A Phase Ib/II Study Investigating the Safety, Tolerability, Pharmacokinetics, and Efficacy of Mosunetuzumab (BTCT4465A) in Combination With CHOP or CHP-Polatuzumab Vedotin in Participants With B-Cell Non-Hodgkin Lymphoma

Sponsor

Hoffmann-La Roche (Industry)

Overall Status

Active, not recruiting

CT.gov ID

NCT03677141

Collaborator

(none)

160

Enrollment

Locations

Arms

44.6

Anticipated Duration (Months)

3.9

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This study will evaluate the safety, pharmacokinetics, and preliminary efficacy of mosunetuzumab in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (M-CHOP) and, subsequently, in combination with cyclophosphamide, doxorubicin, and prednisone (CHP) plus polatuzumab vedotin (CHP-pola) in participants with relapsed or refractory (R/R) B-cell non-Hodgkin lymphoma (NHL), and in previously untreated participants with diffuse large B-cell lymphoma (DLBCL).

Condition or Disease	Intervention/Treatment	Phase
B-cell Non-Hodgkin Lymphoma	Drug: Mosunetuzumab Drug: Polatuzumab Vedotin Drug: Rituxumab Drug: Cyclophosphamide Drug: Doxorubicin Drug: Vincristine Drug: Prednisone Drug: Tocilizumab	Phase 1/Phase 2

Study Design

Study Type:

Interventional

Actual Enrollment :

160 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase Ib/II, Open-Label, Multicenter, Randomized, Controlled Study Investigating the Safety, Tolerability, Pharmacokinetics, and Efficacy of Mosunetuzumab (BTCT4465A) in Combination With CHOP or CHP-Polatuzumab Vedotin in Patients With B-Cell Non-Hodgkin Lymphoma

Actual Study Start Date :

Feb 8, 2019

Anticipated Primary Completion Date :

Oct 28, 2022

Anticipated Study Completion Date :

Oct 28, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Phase Ib: Mosunetuzumab (M)-CHOP Dose Finding Participants will receive M-CHOP up to the phase II recommended dose (RP2D).	Drug: Mosunetuzumab Participants will receive intravenous (IV) mosunetuzumab. Drug: Polatuzumab Vedotin Participants will receive polatuzumab vedotin via IV. Drug: Cyclophosphamide Participants will receive cyclophosphamide via IV. Drug: Doxorubicin Participants will receive doxorubicin via IV. Drug: Vincristine Participants will receive vincristine via IV. Drug: Prednisone Participants will receive oral prednisone. Drug: Tocilizumab Participants will receive tocilizumab via IV.
Experimental: Phase Ib: M-CHP-Pola Dose-Finding Participants will receive M-CHP-Pola up to the RP2D.	Drug: Mosunetuzumab Participants will receive intravenous (IV) mosunetuzumab. Drug: Polatuzumab Vedotin Participants will receive polatuzumab vedotin via IV. Drug: Cyclophosphamide Participants will receive cyclophosphamide via IV. Drug: Doxorubicin Participants will receive doxorubicin via IV. Drug: Prednisone Participants will receive oral prednisone. Drug: Tocilizumab Participants will receive tocilizumab via IV.
Experimental: Phase II: M-CHOP Previously Untreated (1L) DLBCL Safety Cohort Participants with 1L DLBCL will receive mosunetuzumab at the RP2D in combination with CHOP.	Drug: Mosunetuzumab Participants will receive intravenous (IV) mosunetuzumab. Drug: Cyclophosphamide Participants will receive cyclophosphamide via IV. Drug: Doxorubicin Participants will receive doxorubicin via IV. Drug: Vincristine Participants will receive vincristine via IV. Drug: Prednisone Participants will receive oral prednisone. Drug: Tocilizumab Participants will receive tocilizumab via IV.
Experimental: Phase II: M-CHP-Pola 1L DLBCL Participants with 1L DLBCL will receive M-CHP-Pola at a dose determined in the dose finding stage.	Drug: Mosunetuzumab Participants will receive intravenous (IV) mosunetuzumab. Drug: Polatuzumab Vedotin Participants will receive polatuzumab vedotin via IV. Drug: Cyclophosphamide Participants will receive cyclophosphamide via IV. Drug: Doxorubicin Participants will receive doxorubicin via IV. Drug: Prednisone Participants will receive oral prednisone. Drug: Tocilizumab Participants will receive tocilizumab via IV.
Active Comparator: Phase II: Rituxumab (R)-CHP-Pola 1L DLBCL Participants with 1L DLBCL will receive R-CHP-Pola at a dose determined in the dose finding stage.	Drug: Polatuzumab Vedotin Participants will receive polatuzumab vedotin via IV. Drug: Rituxumab Participants will receive rituxumab via IV. Drug: Cyclophosphamide Participants will receive cyclophosphamide via IV. Drug: Doxorubicin Participants will receive doxorubicin via IV. Drug: Prednisone Participants will receive oral prednisone.
Experimental: Phase II: M-CHOP 1L DLBCL Participants with 1L DLBCL will receive M-CHOP at a dose determined in the dose finding stage.	Drug: Mosunetuzumab Participants will receive intravenous (IV) mosunetuzumab. Drug: Cyclophosphamide Participants will receive cyclophosphamide via IV. Drug: Doxorubicin Participants will receive doxorubicin via IV. Drug: Vincristine Participants will receive vincristine via IV. Drug: Prednisone Participants will receive oral prednisone. Drug: Tocilizumab Participants will receive tocilizumab via IV.

Outcome Measures

Primary Outcome Measures

Percentage of Participants with Adverse Events (AE) [Baseline through approximately 90 days after the last study treatment]
Complete Response (CR) Rate at the Time of Primary Response Assessment Based on Positron Emission Tomography - Computed Tomography (PET-CT) as Assessed According to Lugano 2014 Response Criteria [Approximately 6-8 weeks after Cycle 6 (cycle = 21 days), or at early treatment discontinuation]

Secondary Outcome Measures

Maximum Serum Concentration (Cmax) of Mosunetuzumab [At pre-defined intervals from Cycle 1, Day 1 through approximately 90 days after the last study treatment (cycle = 21 days)]
Minimum Serum Concentration (Cmin) of Mosunetuzumab [At pre-defined intervals from Cycle 1, Day 1 through approximately 90 days after the last study treatment (cycle = 21 days)]
Area Under the Curve (AUC) of Mosunetuzumab [At pre-defined intervals from Cycle 1, Day 1 through approximately 90 days after the last study treatment (cycle = 21 days)]
Clearance (CL) of Mosunetuzumab [At pre-defined intervals from Cycle 1, Day 1 through approximately 90 days after the last study treatment (cycle = 21 days)]
Volume of Distribution at Steady State (Vss) of Mosunetuzumab [At pre-defined intervals from Cycle 1, Day 1 through approximately 90 days after the last study treatment (cycle = 21 days)]
Maximum Plasma Concentration (Cmax) of Polatuzumab Vedotin [At pre-defined intervals from Cycle 1, Day 1 through approximately 90 days after the last study treatment (cycle = 21 days)]
Minimum Plasma Concentration (Cmin) of Polatuzumab Vedotin [At pre-defined intervals from Cycle 1, Day 1 through approximately 90 days after the last study treatment (cycle = 21 days)]
AUC of Polatuzumab Vedotin [At pre-defined intervals from Cycle 1, Day 1 through approximately 90 days after the last study treatment (cycle = 21 days)]
CL of Polatuzumab Vedotin [At pre-defined intervals from Cycle 1, Day 1 through approximately 90 days after the last study treatment (cycle = 21 days)]
Vss of Polatuzumab Vedotin [At pre-defined intervals from Cycle 1, Day 1 through approximately 90 days after the last study treatment (cycle = 21 days)]
Best Objective Response Rate (ORR), Defined as Complete Response (CR) or Partial Response (PR) at any Time on Study Based on PET-CT and/or CT scan as Assessed According to Lugano 2014 Response Criteria [Baseline through 2 years after partial response assessment (PRA) (up to a total of approximately 2.5 years)]
Duration of Response (DOR) [From the first occurrence of a response to disease progression, relapse, or death, whichever comes first (up to approximately 2.5 years)]
Anti-Drug Antibodies (ADAs) to Mosunetuzumab [At pre-defined intervals from Cycle 1, Day 1 through approximately 90 days after the last study treatment (cycle = 21 days)]
ADAs to Polatuzumab Vedotin [At pre-defined intervals from Cycle 1, Day 1 through approximately 90 days after the last study treatment (cycle = 21 days)]
Progression-Free Survival (PFS) [From randomization to the first occurrence of disease progression, relapse, or death from any cause, whichever occurs first (up to approximately 2.5 years)]
PFS at 1 Year [Randomization to 1 Year]
Event-Free Survival (EFS) [From randomization to the first occurrence of disease progression or relapse, initiation of new anti-lymphoma therapy (NALT), or death from any cause, whichever occurs first (up to approximately 2.5 years)]
Time to Deterioration in the European Organization for Research and Treatment of Cancer Quality of Life - Core 30 Questionnaire (EORTC QLQ-C30) Physical Functioning and Fatigue [From baseline through follow-up (up to approximately 2.5 years)]
Time to Deterioration in the Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym) Subscale [From baseline through follow-up (up to approximately 2.5 years)]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria for Phase Ib and Phase II Portions

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
Eastern Cooperative Oncology Group Performance Status of 0, 1, or 2
Adequate hematologic function

Inclusion Criteria for Phase Ib Portion

Participants must also meet the following criteria for study entry into the Phase Ib portion:

Histologically confirmed B-cell NHL according to the World Health Organization (WHO) 2016 classification expected to express the cluster of differentiation-20 (CD20) antigen
Relapsed or refractory (R/R) B-cell NHL after at least one prior systemic lymphoma therapy
Treatment with at least one prior CD20-directed therapy
Group B only: no prior treatment with polatuzumab vedotin

Inclusion Criteria for Phase II Portion

Participants must also meet the following criteria for study entry in the Phase II portion:

Previously untreated, histologically confirmed DLBCL according to WHO 2016 classification
International Prognostic Index (IPI) score of 2-5

Exclusion Criteria

Prior treatment with mosunetuzumab
Prior allogenic stem-cell transplant
Current Grade >1 peripheral neuropathy
Participants with 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)
Prior solid organ transplantation
History of autoimmune disease
Current or past history of central nervous system (CNS) lymphoma
Current or past history of CNS disease, such as stroke, epilepsy, CNS vasculitis, or neurodegenerative disease
Significant cardiovascular disease or pulmonary disease
Clinically significant history of liver disease
Recent major surgery within 4 weeks before the start of C1D1, other than superficial lymph node biopsies for diagnosis

Exclusion Criteria for Phase Ib Portion

Participants who also meet any of the following criteria will be excluded from study entry in the Phase Ib portion:

Prior treatment with chemotherapy, immunotherapy, and biologic therapy 4 weeks prior to C1D1
Prior treatment with radiotherapy within 2 weeks prior to C1D1
Adverse events from prior anti-cancer therapy resolved to ≤Grade 1 (with the exception of alopecia and anorexia)
Prior treatment with >250 mg/m^2 doxorubicin (or equivalent anthracycline dose)

Exclusion Criteria for Phase II Portion

Participants who also meet any of the following criteria will be excluded from study entry in the Phase II portion:

Participants with transformed lymphoma
Prior therapy for B-cell NHL

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama Birmingham	Birmingham	Alabama	United States	35294
2	University of California; Moores Cancer Center	La Jolla	California	United States	92093
3	University of California, Los Angeles (UCLA) - Hematology/Oncology Santa Monica	Santa Monica	California	United States	90404-2023
4	Banner MD Anderson Cancer Center	Greeley	Colorado	United States	85234
5	Georgetown University Medical Center	Washington	District of Columbia	United States	20007
6	University of Miami Miller School of Medicine	Miami	Florida	United States	33136
7	University of Kansas Cancer Center	Westwood	Kansas	United States	66205
8	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02215
9	University of Michigan	Ann Arbor	Michigan	United States	48109-0934
10	Mayo Clinic Cancer Center	Rochester	Minnesota	United States	55905
11	Rhode Island Hospital	Providence	Rhode Island	United States	02903-4801
12	Vanderbilt University Medical Center	Nashville	Tennessee	United States	37232
13	The University of Texas MD Anderson Cancer Center	Houston	Texas	United States	77030-4009
14	Scott and White Hospital; Cancer Center	Temple	Texas	United States	76508
15	Medical College of Wisconsin, Inc.	Milwaukee	Wisconsin	United States	53226-3596
16	Uniklinikum Salzburg, LKH; Univ.Klinik f. Innere Medizin III der PMU	Salzburg		Austria	5020
17	LKH Steyr	Steyr		Austria	4400
18	Medizinische Universität Wien, Allgemeines Krankenhaus der Stadt Wien	Wien		Austria	1090
19	Hanusch-Krankenhaus	Wien		Austria	1140
20	CHU Henri Mondor; Service d'Oncologie Medicale	Creteil		France	94010
21	Centre Leon Berard	Lyon		France	69008
22	Hôpital Saint-Louis	Paris		France	75475
23	Centre Henri Becquerel- Centre de Lutte Contre le Cancer	Saint Herblain		France	44805
24	Gustave Roussy	Villejuif CEDEX		France	94800
25	Pusan National University Yangsan Hospital	Gyeongsangnam-do		Korea, Republic of	50612
26	Seoul National University Hospital	Seoul		Korea, Republic of	03080
27	Asan Medical Center	Seoul		Korea, Republic of	05505
28	Samsung Medical Center	Seoul		Korea, Republic of	06351
29	Maria Sklodowska-Curie Memorial Cancer Centre	Gliwice		Poland	44-102
30	Małopolskie Centrum Medyczne	Kraków		Poland	31-501
31	Wojewodzki Szpital Specjalistyczny im. Janusza Korczaka	Slupsk		Poland	76-200
32	Instytut Hematologii i Transfuzjologii; Klinika Zaburzeń Hemostazy i Chorób Wewnętrznych	Warsaw		Poland	02-776
33	Katedra i Klinika Hematologii; Nowotworów Krwi i Transplantacji Szpiku	Wrocław		Poland
34	Institut Catala d´Oncologia Hospital Germans Trias i Pujol	Badalona	Barcelona	Spain	08916
35	Clinica Universidad de Navarra	Pamplona	Navarra	Spain	31008
36	Hospital Universitario Virgen Macarena	Seville	Sevilla	Spain	41071
37	Hospital de la Santa Creu i Sant Pau	Barcelona		Spain	08025
38	Hospital San Pedro de Alcantara; Servicio de Hematología	Caceres		Spain	10003
39	Hospital General Universitario Gregorio Marañon	Madrid		Spain	28007
40	Hospital Universitario La Paz	Madrid		Spain	280146
41	Hospital Universitario 12 de Octubre	Madrid		Spain	28041