Diffuse Large B-cell Lymphoma, High-Grade B-cell Lymphoma
Conditions
Brief summary
The purpose of this study is to evaluate the safety, tolerability and clinical activity of RO6870810 in combination with venetoclax and when co-administered with rituximab in participants with relapse/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) and/or high-grade B-cell lymphoma with myelocytomatosis oncogene (MYC) and/or B-cell lymphoma 2 (BCL2) and/or B-cell lymphoma 6 (BCL6) gene rearrangements (HGBL-DH/TH).
Interventions
DRUGRO6870810
RO6870810 subcutaneously (SC) at dose of 0.30, 0.45, or 0.65 milligram per kilogram (mg/kg) on Days 1-14 of 21-day cycles.
DRUGVenetoclax
Venetoclax tablets orally at dose of 400 mg once daily (QD) continuously for 21 days.
DRUGRituximab
Rituximab intravenously (IV) at dose of 375 mg/m\^2 weekly during the first 21-day cycle (C1) and on day 1 of each cycle thereafter.
Sponsors
Hoffmann-La Roche
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2. * Life expectancy \>3 months as per investigator's assessment. * Part 1 and Part 2 Group 1: Participantts with diffuse large B-cell lymphoma (DLBCL) relapsed or refractory to ≥ 1 course of chemotherapy including an anti-CD20 monoclonal antibody, and not eligible for autologous stem cell transplantation (ASCT) (including due to chemorefractory disease). Participants with transformed FL are eligible, provided DLBCL or HGBL-DH/TH histology is biopsy-confirmed prior to study entry and a treatment regimen as described above has been administered. The Sponsor retains the option to limit the number of participants enrolled with transformed FL. Part 2, Group 2: Patients identified with DE-DLBCL (expression MYC ≥40%, BCL2 \> 50%) and or HGBL-DH/TH, relapsed or refractory to \>= 1 course of chemotherapy including an anti-CD20 monoclonal antibody, and not eligible for ASCT (including due to chemorefractory disease). Patients with transformed follicular lymphoma (FL) are eligible, provided DE-DLBCL and/or HGBL-DH/TH histology is biopsy-confirmed prior to study entry and a treatment regimen as described above has been administered. The Sponsor retains the option to limit the number of participants enrolled with transformed FL. * Part 1 and Part 2: Willing to provide the protocol specified tumor biopsy(ies): at screening a fresh biopsy (if no archival biopsy tissue of less than 3 months prior to treatment and without intercurrent treatment is available); Part 2: Willing to provide an additional biopsy on Cycle 2 Day 15 (+ 2 days). * Acceptable liver function, as specified below: * Total bilirubin ≤ 2 times upper limit of normal (ULN). (Participants with known Gilbert's disease who has serum bilirubin ≤ 3 × ULN may be enrolled). * Aspartate transaminase (AST; SGOT), alanine transaminase (ALT; SGPT) ≤ 2.5 × ULN, (or ≤ 5 × ULN if tumor involvement (liver) is present). * Gamma-glutamyl transferase (GGT) alkaline phosphatase ≤ 2.5 × ULN. * Acceptable renal function, as specified below: • Creatinine clearance (CrCl) calculated by Cockroft-Gault formula of ≥ 60 mL/min. * Acceptable hematologic status (growth factors cannot be used within the previous 7 days), as specified below: * Absolute neutrophil count (ANC) ≥ 1000 cells/μL * Hemoglobin ≥ 9 g/dL * Platelet count ≥ 75,000 (platelets/μL) * Uncontrolled symptomatic hypercalcemia. * Acceptable coagulation status, as specified below: * Prothrombin time (PT) and partial thromboplastin time (PTT) ≤ 1.2 × ULN (unless receiving anticoagulation therapy, if receiving anticoagulation therapy, eligibility will be based upon international normalized ratio \[INR\]). * INR ≤ 1.6 (unless receiving anticoagulation therapy). * If receiving warfarin: INR ≤ 3.0 and no active bleeding (i.e., no bleeding within 14 days prior to first dose of study therapy). * Acceptable method of contraception
Exclusion criteria
* Current central nervous system (CNS) lymphoma or leptomeningeal infiltration. * New York Heart Association (NYHA) Class III or IV cardiac disease, myocardial infarction, within the past 6 months, unstable arrhythmia, or known pericardial disease. * Fredericia-corrected QT interval (QTcF) \>470 msec (female) or \>450 msec (male), or history of congenital long QT syndrome. * Any electrocardiogram (ECG) abnormality, which in the opinion of the Investigator would preclude safe participation in the study. * Active, uncontrolled bacterial, viral, or fungal infections, within 7 days of study entry requiring systemic therapy. * Clinically important respiratory impairment * Grade ≥ 3 sensory or motor neuropathy. * Any Grade \>1 (according to the NCI CTCAE 4.03) adverse reaction unresolved from previous treatments and not readily managed and controlled with supportive care. * Serious non-malignant disease that could compromise protocol objectives in the opinion of the Investigator and/or the Sponsor. * History of progressive multifocal leukoencephalopathy (PML). * History of other malignancy within 2 years prior to screening, except for ductal carcinoma in situ not requiring chemotherapy, appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, low-grade, localized prostate cancer (Gleason score ≤ 7) not requiring treatment or appropriately treated Stage I uterine cancer. * Completion of ASCT within 100 days prior to Day 1 of Cycle1. * Prior standard or investigational anti-cancer therapy, as specified below: * Radio-immunoconjugate 4 weeks or 5 half-lives, whichever is longer prior to Day 1 of Cycle 1. * Monoclonal antibody or antibody-drug conjugate (ADC) therapy within 3 weeks prior to Day 1 of Cycle 1. * Radiotherapy, chemotherapy, or targeted small-molecule therapy within 2 weeks prior to Day 1 of Cycle 1. * CAR T-cell therapy 30 days prior to Day 1 of Cycle 1. * History of major solid organ transplant (i.e., heart, lungs, liver and kidney). * History of an allogeneic bone marrow transplant. * Major surgical procedure within 28 days prior to Day 1 of Cycle 1. * Treatment with systemic corticosteroids ≥ 20 mg/day prednisone or equivalent, for non-lymphoma treatment reasons. For lower acceptable doses, documentation of a stable dose for at least 4 weeks prior to Day 1 of Cycle 1 is required. 18\. Treatment with strong to moderate CYP3A inhibitors or moderate CYP3A inducers within 7 days prior to the first dose of study treatment. * Treatment with strong CYP3A inducers within 14 days prior to the first dose of study treatment of RO6870810/venetoclax. * Consumption of grapefruits, grapefruit products, Seville oranges (including marmalade that contains Seville oranges), or star fruit within 3 days prior to the first dose of venetoclax. * Participants who are currently receiving any other investigational agent ((other than anti-cancer therapy as specified in
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Dose-Limiting Toxiciities (DLT)- Part 1 | Cycle (C) 1 (21 days) | DLT is defined as any of the toxicities- occurs within the first cycle for which the participant receives the full intended combination doses and number of administrations; is considered to be related to study treatment by the investigator; is not attributed to disease progression or another clearly identifiable cause. |
| Percentage of Participants With Adverse Events (AEs) - Part 1 | Up to 36 months | An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. |
| Percentage of Participants With Clinically Significant Changes in Vital Signs, Physical Examination, Clinical Laboratory Results and Electrocardiogram (ECG) Findings- Part 1 | Up to 36 months | — |
| Complete Response (CR) Rate as Determined by Independent Radiological Central Review (ICR) Using Modified Lugano Response Criteria- Recommended Dose (RD) Expansion - Part 2 | Up to 36 months | — |
| Overall Response (OR) Rate as Determined by Independent Radiological Central Review (ICR) Using Modified Lugano Response Criteria- RD Expansion - Part 2 | Up to 36 months | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Concentration (Cmax) of RO6870810 and its Potential Metabolites- Part 1 and Part 2 | Pre-dose Day 1,8,15; 0.25,0.5,1,2,4,6,8 hour (h) post-dose Day 1, 15; Day 2 C1; Pre-dose Day 1,8,15; 0.25h post-dose Day 1,8 C2; Pre-dose Day 1,15 C4; 0.25h post-dose Day 1 C4; Pre-dose, 0.25h post-dose Day 1 of subsequent even Cycles (Up to 36 months) | — |
| Trough Serum Concentration (Cmin) of RO6870810 and its Potential Metabolites- Part 1 and Part 2 | Pre-dose Cycle 2 and all other subsequent even Cycles (Up to 36 months) | — |
| Time of Maximum Concentration (tmax) of RO6870810 and its Potential Metabolites- Part 1 and Part 2 | Pre-dose Day 1,8,15; 0.25,0.5,1,2,4,6,8 hour (h) post-dose Day 1, 15; Day 2 C1; Pre-dose Day 1,8,15; 0.25h post-dose Day 1,8 C2; Pre-dose Day 1,15 C4; 0.25h post-dose Day 1 C4; Pre-dose, 0.25h post-dose Day 1 of subsequent even Cycles (Up to 36 months) | — |
| Clearance (CL) of RO6870810 and its Potential Metabolites- Part 1 and Part 2 | Pre-dose Day 1,8,15; 0.25,0.5,1,2,4,6,8 hour (h) post-dose Day 1, 15; Day 2 C1; Pre-dose Day 1,8,15; 0.25h post-dose Day 1,8 C2; Pre-dose Day 1,15 C4; 0.25h post-dose Day 1 C4; Pre-dose, 0.25h post-dose Day 1 of subsequent even Cycles (Up to 36 months) | — |
| Volume of Distribution (Vd) of RO6870810 and its Potential Metabolites- Part 1 and Part 2 | Pre-dose Day 1,8,15; 0.25,0.5,1,2,4,6,8 hour (h) post-dose Day 1, 15; Day 2 C1; Pre-dose Day 1,8,15; 0.25h post-dose Day 1,8 C2; Pre-dose Day 1,15 C4; 0.25h post-dose Day 1 C4; Pre-dose, 0.25h post-dose Day 1 of subsequent even Cycles (Up to 36 months) | — |
| Area Under the Curve (AUC) of RO6870810 and its Potential Metabolites- Part 1 and Part 2 | Pre-dose Day 1,8,15; 0.25,0.5,1,2,4,6,8 hour (h) post-dose Day 1, 15; Day 2 C1; Pre-dose Day 1,8,15; 0.25h post-dose Day 1,8 C2; Pre-dose Day 1,15 C4; 0.25h post-dose Day 1 C4; Pre-dose, 0.25h post-dose Day 1 of subsequent even Cycles (Up to 36 months) | — |
| Objective Response Rate, as Determined by the ICR and by the Investigator on the Basis of CT Scans Alone- Part 1 and Part 2 | Up to 36 months | — |
| Complete Response (CR) Rate, as Determined by the ICR and by the Investigator on the Basis of CT Scans Alone- Part 1 and Part 2 | Up to 36 months | — |
| Progression-Free Survival (PFS)- Part 1 and Part 2 | Up to 36 months | — |
| Event-Free Survival (EFS)- Part 1 and Part 2 | Up to 36 months | — |
| Disease-Free Survival (DFS)- Part 1 and Part 2 | Up to 36 months | — |
| Overall Survival (OS)- Part 1 and Part 2 | Up to 36 months | — |
| Half-Life (t1/2) of RO6870810 and its Potential Metabolites- Part 1 and Part 2 | Pre-dose Day 1,8,15; 0.25,0.5,1,2,4,6,8 hour (h) post-dose Day 1, 15; Day 2 C1; Pre-dose Day 1,8,15; 0.25h post-dose Day 1,8 C2; Pre-dose Day 1,15 C4; 0.25h post-dose Day 1 C4; Pre-dose, 0.25h post-dose Day 1 of subsequent even Cycles (Up to 36 months) | — |
| Percentage of Ant-Drug Antibodies (ADA) Against Rituximab - Part 1 and Part 2 | Pre-dose, End of Infusion Day 1 Cycle 1; Pre-dose Day 1 Cycle 2, 3, 4 , 6 and all other even Cycles (Up to 36 months) | — |
| Duration of Response (DoR)- Part 1 and Part 2 | Up to 36 months | — |
| Objective Response Rate, as Determined by the ICR and by the Investigator on the Basis of Modified Lugano Response Criteria- Part 1 and Part 2 | Up to 36 months | — |
| Percentage of Participants With Adverse Events (AEs) - Part 2 | Up to 36 months | An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. |
| Complete Response (CR) Rate as Determined by the Investigator Based on the Modified Lugano Response Criteria- Part 1 and Part 2 | Up to 36 months | — |
| Percentage of Participants With Clinically Significant Changes in Vital Signs, Physical Examination, Clinical Laboratory Results and Electrocardiogram (ECG) Findings- Part 2 | Up to 36 months | — |
Countries
Australia, Denmark, Spain, United States
Outcome results
None listed