Linperlisib Combined With Immunochemotherapy in Relapsed/Refractory LBCL

An Open-label, Multicenter, Multi-cohort Clinical Study of Linperlisib Combined With Standard Immunochemotherapy in the Treatment of Relapsed/Refractory Large B-Cell Lymphoma Failing to First-line Therapy

To evaluate the efficacy and safety of Linperlisib combined with standard immunochemotherapy in patients with R/R LBCL.

Study Overview

• Status: Recruiting
• Conditions: Relapsed/Refractory Large B-Cell Lymphoma
• Intervention / Treatment: Drug: Linperlisib; Drug: Rituximab; Drug: Gemcitabine; Drug: Oxaliplatin; Drug: Ifosfamide; Drug: Carboplatin; Drug: Etoposide; Drug: Dexamethasone; Drug: Cisplatin; Drug: Ara-C; Drug: Vinorelbine; Drug: Mitoxantrone hydrochloride liposome

Detailed Description

This is a phase 2, open-label, multicenter, multi-cohort study evaluating the efficacy and safety of Linperlisib combined with standard immunochemotherapy in the treatment of relapsed/refractory LBCL after first-line treatment. This study is divided into a safety run-in phase and a dose expansion phase.The primary objective of the safety run-in phase was to determine the recommended dose for the dose expansion phase based on dose-limiting toxicities (DLTs).

The dose expansion phase consisted of Cohort 1 and Cohort 2.Cohort 1 was transplant-ineligible patients who received Linperlisib in combination with R-Gemox at RP2D for 6 cycles.Cohort 2 consisted of patients scheduled for transplantation who received 3 cycles of Linperlisib combined with R-ICE/DHAP/GVM regimen, followed by autologous hematopoietic stem cell transplantation in responding patients

• Study Type: Interventional
• Enrollment (Estimated): 89
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Wei Liu, MD; Phone Number: +86 022-23608463; Email: liuwei@ihcams.ac.cn
• Study Contact Backup: Name: Lugui Qiu, MD; Phone Number: +86 022-23908461; Email: qiulg@ihcams.ac.cn

Study Locations

• China
  • Tianjin
    • Tianjin, Tianjin, China, 300020
      • Recruiting
      • Institute of Hematology & Blood Disease Hospital
      • Principal Investigator: Wei Liu, MD
      • Contact: Wei Liu, MD; Phone Number: 86-022-23908463; Email: liuwei@ihcams.ac.cn

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Histologically confirmed large B-cell lymphoma (LBCL), including diffuse large B-cell lymphoma unspecified (DLBCL, NOS), follicular lymphoma grade 3B (FL, 3B), high-grade B-cell lymphoma unspecified (HGBCL, NOS), DLBCL/HGBCL with MYC and BCL2 rearrangements, FL transformed DLBCL without a previous history of indolent lymphoma.
2. Relapsed or refractory after first-line immunochemotherapy (which must include CD20 monoclonal antibody and anthracycline) 1)Refractory is defined as failure to achieve a complete response to first-line therapy (excluding patients who are intolerant to first-line therapy), including progressive disease (PD) as the best response to first-line therapy; stable disease (SD) as the best response after at least 4 cycles of first-line therapy (eg, 4 cycles of R-CHOP); partial response (PR) as the best response after at least 6 cycles of first-line therapy with biopsy-confirmed residual disease or disease progression within 12 months of initiating first-line therapy; complete response to first-line therapy followed by progression within 12 months after the end of therapy. 2)Relapse was defined as a complete response to first-line therapy followed by progression confirmed more than 12 months after the end of therapy.
3. Subjects must have at least 1 measurable lesion/evaluable lesion that meets the 2014 version of the Lugano Lymphoma Evaluation Criteria.
4. Subjects has no known or suspected central nervous system involvement by lymphoma.
5. Previous treatment with any antineoplastic therapy (including radiation therapy, chemotherapy, hormonal therapy, surgery, or molecular targeted therapy) for which participation in this trial must have exceeded 2 weeks or 5 drug half-lives, whichever is shorter.
6. Age ≥ 18 years.
7. ECOG score 0-2.
8. Expected survival ≥ 3 months.
9. Women of Childbearing Potential subjects must have a negative serum/urine pregnancy test within 7 days prior to the first dose; female subjects of childbearing potential and male subjects with partners of childbearing potential, as well as their partners, should agree to use effective contraception from signing the ICF until 6 months after the last dose of study drug.
10. Able to comply with the trial protocol as judged by the investigator.

11. Each subject (or legally acceptable representative) voluntarily joined the study and signed an informed consent form.

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Exclusion Criteria:

1. Other malignancies within the last 5 years, except radically treated basal cell carcinoma of the skin, squamous cell carcinoma of the skin, carcinoma in situ of the breast, and carcinoma in situ of the cervix.
2. Previous autologous or allogeneic hematopoietic stem cell transplantation.
3. History of Richter transformation.
4. Received > 1 line of systemic antineoplastic therapy.
5. Prior treatment with PI3K inhibitors.
6. Known hypersensitivity to trial products.
7. Active viral, bacterial, or fungal infection requiring treatment (eg, pneumonia, etc.).
8. Requiring prolonged systemic hormones (at doses equivalent to > 10 mg prednisone/day) or any other form of immunosuppressive therapy. Subjects taking inhaled or topical corticosteroids may be enrolled.

9. Concomitant diseases and medical history:

   1. Multiple factors affecting oral medication (e.g. inability to swallow, chronic diarrhea, ileus, etc.).
   2. Patients with a history of psychotropic substance abuse who cannot quit or have mental disorders.

   3. Subjects with any severe and/or uncontrolled disease including:

      1)Unsatisfactory blood pressure control (systolic blood pressure ≥ 150 mmHg or diastolic blood pressure ≥ 100 mmHg). 2)Patients with ≥ grade 2 myocardial ischemia or myocardial infarction, arrhythmia (including QTc ≥ 450 ms (male), QTc ≥ 470 ms (female)) and ≥ grade 2 congestive heart failure (New York Heart Association (NYHA) classification). 3)Active interstitial pneumonia or other chronic lung disease resulting in severely impaired lung function defined as FEV1 and DLCOc < 60% of predicted normal; history of interstitial pneumonia due to COVID-19. 4)Abnormal liver: I.Decompensated cirrhosis (Child-Pugh class B or C). II.Known history of clinically significant liver disease. 5)Renal failure requiring hemodialysis or peritoneal dialysis. 6)Subjects with uncontrolled pleural effusion, pericardial effusion, or ascites requiring repeated drainage. 7)Urine routine showed urine protein ≥ + +, and confirmed 24-hour urine protein quantification > 1.0 g.

   4. Patients with active or history of autoimmune diseases that may relapse (e.g., systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, autoimmune thyroid disease, multiple sclerosis, vasculitis, glomerulonephritis, etc.), or patients at high risk. Patients with autoimmune hypothyroidism requiring only hormone replacement therapy may be considered for enrollment if the disease is stable as assessed by the investigator.
10. Known history of human immunodeficiency virus (HIV) infection and/or acquired immunodeficiency syndrome.
11. Positive pregnancy test at baseline in female patients who are pregnant, lactating, or of childbearing potential.

12. Concurrent medical conditions that, in the investigator 's judgment, would seriously compromise the patient' s safety or the patient 's completion of the study.

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Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1 transplant-ineligible patients: Linperlisib combined with R-Gemox regimen; Cohort 1 consisted of transplant-ineligible patients who received Linperlisib in combination with R-Gemox. The treatment regimen was as follows: Linperlisib (RP2D dosage) on Days 1-14, rituximab 375 mg/m² on Day 0, gemcitabine 1000 mg/m² on Day 1, and oxaliplatin 130 mg/m² on Day 1, every 21 days for 6 cycles.	Drug: Linperlisib; Linperlisib RP2D D1-14; Drug: Rituximab; rituximab 375 mg/m2 D0; Drug: Gemcitabine; gemcitabine per regimen dosage; Drug: Oxaliplatin; Oxaliplatin 130 mg/m2 D1
Experimental: Cohort 2 patients scheduled for transplantation:Linperlisib combined with R-ICE/DHAP/GVM regimens; Cohort 2 consisted of patients scheduled for transplantation who received 3 cycles of Linperlisib (RP2D, D1-14) combined with R-ICE/DHAP/GVM regimen (R-ICE regimen: rituximab, ifosfamide, carboplatin, etoposide; R-DHAP regimen: rituximab, cytarabine, dexamethasone, cisplatin; R-GVM regimen: rituximab, gemcitabine, vinorelbine, mitoxantrone liposome), followed by autologous hematopoietic stem cell transplantation in responding patients.	Drug: Linperlisib; Linperlisib RP2D D1-14; Drug: Rituximab; rituximab 375 mg/m2 D0; Drug: Gemcitabine; gemcitabine per regimen dosage; Drug: Ifosfamide; Ifosfamide 5g/m2 D2; Drug: Carboplatin; Carboplatin AUC=5mg/mL · min (maximum absolute dose/cycle = 800 mg); Drug: Etoposide; Etoposide 100mg/m2 D1-3; Drug: Dexamethasone; Dexamethasone 40mg D1-4; Drug: Cisplatin; Cisplatin 100mg/m2 D1, continuous intravenous infusion; Drug: Ara-C; Ara-C 2g/m2 q12h D2; Drug: Vinorelbine; Vinorelbine 20mg/m2 D1; Drug: Mitoxantrone hydrochloride liposome; Mitoxantrone hydrochloride liposome 18mg/m2 D1

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dose-Limiting Toxicities	Dose-Limiting Toxicities per study protocol defination	Safety Run-in Period, up to the end of cycle 1 (each cycle is 21 days)
ORR	Response is assessed according to the Lugano criteria	up to 2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Treatment-Emergent Adverse Events	The adverse events were evaluated by NCI-CTCAE 5.0 standard Hematologic and non-hematologic toxicity	up to 2 years
Complete Response Rate (CRR)	Response is assessed according to the Lugano criteria	up to 2 years
Duration of Response (DOR)	From the date of achieving complete or partial response until disease progression, death or last follow-up	up to 2 years
Duration of Complete Response (DOCR)	From the date of achieving complete response until disease progression, death or last follow-up	up to 2 years
Progression-free Survival (PFS)	From the date of the first dose of therapy is given until disease progression, death or last follow-up	up to 2 years
Overall Survival (OS)	From the date of the first dose of therapy is given until death, irrespective of cause	up to 2 years

Collaborators and Investigators

• Sponsor: Institute of Hematology & Blood Diseases Hospital, China
• Investigators: Principal Investigator: Lugui Qiu, Institute of Hematology & Blood Diseases Hospital, CAMS & PUMC

Study record dates

Study Major Dates

• Study Start (Actual): May 28, 2024
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): May 31, 2027

Study Registration Dates

• First Submitted: June 28, 2024
• First Submitted That Met QC Criteria: July 4, 2024
• First Posted (Actual): July 8, 2024

Study Record Updates

• Last Update Posted (Actual): July 8, 2024
• Last Update Submitted That Met QC Criteria: July 4, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: Immunochemotherapy; Linperlisib
• 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; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Alkylating; Alkylating Agents; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Dexamethasone; Carboplatin; Etoposide; Oxaliplatin; Ifosfamide; Rituximab; Vinorelbine; Mitoxantrone; Gemcitabine
• Other Study ID Numbers: IIT2024030

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