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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 Glofitamab 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 glofitamab. 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 glofitamab. 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:
  • Diffuse Large B-Cell Lymphoma
  • Follicular Lymphoma
  • 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 Glofitamab 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 Glofitamab 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
ObinutuzumabGpt, RO5072759, Gazyva, GazyvaroPart I
GlofitamabCD20-TCB, RO7082859Part II
TocilizumabActemra, RoActemraPart I

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 glofitamab. 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 glofitamab. 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
  • Tocilizumab
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 glofitamab in a three-weekly schedule (Q3W).
  • RO7227166
  • Obinutuzumab
  • Glofitamab
  • Tocilizumab
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 glofitamab in a three-weekly schedule (Q3W).
  • RO7227166
  • Obinutuzumab
  • Glofitamab
  • Tocilizumab

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 two prior treatment regimens; 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

          -  The contraception and abstinence requirements are intended to prevent exposure of an
             embryo to the study treatment. The reliability of sexual abstinence for male and/or
             female enrollment eligibility needs to be evaluated in relation to the duration of the
             clinical study and the preferred and usual lifestyle of the participant. Periodic
             abstinence (e.g., calendar, ovulation, symptothermal, or post-ovulation methods) and
             withdrawal are not acceptable methods of preventing drug exposure

          -  Female participants: A female participant is eligible to participate if she is not
             pregnant and not breastfeeding, and if at least one of the following applies: women of
             non-childbearing potential (WONCBP); women of child bearing potential (WOCBP) who
             agree to remain abstinent or use two highly effective contraceptive methods with a
             failure rate of <1% per year during the treatment period and for at least 18 months
             after obinutuzumab or 3.5 months after the last dose of RO7227166, 2 months after last
             dose of glofitamab, or 3 months after the last dose of tocilizumab, whichever is
             longer. Examples of contraceptive methods with a failure rate of < 1% per year include
             bilateral tubal occlusion/ ligation, male sexual partner who is sterilized,
             established proper use of hormonal contraceptives that inhibit ovulation,
             hormone-releasing intrauterine devices and copper intrauterine devices. Hormonal
             contraceptive methods must be supplemented by a barrier method; have a negative
             pregnancy test (blood) within the 7 days prior to the first study treatment
             administration

          -  Male participants: During the treatment period and for at least 3 months after
             obinutuzumab, or 2 months after the last dose of RO7227166, glofitamab, or tocilizumab
             whichever is longer, agreement to: Remain abstinent or use contraceptive measures such
             as a condom plus an additional contraceptive method that together result in a failure
             rate of < 1% per year, with a partner who is a women of childbearing potential. With
             pregnant female partner, remain abstinent or use contraceptive measures such as a
             condom to avoid exposing the embryo; refrain from donating sperm during this same
             period

        Exclusion Criteria:

          -  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 or approved anti-cancer agent within 4 weeks or 5 half-lives
             of the drug, whichever is longer, 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 (including but not limited to
             cyclohosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis
             factor agents) with the exception of corticosteroid treatment <=25 mg/day of
             prednisone or equivalent, however there must be documentation that the participant was
             on a stable dose of at least a 2-week duration prior to Gpt infusion. Inhaled and
             topical steriods 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 glofitamab
Time Frame:Part I: Up to 24 months; Part II: Up to 18 months
Safety Issue:
Description:
Measure:Maximum serum concentration (peak concentration, Cmax) of RO7227166 in combination with obinutuzumab and glofitamab
Time Frame:Part I: Up to 24 months; Part II: Up to 18 months
Safety Issue:
Description:
Measure:Minimum serum concentration (trough concentration, Cmin) of RO7227166 in combination with obinutuzumab and glofitamab
Time Frame:Part I: Up to 24 months; Part II: Up to 18 months
Safety Issue:
Description:
Measure:Clearance (CL) of RO7227166 in combination with obinutuzumab and glofitamab
Time Frame:Part I: Up to 24 months; Part II: Up to 18 months
Safety Issue:
Description:
Measure:Volume of distribution of steady state (Vss) and half-life (t1/2) of RO7227166 in combination with obinutuzumab and glofitamab
Time Frame:Part I: Up to 24 months; Part II: Up to 18 months
Safety Issue:
Description:
Measure:ORR
Time Frame:Part I: Up to 24 months; Part II/III Up to 18 months
Safety Issue:
Description:
Measure:DCR
Time Frame:Part I: Up to 24 months; Part II/III Up to 18 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 glofitamab
Time Frame:Part III: Up to 18 months
Safety Issue:
Description:
Measure:Maximum serum concentration (peak concentration, Cmax) of RO7227166 in combination with glofitamab
Time Frame:Part III: Up to 18 months
Safety Issue:
Description:
Measure:Minimum serum concentration (trough concentration, Cmin) of RO7227166 in combination with glofitamab
Time Frame:Part III: Up to 18 months
Safety Issue:
Description:
Measure:Clearance (CL) of RO7227166 in combination with glofitamab
Time Frame:Part III: Up to 18 months
Safety Issue:
Description:
Measure:Volume of distribution of steady state (Vss) and half-life (t1/2) of RO7227166 in combination with glofitamab Part I/II/III
Time Frame:Part III: Up to 18 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 18 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 18 months
Safety Issue:
Description:
Measure:Change from Baseline in RO7227166 Anti-Drug Antibody (ADA) Titer
Time Frame:Part 1: Up to 24 months; Part ll/lll: Up to 18 months
Safety Issue:
Description:
Measure:Time to First Complete Response (TFCR)
Time Frame:Up to 18 months
Safety Issue:
Description:
Measure:Time to First Overall Response (TFOR)
Time Frame:Up to 18 months
Safety Issue:
Description:

Details

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

Last Updated

August 20, 2021