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
Overview
- Phase
- Phase 1
- Intervention
- Glofitamab
- Conditions
- Non-Hodgkin's Lymphoma
- Sponsor
- Hoffmann-La Roche
- Enrollment
- 940
- Locations
- 75
- Primary Endpoint
- Part I and II: Percentage of Participants With Dose Limiting Toxicities (DLTs)
- Status
- Recruiting
- Last Updated
- last month
Overview
Brief Summary
This is a Phase I/II, multicenter, open-label, dose-escalation study designed to evaluate the efficacy, safety, tolerability and pharmacokinetics (PK) of a novel T-Cell bispecific (TCB), glofitamab, administered by intravenous (IV) infusion as a single agent and in combination with obinutuzumab, following pre-treatment with a one-time, fixed dose of obinutuzumab. This entry-into-human (EIH) study is divided in 3 parts: dose escalation (Parts I and II) and dose expansion (Part III). Single-participant dose-escalation cohorts will be used in Part I, followed by conversion to multiple participant dose-escalation cohorts (Part II), in order to define a tentative maximum tolerated dose (MTD) or optimal biological dose (OBD). The expansion cohorts (Part III) will be initiated when the tentative MTD/OBD is defined, to further evaluate the safety, PK and therapeutic activity of glofitamab.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Depending upon study part, a history or status of: 1) a histologically-confirmed hematological malignancy that is expected to express cluster of differentiation (CD)20; 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 \[ASCT\])
- •Measurable disease, defined as at least one bi-dimensionally measurable nodal lesion, defined as \> 1.5 cm in its longest dimension, or at least one bi-dimensionally measurable extranodal lesion, defined as \> 1.0 cm in its longest dimension
- •Able to provide a tumor tissue pretreatment biopsy at last relapse or during screening from a safely accessible site, per investigator determination, providing the patient has more than one measurable target lesion
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- •Life expectancy of \>/=12 weeks
- •AEs from prior anti-cancer therapy must have resolved to Grade less than or equal to (\</=) 1
- •Adequate liver, hematological and renal function
- •Negative serologic or polymerase chain reaction (PCR) test results for acute or chronic Hepatitis B virus (HBV) infection
- •Negative test results for Hepatitis C virus (HCV) and human immunodeficiency virus (HIV)
- •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 (at least 12 months of non-therapy amenorrhea) or surgically sterile (absence of ovaries and/or uterus) are not required to have a pregnancy test
Exclusion Criteria
- •Inability to comply with protocol mandated hospitalizations and restrictions
- •Participants with chronic lymphocytic leukemia (CLL), Burkitt lymphoma and lymphoplasmacytic lymphoma
- •Participants with a known or suspected history of hemophagocytic lymphohistiocytosis (HLH)
- •Participants with acute bacterial, viral, or fungal infection at baseline, confirmed by a positive blood culture within 72 hours prior to obinutuzumab infusion or by clinical judgment in the absence of a positive blood culture
- •Participants with known active infection, or reactivation of a latent infection, whether bacterial, viral, fungal, mycobacterial, or other pathogens or any major episode of infection requiring hospitalization or treatment with IV antibiotics within 4 weeks of dosing
- •Prior treatment with systemic immunotherapeutic agents, including, but not limited to, radio-immunoconjugates, antibody-drug conjugates, immune/cytokines and monoclonal antibodies (e.g., anti-cytotoxic T-lymphocyte-associated protein 4 \[anti-CTLA4\], anti-programmed death 1 \[anti-PD1\] and anti-programmed death ligand 1 \[anti-PDL1\]) within 4 weeks or five half-lives of the drug, whichever is shorter, before obinutuzumab infusion on Cycle 1 Day -7
- •History of treatment-emergent immune-related AEs associated with prior immunotherapeutic agents
- •Documented refractoriness to an obinutuzumab-containing regimen
- •Treatment with standard radiotherapy, any chemotherapeutic agent, or treatment with any other investigational anti-cancer agent, including chimeric antigen receptor therapy (CAR-T) within 4 weeks prior to obinutuzumab infusion
- •Prior solid organ transplantation
Arms & Interventions
Part I: Dose Escalation
Participants (single participant cohorts) will receive obinutuzumab pretreatment (Gpt) 1000 milligrams (mg) single dose IV infusion on Day -7 followed by glofitamab IV infusion on Day 1 and Day 8 of Cycle 1. From Cycle 2 onwards, ascending doses of glofitamab will be administered on Day 1 of every 2 week (Q2W) cycle up to Cycle 12 (24 weeks) or until unacceptable toxicity or disease progression. Glofitamab dosing will be initiated at 5 micrograms (mcg) (flat dose) followed by doses of 15 mcg, 45 mcg, 135 mcg, 405 mcg and 810 mcg.
Intervention: Glofitamab
Part I: Dose Escalation
Participants (single participant cohorts) will receive obinutuzumab pretreatment (Gpt) 1000 milligrams (mg) single dose IV infusion on Day -7 followed by glofitamab IV infusion on Day 1 and Day 8 of Cycle 1. From Cycle 2 onwards, ascending doses of glofitamab will be administered on Day 1 of every 2 week (Q2W) cycle up to Cycle 12 (24 weeks) or until unacceptable toxicity or disease progression. Glofitamab dosing will be initiated at 5 micrograms (mcg) (flat dose) followed by doses of 15 mcg, 45 mcg, 135 mcg, 405 mcg and 810 mcg.
Intervention: Obinutuzumab
Part I: Dose Escalation
Participants (single participant cohorts) will receive obinutuzumab pretreatment (Gpt) 1000 milligrams (mg) single dose IV infusion on Day -7 followed by glofitamab IV infusion on Day 1 and Day 8 of Cycle 1. From Cycle 2 onwards, ascending doses of glofitamab will be administered on Day 1 of every 2 week (Q2W) cycle up to Cycle 12 (24 weeks) or until unacceptable toxicity or disease progression. Glofitamab dosing will be initiated at 5 micrograms (mcg) (flat dose) followed by doses of 15 mcg, 45 mcg, 135 mcg, 405 mcg and 810 mcg.
Intervention: Tocilizumab
Part II: Dose Escalation
In each treatment regimen, participants will receive Gpt 1000 mg IV infusion on Day -7; or 2000 mg either administered on Day -7, or split into two 1000 mg doses on Days -1 and -7. The first glofitamab IV infusion will be given on Day 1 of Cycle 1 and a total of 12 cycles will be administered. Monotherapy, glofitamab as a single agent: ascending doses of glofitamab administered on Day 1 of Q2W or every 3 week (Q3W) cycle until either the MTD/OBD is defined. Combination Therapy: From Cycle 2 onwards, a fixed dose of 1000 mg obinutuzumab will be administered via IV infusion in combination with ascending doses of glofitamab on Day 1 of Q3W cycle until either the MTD/OBD is defined. Step-up dosing: Q3W, participants will receive an initial low dose of glofitamab on Cycle 1 Day 1, followed by a higher dose on Cycle 1 Day 8; the total dose in Cycle 1 will not exceed the previously determined MTD. Higher doses may be explored from Cycle 2 or later cycles.
Intervention: Glofitamab
Part II: Dose Escalation
In each treatment regimen, participants will receive Gpt 1000 mg IV infusion on Day -7; or 2000 mg either administered on Day -7, or split into two 1000 mg doses on Days -1 and -7. The first glofitamab IV infusion will be given on Day 1 of Cycle 1 and a total of 12 cycles will be administered. Monotherapy, glofitamab as a single agent: ascending doses of glofitamab administered on Day 1 of Q2W or every 3 week (Q3W) cycle until either the MTD/OBD is defined. Combination Therapy: From Cycle 2 onwards, a fixed dose of 1000 mg obinutuzumab will be administered via IV infusion in combination with ascending doses of glofitamab on Day 1 of Q3W cycle until either the MTD/OBD is defined. Step-up dosing: Q3W, participants will receive an initial low dose of glofitamab on Cycle 1 Day 1, followed by a higher dose on Cycle 1 Day 8; the total dose in Cycle 1 will not exceed the previously determined MTD. Higher doses may be explored from Cycle 2 or later cycles.
Intervention: Obinutuzumab
Part II: Dose Escalation
In each treatment regimen, participants will receive Gpt 1000 mg IV infusion on Day -7; or 2000 mg either administered on Day -7, or split into two 1000 mg doses on Days -1 and -7. The first glofitamab IV infusion will be given on Day 1 of Cycle 1 and a total of 12 cycles will be administered. Monotherapy, glofitamab as a single agent: ascending doses of glofitamab administered on Day 1 of Q2W or every 3 week (Q3W) cycle until either the MTD/OBD is defined. Combination Therapy: From Cycle 2 onwards, a fixed dose of 1000 mg obinutuzumab will be administered via IV infusion in combination with ascending doses of glofitamab on Day 1 of Q3W cycle until either the MTD/OBD is defined. Step-up dosing: Q3W, participants will receive an initial low dose of glofitamab on Cycle 1 Day 1, followed by a higher dose on Cycle 1 Day 8; the total dose in Cycle 1 will not exceed the previously determined MTD. Higher doses may be explored from Cycle 2 or later cycles.
Intervention: Tocilizumab
Part III: Dose Expansion
Part III will start once MTD/OBD is defined. Participants will receive Gpt 1000 mg single dose IV infusion on Day -7, followed by glofitamab at a fixed dose regimen or step-up dose regimen on a Q2W or Q3W dosing schedule as determined in Part II. A total of 12 cycles will be administered. Combination Therapy: From Cycle 2 onwards, a fixed dose of 1000 mg obinutuzumab will be administered via IV infusion in combination with glofitamab at the dosing regimen determined in Part II.
Intervention: Glofitamab
Part III: Dose Expansion
Part III will start once MTD/OBD is defined. Participants will receive Gpt 1000 mg single dose IV infusion on Day -7, followed by glofitamab at a fixed dose regimen or step-up dose regimen on a Q2W or Q3W dosing schedule as determined in Part II. A total of 12 cycles will be administered. Combination Therapy: From Cycle 2 onwards, a fixed dose of 1000 mg obinutuzumab will be administered via IV infusion in combination with glofitamab at the dosing regimen determined in Part II.
Intervention: Obinutuzumab
Part III: Dose Expansion
Part III will start once MTD/OBD is defined. Participants will receive Gpt 1000 mg single dose IV infusion on Day -7, followed by glofitamab at a fixed dose regimen or step-up dose regimen on a Q2W or Q3W dosing schedule as determined in Part II. A total of 12 cycles will be administered. Combination Therapy: From Cycle 2 onwards, a fixed dose of 1000 mg obinutuzumab will be administered via IV infusion in combination with glofitamab at the dosing regimen determined in Part II.
Intervention: Tocilizumab
Outcomes
Primary Outcomes
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
Part II: Recommended Phase II Dose (RP2D) of Glofitamab
Time Frame: From Baseline 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 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: 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
Secondary Outcomes
- Parts I and II: Percentage of Participants With Overall Response (Partial Response [PR] or Complete Response [CR]) as Determined by the Lugano Classification(From Baseline up to end of study or discontinuation due to disease progression (up to 5 years))
- Part I, II and III: Cmin of Obinutuzumab(Pre-dose of obinutuzumab on Day -7; pre-dose (Hr 0) of glofitamab on Day 1 of Cycle 1)
- Part I, II and III: Cmax of Obinutuzumab(Pre-dose of obinutuzumab on Day -7; pre-dose (Hr 0) of glofitamab on Day 1 of Cycle 1)
- Overall Survival (OS)(From the time of first study treatment to death from any cause (up to 5 years))
- Part I, II and III: Anti-drug Antibodies (ADA) to Glofitamab(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))
- Part I, II and III: Percentage of Participants With PR or CR (Overall Response Rate [ORR]) as Determined by the Lugano Classifications(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(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(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(From first study treatment to the first occurrence of disease progression or death due to any cause (up to 5 years))
- Time to First Overall Response (TFOR)(From time of treatment start to first documented response (up to 5 years))
- Time to First Complete Response (TFCR)(From treatment start to first documented complete response (up to 5 years))
- Part III: 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)(From baseline through follow-up or until disease progression (up to 5 years))
- Part III: HRQoL as Assessed by the Functional Assessment of Cancer Therapy-lymphoma (FACT-lym) Scale(From baseline through follow-up or until disease progression (up to 5 years))