Efficacy of Pola-RCHP-X vs Pola-RCHP in Untreated DLBCL

A Study to Evaluate the Efficacy and Safety of Genotype-guided Targeted Agents in Combination With POLA-RCHP VERSUS POLA-RCHP in Patients With Previously Untreated Diffuse Large B-cell Lymphoma

The purpose of this study is to compare the efficacy and safety of genotype-guided targeted agents in combination with polatuzumab vedotin plus rituximab, cyclophosphamide, doxorubicin, and prednisone (Pola RCHP-X) versus Pola RCHP in Chinese patients with previously untreated diffuse large B-cell lymphoma (DLBCL).

Study Overview

• Status: Not yet recruiting
• Conditions: Diffuse Large B-Cell Lymphoma
• Intervention / Treatment: Drug: Rituximab; Drug: Cyclophosphamide; Drug: Doxorubicin; Drug: Prednisone; Drug: Lenalidomide; Drug: Decitabine; Drug: Polatuzumab vedotin; Drug: Acalabrutinib

• Study Type: Interventional
• Enrollment (Estimated): 152
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Weili Zhao; Phone Number: 610707 +862164370045; Email: zwl_trial@163.com
• Study Contact Backup: Name: Pengpeng Xu; Phone Number: 610707 +862164370045; Email: pengpeng_xu@126.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Signed Informed Consent Form
• Age 18-75 years at the time of signing Informed Consent Form and willingness to comply with study protocol procedures
• Previously untreated participants with CD20-positive DLBCL
• IPI score 2-5
• ECOG Performance Status of 0, 1, or 2
• After 1 cycle of Pola-R-CHP, ctDNA decreased by < 3.0 LFC
• Life expectancy ≥ 6 months
• Left ventricular ejection fraction (LVEF) ≥ 50% on cardiac multiple-gated acquisition (MUGA) scan or cardiac echocardiogram (ECHO)

• Adequate hematologic function (unless due to underlying disease, as established for example, by extensive bone marrow involvement or due to hypersplenism secondary to involvement of the spleen by DLBCL per the investigator for which blood product transfusions are permitted) defined as follows:

  • Hemoglobin ≥ 9.0 g/dL without packed RBC transfusion during 7 days before first treatment
  • ANC ≥ 1.0 x 10^9/L
  • PLT ≥ 75 x 10^9/L

Exclusion Criteria:

• Contraindication to any of the individual components of Pola-RCHP or Acalabrutinib/Lenalidomide/ Decitabine
• Prior solid organ transplantation or SCT
• Current diagnosis of the following: Follicular lymphoma grade 3B; mediastinal grey zone lymphoma; primary mediastinal (thymic) large B-cell lymphoma; Burkitt lymphoma; PCNSL

• History of other malignancy that could affect compliance with the protocol or interpretation of results

  • Participants with a history of curatively treated basal or squamous cell carcinoma or melanoma of the skin or in situ carcinoma of the cervix at any time prior to the study are eligible
  • Participants with low-grade, early-stage prostate cancer (Gleason score 6 or below, Stage 1 or 2) with no requirement for therapy at any time prior to study are eligible
  • Participants receiving adjuvant endocrine therapy for non-metastatic, hormone receptor-positive breast cancer for ≥ 2 years prior to enrollment are eligible
  • Participants with any other malignancy appropriately treated with curative intent and the malignancy has been in remission without treatment for ≥ 2 years prior to enrollment are eligible
• Significant or extensive history of cardiovascular disease such as New York Heart Association Class III or IV cardiac disease or Objective Assessment Class C or D, myocardial infarction within the last 6 months prior to the start of Cycle 1, unstable arrhythmias, or unstable angina

• Current or past history of CNS disease, such as stroke, epilepsy, CNS vasculitis, or neurodegenerative disease.

  - Participants with a history of stroke who have not experienced a stroke or transient ischemic attack in the past 2 years and have no residual neurological deficits, as judged by the investigator, are allowed

• History or presence of an abnormal ECG that is clinically significant in the investigator's opinion

• History of treatment-emergent immune-related adverse events associated with prior immunotherapeutic agents, as follows:

  - Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) at study enrollment or significant infections within 4 weeks before the start of Cycle 1

• Active autoimmune disease which is not well controlled by therapy

  • Participants with a history of autoimmune-related hypothyroidism on a stable dose of thyroid-replacement hormone may be eligible
  • Participants with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study
  • Participants with active autoimmune disease with dermatologic manifestations are eligible for the study
  • Participants with a history of autoimmune hepatitis, systemic lupus erythematosus, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener granulomatosis, Sjögren syndrome, multiple sclerosis, or glomerulonephritis will be excluded
  • Participants with a history of immune thrombocytopenic purpura, autoimmune hemolytic anemia, Guillain-Barré syndrome, myasthenia gravis, myositis, rheumatoid arthritis, vasculitis, or other autoimmune disease will be excluded unless they have not required systemic therapy in the last 12 months

• Any of the following abnormal laboratory values (unless any of these abnormalities are due to underlying lymphoma):

  • ANC < 1.0 x 10^9/L
  • PLT < 75 x 10^9/L
  • Serum AST and ALT ≥ 2.5 x ULN
  • Total bilirubin ≥ 1.5 x ULN
  • Serum creatinine clearance < 30 mL/min (using Cockcroft-Gault formula)
• Any active infection within 7 days prior to Cycle 1 Day 1 that would impact participant safety
• Suspected active or latent tuberculosis (as confirmed by a positive interferon-gamma release assay)

• Positive test results for chronic hepatitis B infection (defined as positive hepatitis B surface antigen [HBsAg] serology)

  - Participants with occult or prior hepatitis B infection (defined as positive total hepatitis B core antibody and negative HbsAg) may be included if hepatitis B virus (HBV) DNA is undetectable at the time of screening. Such participants must be willing to undergo HBV DNA testing every month and appropriate antiviral therapy as indicated

• Positive test results for hepatitis C (hepatitis C virus [HCV] antibody serology testing)

  - Participants positive for HCV antibody are eligible only if PCR is negative for HCV RNA

• Participants with a history of progressive multifocal leukoencephalopathy
• Pregnancy or breastfeeding, or intention of becoming pregnant during the study or within 12 months after final dose of Pola-RCHP-X
• Other concurrent and uncontrolled medical conditions that, in the opinion of the investigator, would affect the patient's participation in the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Pola-RCHP-X; Participants will receive polatuzumab vedotin 1.8 milligrams per kilogram (mg/kg) intravenously (IV) on Day2, rituximab 375 milligrams per square meter (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 milligrams per day (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 Acalabrutinib 100 mg BID PO on days 1-21, or lenalidomide 25 mg/day PO on days 1-10, or decitabine 10 mg/m²/day IV on days -5 to -1 followed by standard Pola-RCHP of every 21-day cycle.	Drug: Rituximab; Rituximab IV infusion will be administered as per the schedule specified in the respective arm.; Drug: Cyclophosphamide; Cyclophosphamide IV infusion will be administered as per the schedule specified in the respective arm.; Drug: Doxorubicin; Doxorubicin IV infusion will be administered as per the schedule specified in the respective arm.; Drug: Prednisone; Prednisone PO will be administered as per the schedule specified in the respective arm.; Drug: Lenalidomide; Lenalidomide PO will be administered as per the schedule specified in the respective arm.; Drug: Decitabine; Decitabine IV infusion will be administered as per the schedule specified in the respective arm.; Drug: Polatuzumab vedotin; Polatuzumab vedotin IV infusion will be administered as per the schedule specified in the respective arm.; Drug: Acalabrutinib; Acalabrutinib PO will be administered as per the schedule specified in the respective arm.
Active Comparator: Pola-RCHP; Participants will receive polatuzumab vedotin 1.8 milligrams per kilogram (mg/kg) intravenously (IV) on Day2, rituximab 375 milligrams per square meter (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 milligrams per day (mg/day) orally (PO) on Days 2-6 of every 21-day cycle for 6 cycles.	Drug: Rituximab; Rituximab IV infusion will be administered as per the schedule specified in the respective arm.; Drug: Cyclophosphamide; Cyclophosphamide IV infusion will be administered as per the schedule specified in the respective arm.; Drug: Doxorubicin; Doxorubicin IV infusion will be administered as per the schedule specified in the respective arm.; Drug: Prednisone; Prednisone PO will be administered as per the schedule specified in the respective arm.; Drug: Polatuzumab vedotin; Polatuzumab vedotin IV infusion will be administered as per the schedule specified in the respective arm.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival（by IRC）	PFS, defined as the time from randomization to the first occurrence of disease progression or relapse using the 2014 Lugano Response Criteria or death due to any cause, whichever occurs first; as determined by the investigator	From randomization to the first occurrence of disease progression or relapse, or death from any cause, whichever occurs earlier (up to 24 months)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival（by the investigator）	PFS, defined as the time from randomization to the first occurrence of disease progression or relapse using the 2014 Lugano Response Criteria or death due to any cause, whichever occurs first; as determined by the investigator	From randomization to the first occurrence of disease progression or relapse, or death from any cause, whichever occurs earlier (up to 24 months)
Event-free survival	defined as the time from date of randomization to the earliest occurrence of any of the following: Disease progression/relapse as determined by the investigator and IRC (separately); Death due to any cause; The primary efficacy reason determined by the investigator, other than disease progression/relapse, that leads to initiation of NALT; If biopsy is obtained after treatment completion and is positive for residual disease regardless of whether NALT is initiated or not	up to approximately 24 months
Complete response rate	CR rate at the end of treatment by FDG-PET defined as the proportion of participants with CR at the end of treatment according to the 2014 Lugano Response Criteria; as determined by the investigator and IRC (separately)	End of treatment visit (6-8 weeks after last dose on Day 1 of Cycle 6 [Cycle length=21 days]
Objective response rate	ORR at treatment completion or discontinuation defined as the proportion of participants with partial response (PR) or CR at the end of treatment according to the 2014 Lugano Response Criteria; as determined by the investigator and IRC(separately)	End of treatment visit (6-8 weeks after last dose on Day 1 of Cycle 6 [Cycle length=21 days]
Overall survival	OS defined as the time from randomization to death from any cause	up to approximately 2 years
Number of Participants With Treatment-Related Adverse Events as Assessed by CTCAE v5.0	An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.	From enrollment to study completion, a maximum of 3 years

Collaborators and Investigators

• Sponsor: Ruijin Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): December 31, 2024
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): December 31, 2027

Study Registration Dates

• First Submitted: May 26, 2024
• First Submitted That Met QC Criteria: June 2, 2024
• First Posted (Estimated): June 4, 2024

Study Record Updates

• Last Update Posted (Estimated): June 4, 2024
• Last Update Submitted That Met QC Criteria: June 2, 2024
• Last Verified: June 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Lymphoma; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Anti-Inflammatory Agents; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Protein Kinase Inhibitors; Antibiotics, Antineoplastic; Immunoconjugates; Tyrosine Kinase Inhibitors; Cyclophosphamide; Decitabine; Lenalidomide; Rituximab; Prednisone; Doxorubicin; Acalabrutinib; Polatuzumab vedotin
• Other Study ID Numbers: GUIDANCE-005

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No