Linperlisib Combined With Immunochemotherapy in Relapsed/Refractory LBCL

Phase 2

Recruiting

• Conditions: Relapsed/Refractory Large B-Cell Lymphoma
• Interventions: 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

• Registration Number: NCT06489808
• Lead Sponsor: Institute of Hematology & Blood Diseases Hospital, China

Brief Summary

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

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 ...

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Status Verified: 2024-05
• Study Start: 2024-05-28
• Study First Submitted: 2024-06-28
• Study First Submitted QC: 2024-07-04
• Last Update Submitted: 2024-07-04
• Study First Posted: 2024-07-08
• Last Update Posted: 2024-07-08
• Primary Completion: 2026-12-31
• Study Completion: 2027-05-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 89

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Cohort 2 patients scheduled for transplantation:Linperlisib combined with R-ICE/DHAP/GVM regimens	Mitoxantrone hydrochloride liposome	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.
Cohort 1 transplant-ineligible patients: Linperlisib combined with R-Gemox regimen	Gemcitabine	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.
Cohort 1 transplant-ineligible patients: Linperlisib combined with R-Gemox regimen	Linperlisib	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.
Cohort 1 transplant-ineligible patients: Linperlisib combined with R-Gemox regimen	Rituximab	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.
Cohort 1 transplant-ineligible patients: Linperlisib combined with R-Gemox regimen	Oxaliplatin	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.
Cohort 2 patients scheduled for transplantation:Linperlisib combined with R-ICE/DHAP/GVM regimens	Linperlisib	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.
Cohort 2 patients scheduled for transplantation:Linperlisib combined with R-ICE/DHAP/GVM regimens	Rituximab	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.
Cohort 2 patients scheduled for transplantation:Linperlisib combined with R-ICE/DHAP/GVM regimens	Gemcitabine	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.
Cohort 2 patients scheduled for transplantation:Linperlisib combined with R-ICE/DHAP/GVM regimens	Ifosfamide	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.
Cohort 2 patients scheduled for transplantation:Linperlisib combined with R-ICE/DHAP/GVM regimens	Carboplatin	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.
Cohort 2 patients scheduled for transplantation:Linperlisib combined with R-ICE/DHAP/GVM regimens	Etoposide	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.
Cohort 2 patients scheduled for transplantation:Linperlisib combined with R-ICE/DHAP/GVM regimens	Dexamethasone	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.
Cohort 2 patients scheduled for transplantation:Linperlisib combined with R-ICE/DHAP/GVM regimens	Cisplatin	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.
Cohort 2 patients scheduled for transplantation:Linperlisib combined with R-ICE/DHAP/GVM regimens	Ara-C	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.
Cohort 2 patients scheduled for transplantation:Linperlisib combined with R-ICE/DHAP/GVM regimens	Vinorelbine	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.

Primary Outcome Measures

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

Secondary Outcome Measures

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

Trial Locations

Locations (1)

Institute of Hematology & Blood Disease Hospital; 🇨🇳 Tianjin, Tianjin, China