This title slide focuses on "HGBCL Accrual Management – Single arm Phase 2 Trial." It includes a subtitle placeholder for the "[Protocol / Study Name]."

HGBCL Accrual Management – Single arm Phase 2 Trial

[Protocol / Study Name]

This slide outlines a single-arm, nonrandomized pivotal Phase 2 trial for Cohort 1, targeting histologies including DLBCL, tFL, PMBCL, HGBCL, and FL grade 3B. Enrollment happens at apheresis without IRT, with about 20% of participants being HGBCL to date.

Trial Context

• Single arm, nonrandomized pivotal Phase 2 trial
• Cohort 1 histologies: DLBCL, tFL, PMBCL, HGBCL, FL grade 3B
• Enrollment at apheresis, no IRT
• Approx. 20% HGBCL enrolled to date

The objectives of HGBCL Accrual Management focus on maintaining interpretability of study-level efficacy in a single-arm setting and avoiding overrepresentation of high-risk HGBCL relative to other LBCL histologies. They also aim to minimize unnecessary screen fails and treatment delays while continuing to collect and summarize data from already enrolled HGBCL patients.

Objectives of HGBCL Accrual Management

• Maintain interpretability of study level efficacy in a single arm setting
• Avoid overrepresentation of high-risk HGBCL relative to other LBCL histologies
• Minimize unnecessary screen fails and treatment delays
• Continue to collect/summarize data from already enrolled HGBCL patients

The slide "Operational Options Considered" presents four strategies for managing HGBCL enrollment in a clinical trial. Options include capping at 15% via sponsor management, excluding via protocol amendment, controlling as a subgroup with pause/close capabilities, and retaining patients for separate efficacy analysis.

Operational Options Considered

{ "features": [ { "icon": "📊", "heading": "Cap Enrollment at 15%", "description": "Limit HGBCL enrollment to ~15% via sponsor accrual management." }, { "icon": "❌", "heading": "Exclude via Amendment", "description": "Exclude HGBCL (NOS and MYC/BCL2 rearranged) via protocol amendment." }, { "icon": "⏸️", "heading": "Subgroup Accrual Control", "description": "Treat HGBCL as subgroup; pause/close via Enrollment Management Plan." }, { "icon": "📈", "heading": "Retain for Efficacy", "description": "Retain enough HGBCL patients for separate efficacy characterization." } ] }

Effective December 12, 2025, HGBCL patients are ineligible for Cohort 1 screening (Cohorts 3/4 unaffected). Sites must assess HGBCL pathology pre-screening, exclude those patients from Cohort 1, continue enrolled ones in the HGBCL subgroup, and contact the sponsor for uncertain histology.

Interim Operational Approach (Cohort 1)

• Effective 12 Dec 2025: HGBCL ineligible for Cohort 1 (Cohorts 3/4 unaffected)
• Sites assess HGBCL pathology before screening
• Exclude HGBCL patients from Cohort 1 screening
• Enrolled HGBCL patients continue in HGBCL subgroup
• Contact sponsor for uncertain histology classification

The slide outlines FDA adaptive design guidance relevant to single-arm trials, where interim efficacy evaluations unblind the study, and emphasizes prespecifying population changes in protocols/SAPs to preserve interpretability. Unplanned changes undermine results without FDA dialogue, external info-based changes need documentation, and for HGBCL, prospectively define classification rules, analysis sets, and subgroup summaries.

FDA Adaptive Design Guidance – Relevance

• Single arm: any interim efficacy evaluation effectively unblinded
• Population changes ideally prespecified in protocol/SAP
• Unplanned population changes can undermine interpretability without FDA dialogue
• Changes based on external info more acceptable but require documentation
• For HGBCL: prospectively define classification rules, analysis sets, subgroup summaries

This agenda slide outlines four key topics: Trial Context (study design, cohorts, and HGBCL enrollment), Accrual Management Objectives (maintaining efficacy interpretability and minimizing screen fails), Operational Options and Approach (options considered and interim Cohort 1 strategy), and FDA Guidance and Next Steps (regulatory relevance and implementation). It provides a structured overview for discussing trial accrual management.

Agenda

1. Trial Context

Study design, cohorts, and HGBCL enrollment to date

2. Accrual Management Objectives

Maintain efficacy interpretability and minimize screen fails

3. Operational Options and Approach

Options considered and interim Cohort 1 strategy

4. FDA Guidance and Next Steps

Regulatory relevance and implementation considerations Source: HGBCL Accrual Management – Single arm Phase 2 Trial