Clinical trial NCT03677154: Trial of Mosunetuzumab (BTCT4465A) as Consolidation Therapy in Participants With Diffuse Large B-Cell Lymphoma Following First-Line Immunochemotherapy and as Monotherapy or in Combination With Polatuzumab Vedotin in Elderly/Unfit Participants With Previously Untreated Diffuse Large B-Cell Lymphoma
Official title: A Phase I/II Trial of Mosunetuzumab (BTCT4465A) as Consolidation Therapy in Patients With Diffuse Large B-Cell Lymphoma Following First-Line Immunotherapy and as Monotherapy or in Combination With Polatuzumab Vedotin in Elderly/Unfit Patients With Previously Untreated Diffuse Large B-Cell Lymphoma
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Diffuse Large B-cell Lymphoma
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2018-09-19
Enrollment: 188
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study will evaluate the safety, pharmacokinetics, and preliminary efficacy of mosunetuzumab following first-line diffuse large B-cell lymphoma (DLBCL) immunochemotherapy in participants with a best response of stable disease or partial response, or in elderly/unfit participants with previously untreated DLBCL, or subcutaneous mosunetuzumab in combination with polatuzumab vedotin IV in elderly/unfit participants with previously untreated DLBCL.


Eligibility criteria: Inclusion Criteria for All Cohorts

* At least one bi-dimensionally measurable nodal lesion, defined as \> 1.5 cm in its longest dimension, or one bi-dimensionally measurable extranodal lesion, defined as \> 1.0 cm in its longest diameter
* Adequate hematologic function
* Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2; with the exception of South Korea, where participants 80 years or older with ECOG \>/= 2 will not be eligible

Inclusion Criteria Specific to Cohort A

Participants in Cohort A must also meet the following criteria for study entry:

* Histologically confirmed DLBCL according to World Health Organization (WHO) 2016 expected to express the cluster of differentiation-20 (CD20) antigen
* One prior therapy with any systemic anthracycline-based chemoimmunotherapy containing regimen for previously untreated DLBCL
* Best response of SD or PR to prior systemic chemoimmunotherapy at the end of induction treatment in accordance with the Lugano 2014 criteria

Inclusion Criteria Specific to Cohorts B and C

Participants in Cohorts B and C must also meet the following criteria for study entry:

* Previously untreated, histologically confirmed, DLBCL according to WHO 2016 classification
* Age \>/= 80 years, or
* Age 65-79 years and considered ineligible for chemoimmuotherapy (R-CHOP) with at least one of the following: Impairment in at least two activity of daily living (ADL) components as defined in the protocol; impairment in at least two instrumental ADL components as defined in the protocol; cumulative illness rating scale - geriactic (CIRS-G) score of at least one cormorbidity with a severity score of 3-4 (not including lymphoma and hematologic deficiencies due to lymphoma) or a score of 2 in \>/= 8 comorbidities; impairment in cardiac function, renal function, liver function, or other comorbidities such that the participant is unfit for full-dose immunochemotherapy, such as rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP)
* Participants with an initial ECOG performance status of 3 may be considered during screening if the performance status is DLBCL-related and if pre-phase treatment during the screening phase (not more than 100 mg/day up to 7 days prior to Cycle 1 Day 1) results in an improvement of ECOG performance status to \</= 2 prior to enrollment

Exclusion Criteria for All Cohorts

Participants who meet any of the following criteria will be excluded from study entry:

* Transformed lymphoma
* CNS lymphoma
* Prior treatment with mosunetuzumab
* Prior stem cell transplant (autologous and allogeneic)
* History of confirmed progressive multifocal leukoencephalopathy (PML)
* Known or suspected chronic active Epstein Barr virus (CAEBV), hepatitis B, hepatitis C (HCV), or Human Immunodeficiency Virus (HIV)
* Known or suspected history of hemophagocytic lymphohistiocytosis (HLH)
* Positive SARS-CoV-2 antigen or PCR test within 30 days prior to Cycle 1 Day 1
* Prior solid organ transplantation
* Current or past history of central nervous system (CNS) disease, such as stroke, epilepsy, CNS vasculitis, or neurodegenerative disease
* Clinically significant history of liver disease
* Prior treatment with radiotherapy within 2 weeks prior to Cycle 1, Day 1 (C1D1)
* Significant cardiovascular disease

Exclusion Criteria Specific to Cohort A

Participants in Cohort A who meet the following criteria will be excluded from study entry:

- Prior anti-lymphoma treatment with chemotherapy, immunotherapy, or biologic therapy 4 weeks prior to C1D1

Exclusion Criterion Specific to Cohorts B and C

Participants in Cohorts B and C who meet the following criterion will be excluded from study entry:

- Prior treatment for DLBCL with chemotherapy, immunotherapy, and biologic therapy

Exclusion Criteria Specific to Cohort C

Participants in Cohort C who meet the following criteria will be excluded from study entry:

- Current Grade \>1 peripheral neuropathy by clinical examination or demyelinating form of Charcot-Marie-Tooth disease

Primary outcomes:
measure: Percentage of Participants with Adverse Events
timeFrame: Baseline through approximately 90 days after last study treatment
measure: Positron Emission Tomography-Computed Tomography (PET-CT) Complete Response (CR) Rate at Time of Primary Response Assessment (PRA) According to Lugano 2014 Response Criteria (Cohort A)
timeFrame: 6-8 weeks after Cycle 8 Day 1 or the final dose of study treatment (cycle = 21 days)
measure: PET-CT Objective Response Rate (ORR) at PRA According to Lugano 2014 Response Criteria as Determined by the Investigator (Cohort B)
timeFrame: 6-8 weeks after Cycle 8 Day 1 or the final dose of study treatment (cycle = 21 days)
measure: PET-CT ORR at PRA According to the Lugano 2014 Criteria as Determined by an Independent Review Committee (IRC) (Cohort C)
timeFrame: 6-8 weeks after Cycle 8 Day 1 or the final dose of study treatment (cycle = 21 days)
Secondary outcomes:
measure: Maximum Serum Concentration (Cmax) of Mosunetuzumab IV
timeFrame: At pre-defined intervals from Cycle 1 Day 1 through approximately 90 days after the last study treatment (cycle = 21 days)
measure: Minimum Serum Concentration (Cmin) of Mosunetuzumab IV
timeFrame: At pre-defined intervals from Cycle 1 Day 1 through approximately 90 days after the last study treatment (cycle = 21 days)
measure: Area Under the Curve (AUC) of Mosunetuzumab IV
timeFrame: At pre-defined intervals from Cycle 1 Day 1 through approximately 90 days after the last study treatment (cycle = 21 days)
measure: Clearance (CL) of Mosunetuzumab IV
timeFrame: At pre-defined intervals from Cycle 1 Day 1 through approximately 90 days after the last study treatment (cycle = 21 days)
measure: Volume of Distribution at Steady State (Vss) of Mosunetuzumab IV
timeFrame: At pre-defined intervals from Cycle 1 Day 1 through approximately 90 days after the last study treatment (cycle = 21 days)
measure: Maximum Serum Concentration (Cmax) of Mosunetuzumab SC
timeFrame: At pre-defined intervals from Cycle 1 Day 1 through approximately 90 days after the last study treatment (cycle = 21 days)
measure: Time to Maximum Serum Concentration (Tmax) of Mosunetuzumab SC
timeFrame: At pre-defined intervals from Cycle 1 Day 1 through approximately 90 days after the last study treatment (cycle = 21 days)
measure: Minimum Serum Concentration (Cmin) of Mosunetuzumab SC
timeFrame: At pre-defined intervals from Cycle 1 Day 1 through approximately 90 days after the last study treatment (cycle = 21 days)
measure: Area Under the Curve (AUC) of Mosunetuzumab SC
timeFrame: At pre-defined intervals from Cycle 1 Day 1 through approximately 90 days after the last study treatment (cycle = 21 days)
measure: Clearance (CL) of Mosunetuzumab SC
timeFrame: At pre-defined intervals from Cycle 1 Day 1 through approximately 90 days after the last study treatment (cycle = 21 days)
measure: Volume of Distribution at Steady State (Vss) of Mosunetuzumab SC
timeFrame: At pre-defined intervals from Cycle 1 Day 1 through approximately 90 days after the last study treatment (cycle = 21 days)
measure: Maximum Serum Concentration (Cmax) of Polatuzumab Vedotin IV
timeFrame: At pre-defined intervals from Cycle 1 Day 1 through approximately 90 days after the last study treatment (cycle = 21 days)
measure: Minimum Serum Concentration (Cmin) of Polatuzumab Vedotin IV
timeFrame: At pre-defined intervals from Cycle 1 Day 1 through approximately 90 days after the last study treatment (cycle = 21 days)
measure: Area Under the Curve (AUC) of Polatuzumab Vedotin IV
timeFrame: At pre-defined intervals from Cycle 1 Day 1 through approximately 90 days after the last study treatment (cycle = 21 days)
measure: Clearance (CL) of Polatuzumab Vedotin IV
timeFrame: At pre-defined intervals from Cycle 1 Day 1 through approximately 90 days after the last study treatment (cycle = 21 days)
measure: Volume of Distribution at Steady State (Vss) of Polatuzumab Vedotin IV
timeFrame: At pre-defined intervals from Cycle 1 Day 1 through approximately 90 days after the last study treatment (cycle = 21 days)
measure: End of Infusion Concentration (Ceoi) of Polatuzumab Vedotin IV
timeFrame: At pre-defined intervals from Cycle 1 Day 1 through approximately 90 days after the last study treatment (cycle = 21 days)
measure: Trough Concentration (Ctrough) of Polatuzumab Vedotin IV
timeFrame: At pre-defined intervals from Cycle 1 Day 1 through approximately 90 days after the last study treatment (cycle = 21 days)
measure: PET-CT Rate According to the Lugano 2014 Criteria at PRA as Determined by the Investigator (Cohorts B and C) and IRC (Cohort C)
timeFrame: 6-8 weeks after Cycle 8 Day 1 or the final dose of study treatment (cycle = 21 days)
measure: Objective Response Rate (ORR), Defined as the Proportion of Participants with a Complete Response (CR) or Partial Response (PR) at PRA as Determined by the Investigator (Cohorts A and C)
timeFrame: Baseline through 2 years after PRA (up to a total of approximately 2.5 years)
measure: Best ORR (CR or PR at any time) During the Study Based on PET-CT and/or CT Scans as Determined by the Investigator (All Cohorts) and by IRC (Cohort C)
timeFrame: Baseline through 2 years after PRA (up to a total of approximately 2.5 years)
measure: Duration of Response (DOR) as Determined by the Investigator (All Cohorts) and by IRC (Cohort C)
timeFrame: From the first occurrence of a documented objective response to disease progression, relapse, or death, whichever occurs first (up to approximately 2.5 years)
measure: Duration of Confirmed Response (DOCR) as Determined by the Investigator (All Cohorts) and by IRC (Cohort C)
timeFrame: From the first occurrence of a documented CR to disease progression or relapse, or death from any cause, whichever occurs first (up to approximately 2.5 years)
measure: Progression-Free Survival (PFS) as Determined by the Investigator (All Cohorts) and by IRC (Cohort C)
timeFrame: From the first study treatment to the first occurrence of disease progression, relapse, or death, whichever occurs first (up to approximately 2.5 years)
measure: Overall Survival (OS)
timeFrame: From the first study treatment to death from any cause
measure: Time to Deterioration in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Physical Functioning and Fatigue (Cohorts B and C)
timeFrame: From the first study treatment to the first occurrence of disease progression, relapse, initiation of new anti-lymphoma treatment, or death from any cause, whichever occurs first (up to approximately 2.5 years)
measure: Time to Deterioration in European Organization for Research and Treatment of Cancer Item Library (EORTC-IL17) Physical Functioning (Cohorts B and C)
timeFrame: From the first study treatment to the first occurrence of disease progression, relapse, initiation of new anti-lymphoma treatment, or death from any cause, whichever occurs first (up to approximately 2.5 years)
measure: Time to Deterioration in the Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym) Subscale (Cohorts B and C)
timeFrame: From the first study treatment to the first occurrence of disease progression, relapse, initiation of new anti-lymphoma treatment, or death from any cause, whichever occurs first (up to approximately 2.5 years)
measure: Proportion of Participants Achieving a Clinically Meaningful Improvement in Physical Functioning as Measured by EORTC QLQ-C30 (Cohorts B and C)
timeFrame: From the first study treatment to the first occurrence of disease progression, relapse, initiation of new anti-lymphoma treatment, or death from any cause, whichever occurs first (up to approximately 2.5 years)
measure: Proportion of Participants Achieving a Clinically Meaningful Improvement in Physical Functioning as Measured by EORTC IL17 (Cohorts B and C)
timeFrame: From the first study treatment to the first occurrence of disease progression, relapse, initiation of new anti-lymphoma treatment, or death from any cause, whichever occurs first (up to approximately 2.5 years)
measure: Anti-Drug Antibodies (ADAs) to Mosunetuzumab
timeFrame: At pre-defined intervals from Cycle 1 Day 1 through approximately 90 days after the last study treatment (cycle = 21 days)
measure: Anti-Drug Antibodies (ADAs) to Polatuzumab Vedotin (Cohort C)
timeFrame: At pre-defined intervals from Cycle 1 Day 1 through approximately 90 days after the last study treatment (cycle = 21 days)
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham School of Medicine
state: Alabama
city: Santa Monica
country: United States
facility: University of California, Los Angeles (UCLA) - Hematology/Oncology Santa Monica
state: California
city: Fort Wayne
country: United States
facility: Fort Wayne Medical Institute
state: Indiana
city: Baltimore
country: United States
facility: University of Maryland Medical Center
state: Maryland
city: Philadelphia
country: United States
facility: Fox Chase Cancer Center
state: Pennsylvania
city: Dallas
country: United States
facility: Texas Oncology - Baylor Charles A. Sammons Cancer Center
state: Texas
city: Beer Sheva
country: Israel
facility: Soroka Medical Center
city: Haifa
country: Israel
facility: Rambam Medical Center
city: Haifa
country: Israel
facility: Carmel medical center
city: Jerusalem
country: Israel
facility: Shaare Zedek Medical Center
city: Jerusalem
country: Israel
facility: Hadassah Ein-Karem
city: Kfar- Saba
country: Israel
facility: Meir Medical Center
city: Ramat Gan
country: Israel
facility: Sheba Medical Center
city: Busan
country: Korea, Republic of
facility: Pusan National University Hospital
city: Daegu
country: Korea, Republic of
facility: Keimyung University Dongsan Hospital
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Seoul
country: Korea, Republic of
facility: The Catholic University of Korea Yeouido St. Mary's Hospital
city: Seoul
country: Korea, Republic of
facility: Severance Hospital, Yonsei University
city: Gdansk
country: Poland
facility: Uniwersyteckie Centrum Kliniczne
city: Kraków
country: Poland
facility: PRATIA MCM Kraków
city: Seville
country: Spain
facility: Hospital Universitario Virgen Macarena
state: Sevilla
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d Hebron
city: Barcelona
country: Spain
facility: Institut Catala d Oncologia Hospitalet
city: Caceres
country: Spain
facility: Hospital San Pedro de Alcantara
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Marañon
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References: