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Protocol NumberNP30179
NCT Number(ClinicalTrials.gov Identfier)NCT03075696

2019-02-01 - 2022-12-31

Phase I/II

Recruiting2

A Multicenter, Open-Label, Phase I/II Study to Evaluate the Safety, Efficacy, Tolerability and Pharmacokinetics of Escalating Doses of Glofitamab (RO7082859) as a Single Agent and in Combination With Obinutuzumab Administered After a Fixed, Single Dose Pre-Treatment of Obinutuzumab (Gazyva®/Gazyvaro™) in Patients With Relapsed/Refractory B-Cell Non-Hodgkin's Lymphoma

  • Trial Applicant

  • Sponsor

    Hoffmann-La Roche

  • Trial scale

    Multi-Regional Multi-Center

  • Update

    2025/08/20

Investigators and Locations

Principal Investigator Su-Peng Yeh Division of Hematology & Oncology
China Medical University Hospital

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Recruiting

Principal Investigator Shang-Ju Wu Division of General Internal Medicine
National Taiwan University Hospital

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Recruiting

Condition/Disease

Relapsed/Refractory B-Cell Non-Hodgkin's Lymphoma

Objectives

PRIMARY OBJECTIVES The primary objectives of this study are as follows: • To evaluate the safety, tolerability, and PK of RO7082859 as single agent and in combination with obinutuzumab following obinutuzumab pretreatment (Gpt) in patients with relapsed/refractory CD20+ B-cell Non-Hodgkin’s Lymphoma (r/r NHL). • To determine the MTD or optimal biologic dose (OBD) and DLTs of RO7082859 as single agent and in combination with obinutuzumab following Gpt in patients with r/r NHL. • To determine a recommended dose and schedule of RO7082859 as a single agent and in combination with obinutuzumab following Gpt. • In Part III of the study, to evaluate the efficacy of RO7082859 as single agent following Gpt in patients diagnosed with DLBCL (r/r DLBCL NOS, high-grade BCell lymphoma, PMBCL, DLBCL arising from FL) and r/r FL as measured by Independent Review Committee (IRC)-assessed complete response rate according to standard NHL response criteria [modified Lugano criteria, Cheson et al. 2014]).

Test Drug

Glofitamab、Obinutuzumab、Tocilizumab

Active Ingredient

Glofitamab
Obinutuzumab
Tocilizumab

Dosage Form

injection

Dosage

200mg/10ml
1000mg/40ml
10mg/2ml

Endpoints

Primary Outcome Measures :
Part I and II: Percentage of Participants With Dose Limiting Toxicities (DLTs) [ Time Frame: From Baseline up to 4 weeks ]
Part I, II and III: Percentage of Participants With Adverse Events (AEs) [ Time Frame: From Baseline up to 90 days after last dose of study drug or until study completion or participant withdrawal (up to 5 years) ]
Part II: MTD or OBD of Glofitamab [ Time Frame: From Baseline up to 4 weeks ]

Secondary Outcome Measures :
Part I, II and III: Cmax of Obinutuzumab [ Time Frame: Pre-dose of obinutuzumab on Day -7; pre-dose (Hr 0) of glofitamab on Day 1 of Cycle 1 ]
Part I, II and III: Cmin of Obinutuzumab [ Time Frame: Pre-dose of obinutuzumab on Day -7; pre-dose (Hr 0) of glofitamab on Day 1 of Cycle 1 ]
Part I, II and III: Anti-Drug Antibodies (ADA) to Glofitamab [ Time Frame: Pre-dose of obinutuzumab on Day -7; pre-dose (Hr 0) of glofitamab on Day 1 of each cycle from Cycle 2 onwards for a maximum of 8-12 cycles, and at EOT/follow-up visit (up to 5 years) ]
Parts I and II: Percentage of Participants With Overall Response (Partial Response [PR] or Complete Response [CR]) as Determined by the Lugano Classification [ Time Frame: From Baseline up to end of study or discontinuation due to disease progression (up to 5 years) ]
Part I, II and III: Percentage of Participants With PR or CR (Overall Response Rate) as Determined by the Lugano Classifications [ Time Frame: From Baseline up to end of study or discontinuation due to disease progression (up to 5 years) ]
Part I, II and III: Duration of Response (DOR) as Determined by the Lugano Classification [ Time Frame: From first occurrence of documented objective response until disease progression, relapse or death due to any cause (up to 5 years) ]
Part I, II and III: Duration of Complete Response (DOCR) as Determined by the Lugano Classification [ Time Frame: From the first occurrence of a documented, complete response, until the time of relapse or death from any cause (up to 5 years) ]
Part I, II and III: Progression-Free Survival (PFS) as Determined by the Lugano Classification [ Time Frame: From first study treatment to the first occurrence of disease progression or death due to any cause (up to 5 years) ]
Overall Survival (OS) [ Time Frame: From the time of first study treatment to death from any cause (up to 5 years) ]
Time to First Overall Response (TFOR) [ Time Frame: From time of treatment start to first documented response (up to 5 years) ]
Time to First Complete Response (TFCR) [ Time Frame: From treatment start to first documented complete response (up to 5 years) ]
Health Related Quality of Life (HRQoL) as Assessed by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) [ Time Frame: From baseline through follow-up or until disease progression (up to 5 years) ]
HRQoL as Assessed by the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) Lymphoma Scale [ Time Frame: From baseline through follow-up or until disease progression (up to 5 years) ]

Part II: Recommended Phase II Dose (RP2D) of Glofitamab [ Time Frame: Baseline up to 5 years ]
Part III: Complete Response (CR) Rate as Assessed by Independent Review Committee (IRC) According to Standard Non-Hodgkin's Lymphoma (NHL) Response Criteria (Lugano Classification) [ Time Frame: From treatment start up to 5 years ]
Part I, II and III: Area Under the Serum Concentration Versus Time Curve (AUC) of Glofitamab [ Time Frame: At pre-defined intervals from Cycle 1 Day 1 to Day 71 ]
Part I, II and III: Maximum Serum Concentration (Cmax) of Glofitamab [ Time Frame: At pre-defined intervals from Cycle 1 Day 1 to Day 198 ]
Part I, II and III: Minimum Serum Concentration (Cmin) of Glofitamab [ Time Frame: At pre-defined intervals from Cycle 1 Day 1 up to Day 198 ]
Part I, II and III: Clearance (CL) of Glofitamab [ Time Frame: At pre-defined intervals from Cycle 1 Day 1 to Day 71 ]
Part I, II and III: Volume of Distribution at Steady-State (Vss) of Glofitamab [ Time Frame: At pre-defined intervals from Cycle 1 Day 1 to Day 71 ]
Part I, II and III: Half-Life (t1/2) of Glofitamab [ Time Frame: At pre-defined intervals from Cycle 1 Day 1 to Day 71 ]

Inclution Criteria

1. Signed Informed Consent(s) Forms.
2. Patient must be willing and able to comply with protocol-mandated hospitalization
upon administration of the first dose of RO7082859. Patient must also be willing to
comply with all study-related procedures, including completion of PROs.
3. Age ≥18 years.
4. Depending upon study part, a history or status of: 1) a histologically-confirmed
hematological malignancy that is expected to express CD20; 2) relapse after or
failure to respond to at least one prior treatment regimen; and 3) no available
treatment options that are expected to prolong survival (e.g., standard
chemotherapy or autologous stem cell transplant [SCT]). Eligible r/r NHL patients
include:
• For Parts I and II: Grades 1-3b FL; MZL (splenic; nodal; extra-nodal); MCL;
DLBCL; PMBCL; Richter’s transformation; and/or transformed FL
• For Part III expansion cohorts:
a) DLBCL cohort (DLBCL NOS, high-grade B-cell lymphoma, PMBCL and
DLBCL arising from follicular lymphoma ([transformed FL]). Patients must
have relapsed after or failed to respond to at least two prior systemic
treatment regimens (including at least one prior regimen containing
anthracycline, and at least one containing an anti CD20-directed therapy).
The Sponsor retains the option to limit the number of patients enrolled with
transformed FL and PMBCL. Patients with Richter’s transformation are not
considered eligible for Part III.
b) FL cohort: Follicular lymphoma cohort: Grades 1-3 a FL; patients must have
relapsed after or failed to respond to at least two prior lines of systemic
therapy and must have received prior treatment with rituximab and
alkylating agents.
c) For patients in the DLBCL cohort (DLBCL NOS, high-grade B-cell
lymphomas, PMBCL or transformed FL) the pathology report for the initial
histopathology diagnosis must be provided, if available. Patients with
transformed FL must also provide the pathology report at the time of disease
transformation, if available. The results of all tests conducted on the tissue
at initial diagnosis, including but not limited to tests assessing cell of
origin, BCL2 and MYC abnormalities, should be provided if done.
5. Patient must have at least one measureable target lesion (≥1.5 cm) in its largest
dimension by computerized tomography [CT] scan).
6. Able to provide the most recent archival tumor tissue samples (FFPE blocks
preferred; if not available, slides accepted). Archival tumor tissue samples obtained
at any time between the last dose of the last prior cancer regimen and C1/D-7) are
preferred.
• In the absence of sufficient archival tissue, a fresh biopsy from a safely
accessible site, per Investigator determination and patient consent, will be
requested, providing the patient has more than one measurable target lesion.
Note: if fresh biopsy cannot be obtained, please contact the Medical Monitor.
7. ECOG performance status of 0 or 1.
8. Life expectancy (in the opinion of the Investigator) of ≥ 12 weeks.
9. Adverse events from prior anti-cancer therapy must have resolved to Grade ≤ 1.
10. Adequate liver function: Total bilirubin ≤ 1.5 × ULN. Patients with documented
history of Gilbert’s Syndrome and in whom total bilirubin elevations are
accompanied by elevated indirect bilirubin are eligible); aspartate aminotransferase
(AST)/alanine aminotransferase (ALT) ≤ 3 × the ULN.
11. Adequate hematological function: Neutrophil count of ≥ 1.5 × 109 cells/L; Platelet
count of ≥ 75,000/µL (and platelet transfusion free within 14 days prior to
administration of Gpt); Hemoglobin (Hb) ≥ 10.0 g/dL (6.2 mmol/L); transfusion free
within 21 days prior to administration of Gpt.
• Note: patients who do not meet the above hematologic criteria, due to bone
marrow suppression from prior therapies and/or extensive tumor involvement in
the marrow may be enrolled into the trial after consultation with the Medical
Monitor. For patients who enter the study with monitor approved hematological
indices that are below those defined above, please consult the medical monitor
on the need for transfusion support within 21 days of Gpt.
Note: specific platelet levels are required prior to administration of Gpt
(i.e., 75,000/µL) and RO7082859 at C1/D1 as described in Section 5.2.2.
12. Adequate renal function: serum creatinine ≤ 1.5 ULN or a creatinine clearance
(CrCl) calculated by Cockroft-Gault formula of ≥ 50 mL/min for patients in whom, in
the investigator’s judgment, serum creatinine levels do not adequately reflect renal
function.
13. Negative serum pregnancy test within 7 days prior to study treatment in women of
childbearing potential. Women who are not of childbearing potential who are
considered to be post-menopausal (≥ 12 months of non-therapy amenorrhea) or
surgically sterile (absence of ovaries and/or uterus) are not required to have a
pregnancy test.
14. Negative serologic or PCR test results for acute or chronic HBV infection. (Note:
Patients whose HBV infection status cannot be determined by serologic test results
(https://www.cdc.gov/hepatitis/hbv/pdfs/serologicchartv8.pdf) must be negative for
HBV by PCR to be eligible for study participation).
15. Negative test results for HCV and HIV. Note: Patients who are positive for HCV
antibody must be negative for HCV by PCR to be eligible for study participation.
16. Patients must agree to either remain completely abstinent or to use two effective
contraceptive methods that result in a failure rate of <1% per year from screening
until (a) at least 3 months after pre-treatment with obinutuzumab or 2 months after
the last dose of RO7082829, whichever is longer, if the patient is a male or (b) until
at least 18 months after pre-treatment with obinutuzumab or 2 months after the last
dose of RO7082829, whichever is longer, if patient is a female.

Exclusion Criteria

1. Inability to comply with protocol mandated hospitalization and restrictions. Patients
with CLL, Burkitt lymphoma and lymphoplasmacytic lymphoma.
2. Patients with acute bacterial, viral, or fungal infection at baseline, confirmed by a
positive blood culture within 72 hours prior to Gpt infusion or by clinical judgment in
the absence of a positive blood culture.
3. Patients with known active infection, or reactivation of a latent infection, whether
bacterial, viral (including, but not limited to, EBV, hepatitis B, hepatitis C, and HIV),
fungal, mycobacterial, or other pathogens (excluding fungal infections of nail beds)
or any major episode of infection requiring hospitalization or treatment with IV
antibiotics (for IV antibiotics this pertains to completion of last course of antibiotic
treatment) within 4 weeks of dosing.
4. Pregnant or breast-feeding or intending to become pregnant during the study.
5. Prior treatment with systemic immunotherapeutic agents, including, but not limited
to, radio-immunoconjugates, antibody-drug conjugates, immune/cytokines and
monoclonal antibodies (e.g., anti-CTLA4, anti-PD1 and anti-PDL1) within 4 weeks or
five half-lives of the drug, whichever is shorter, before Gpt infusion on C1/D-7.
6. History of treatment-emergent immune-related adverse events associated with prior
immunotherapeutic agents, as follows:
• Grade ≥ 3 adverse events with the exception of Grade 3 endocrinopathy
managed with replacement therapy
• Grade 1-2 adverse events that did not resolve to baseline after treatment
discontinuation
7. Documented refractoriness to an obinutuzumab monotherapy containing regimen.
8. Treatment with standard radiotherapy, any chemotherapeutic agent, or treatment
with any other investigational anti-cancer agent (defined as treatment for which
there is currently no regulatory authority approved indication) within 4 weeks prior to
Gpt infusion.
9. Prior solid organ transplantation.
10. Prior allogeneic SCT.
11. Autologous SCT within 100 days prior to Gpt infusion.
12. History of autoimmune disease, including but not limited to myasthenia gravis,
myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis,
inflammatory bowel disease, vascular thrombosis associated with antiphospholipid
syndrome, Wegener’s granulomatosis, Sjögren’s syndrome, Guillain-Barré
syndrome, multiple sclerosis, vasculitis, or glomerulonephritis.
• Patients with a history of autoimmune-related hypothyroidism on a stable dose
of thyroid replacement hormone may be eligible for this study.
• Patients with a history of disease-related immune thrombocytopenic purpura or
autoimmune hemolytic anemia may be eligible for this study.
• Patients with a history of Type I Diabetes Mellitus who are well controlled
(defined as a screening hemoglobin A1c <8% and no urinary ketoacidosis) are
eligible.
13. History of severe allergic or anaphylactic reactions to monoclonal antibody therapy
(or recombinant antibody-related fusion proteins).
14. Patient with history of confirmed progressive multifocal leukoencephalopathy (PML).
15. Current or past history of CNS lymphoma.
16. Current or past history of CNS disease, such as stroke, epilepsy, CNS vasculitis, or
neurodegenerative disease.
• Note: Patients with a history of stroke who have not experienced a stroke or
transient ischemic attack in the past 2 years and have no residual neurologic
deficits, as judged by the investigator, are allowed.
17. Evidence of significant, uncontrolled concomitant diseases that could affect
compliance with the protocol or interpretation of results, including diabetes mellitus,
history of relevant pulmonary disorders (bronchospasm, obstructive pulmonary
disease) and known autoimmune diseases.
18. Major surgery or significant traumatic injury <28 days prior to the Gpt infusion
(excluding biopsies) or anticipation of the need for major surgery during study
treatment.
19. Patients with another invasive malignancy in the last 2 years (with the exception of
basal cell carcinoma and tumors deemed by the Investigator to be of low likelihood
for recurrence).
20. Significant cardiovascular disease such as New York Heart Association Class III or
IV cardiac disease, myocardial infarction within the last 6 months, unstable
arrhythmias, or unstable angina).
21. Administration of a live, attenuated vaccine within 4 weeks before Gpt infusion or
anticipation that such a live attenuated vaccine will be required during the study.
(Note: Influenza vaccination should be given during influenza season only). Patients
must not receive live, attenuated influenza vaccine (e.g., Flumist) at any time
during the study treatment period.
22. Received systemic immunosuppressive medications (including but not limited to
cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor
necrosis factor agents) with the exception of corticosteroid treatment ≤ 25 mg/day
prednisone or equivalent within 2 weeks prior to Gpt infusion.
Inhaled and topical steroids are permitted.
23. History of illicit drug or alcohol abuse within 12 months prior to screening, in the
Investigator’s judgment.
24. Any other diseases, metabolic dysfunction, physical examination finding, or clinical
laboratory finding giving reasonable suspicion of a disease or condition that would
contraindicate the use of an investigational drug.

The Estimated Number of Participants

  • Taiwan

    20 participants

  • Global

    485 participants

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