A Safety, Efficacy and Pharmacokinetic Study of BTCT4465A (Mosunetuzumab) as a Single Agent and Combined with Atezolizumab in Non-Hodgkin's Lymphoma (NHL) and Chronic Lymphocytic Leukemia (CLL)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Genentech Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

11 Jun 2024 → 2 Sep 2025

Decision date (initial)

2024-06-25

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Genentech Inc.

External identifiers

EU CT number

2023-506820-10-00

EudraCT number

2017-003267-35

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Others, Safety, Pharmacokinetic, Efficacy

In pre-specified cohorts: • To evaluate safety, tolerability, and pharmacokinetics of mosunetuzumab as a single agent and in combination with atezolizumab in patients with relapsed or refractory (R/R) non-Hodgkin’s lymphoma (NHL) and chronic lymphocytic leukemia (CLL) • To determine maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of mosunetuzumab as a single agent and in combination with atezolizumab in patients with R/R NHL and CLL • To identify, on the basis of safety, PK, and pharmacodynamic data, recommended Phase II dose(s) (RP2D) and schedule(s) of mosunetuzumab as a single agent and in combination with atezolizumab in patients with R/R NHL and CLL • To evaluate efficacy of mosunetuzumab as a single agent and in combination with atezolizumab in patients with R/R NHL, as measured by IRF-assessed CR rate according to standard NHL response criteria • To evaluate PK non-inferiority (PKNI) of mosunetuzumab subcutaneous (SC) compared to the reference mosunetuzumab Intravenous (IV) RP2D in patients with R/R FL with at least two prior lines of systemic therapy

Secondary objectives 4

1. To assess the incidence of anti-drug antibodies (ADAs) to mosunetuzumab and atezolizumab (when given in combination with mosunetuzumab), and their relationship to relevant clinical outcomes
2. Where evaluation of efficacy of mosunetuzumab as single agent and in combination with atezolizumab is not a primary objective as described above, to make a preliminary assessment of the anti-tumor activity of mosunetuzumab, as a single agent and in combination with atezolizumab, in patients with R/R NHL and CLL
3. To assess impact of treatment- and disease-related symptoms on health-related quality of life (HRQoL) and health status in the NHL expansion cohorts
4. To further assess the PKNI of mosunetuzumab SC RP2D compared to the reference mosunetuzumab IV RP2D in patients with R/R FL with at least two prior lines of systemic therapy based on additional PK parameters

Conditions and MedDRA coding

B-Cell Malignancies

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 5

1. 1. Agreement to provide tumor samples as follows: – For NHL patients with more than one bi-dimensionally measurable lesion (>1.5 cm in the largest dimension for nodal lesions, or >1.0 cm in its largest dimension for extranodal lesions by CT scan or MRI), agreement to undergo biopsy from a safely accessible site per investigator determination. Biopsies obtained at any time between the last dose of last prior anti-cancer therapy and the first dose of mosunetuzumab may be acceptable. – For patients with CLL: -Bone marrow biopsy and aspirate -Must have a circulating lymphocyte count of >5000/micro Litre blood
2. 2. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and life expectancy of at least 12 weeks
3. 3. Histologically-documented relapsed or refractory NHL or CLL expected to express the cluster of differentiation 20 (CD20) antigen and for which there is no available therapy expected to improve survival
4. 4. NHL patients only: must have at least one bi-dimensionally measurable lesion (>1.5 cm in its largest dimension for nodal lesions, or >1.0 cm in its largest dimension for extranodal lesions by CT or MRI scan)
5. 5. Adequate hepatic, hematologic, and renal function

Exclusion criteria 6

1. 1. Prior treatment with systemic immunotherapeutic agents for which the mechanism of action involves T cells within 12 weeks or five half-lives of the drug, whichever is shorter, before first mosunetuzumab administration - Treatment with any chemotherapeutic agent, or treatment with any other anti-cancer agent (investigational or otherwise) within 4 weeks or five half-lives of the drug, whichever is shorter, prior to first mosunetuzumab administration - Treatment with radiotherapy within 2 weeks prior to the first mosunetuzumab administration. - Received systemic immunosuppressive medications (with exceptions) within 2 weeks prior to first mosunetuzumab administration
2. 2. Prior anti-lymphoma treatment with monoclonal antibodies, radioimmunoconjugates or antibody-drug conjugates within 4 weeks before first mosunetuzumab administration Autologous SCT within 100 days prior to first mosunetuzumab administration Prior treatment with CAR-T therapy within 30 days before first mosunetuzumab administration
3. 3. Prior allogeneic stem cell transplantation (SCT) Prior solid organ transplantation
4. 4. Patients with history of macrophage activation syndrome/hemophagocytic lymphohistiocytosis or confirmed progressive multifocal leukoencephalopathy (PML)
5. 5. History of central nervous system (CNS) lymphoma or other CNS disease, autoimmune disease, other malignancy, significant cardiovascular disease, significant active pulmonary disease, known active infection (or any major episode of infection requiring treatment with IV antibiotics or hospitalization within 4 weeks prior to first mosunetuzumab administration), or major surgery within 4 weeks prior to first mosunetuzumab administration
6. 6. Administration of a live, attenuated vaccine within 4 weeks before first dose of study treatment or anticipation that such a live attenuated vaccine will be required during the study

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 8

1. 1. Safety: Incidence and nature of dose-limiting toxicity (DLTs) when mosunetuzumab is given as a single agent IV or SC
2. 2. Safety: Incidence and nature of DLTs when mosunetuzumab is given in combination with atezolizumab
3. 3. Efficacy: Independent Review Facility (IRF)-assessed complete response (CR) rate, defined as the proportion of patients whose best overall response is a CR based upon IRF assessment using standard criteria for NHL
4. 4. PK: Serum concentration of mosunetuzumab at specified timepoints
5. 5. PK: The following PK parameters (if data allows): AUC, Cmax, Cmin, CL, and Vss
6. 6. PK: Other parameters such as accumulation ratio, half-life, and dose proportionality may also be calculated
7. 7. PKNI: Observed Cycle 3 (i.e., pre-dose Cycle 4) serum Ctrough concentration (CtroughCYC3_OBS)
8. 8. PKNI: Cumulative AUC over 0−84 days (AUC0-84)

Secondary endpoints 14

1. 1. Safety: Incidence, nature, and severity of adverse events (AEs)
2. 2. Safety: Incidence of anti-drug antibodies (ADAs) against mosunetuzumab and atezolizumab, and their relationship to clinical outcomes
3. 3. Safety: Changes in vital signs and clinical laboratory values
4. 4. Efficacy: Investigator-assessed CR rate, defined as the proportion of patients whose best overall response is a CR based upon investigator assessment using standard criteria for NHL
5. 5. Efficacy: IRF and investigator assessed objective response rate (ORR), defined as the proportion of patients whose best overall response is a PR or CR using standard criteria for NHL
6. 6. Efficacy: IRF and investigator assessed duration of complete response, defined as the time from the initial occurrence of a documented CR until documented disease progression or death due to any cause, whichever occurs first, using standard criteria for NHL
7. 7. Efficacy: IRF and investigator assessed duration of response, defined as the time from the initial occurrence of a documented PR or CR until documented disease progression or death due to any cause, whichever occurs first, using standard criteria for NHL
8. 8. Efficacy: IRF and investigator assessed progression-free survival (PFS), defined as the time from the first study treatment to the first occurrence of disease progression or death from any cause, whichever occurs first, using standard criteria for NHL
9. 9. Efficacy: Overall survival (OS), defined as the time from the first study treatment to the date of death from any cause
10. 10. PRO: The HRQoL and health status measures that will be used in NHL expansion cohorts to evaluate PROs are as follows: Summary statistics and change from baseline in HRQoL based on EORTC QLQ C30 Summary statistics and change from baseline in disease-related symptoms based on the FACT-Lym subscale Descriptive results of the EQ-5D-5L data during patients’ participation in the study
11. 11. Pharmacokinetic Non-Inferiority (PKNI): Observed Cycle 2 (i.e., pre-dose Cycle 3) serum Ctrough concentration (CtroughCYC2_OBS)
12. 12. PKNI: Modeled Cycle 2 (i.e., pre-dose Cycle 3) serum Ctrough concentration (CtroughCYC2), derived using EBEs or virtual trial simulations, data permitting
13. 13. PKNI: Modeled Cycle 3 (pre-dose Cycle 4) serum Ctrough concentration (CtroughCYC3), derived using EBEs or virtual trial simulations, data permitting
14. 14. PKNI: Modeled AUC at steady state (AUCSS), as approximated by AUC of Cycle 4 using EBEs or virtual trial simulations, data permitting

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 8

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Genentech Inc.

Sponsor organisation

Genentech Inc.

Address

1 Dna Way

City

South San Francisco

Postcode

94080-4918

Country

United States

Scientific contact point

Organisation

Genentech Inc.

Contact name

US Program Manager Product Development Regulatory

Public contact point

Organisation

Genentech Inc.

Contact name

US Program Manager Product Development Regulatory

Third parties 6

Locations

2 EU/EEA countries · 8 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Layperson summary Annex V

Documents 18 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications