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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

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ClinicalTrials.gov Identifier: NCT03075696
Recruitment Status : Recruiting
First Posted : March 9, 2017
Last Update Posted : August 28, 2018
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Non-Hodgkin's Lymphoma Drug: RO7082859 Drug: Obinutuzumab Drug: Tocilizumab Phase 1

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 160 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : February 21, 2017
Estimated Primary Completion Date : March 6, 2020
Estimated Study Completion Date : March 6, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lymphoma

Arm Intervention/treatment
Experimental: Part I: Dose Escalation
Participants (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).
Drug: RO7082859
RO7082859 will be administered at a dose and as per the schedule specified in the respective arms.

Drug: Obinutuzumab
Obinutuzumab 1000 mg single dose IV infusion on Day -7
Other Name: RO5072759, GA101, Gazyva®, Gazyvaro™

Drug: Tocilizumab
Tocilizumab will be administered as an IV infusion as per the methods described in the Summary of Product Characteristics (SmPC) or other similar local prescribing documents.
Other Name: Actemra®, Roactemra®

Experimental: Part II: Dose Escalation

Participants 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.

Drug: RO7082859
RO7082859 will be administered at a dose and as per the schedule specified in the respective arms.

Drug: Obinutuzumab
Obinutuzumab 1000 mg single dose IV infusion on Day -7
Other Name: RO5072759, GA101, Gazyva®, Gazyvaro™

Drug: Tocilizumab
Tocilizumab will be administered as an IV infusion as per the methods described in the Summary of Product Characteristics (SmPC) or other similar local prescribing documents.
Other Name: Actemra®, Roactemra®

Experimental: Part III: Dose Expansion

Part 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.

Drug: RO7082859
RO7082859 will be administered at a dose and as per the schedule specified in the respective arms.

Drug: Obinutuzumab
Obinutuzumab 1000 mg single dose IV infusion on Day -7
Other Name: RO5072759, GA101, Gazyva®, Gazyvaro™

Drug: Tocilizumab
Tocilizumab will be administered as an IV infusion as per the methods described in the Summary of Product Characteristics (SmPC) or other similar local prescribing documents.
Other Name: Actemra®, Roactemra®




Primary Outcome Measures :
  1. Part I and II: Percentage of Participants With Dose Limiting Toxicities (DLTs) [ Time Frame: From Baseline up to 4 weeks ]
  2. 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 3 years) ]
  3. Part II: MTD or OBD of RO7082859 [ Time Frame: From Baseline up to 4 weeks ]
  4. Part II: Recommended Phase II Dose (RP2D) of RO7082859 [ Time Frame: Baseline up to 3 years ]
  5. Part I, II and III: Area Under the Serum Concentration Versus Time Curve (AUC) of RO7082859 [ Time Frame: Part I: Cycle 1 Day 1 to Day 8 (pre-dosing of the second infusion). Part II and III: Cycle 1 Day 1 up to Day 71 (pre-infusion of Cycle 6) [detailed time frame is provided in the outcome measure 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)

  6. Part I, II and III: Maximum Serum Concentration (Cmax) of RO7082859 [ Time Frame: Cycle 1 Day 1 up to 198 days (detailed time is provided in the outcome measure description) ]
    Part I: Pre-dose (Hr 0), 2 hrs post-infusion start, 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; EOI on Day 1 of Cycles 3, 4, 6 - 12 (Cycle length=14 days); EOT/early termination visit (up to 198 days)

  7. Part I, II and III: Minimum Serum Concentration (Cmin) of RO7082859 [ Time Frame: Cycle 1 Day 1 up to 198 days (detailed time is provided in the outcome measure description) ]
    Part I: Pre-dose (Hr 0), 2 hrs post-infusion start, 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; EOI on Day 1 of Cycles 3, 4, 6 - 12 (Cycle length=14 days); EOT/early termination visit (up to 198 days)

  8. Part I, II and III: Clearance (CL) of RO7082859 [ Time Frame: Part I: Cycle 1 Day 1 to Day 8 (pre-dosing of the second infusion). Part II and III: Cycle 1 Day 1 up to Day 71 (pre-infusion of Cycle 6) [detailed time frame is provided in the outcome measure description] ]
    Part I: Pre-dose (Hr 0), 2 hrs post-infusion start, 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)

  9. Part I, II and III: Volume of Distribution at Steady-State (Vss) of RO7082859 [ Time Frame: Part I: Cycle 1 Day 1 to Day 8 (pre-dosing of the second infusion). Part II and III: Cycle 1 Day 1 up to Day 71 (pre-infusion of Cycle 6) [detailed time frame is provided in the outcome measure description] ]
    Part I: Pre-dose (Hr 0), 2 hrs post-infusion start, 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)

  10. Part I, II and III: Half-Life (t1/2) of RO7082859 [ Time Frame: Part I: Cycle 1 Day 1 to Day 8 (pre-dosing of the second infusion). Part II and III: Cycle 1 Day 1 up to Day 71 (pre-infusion of Cycle 6) [detailed time frame is provided in the outcome measure description] ]
    Part I: Pre-dose (Hr 0), 2 hrs post-infusion start, 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 :
  1. 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) ]
  2. 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) ]
  3. 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) ]
  4. 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) ]
  5. 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) ]
  6. 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) ]
  7. 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) ]
  8. 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) ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03075696


Contacts
Contact: Reference Study ID Number: NP30179 www.roche.com/about_roche/roche_worldwide.htm 888-662-6728 (U.S. and Canada) global-roche-genentech-trials@gene.com

Locations
Australia, Victoria
Peter Maccallum Cancer Centre Recruiting
Melbourne, Victoria, Australia, 3000
Belgium
UZ Gent; Neurology Active, not recruiting
Gent, Belgium, 9000
Canada, Ontario
Princess Margaret Hospital, Medical Oncology & Haematology Recruiting
Toronto, Ontario, Canada, M5G 2M9
Denmark
Righospitalet; Haematologisk Klinik Recruiting
København Ø, Denmark, 2100
France
Hopital Claude Huriez; Hematologie Recruiting
Lille, France, 59037
Ch Lyon Sud; Hemato Secteur Jules Courmont Recruiting
Pierre Benite, France, 69495
Italy
Istituto Clinico Humanitas;U.O. Oncologia Medica Ed Ematologia Active, not recruiting
Rozzano, Lombardia, Italy, 20089
A.O.U. Citta' Della Salute E Della Scienza-P.O. Molinette;S.C. Ematologia Recruiting
Torino, Piemonte, Italy, 10126
Spain
Hospital Duran i Reynals L'Hospitalet; Hematology Department Recruiting
L'Hospitalet de Llobregat, Barcelona, Spain, 08908
Hospital Universitari Vall d'Hebron; Servicio de Hematologia Recruiting
Barcelona, Spain, 08035
Hospital Univ. 12 de Octubre; Servicio de Hematologia Recruiting
Madrid, Spain, 28041
Sponsors and Collaborators
Hoffmann-La Roche
Investigators
Study Director: Clinical Trials Hoffmann-La Roche

Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT03075696     History of Changes
Other Study ID Numbers: NP30179
2016-001185-28 ( EudraCT Number )
First Posted: March 9, 2017    Key Record Dates
Last Update Posted: August 28, 2018
Last Verified: August 2018

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Lymphoma
Lymphoma, Non-Hodgkin
Lymphoma, B-Cell
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Obinutuzumab
Antineoplastic Agents