01 in Cycle 6) [approximately 16 months] | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum concentration (Cmax) (Phase I and Phase IIa) | To characterize the PK of CHO-H01. | Cycle 1 Day 1 and Cycle 2 Day 1 (Cycle 1 is of 28 days and Cycle 2 is of 21 days) | 
| Time to Cmax (tmax) (Phase I and Phase IIa) | To characterize the PK of CHO-H01. | Cycle 1 Day 1 and Cycle 2 Day 1 (Cycle 1 is of 28 days and Cycle 2 is of 21 days) | 
| Area under the concentration-time curve from zero to the last quantifiable concentration [AUC(0-last)] (Phase I and Phase IIa) | To characterize the PK of CHO-H01. | Cycle 1 Day 1 and Cycle 2 Day 1 (Cycle 1 is of 28 days and Cycle 2 is of 21 days) | 
| Area under the concentration-time curve over the 7-day dosing interval [AUC(0-tau)] (Phase I and Phase IIa) | To characterize the PK of CHO-H01. | Cycle 1 Day 1 and Cycle 2 Day 1 (Cycle 1 is of 28 days and Cycle 2 is of 21 days) | 
| Accumulation ratio for Cmax (Phase I and Phase IIa) | To characterize the PK of CHO-H01. | Cycle 2 Day 1 (each cycle is of 21 days) | 
| Accumulation ratio for AUC(0-tau) (Phase I and Phase IIa) | To characterize the PK of CHO-H01. | Cycle 2 Day 1 (each cycle is of 21 days) | 
| Systemic clearance (CL) (Phase I and Phase IIa) | To characterize the PK of CHO-H01, if steady-state conditions have been reached. | Cycle 2 Day 1 (Cycle 2 is of 21 days) | 
| Volume of distribution at steady-state (Vss) (Phase I and Phase IIa) | To characterize the PK of CHO-H01. | Cycle 1 Day 1 and Cycle 2 Day 1 (Cycle 1 is of 28 days and Cycle 2 is of 21 days) | 
| Terminal rate constant (λz) (Phase I and Phase IIa) | To characterize the PK of CHO-H01. | Cycle 1 Day 1 and Cycle 2 Day 1 (Cycle 1 is of 28 days and Cycle 2 is of 21 days) | 
| Terminal half-life (t1/2) (Phase I and Phase IIa) | To characterize the PK of CHO-H01. | Cycle 1 Day 1 and Cycle 2 Day 1 (Cycle 1 is of 28 days and Cycle 2 is of 21 days) | 
| Area under the concentration-time curve from zero extrapolated to infinity [AUC(0-inf)] (Phase I and Phase IIa) | To characterize the PK of CHO-H01. | Cycle 1 Day 1 (Cycle 1 is of 28 days) | 
| CL (Phase I and Phase IIa) | To characterize the PK of CHO-H01. | Cycle 1 Day 1 (Cycle 1 is of 28 days) | 
| Time linearity (Phase I and Phase IIa) | To characterize the PK of CHO-H01. | Cycle 1 Day 1 and Cycle 2 Day 1 (Cycle 1 is of 28 days and Cycle 2 is of 21 days) | 
| Volume of distribution (Vz) (Phase I and Phase IIa) | To characterize the PK of CHO-H01. | Cycle 1 Day 1 and Cycle 2 Day 1 (Cycle 1 is of 28 days and Cycle 2 is of 21 days) | 
| Incidence of antidrug antibodies (ADA) (Phase I and Phase IIa) | To investigate the immunogenicity of CHO-H01, using a validated bridging ADA assay. | From Cycle 1 Day 1 (Cycle 1 is of 28 days) up to Final Follow-up Visit (30 days after the last administration of CHO-H01 in Cycle 6) [approximately 16 months] | 
| Objective Response Rate (Phase I) | Objective response rate (ORR) is the proportion of subjects with a best overall response of complete response (CR) or partial response (PR). ORR will be measured based on Modified (not using PET imaging) Lugano Revised Criteria for Response assessment. | Cycle 3 Day 1 Up to End of treatment (EOT) or Final Follow-up Visit (30 days after the last administration of CHO-H01 in Cycle 6) [approximately 16 months] | 
| Best overall response (Phase I) | The best overall response (CR, PR, stable disease [SD], or progressive disease [PD]) is defined as the best response across all time points. | Cycle 3 Day 1 Up to End of treatment (EOT) or Final Follow-up Visit (30 days after the last administration of CHO-H01 in Cycle 6) [approximately 16 months] | 
| Clinical benefit rate (Phase I and IIa) | The clinical benefit rate (CBR) is the proportion of subjects who achieve CR, PR, and durable SD (SD ≥12 weeks) based on the Modified (not using PET imaging) Lugano Revised Criteria for Response assessment. | Cycle 3 Day 1 Up to End of treatment (EOT) or Final Follow-up Visit (30 days after the last administration of CHO-H01 in Cycle 6) [approximately 16 months] | 
| Time to event endpoints of time to progression (TTP) (Phase I and IIa) | Time to progression is the time from the date of first study dose to disease progression, evaluated using Modified (not using PET imaging)Lugano Revised Criteria for Response assessment. | Cycle 3 Day 1 Up to End of treatment (EOT) or Final Follow-up Visit (30 days after the last administration of CHO-H01 in Cycle 6) [approximately 16 months] | 
| Duration of stable disease (Phase I) | Duration of SD defined as the time interval, in the absence of either CR or PR, will be calculated between the date of the first CHO-H01 administration and the date of disease progression or death for any cause, whichever occurs earlier; based on the Modified (not using PET imaging) Lugano Revised Criteria for Response assessment. | Cycle 3 Day 1 Up to End of treatment (EOT) or Final Follow-up Visit (30 days after the last administration of CHO-H01 in Cycle 6) [approximately 16 months] | 
| Progression-free survival (Phase I and IIa) | Progression-free survival (PFS) is the time from the date of first study dose to disease progression or death whichever occurs first in subjects, evaluated using Modified (not using PET imaging) Lugano Revised Criteria for Response assessment. | Cycle 3 Day 1 Up to End of treatment (EOT) or Final Follow-up Visit (30 days after the last administration of CHO-H01 in Cycle 6) [approximately 16 months] | 
| Duration of response (Phase I) | Duration of response for responders (CR or PR) is the time interval between the date of the earliest qualifying response and the date of disease progression or death for any cause, whichever occurs earlier; based on the Modified (not using PET imaging) Lugano Revised Criteria for Response assessment. | Cycle 3 Day 1 Up to End of treatment (EOT) or Final Follow-up Visit (30 days after the last administration of CHO-H01 in Cycle 6) [approximately 16 months] | 
| Overall survival (Phase I and IIa) | The overall survival (OS) is the time from the date of the first study dose to the date of death (any cause), evaluated using Modified (not using PET imaging) Lugano Revised Criteria for Response assessment. | up to 9 months after the last CHO-H01 administration (approximately 16 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CHO-H01, Anti-CD20 Antibodies, Large B-cell lymphoma, Follicular lymphoma, Glyco-engineered anti-CD20 antibody