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A Study to Evaluate the Safety, Pharmacokinetics and Preliminary Anti-Tumor Activity of RO7227166 in Combination With Obinutuzumab and in Combination With CD20-TCB Following a Pre-Treatment Dose of Obinutuzumab Administered in Participants With Relapsed/Refractory B-Cell Non-Hodgkin's Lymphoma

NCT04077723

Description:

This is a phase I, open-label, dose-escalation study designed to evaluate the safety, tolerability, and efficacy of RO7227166 in participants with relapsed/refractory Non-Hodgkin's Lymphoma (r/r NHL). RO7227166 will be administered by intravenous (IV) infusion in combination with obinutuzumab and in combination with CD20-TCB. A fixed dose of obinutuzumab (Gpt; pre-treatment) will be administered seven days prior to the first administration of RO7227166 and seven days prior to the first administration of CD20-TCB. This entry-into-human study is divided into a dose-escalation stage (Part I and Part II) and a dose expansion stage (Part III).

Related Conditions:
  • Non-Hodgkin Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: A Study to Evaluate the Safety, Pharmacokinetics and Preliminary Anti-Tumor Activity of RO7227166 in Combination With Obinutuzumab and in Combination With CD20-TCB Following a Pre-Treatment Dose of Obinutuzumab Administered in Participants With Relapsed/Refractory B-Cell Non-Hodgkin's Lymphoma
  • Official Title: An Open-Label, Phase I Study to Evaluate the Safety, Pharmacokinetics and Preliminary Antitumor Activity of RO7227166 (a CD19 Targeted 4-1BB Ligand) in Combination With Obinutuzumab and in Combination With RO7082859 (CD20-TCB) Following a Pre-Treatment Dose of Obinutuzumab Administered in Participants With Relapsed/Refractory B-Cell Non-Hodgkin's Lymphoma

Clinical Trial IDs

  • ORG STUDY ID: BP41072
  • SECONDARY ID: 2019-000416-28
  • NCT ID: NCT04077723

Conditions

  • Lymphoma, Non-Hodgkin

Interventions

DrugSynonymsArms
RO7227166A CD19 Targeted 4-1BB LigandPart I
ObinutuzumabGptPart I
RO7082859CD20-TCBPart II

Purpose

This is a phase I, open-label, dose-escalation study designed to evaluate the safety, tolerability, and efficacy of RO7227166 in participants with relapsed/refractory Non-Hodgkin's Lymphoma (r/r NHL). RO7227166 will be administered by intravenous (IV) infusion in combination with obinutuzumab and in combination with CD20-TCB. A fixed dose of obinutuzumab (Gpt; pre-treatment) will be administered seven days prior to the first administration of RO7227166 and seven days prior to the first administration of CD20-TCB. This entry-into-human study is divided into a dose-escalation stage (Part I and Part II) and a dose expansion stage (Part III).

Trial Arms

NameTypeDescriptionInterventions
Part IExperimentalCombination Dose-Escalation: Mixed r/r NHL participants will receive a fixed dose of obinutuzumab seven days prior to first administration of RO7227166. RO7227166 will be administered by intravenous (IV) infusion in combination with obinutuzumab in a three-weekly schedule (Q3W).
  • RO7227166
  • Obinutuzumab
Part IIExperimentalCombination Dose-Escalation: Mixed r/r NHL participants will receive a fixed dose of obinutuzumab seven days prior to first administration of RO7227166. RO7227166 will be administered by IV infusion in combination with CD20-TCB in a three-weekly schedule (Q3W).
  • RO7227166
  • Obinutuzumab
  • RO7082859
Part IIIExperimentalDose-Expansion Stage: Participants with r/r follicular lymphoma (FL) and r/r diffuse large B-cell lymphoma (DLBCL) will receive RO7227166 administered by IV infusion in combination with CD20-TCB in a three-weekly schedule (Q3W).
  • RO7227166
  • RO7082859

Eligibility Criteria

        Inclusion Criteria:

          -  Depending upon study part: a history or status of a histologically-confirmed
             hematological malignancy that is expected to express CD19 and CD20; relapse after or
             failure to respond to at least one prior treatment regimen; and no available treatment
             options that are expected to prolong survival

          -  Must have at least one measureable target lesion (>/= 1.5 cm) in its largest dimension
             by computed tomography scan

          -  Able and willing to provide a fresh biopsy from a safely accessible site, per
             Investigator's determination, providing the participant has more than one measurable
             target lesion

          -  Eastern Cooperative Oncology Group performance status of 0 or 1

          -  Life expectancy of >/= 12 weeks

          -  Adverse events from prior anti-cancer therapy must have resolved to Grade </= 1

          -  Adequate liver, haematological, and renal function

          -  Negative test results for acute or chronic hepatitis B virus infection

          -  Negative test results for hepatitis C virus and HIV

          -  Negative serum pregnancy test within 7 days prior to first dose of obinutuzumab in
             women of childbearing potential. Women who are not of childbearing potential or
             surgically sterile are not required to have a pregnancy test

          -  Participants 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 RO7227166, whichever is longer, if the participant is a male or b) until
             at least 18 months after pre-treatment with obinutuzumab or 2 months after the last
             dose of RO7227166, whichever is longer

        Exclusion Criteria:

          -  Participants with lymphomatous bone marrow involvement at baseline as detected by
             histology or cytology.

          -  Circulating lymphoma cells, defined by out of range (high) absolute lymphocyte count
             or the presence of abnormal cells in the peripheral blood differential signifying
             circulating lymphoma cells

          -  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 (excluding fungal
             infections of nail beds) or any major episode of infection requiring hospitalization
             or treatment with IV antibiotics

          -  Pregnant or breast-feeding or intending to become pregnant during the study

          -  Prior treatment with systemic immunotherapeutic agents, including, but not limited to,
             radio-immunoconjugates, antibody-drug conjugates, immune/cytokines or monoclonal
             antibodies within 4 weeks or five half-lives of the drug, whichever is longer, before
             obinutuzumab infusion on D-7

          -  History of treatment-emergent immune-related AEs associated with prior
             immunotherapeutic agents and auto-immune disease

          -  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 stem cell transplant (SCT) and prior chimeric antigen receptor
             -T-cell therapy

          -  Autologous SCT within 100 days prior to obinutuzumab infusion

          -  History of severe allergic or anaphylactic reactions to monoclonal antibody therapy
             and confirmed progressive multifocal leukoencephalopathy

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

          -  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

          -  Major surgery or significant traumatic injury < 28 days prior to the Gpt infusion or
             anticipation of the need for major surgery during study treatment

          -  Participants with another invasive malignancy in the last 2 years

          -  Significant cardiovascular disease

          -  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

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

Primary Outcome Measures

Measure:Nature and frequency of dose-limiting toxicities (DLTs)
Time Frame:28 days in Part I and Part II
Safety Issue:
Description:Incidence, nature, and severity of AEs graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0

Secondary Outcome Measures

Measure:Total exposure (area under the concentration time curve [AUC]) of RO7227166 in combination with obinutuzumab and CD20-TCB
Time Frame:Part I: Up to 24 months; Part II: Up to 15 months
Safety Issue:
Description:
Measure:Maximum serum concentration (peak concentration, Cmax) of RO7227166 in combination with obinutuzumab and CD20-TCB
Time Frame:Part I: Up to 24 months; Part II: Up to 15 months
Safety Issue:
Description:
Measure:Minimum serum concentration (trough concentration, Cmin) of RO7227166 in combination with obinutuzumab and CD20-TCB
Time Frame:Part I: Up to 24 months; Part II: Up to 15 months
Safety Issue:
Description:
Measure:Clearance (CL) of RO7227166 in combination with obinutuzumab and CD20-TCB
Time Frame:Part I: Up to 24 months; Part II: Up to 15 months
Safety Issue:
Description:
Measure:Volume of distribution of steady state (Vss) and half-life (t1/2) of RO7227166 in combination with obinutuzumab and CD20-TCB
Time Frame:Part I: Up to 24 months; Part II: Up to 15 months
Safety Issue:
Description:
Measure:ORR
Time Frame:Part I: Up to 24 months; Part II/III Up to 15 months
Safety Issue:
Description:
Measure:DCR
Time Frame:Part I: Up to 24 months; Part II/III Up to 15 months
Safety Issue:
Description:
Measure:DOR
Time Frame:After end of Study approximately every 3 months until death, loss to follow-up or study termination
Safety Issue:
Description:
Measure:PFS
Time Frame:After end of Study approximately every 3 months until death, loss to follow-up or study termination
Safety Issue:
Description:
Measure:OS
Time Frame:After end of Study approximately every 3 months until death, loss to follow-up or study termination
Safety Issue:
Description:
Measure:Proportion of Participants with Adverse Event (AE)
Time Frame:After end of Study approximately every 3 months until death, loss to follow-up or study termination
Safety Issue:
Description:Incidence, nature, and severity of AEs graded according to the NCI CTCAE v5.0
Measure:Total exposure (area under the concentration time curve [AUC]) of RO7227166 in combination with CD20-TCB
Time Frame:Part III: Up to 15 months
Safety Issue:
Description:
Measure:Maximum serum concentration (peak concentration, Cmax) of RO7227166 in combination with CD20-TCB
Time Frame:Part III: Up to 15 months
Safety Issue:
Description:
Measure:Minimum serum concentration (trough concentration, Cmin) of RO7227166 in combination with CD20-TCB
Time Frame:Part III: Up to 15 months
Safety Issue:
Description:
Measure:Clearance (CL) of RO7227166 in combination with CD20-TCB
Time Frame:Part III: Up to 15 months
Safety Issue:
Description:
Measure:Volume of distribution of steady state (Vss) and half-life (t1/2) of RO7227166 in combination with CD20-TCB Part I/II/III
Time Frame:Part III: Up to 15 months
Safety Issue:
Description:
Measure:T-cell and Natural killer (NK)-cell status in blood, using markers of T and NK-cell lineage, function and activation including, but not limited to, CD3, CD8, 41BB, and Ki67 expression
Time Frame:Part I: Up to 24 months; Part II/III: Up to 15 months
Safety Issue:
Description:
Measure:B-cell reduction in blood and tumor tissue
Time Frame:Part I: Up to 24 months; Part II/III: Up to 15 months
Safety Issue:
Description:

Details

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

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