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A Dose Escalation Study of RO7082859 as a Single Agent and in Combination With Obinutuzumab, Administered After a Fixed, Single Pre-Treatment Dose of Obinutuzumab in Participants With Relapsed/Refractory B-Cell Non-Hodgkin's Lymphoma

NCT03075696

Description:

This is a Phase I, multicenter, open-label, dose-escalation study designed to evaluate the efficacy, safety, tolerability and pharmacokinetics (PK) of a novel T-Cell bispecific (TCB), RO7082859, administered by intravenous (IV) infusion as a single agent and in combination with obinutuzumab, following the pre-treatment with a one-time, fixed dose of obinutuzumab. This entry-to-human 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 RO7082859.

Related Conditions:
  • B-Cell Non-Hodgkin Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: NP30179
  • SECONDARY ID: 2016-001185-28
  • NCT ID: NCT03075696

Conditions

  • Non-Hodgkin's Lymphoma

Interventions

DrugSynonymsArms
RO7082859Part I: Dose Escalation
ObinutuzumabRO5072759, GA101, Gazyva®, GazyvaroPart I: Dose Escalation
TocilizumabActemra®, Roactemra®Part I: Dose Escalation

Purpose

This is a Phase I, multicenter, open-label, dose-escalation study designed to evaluate the safety, tolerability and pharmacokinetics (PK) of a novel T-Cell bispecific (TCB), RO7082859, administered by intravenous (IV) infusion as a single agent and in combination with obinutuzumab, following the pre-treatment with a one-time, fixed dose of obinutuzumab. This entry-to-human 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 RO7082859.

Trial Arms

NameTypeDescriptionInterventions
Part I: Dose EscalationExperimentalParticipants (single participant cohorts) will receive obinutuzumab (Gpt) 1000 milligrams (mg) single dose IV infusion on Day -7 (pre-treatment) followed by RO7082859 IV infusion on Day 1 and Day 8 of Cycle 1. From Cycle 2 onwards, ascending doses of RO7082859 will be administered on Day 1 of every 2 week cycle up to Cycle 12 (24 weeks) or until unacceptable toxicity or disease progression. RO7082859 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. Tocilizumab will be administered if required, for the management of severe Cytokine Release Syndrome (CRS) (if a study participant experiences severe CRS during or after any infusion of RO7082859).
  • RO7082859
  • Obinutuzumab
  • Tocilizumab
Part II: Dose EscalationExperimentalParticipants will receive 1000 mg Gpt single dose IV infusion on Day -7 (pre-treatment). Participants (multiple participant cohorts) will start when either RO7082859 flat dose of 810 mcg is reached or a RO7082859-related greater than or equal to (>/=) Grade 2 AE or DLT occurs, whichever comes first. Participants will receive RO7082859 IV infusion on Day 1 of Cycle 1. Monotherapy, RO7082859 as a single agent: From Cycle 2 onwards, ascending doses of RO7082859 will be administered on Day 1 of every 2 or 3 week cycle until either the MTD/OBD is defined. Combination Therapy: From Cycle 2 onwards, a fixed dose of 1000 mg Gpt will be administered via IV infusion in combination with ascending doses of RO7082859 on Day 1 of every 3 week cycle until either the MTD/OBD is defined.
  • RO7082859
  • Obinutuzumab
  • Tocilizumab
Part III: Dose ExpansionExperimentalPart III will start once OBD is defined. Participants will receive Gpt 1000 mg single dose IV infusion on Day -7 (pre-treatment) followed by RO7082859 IV infusion at OBD on Day 1 of Cycle 1. Monotherapy: From Cycle 2 onwards, RO7082859 will be administered at OBD on Day 1 of every 3 week cycle up to Cycle 8 (24 weeks) or until unacceptable toxicity or disease progression. Combination Therapy: From Cycle 2 onwards, a fixed dose of 1000 mg Gpt will be administered via IV infusion in combination with RO7082859 at OBD.
  • RO7082859
  • Obinutuzumab
  • Tocilizumab

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 [SCT])

          -  Participant must have at least one measureable target lesion (>/=1.5 centimeters [cm])
             in its largest dimension by computerized tomography [CT] scan)

          -  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)

        Exclusion Criteria:

          -  Participants with chronic lymphocytic leukemia (CLL), Burkitt lymphoma and
             lymphoplasmacytic lymphoma

          -  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 within 4 weeks prior to obinutuzumab
             infusion

          -  Prior solid organ transplantation

          -  Prior allogeneic SCT

          -  Autologous SCT within 100 days prior to obinutuzumab infusion

          -  Participant with history of confirmed progressive multifocal leukoencephalopathy (PML)

          -  Current or past history of central nervous system (CNS) lymphoma

          -  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 and known autoimmune diseases

          -  Participants 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)

          -  Administration of a live, attenuated vaccine within 4 weeks before obinutuzumab
             infusion or anticipation that such a live attenuated vaccine will be required during
             the study

          -  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 obinutuzumab infusion

          -  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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Part I and II: Percentage of Participants With Dose Limiting Toxicities (DLTs)
Time Frame:From Baseline up to 4 weeks
Safety Issue:
Description:Part I: Pre-dose (Hour [Hr] 0), 2 hrs post-infusion start, end of infusion (EOI) (infusion duration=4 hrs), 0.5, 2, 6, 12 hrs post EOI on Day 1 of Cycle 1; 20, 44, 68, 116 hrs post EOI on Days 2, 3, 4, 6 of Cycle 1 respectively; and pre-dose on Day 8 of Cycle 1 right prior to second infusion Part II and III: Pre-dose (Hr 0), 2 hrs post-infusion start, EOI (infusion duration=4 hrs), 0.5, 2, 6 hrs post EOI on Day 1 of Cycle 2 and Cycle 5; 20, 68, 116, 164, 232 hrs post EOI on Days 2, 4, 6, 8, 11 respectively of Cycles 2 and 5; and pre-dose on Day 1 of Cycles 3 and 6, respectively (Cycle length=14 days)

Secondary Outcome Measures

Measure:Part I, II and III: Cmax of Obinutuzumab
Time Frame:Pre-dose of obinutuzumab on Day -7; pre-dose (Hr 0) of RO7082859 on Day 1 of Cycle 1 (Cycle length=14 days)
Safety Issue:
Description:
Measure:Part I, II and III: Cmin of Obinutuzumab
Time Frame:Pre-dose of obinutuzumab on Day -7; pre-dose (Hr 0) of RO7082859 on Day 1 of Cycle 1 (Cycle length=14 days)
Safety Issue:
Description:
Measure:Part I, II and III: Anti-Drug Antibodies (ADA) to RO7082859
Time Frame:Pre-dose of obinutuzumab on Day -7; pre-dose (Hr 0) of RO7082859 on Day 8 of Cycle 1, Day 1 of Cycles 2-12 (Cycle length=14 days); EOT/follow-up visit (up to 3 years)
Safety Issue:
Description:
Measure:Part I, II and III: Percentage of Participants With Overall Response (Partial Response [PR] or Complete Response [CR]) as Determined by the Modified Lugano Classification
Time Frame:From Baseline up to end of study or discontinuation due to disease progression (up to 3 years)
Safety Issue:
Description:
Measure:Part I, II and III: Percentage of Participants With Stable disease (SD) as Determined by the Modified Lugano Classification
Time Frame:From Baseline up to end of study or discontinuation due to disease progression (up to 3 years)
Safety Issue:
Description:
Measure:Part I, II and III: Percentage of Participants With PR, CR or SD (Disease Control Rate) as Determined by the Modified Lugano Classification
Time Frame:From Baseline up to end of study or discontinuation due to disease progression (up to 3 years)
Safety Issue:
Description:
Measure:Part I, II and III: Duration of Response as Determined by the Modified Lugano Classification
Time Frame:From first occurrence of documented objective response until disease progression, relapse or death due to any cause (up to 3 years)
Safety Issue:
Description:
Measure:Part I, II and III: Progression-Free Survival (PFS) as Determined by the Modified Lugano Classification
Time Frame:From first study treatment to the first occurrence of disease progression or death due to any cause (up to 3 years)
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Hoffmann-La Roche

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