Clinical trial NCT03533283: An Open-Label Phase lB/II Study of Glofitamab and Atezolizumab or Polatuzumab Vedotin in Adult Patients With Relapsed/Refractory B-Cell Non-Hodgkin's Lymphoma
Official title: An Open-Label, Multi-Center, Phase IB/II Study of Glofitamab and Atezolizumab or Polatuzumab Vedotin (Plus a Single Pre-Treatment Dose of Obinutuzumab) in Adult Patients With Relapsed/Refractory B-Cell Non-Hodgkin's Lymphoma
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Non-Hodgkins Lymphoma
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2018-05-23
Enrollment: 211
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


Eligibility 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

Exclusion Criteria Specific to Imaging Substudy

* Circulating lymphoma cells, defined by out of range (high) absolute lymphocyte count and/or the presence of abnormal/malignant cells in the peripheral blood differential signifying circulating lymphoma cell
* Participants who have had splenectomy or functional asplenia that could compromise protocol objectives

Primary outcomes:
measure: Best Objective Response Rate (ORR) as Measured by Independent Review Committee (IRC)
timeFrame: 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)
measure: Dose Limiting Toxicities (DLTs)
timeFrame: 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 outcomes:
measure: Best ORR as Measured by Investigator
timeFrame: 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)
measure: Best Complete Response (CR) Rate, as Assessed by Fluorodeoxyglucose-Positron Emission Tomography/Computed Tomography (FDG-PET/CT) Scan
timeFrame: 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)
measure: Duration of Complete Response (DOCR)
timeFrame: 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)
measure: Duration of Response (DOR)
timeFrame: 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)
measure: Progression-Free Survival (PFS)
timeFrame: 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)
measure: Event-Free Survival (EFS)
timeFrame: 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)
measure: Time to First Complete Response (TFCR)
timeFrame: 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)
measure: Time to First Overall Response (TFOR)
timeFrame: 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)
measure: Overall Survival (OS)
timeFrame: 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)
measure: Percentage of Participants with Adverse Events (AEs)
timeFrame: 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)
measure: Incidence and Severity of Cytokine Release Syndrome (CRS) Following Glofitamab Administration
timeFrame: 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)
measure: Anti-Drug Antibody (ADA) Formation
timeFrame: 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)
measure: Elimination Half-Life (T1/2) of Glofitamab Administered in Combination with Atezolizumab or Polatuzumab Vedotin
timeFrame: At pre-defined intervals through the end of study (EoS) visit (to occur within 4 weeks of disease progression)
measure: Area Under the Concentration-Time Curve (AUC) for Glofitamab Administered in Combination with Atezolizumab or Polatuzumab Vedotin
timeFrame: At pre-defined intervals through the end of study (EoS) visit (to occur within 4 weeks of disease progression)
measure: Time to Maximum Observed Serum Concentration (Tmax) of Glofitamab Administered in Combination with Atezolizumab or Polatuzumab Vedotin
timeFrame: At pre-defined intervals through the end of study (EoS) visit (to occur within 4 weeks of disease progression)
measure: Maximum Observed Serum Concentration (Cmax) of Glofitamab Administered in Combination with Atezolizumab or Polatuzumab Vedotin
timeFrame: At pre-defined intervals through the end of study (EoS) visit (to occur within 4 weeks of disease progression)
measure: Minimum Serum Concentration (Cmin) of Glofitamab Administered in Combination with Atezolizumab or Polatuzumab Vedotin
timeFrame: At pre-defined intervals through the end of study (EoS) visit (to occur within 4 weeks of disease progression)
measure: Clearance (CL) of Glofitamab Administered in Combination with Atezolizumab or Polatuzumab Vedotin
timeFrame: At pre-defined intervals through the end of study (EoS) visit (to occur within 4 weeks of disease progression)
measure: Volume of Distribution at Steady-State (Vss) of Glofitamab Administered in Combination with Atezolizumab or Polatuzumab Vedotin
timeFrame: At pre-defined intervals through the end of study (EoS) visit (to occur within 4 weeks of disease progression)
measure: CD8-Positive T Cell Proliferation
timeFrame: At pre-defined intervals during the study treatment period (up to 17 cycles; Cycle = 21 days)
measure: CD20-Positive B-Cell Reduction
timeFrame: At pre-defined intervals during the study treatment period (up to 17 cycles; Cycle = 21 days)
measure: SUVmax of 89Zr-Df-IAB22M2C (Imaging Sub-study)
timeFrame: From baseline to Day 13
measure: SUVpeak of 89Zr-Df-IAB22M2C (Imaging Sub-study
timeFrame: From baseline to Day 13
measure: SUVmean of 89Zr-Df-IAB22M2C (Imaging Sub-study)
timeFrame: From baseline to Day 13
measure: Tumor Volume Based on 89Zr-Df-IAB22M2C PET-uptake (Imaging Sub-study)
timeFrame: From baseline to Day 13
measure: Quantitation of CD8+ Cells on Biopsy Samples (Imaging Sub-study)
timeFrame: From baseline to Day 13
Other outcomes:
Locations:
city: Gent
country: Belgium
facility: UZ Gent
city: Aarhus N
country: Denmark
facility: Aarhus Universitetshospital Skejby
city: København Ø
country: Denmark
facility: Rigshospitalet
city: Odense C
country: Denmark
facility: Odense Universitetshospital
city: Jerusalem
country: Israel
facility: Hadassah Ein Karem Hospital
city: Petach Tikva
country: Israel
facility: Rabin Medical Center-Beilinson Campus
city: Ramat-Gan
country: Israel
facility: Chaim Sheba Medical Center
city: Napoli
country: Italy
facility: Istituto Nazionale Tumori Irccs Fondazione g. Pascale
state: Campania
city: Bologna
country: Italy
facility: Policlinico S.Orsola-Malpighi
state: Emilia-Romagna
city: Bergamo
country: Italy
facility: Asst Papa Giovanni Xxiii
state: Lombardia
city: Milano
country: Italy
facility: Fond. IRCCS Istituto Nazionale Tumori
state: Lombardia
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
city: Barcelona
country: Spain
facility: Hospital Duran i Reynals
city: Madrid
country: Spain
facility: START Madrid-FJD, Hospital Fundacion Jimenez Diaz
city: Malaga
country: Spain
facility: Hospital Clinico Universitario Virgen de la Victoria
city: Valencia
country: Spain
facility: Hospital Clinico Universitario de Valencia
city: Leicester
country: United Kingdom
facility: The HOPE Clinical Trials Unit
city: London
country: United Kingdom
facility: University College London Hospitals NHS Foundation Trust
city: Newcastle upon Tyne
country: United Kingdom
facility: The Newcastle upon Tyne Hospitals NHS Foundation Trust
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References: