A Phase Ib Study to Assess Safety and Preliminary Efficacy of Rocbrutinib in Combination with R-CHOP in Patients with Newly Diagnosed B-NHL
Overview
- Phase
- Phase 1
- Intervention
- Rocbrutinib
- Conditions
- B-cell Non-Hodgkin Lymphoma
- Sponsor
- Guangzhou Lupeng Pharmaceutical Company LTD.
- Enrollment
- 112
- Locations
- 1
- Primary Endpoint
- Recommended Dose
- Status
- Recruiting
- Last Updated
- last year
Overview
Brief Summary
This is an open-label, multicentre Phase Ib study to evaluate the safety and preliminary efficacy of new generation Bruton Tyrosine Kinase inhibitor Rocbrutinib in combination to R-CHOP (Rituximab, Cyclophosphamide, Doxorubicin, Vincristin, Prednison) in adult patients with newly diagnosed, previously untreated B-cell Non-Hodgkin Lymphoma [Diffuse Large B-cell Lymphoma (DLBCL), Marginal Zone Lymphoma (MZL) or Mantle Cell Lymphoma (MCL)].
Detailed Description
OUTLINE: Dose escalation portion(Part A): In the dose escalation portion of the study, the escalating doses of Rocbrutinib combined with R-CHOP may be explored, using the 3+3 principle for dose determination. If dose escalation is acceptable, and subsequently will determine the recommended Phase 2 dose. Dose expansion portion(Part B): This will be conducted as a multicenter, open-label study, including three cohorts(Cohort 1: non-GCB DLBCL; Cohort 2: MZL; Cohort 3: MCL). Eligible subjects will receive Rocbrutinib combined with R-CHOP for 6 cycles, then Rocbrutinib plus Rituximab for 2 cycles, and followed by Rocbrutinib maintenance for 2 years. After completion of study treatment, patients are followed up every 12 weeks for 1 year, then every 24 weeks for 4 year. PRIMARY OBJECTIVES: I. To evaluate the safety of Rocbrutinib in combination to R-CHOP in B-cell Non-Hodgkin Lymphoma, including the maximum tolerated dose (MTD), dose limiting toxicities(DLT), adverse events (AEs), clinically significant laboratory abnormalities. 2. To determine the recommended dose. 3. To determine the pharmacokinetic characteristics of Rocbrutinib in combination to R-CHOP. SECONDARY OBJECTIVES: I. To determine the overall response rate, the complete response rate, duration of remission, survival outcomes (progression free survival, event free survival, overall survival) in DLBCL/ Non-germinal Center(non-GCB) DLBCL. 2. To determine the overall response rate, the complete response rate, duration of remission, survival outcomes (progression free survival, event free survival, overall survival) in MZL. 3. To determine the overall response rate, the complete response rate, duration of remission, survival outcomes (progression free survival, event free survival, overall survival) in MCL.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Participants was histopathologically diagnosed with any of the following diseases: DLBCL, MZL or MCL (if enrolled in the dose expansion phase, histological confirmation of non-GCB subtype), and have not previously received anti-tumor systemic therapy or local radiation therapy for the above diseases.
- •Participants must have at least one measurable lesion.
- •ECOG physical status score 0-
- •Life expectancy ≥6 months.
- •International Prognostic Index (IPI) score ≥ 2 (only participants with DLBCL in dose expansion portion).
- •Adequate coagulation, liver, kidney, and hematopoietic functions：PT and APTT \<1.5x ULN; serum bilirubin \<1.5x ULN except in participants with Gilbert's syndrome who must have a serum bilirubin of \<3x ULN, AST and ALT ≤ 3x ULN or \< 5x ULN if hepatic involvement are present; serum creatinine (Scr) ≤1.5 x ULN, or calculated creatinine clearance ≥ 30ml/min by Cockcroft-Gault formula.; ANC≥1500/mm3, hemoglobin≥8.0 g/dL, and platelets \>100,000/mm3 unless deemed related to lymphoma involvement in the bone marrow and felt potentially reversible by the treating physician.
- •Women of childbearing potential must have a negative serum or urine (beta-human chorionic gonadotropin \[beta-hCG\]) at screening.
- •Women of childbearing potential and men who are sexually active with a woman of childbearing potential must be practicing a highly effective contraceptive measures of during and after the study (90 days after the last dose of ROCBRUTINIB and 12 months after the last dose of Rituximab). Men must agree to not donate sperm during and for up to 90 days after he last dose of ROCBRUTINIB.
- •Participants voluntarily enrolled and signed the informed consent form, and followed the trial treatment and visits.
Exclusion Criteria
- •Participants are allergic to Rocbrutinib or any of its excipients; Participants who are assessed by the investigator as being unable to tolerate the R-CHOP regimen.
- •Participants with known central nervous system involvement with lymphoma. or diagnosis of primary central nervous system lymphoma (PCNSL) or primary mediastinal large B-cell lymphoma (PMBL).
- •Participants with DLBCL had a history of indolent lymphoma such as FL or CLL (Richter's transformation), or was histopathologically comfirmed with FL (regardless of grade) coexistentially.
- •Prior treatment with solid organ transplantation or hematopoietic stem cell transplantation(HSCT) ; expected HSCT during the study.
- •Major surgery within 4 weeks of study entry or expected major surgery during the study.
- •Prior another non-antitumor or medical instruments clinical trials within 4 weeks.
- •Known bleeding diseases (such as von Willebrand's disease or hemophilia A, hemophilia B, etc.), or have bleeding tendency.
- •Prior treatment with warfarin or equivalent vitamin K antagonists within 14 days; requires anticoagulation with warfarin or equivalent vitamin K antagonists.
- •Prior treatment with strong/moderate CYP3A4 inhibitors within 5 days or prior foods with inhibitory effects on CYP3A4 within 3 days at screening; requires chronic treatment with moderate/strong CYP3A inhibitors or inducers, or OATP1B1/OATP1B3 sensitive substrates during the study.
- •Participants with other malignancies other than the target indications of this study within the past three years.
Arms & Interventions
Dose Escalation
Patients with DLBCL or MCL or MZL receive Rocbrutinib（at escalating dose）+R-CHOP
Intervention: Rocbrutinib
Dose Escalation
Patients with DLBCL or MCL or MZL receive Rocbrutinib（at escalating dose）+R-CHOP
Intervention: Rituximab
Dose Escalation
Patients with DLBCL or MCL or MZL receive Rocbrutinib（at escalating dose）+R-CHOP
Intervention: Cyclophosphamide
Dose Escalation
Patients with DLBCL or MCL or MZL receive Rocbrutinib（at escalating dose）+R-CHOP
Intervention: doxorubicin
Dose Escalation
Patients with DLBCL or MCL or MZL receive Rocbrutinib（at escalating dose）+R-CHOP
Intervention: Vincristin
Dose Escalation
Patients with DLBCL or MCL or MZL receive Rocbrutinib（at escalating dose）+R-CHOP
Intervention: Prednisone
Dose Expansion [non-GCB DLBCL]
Patients with non-GCB DLBCL receive Rocbrutinib（at recommended dose )+R-CHOP
Intervention: Rocbrutinib
Dose Expansion [non-GCB DLBCL]
Patients with non-GCB DLBCL receive Rocbrutinib（at recommended dose )+R-CHOP
Intervention: Rituximab
Dose Expansion [non-GCB DLBCL]
Patients with non-GCB DLBCL receive Rocbrutinib（at recommended dose )+R-CHOP
Intervention: Cyclophosphamide
Dose Expansion [non-GCB DLBCL]
Patients with non-GCB DLBCL receive Rocbrutinib（at recommended dose )+R-CHOP
Intervention: doxorubicin
Dose Expansion [non-GCB DLBCL]
Patients with non-GCB DLBCL receive Rocbrutinib（at recommended dose )+R-CHOP
Intervention: Vincristin
Dose Expansion [non-GCB DLBCL]
Patients with non-GCB DLBCL receive Rocbrutinib（at recommended dose )+R-CHOP
Intervention: Prednisone
Dose Expansion [MCL]
Patients with MCL receive Rocbrutinib（at recommended dose )+R-CHOP
Intervention: Rocbrutinib
Dose Expansion [MCL]
Patients with MCL receive Rocbrutinib（at recommended dose )+R-CHOP
Intervention: Rituximab
Dose Expansion [MCL]
Patients with MCL receive Rocbrutinib（at recommended dose )+R-CHOP
Intervention: Cyclophosphamide
Dose Expansion [MCL]
Patients with MCL receive Rocbrutinib（at recommended dose )+R-CHOP
Intervention: doxorubicin
Dose Expansion [MCL]
Patients with MCL receive Rocbrutinib（at recommended dose )+R-CHOP
Intervention: Vincristin
Dose Expansion [MCL]
Patients with MCL receive Rocbrutinib（at recommended dose )+R-CHOP
Intervention: Prednisone
Dose Expansion [MZL]
Patients with MZL receive Rocbrutinib（at recommended dose )+R-CHOP
Intervention: Rocbrutinib
Dose Expansion [MZL]
Patients with MZL receive Rocbrutinib（at recommended dose )+R-CHOP
Intervention: Rituximab
Dose Expansion [MZL]
Patients with MZL receive Rocbrutinib（at recommended dose )+R-CHOP
Intervention: Cyclophosphamide
Dose Expansion [MZL]
Patients with MZL receive Rocbrutinib（at recommended dose )+R-CHOP
Intervention: doxorubicin
Dose Expansion [MZL]
Patients with MZL receive Rocbrutinib（at recommended dose )+R-CHOP
Intervention: Vincristin
Dose Expansion [MZL]
Patients with MZL receive Rocbrutinib（at recommended dose )+R-CHOP
Intervention: Prednisone
Outcomes
Primary Outcomes
Recommended Dose
Time Frame: Up to 1.5 years
Recommended Dose will be determined using available safety and pharmacokinetics data upon completion of the dose escalation phase.
MTD
Time Frame: Up to 21 days after the initial dose
Standard phase I 3+3 design.
Incidence of AEs
Time Frame: From first dose of study drug to 28 days after the last dose of study drugs
Type, frequency and severity of AEs, relationship of AEs to study treatment Graded According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0 Type, frequency and severity of AEs, relationship of AEs to study treatment Graded According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0
Cmax of Rocbrutinib
Time Frame: Up to 24 hours post dose
Maximum plasma concentration (Cmax) of Rocbrutinib.
Incidence of clinically significant laboratory abnormalities
Time Frame: From first dose of study drug to 28 days after last dose of study drug
Clinically significant abnormalities in hematology, chemistry, coagulation and urinalysis.
Tmax of Rocbrutinib
Time Frame: Up to 24 hours post dose
Time to maximum plasma concentration (Tmax) of Rocbrutinib.
T1/2 of Rocbrutinib
Time Frame: Up to 24 hours post dose
The terminal elimination half-life (t1/2).
AUC0-t of Rocbrutinib
Time Frame: Up to 24 hours post dose
Area under the plasma concentration-time curve (AUC) from 0 to the time of the last measurable concentration of Rocbrutinib.
CL/F of Rocbrutinib
Time Frame: Up to 24 hours post dose
Apparent clearance (CL/F) of Rocbrutinib.
Secondary Outcomes
- Objective Response Rate (ORR)(Evey 2 cycles for 8 cycles, and followed every 3cyles for 24 months)
- Duration of Response(DOR)(Measured from the date of the first remission to the date of earliest disease progression or death, and assessed up to 5 years.)
- Complete remission (CR)(Evey 2 cycles for 8 cycles, and followed every 3cyles for 24 months)
- Progression-Free Survival(PFS)(Measured from the date of first dose of study drug to the date of earliest disease progression or death or last visit, and assessed up to 5 years.)
- Event-free Survival (EFS)(Measured from the date of first dose to the date of earliest evidence of disease progression, initiation of new non-protocol-specified antitumor therapy without documented progression, death, and for up to 5 years after the last subject is enrolled.)
- Overall survival (OS)(Measured from the date of date of first dose to the date of death or last visit, and for up to 5 years after the last subject is enrolled.)