Guidance 05: A Prospective, Multicenter, Open-Label, Randomized, Controlled Study to Evaluate the Efficacy and Safety of Genotype-Guided Targeted Agents in Combination with Polatuzumab Vedotin, Rituximab, Cyclophosphamide, Doxorubicin and Prednisone (POLA-RCHP-X) Versus Pola-Rchp in Patients with Previously Untreated Diffuse Large B-Cell Lymphoma

Background and Significance

Improving the first-line treatment efficacy for Diffuse large B-cell lymphoma (DLBCL) remains an unmet need in high-risk patients. The POLARIX study demonstrated that the Pola-R-CHP regimen significantly prolonged progression-free survival (PFS) and reduced the risk of disease progression, relapse, or death by 27%, as compared to the R-CHOP regimen, while maintaining a similar safety profile.

Furthermore, an exploratory analysis of circulating tumor DNA (ctDNA) in the POLARIX study identified a greater unmet treatment need for patients with a ctDNA log-fold change (LFC) < 3 after one cycle of Pola-R-CHP treatment, with a 2-year PFS rate of 68%. DLBCL is characterized by significant biological heterogeneity, and genotyping has further elucidated both pathogenetic and therapeutic significance. The GUIDANCE-01 study demonstrated the feasibility, efficacy and safety of genetic subtype-guided immunochemotherapy (R-CHOP-X).

Therefore, for patients with ctDNA LFC < 3.0 after one cycle of Pola-R-CHP, we plan to combine Pola-R-CHP with targeted agents based on genotype (Pola-R-CHP-X, GUIDANCE-05 study).

Study Design and Methods:

The GUIDANCE 05 study (NCT06441097) is a Phase II, open-label, multicenter, randomized, controlled trial that will evaluate the efficacy and safety of Pola-R-CHP-X in patients with previously untreated DLBCL and a C1D14 ctDNA LFC < 3.0, in comparison with Pola-R-CHP.

Patients must be 18-75 years old with histologically confirmed newly diagnosed DLBCL, an IPI score of 2-5, and an ECOG Performance Status of 0-2. They must also have an LVEF ≥ 50% and adequate hematologic function. Additionally, after one cycle of Pola-R-CHP, their ctDNA must have decreased by less than 3.0 LFC.

Patients will receive one cycle of Pola-R-CHP along with genetic subtyping and ctDNA testing at C1D14. Patients with C1D14 ctDNA LFC≥3 will not be included in the study and will continue to receive Pola-R-CHP for up to 6 cycles. Patients with a C1D14 ctDNA LFC < 3 will be classified into the following subtypes based on genotyping results: MCD-like, BN2-like, N1-like, EZB-like MYC+, EZB-like MYC-, TP53 mutation, ST2-like, and NOS. Eligible patients will be randomly assigned (1:1) to receive either Pola-RCHP-X or Pola-R-CHP stratified by genotype.

For patients assigned to the Pola-RCHP-X arm, they will receive polatuzumab vedotin 1.8 mg/kg intravenously (IV) on Day 2, rituximab 375 mg/m² IV on Day 1, cyclophosphamide 750 mg/m² IV on Day 2, doxorubicin 50 mg/m² IV on Day 2 and prednisone 100 mg/day orally (PO) on Days 2-6 of every 21-day cycle for the first cycle. For the remaining 5 cycles, they will receive either acalabrutinib on Days 1-21 (MCD/BN2/N1-like subtypes), or lenalidomide on Days 1-10 (EZB MYC+/ EZB MYC-/ST2/-like subtypes and NOS), or decitabine on Days -5 to -1 (TP53 mutation subtypes), followed by standard Pola-R-CHP of every 21-day cycle.

For patients assigned to the Pola-R-CHP arm, they will receive polatuzumab vedotin 1.8 mg/kg IV on Day 2, rituximab 375 mg/m² IV on Day 1, cyclophosphamide 750 mg/m² IV on Day 2, doxorubicin 50 mg/m² IV on Day 2 and prednisone 100 mg/day PO on Days 2-6 of every 21-day cycle for 6 cycles.

The primary endpoint is PFS determined by an independent review committee (IRC). Secondary endpoints include PFS (investigator-assessed); IRC- and investigator-assessed event-free survival (EFS); IRC- and investigator-assessed complete response (CR) rate, objective response rate (ORR); overall survival (OS); and safety. Exploratory endpoints include PFS, EFS, CR rate, ORR, and OS in each genetic subtyping group.

An estimated 20 sites in China will enroll approximately 152 patients with newly diagnosed DLBCL (Pola-R-CHP-X n=76; Pola-R-CHP n=76) starting in January 2025.