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 \[Diffuse Large B-cell Lymphoma (DLBCL), Marginal Zone Lymphoma (MZL) or Mantle Cell Lymphoma (MCL)\].
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.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
orally once daily in a 21-day cycle for eight cycles, and as maintenance for 2 years.
375 mg/m2 administered intravenously once on Day 1 in a 21-day cycle for eight cycles.
750 mg/m2 administered intravenously once on Day 1 or 2 in a 21-day cycle for six cycles.
Sun Yat-sen University Cancer Center
Guangzhou, Guangdong, China
MTD
Standard phase I 3+3 design.
Time frame: Up to 21 days after the initial dose
Recommended Dose
Recommended Dose will be determined using available safety and pharmacokinetics data upon completion of the dose escalation phase.
Time frame: Up to 1.5 years
Incidence of AEs
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
Time frame: From first dose of study drug to 28 days after the last dose of study drugs
Incidence of clinically significant laboratory abnormalities
Clinically significant abnormalities in hematology, chemistry, coagulation and urinalysis.
Time frame: From first dose of study drug to 28 days after last dose of study drug
Cmax of Rocbrutinib
Maximum plasma concentration (Cmax) of Rocbrutinib.
Time frame: Up to 24 hours post dose
Tmax of Rocbrutinib
Time to maximum plasma concentration (Tmax) of Rocbrutinib.
Time frame: Up to 24 hours post dose
T1/2 of Rocbrutinib
The terminal elimination half-life (t1/2).
Time frame: Up to 24 hours post dose
AUC0-t of Rocbrutinib
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Masking
NONE
Enrollment
112
50 mg/m2 administered intravenously once on Day 1 or 2 in a 21-day cycle for six cycles.
1.4 mg/m2 administered intravenously once on Day 1 or 2 in a 21-day cycle for six cycles.
100 mg orally once on Day 1 to Day 5 in a 21-day cycle for six cycles.
Area under the plasma concentration-time curve (AUC) from 0 to the time of the last measurable concentration of Rocbrutinib.
Time frame: Up to 24 hours post dose
CL/F of Rocbrutinib
Apparent clearance (CL/F) of Rocbrutinib.
Time frame: Up to 24 hours post dose
Objective Response Rate (ORR)
Assessment using the Lugano Response Criteria for Malignant Lymphoma.
Time frame: Evey 2 cycles for 8 cycles, and followed every 3cyles for 24 months
Complete remission (CR)
Assessment using the Lugano Response Criteria for Malignant Lymphoma.
Time frame: Evey 2 cycles for 8 cycles, and followed every 3cyles for 24 months
Duration of Response(DOR)
DOR is defined as the number of days from the date of the first remission to the date of earliest disease progression or death.
Time frame: Measured from the date of the first remission to the date of earliest disease progression or death, and assessed up to 5 years.
Progression-Free Survival(PFS)
PFS is defined as the number of days from the date of the first dose of study drug to the date of earliest disease progression or death.
Time frame: 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)
EFS is defined as the number of days from the date of first dose to the date of earliest evidence of disease progression/relapse, or initiation of new non-protocol-specified antitumor therapy without documented progression, or death.
Time frame: 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)
OS is defined as the number of days from the date of first dose to the date of death.
Time frame: 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.