Non-Hodgkins Lymphoma
Conditions
Brief summary
This is an open-label, single arm, multicenter, dose finding, Phase Ib study in order to assess the maximum tolerated dose (MTD) and/or recommended Phase II dose (RP2D) for this combination treatment and to evaluate the general safety, tolerability, pharmacokinetic (PK), pharmacodynamic, and preliminary anti-tumor activity of this combination treatment in adult patients. This study includes an additional open-label imaging feasibility sub-study using a tracer in adult participants with relpased/refractory B-cell non-Hodgkin's lymphoma to image CD8+T-cells at baseline and after treatment with glofitamab, including pre-treatment with obinutuzumab.
Interventions
DRUGGlofitamab
Glofitamab will be administered through IV infusion every 3 weeks (Q3W) beginning Cycle 1, Day 1, for up to 17 cycles (Cycle = 21 days). Step-up dosing, in which an initial lower dose will be followed by a higher dose 1 week later, will be considered for the initial treatment phase and for Cycle 9 of the re-treatment phase.
DRUGAtezolizumab
Atezolizumab will be administered in combination with Glofitamab through IV infusion Q3W from Cycle 2, Day 1, for up to 16 cycles (Cycle = 21 days).
DRUGObinutuzumab
Obinutuzumab will be administered once, through IV infusion, at a fixed dose 7 days before the first dose of Glofitamab.
DRUGTocilizumab
Tocilizumab will be administered as necessary to treat cytokine release syndrome (CRS).
DRUGPolatuzumab Vedotin
Polatuzumab vedotin will be administered in combination with Glofitamab (on different days) Q3W from Cycle 1, Day 2, for up to 12 cycles (Cycle = 21 days).
DRUG89Zr-Df-IAB22M2C
Participants will receive 89Zr-Df-IAB22M2C (Cycle 1 only) prior to obinutuzumab pre-treatment and again on Day 10 after dosing with glofitamab, followed by PET/CT.
Sponsors
Hoffmann-La Roche
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Main Inclusion Criteria * Histologically-confirmed hematologic malignancy that is expected to express CD20 (Relapsed after or refractory to respond to at least one prior treatment regimen; no available treatment options that are expected to prolong survival or patients refusing chemotherapy or autologous stem cell transplant (SCT)) * Dose-escalation: Grades 1-3b relapsed or refractory (R/R) follicular lymphoma (FL) or marginal zone lymphoma (MZL) (nodal; extra-nodal; or splenic), diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma (PMBCL), high-grade B-cell lymphoma (HGBCL) with MYC and BCL2 and/or BCL6 rearrangements (double-hit lymphoma), HGBCL not otherwise specified (NOS), DLBCL arising from FL (transformed FL) * Dose-expansion: R/R LBCL, including DLBCL NOS, DLBCL arising from FL (transformed FL), PMBCL, HGBCL with MYC and BCL2 and/or BCL6 rearrangements (i.e., double-hit and triple-hit lymphomas), and HGBCL NOS * At least one measurable target lesion * Fresh pre-treatment biopsy, but if this cannot be taken, a previous archived biopsy from metastatic lesion can be taken as replacement if it is not older than 6 months and not confounded by major events (progression, treatment) * Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 * Adequate organ function (liver, hematological, renal) * Negative test results for hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV) Inclusion Criteria Specific to Imaging Substudy * At least two measurable target lesions * Able to provide two fresh tumor biopsies (baseline and on-treatment) Main
Exclusion criteria
* Participants with Chronic Lymphocytic Leukemia (CLL), acute lymphoblastic leukemia (ALL), lymphoblastic lymphoma, Richter's transformation, CD20-positive ALL, Burkitt lymphoma, or lymphoplasmacytic lymphoma * Current \> Grade 1 peripheral neuropathy (only for participants being treated in the polatuzumab vedotin arm) * Patients with known active infection, or reactivation of a latent infection within 4 weeks prior to Obinutuzumab (Gpt) infusion * Patient with history of confirmed progressive multifocal leukoencephalopathy (PML) * History of leptomeningeal disease * Current or past history of central nervous system (CNS) lymphoma * Current or past history of CNS disease * Major surgery or significant traumatic injury \</=28 days prior to Gpt infusion * Significant cardiovascular disease or significant pulmonary disease * Active or history of autoimmune disease or immune deficiency (with exceptions, e.g. hypothyroidism and Diabetes mellitus Type 1) * History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g. bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan * Treatment with any other standard anti-cancer radiotherapy / chemotherapy including investigational therapy within 4 weeks prior to Gpt infusion * Prior solid organ transplantation * Prior allogenic stem cell transplant (SCT) * Autologous SCT within 100 days prior to Gpt infusion * Documented refractoriness to an obinutuzumab-monotherapy regimen * Prior treatment with anti-cancer/lymphoma therapies and systemic immunotherapeutic/immunostimulating agents within 4 weeks or 5 half-lives of the drug, whichever is shorter, prior to Gpt infusion * Any history of immune related \>/= Grade 3 adverse events (AE) with the exception of endocrinopathy managed with replacement therapy * Ongoing corticosteroid use \>25 milligrams/day of prednisone or equivalent within 4 weeks prior to and during study treatment * Treatment with systemic immunosuppressive medication * Administration of a live, attenuated vaccine within 4 weeks prior to Gpt infusion or anticipation that such a live attenuated vaccine will be required during the study or within 5 months after last dose of study treatment
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Best Objective Response Rate (ORR) as Measured by Independent Review Committee (IRC) | Baseline until the end of treatment (13 to 14 months), then ever 3 months until end of study visit (to occur within 4 weeks of disease progression) |
| Dose Limiting Toxicities (DLTs) | Atezolizumab Arm: During DLT period of 21 days (or up to 42 days in the case of cycle delay), starting on Day 1, Cycle 2; Polatuzumab Vedotin Arm: During 5-week DLT period starting Cycle 1, Day 8 |
Secondary
| Measure | Time frame |
|---|---|
| Best ORR as Measured by Investigator | Baseline until end of treatment (13 to 14 months), then every 3 months until end of study visit (to occur within 4 weeks of disease progression) |
| Best Complete Response (CR) Rate, as Assessed by Fluorodeoxyglucose-Positron Emission Tomography/Computed Tomography (FDG-PET/CT) Scan | Baseline until end of treatment (13 to 14 months), then every 3 months until end of study visit (to occur within 4 weeks of disease progression) |
| Duration of Complete Response (DOCR) | Baseline until end of treatment (13 to 14 months), then every 3 months until end of study visit (to occur within 4 weeks of disease progression) |
| Duration of Response (DOR) | Baseline until end of treatment (13 to 14 months), then every 3 months until end of study visit (to occur within 4 weeks of disease progression) |
| Progression-Free Survival (PFS) | Baseline until end of treatment (13 to 14 months), then every 3 months until end of study visit (to occur within 4 weeks of disease progression) |
| Event-Free Survival (EFS) | Baseline until end of treatment (13 to 14 months), then every 3 months until end of study visit (to occur within 4 weeks of disease progression) |
| Time to First Complete Response (TFCR) | Baseline until end of treatment (13 to 14 months), then every 3 months until end of study visit (to occur within 4 weeks of disease progression) |
| Time to First Overall Response (TFOR) | Baseline until end of treatment (13 to 14 months), then every 3 months until end of study visit (to occur within 4 weeks of disease progression) |
| Overall Survival (OS) | Baseline through end of survival follow-up phase (survival follow-up is every 3 months until death, lost to follow-up, withdrawal of consent, or study termination) |
| Percentage of Participants with Adverse Events (AEs) | Baseline until end of treatment (13 to 14 months), then every 3 months until end of study visit (to occur within 4 weeks of disease progression) |
| Incidence and Severity of Cytokine Release Syndrome (CRS) Following Glofitamab Administration | Baseline until end of treatment (13 to 14 months), then every 3 months until end of study visit (to occur within 4 weeks of disease progression) |
| Anti-Drug Antibody (ADA) Formation | Baseline until end of treatment (13 to 14 months), then every 3 months until end of study visit (to occur within 4 weeks of disease progression) |
| Elimination Half-Life (T1/2) of Glofitamab Administered in Combination with Atezolizumab or Polatuzumab Vedotin | At pre-defined intervals through the end of study (EoS) visit (to occur within 4 weeks of disease progression) |
| Area Under the Concentration-Time Curve (AUC) for Glofitamab Administered in Combination with Atezolizumab or Polatuzumab Vedotin | At pre-defined intervals through the end of study (EoS) visit (to occur within 4 weeks of disease progression) |
| Time to Maximum Observed Serum Concentration (Tmax) of Glofitamab Administered in Combination with Atezolizumab or Polatuzumab Vedotin | At pre-defined intervals through the end of study (EoS) visit (to occur within 4 weeks of disease progression) |
| Maximum Observed Serum Concentration (Cmax) of Glofitamab Administered in Combination with Atezolizumab or Polatuzumab Vedotin | At pre-defined intervals through the end of study (EoS) visit (to occur within 4 weeks of disease progression) |
| Minimum Serum Concentration (Cmin) of Glofitamab Administered in Combination with Atezolizumab or Polatuzumab Vedotin | At pre-defined intervals through the end of study (EoS) visit (to occur within 4 weeks of disease progression) |
| Clearance (CL) of Glofitamab Administered in Combination with Atezolizumab or Polatuzumab Vedotin | At pre-defined intervals through the end of study (EoS) visit (to occur within 4 weeks of disease progression) |
| Volume of Distribution at Steady-State (Vss) of Glofitamab Administered in Combination with Atezolizumab or Polatuzumab Vedotin | At pre-defined intervals through the end of study (EoS) visit (to occur within 4 weeks of disease progression) |
| CD8-Positive T Cell Proliferation | At pre-defined intervals during the study treatment period (up to 17 cycles; Cycle = 21 days) |
| CD20-Positive B-Cell Reduction | At pre-defined intervals during the study treatment period (up to 17 cycles; Cycle = 21 days) |
| SUVmax of 89Zr-Df-IAB22M2C (Imaging Sub-study) | From baseline to Day 13 |
| SUVpeak of 89Zr-Df-IAB22M2C (Imaging Sub-study | From baseline to Day 13 |
| SUVmean of 89Zr-Df-IAB22M2C (Imaging Sub-study) | From baseline to Day 13 |
| Tumor Volume Based on 89Zr-Df-IAB22M2C PET-uptake (Imaging Sub-study) | From baseline to Day 13 |
| Quantitation of CD8+ Cells on Biopsy Samples (Imaging Sub-study) | From baseline to Day 13 |
Countries
Belgium, Denmark, Israel, Italy, Spain, United Kingdom
Contacts
STUDY_DIRECTORClinical Trials
Hoffmann-La Roche
Outcome results
None listed