A Study of Autogene Cevumeran (RO7198457) as a Single Agent and in Combination With Atezolizumab in Participants With Locally Advanced or Metastatic Tumors

Sponsor

Genentech, Inc. (Industry)

Overall Status

Active, not recruiting

CT.gov ID

NCT03289962

Collaborator

BioNTech SE (Industry)

272

Enrollment

Locations

Arms

73.4

Anticipated Duration (Months)

7.4

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is a Phase 1a/1b, open-label, multicenter, global, dose-escalation study designed to evaluate the safety, tolerability, immune response, and pharmacokinetics of autogene cevumeran (RO7198457) as a single agent and in combination with atezolizumab (MPDL3280A, an engineered anti-programmed death-ligand 1 [anti-PD-L1] antibody).

Condition or Disease	Intervention/Treatment	Phase
Melanoma Non-Small Cell Lung Cancer Bladder Cancer Colorectal Cancer Triple Negative Breast Cancer Renal Cancer Head and Neck Cancer Other Solid Cancers	Drug: Autogene cevumeran Drug: Atezolizumab	Phase 1

Study Design

Study Type:

Interventional

Actual Enrollment :

272 participants

Allocation:

Non-Randomized

Intervention Model:

Sequential Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase 1a/1b Open-Label, Dose-Escalation Study of the Safety and Pharmacokinetics of RO7198457 as a Single Agent and in Combination With Atezolizumab in Patients With Locally Advanced or Metastatic Tumors

Actual Study Start Date :

Dec 21, 2017

Anticipated Primary Completion Date :

Feb 1, 2024

Anticipated Study Completion Date :

Feb 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Phase 1a Flat Dose Escalation: Autogene Cevumeran Participants will receive autogene cevumeran at escalated dosages.	Drug: Autogene cevumeran Autogene cevumeran will be administered by intravenous (IV) infusion, in 21-day cycles. Other Names: RO7198457
Experimental: Phase 1b Flat Dose Escalation: Autogene Cevumeran + Atezolizumab Participants will receive autogene cevumeran at escalated dosages along with atezolizumab at a fixed dose of 1200 milligrams (mg)	Drug: Autogene cevumeran Autogene cevumeran will be administered by intravenous (IV) infusion, in 21-day cycles. Other Names: RO7198457 Drug: Atezolizumab Atezolizumab will be administered by IV infusion on Day 1 of every 21-day cycle. Other Names: Tecentriq RO5541267 MPDL3280A An engineered anti-PDL1 antibody
Experimental: Phase Ib: Dose Exploration: Autogene Cevumeran + Atezolizumab Non-small cell lung cancer (NSCLC) or melanoma cancer immunotherapy (CIT)-treated participants will receive autogene cevumeran (at dosage lower than maximum tolerated dose [MTD] based on available safety data) along with atezolizumab at a fixed dose of 1200 mg.	Drug: Autogene cevumeran Autogene cevumeran will be administered by intravenous (IV) infusion, in 21-day cycles. Other Names: RO7198457 Drug: Atezolizumab Atezolizumab will be administered by IV infusion on Day 1 of every 21-day cycle. Other Names: Tecentriq RO5541267 MPDL3280A An engineered anti-PDL1 antibody
Experimental: Phase 1b Expansion: Autogene Cevumeran + Atezolizumab Participants with different indications as per inclusion criteria will receive autogene cevumeran (at multiple dose levels below MTD based on available safety data) along with atezolizumab at a fixed dose of 1200 mg.	Drug: Autogene cevumeran Autogene cevumeran will be administered by intravenous (IV) infusion, in 21-day cycles. Other Names: RO7198457 Drug: Atezolizumab Atezolizumab will be administered by IV infusion on Day 1 of every 21-day cycle. Other Names: Tecentriq RO5541267 MPDL3280A An engineered anti-PDL1 antibody
Experimental: Phase 1b Expansion: Autogene Cevumeran + Atezolizumab (Serial Biopsy) CIT-naive patients with selected tumor types who consent to optional serial biopsies will receive autogene cevumeran (at multiple dose levels below MTD based on available safety data) along with atezolizumab at a dixed dose of 1200 mg.	Drug: Autogene cevumeran Autogene cevumeran will be administered by intravenous (IV) infusion, in 21-day cycles. Other Names: RO7198457 Drug: Atezolizumab Atezolizumab will be administered by IV infusion on Day 1 of every 21-day cycle. Other Names: Tecentriq RO5541267 MPDL3280A An engineered anti-PDL1 antibody

Outcome Measures

Primary Outcome Measures

Percentage of Participants with Dose-Limiting Toxicities (DLTs) [Phase 1a: Days 1 to 14 / Phase 1b: Days 1 to 21]
MTD/Recommended Phase 2 Dose (RP2D) of Autogene Cevumeran [Phase 1a: Days 1 to 14 / Phase 1b: Days 1 to 21]
Percentage of Participants with Adverse Events (AEs) [Baseline up to end of the study (up to approximately 3 years)]
Percentage of Participants with Immune-Mediated Adverse Events (imAEs) [Baseline up to end of the study (up to approximately 3 years)]
Percentage of Participants by Number of Treatment Cycles Received [Baseline up to end of the study (up to approximately 3 years)]
Dose Intensity of Autogene Cevumeran [Baseline up to end of the study (up to approximately 3 years)]
Change from Baseline in Targeted Vital Signs [Baseline up to end of study (up to approximately 3 years)]
Change from Baseline in Targeted Clinical Laboratory Test Results [Baseline up to end of study (up to approximately 3 years)]
Change from Baseline in ECGs [Baseline up to end of study (up to approximately 3 years)]

Secondary Outcome Measures

Percentage of Participants with Objective Response of Complete Response (CR) or Partial Response (PR) According to Response Evaluation Criteria for Solid Tumors Version 1.1 (RECIST v1.1) [Baseline until 90 days after last dose or initiation of another systemic anti-cancer therapy, whichever occurs first (up to approximately 3 years)]
Duration of Response (DoR) According to RECIST v1.1 [From first occurrence of a documented objective response (CR or PR) until disease progression or death due to any cause, whichever occurs first (up to approximately 3 years)]
Percentage of Participants with Objective Response of CR or PR According to Immune-Modified RECIST [Baseline until 90 days after last dose or initiation of another systemic anti-cancer therapy, whichever occurs first (up to approximately 3 years)]
DoR According to Immune-Modified RECIST [From first occurrence of a documented objective response (CR or PR) until disease progression or death due to any cause, whichever occurs first (up to approximately 3 years)]
Progression-Free Survival (PFS) According to RECIST v1.1 [Baseline until 90 days after last dose or initiation of another systemic anti-cancer therapy, whichever occurs first (up to approximately 3 years)]
Overall Survival (OS) [Baseline until 90 days after last dose or initiation of another systemic anti-cancer therapy, whichever occurs first (up to approximately 3 years)]
Percentage of Participants with Anti-Drug Antibodies (ADAs) to Atezolizumab [Pre-infusion (0 hr) until 2 months post treatment discontinuation (up to approximately 3 years)]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
Life expectancy greater than or equal to (>=12 weeks)
Adequate hematologic and end-organ function
Measured or calculated creatinine clearance >=50 milliliters per minute (mL/min) on the basis of the Cockcroft-Gault glomerular filtration rate estimation

Cancer-Specific Inclusion Criteria:

Participants with histologic documentation of locally advanced, recurrent, or metastatic incurable malignancy that has progressed after at least one available standard therapy; or for whom standard therapy has proven to be ineffective or intolerable, or is considered inappropriate; or for whom a clinical trial of an investigational agent is a recognized standard of care
Participants with confirmed availability of representative tumor specimens in formalin-fixed, paraffin-embedded (FFPE) blocks (preferred), or sectioned tissue
Participants with measurable disease per RECIST v1.1

Additional Inclusion Criteria for Participants in Each Indication-Specific

Exploration/Expansion Cohort of Phase 1b:

NSCLC Cohorts (CIT-Naive): Participants with histologically confirmed incurable, advanced NSCLC not previously treated with anti-PD-L1/PD-1 and/or with anti-CTLA-4 (investigational or approved), for whom a clinical trial of an investigational agent in combination with an anti-PD-L1/PD-1 antibody is considered an acceptable treatment option (if CIT [including anti-PD-L1/PD-1 agents] is approved as treatment for NSCLC by local regulatory authorities).
NSCLC Cohort (CIT-Treated): Participants with histologically confirmed incurable, advanced NSCLC previously treated with anti-PD-L1/PD-1 with or without anti-CTLA-4 (investigational or approved)
Triple negative breast cancer (TNBC) Cohort (CIT-Naive): Participants with histologically confirmed incurable, advanced estrogen receptor (ER)-negative, progesterone receptor-negative, and human epidermal growth factor receptor 2 (HER2)-negative adenocarcinoma of the breast (triple-negative) not previously treated with anti-PD-L1/PD-1 and/or anti-CTLA-4 (investigational or approved)
Colorectal cancer (CRC) Cohort (CIT-Naive): Participants with histologically confirmed incurable, advanced adenocarcinoma of the colon or rectum not previously treated with anti-PD-L1/PD-1 and/or anti-CTLA-4 (investigational or approved)
Head and neck squamous cell carcinoma (HNSCC) Cohort (CIT-Naive): Participants with histologically confirmed inoperable, locally advanced or metastatic, recurrent, or persistent HNSCC (oral cavity, oropharynx, hypopharnyx, or larynx) not amenable to curative therapy not previously treated with anti-PD-L1/PD-1 and/or anti-CTLA-4 (investigational or approved)
Urothelial carcinoma (UC) Cohort (CIT-Naive): Participants with histologically confirmed incurable, advanced transitional cell carcinoma of the urothelium including renal pelvis, ureters, urinary bladder, and urethra, not previously treated with anti-PD-L1/PD-1 with or without anti-CTLA-4 (investigational or approved), for whom a clinical trial of an investigational agent in combination with an anti-PD-L1 antibody is considered an acceptable treatment option, if CIT (including anti-PD-L1/PD-1 agents) is approved as treatment for UC by local regulatory authorities
UC Cohort (CIT-Treated): Participants with histologically confirmed incurable advanced transitional cell carcinoma of the urothelium (including renal pelvis, ureters, urinary bladder, and urethra) previously treated with anti-PD-L1/PD-1 with or without anti-CTLA-4 (investigational or approved)
Renal cell carcinoma (RCC) Cohort (CIT-Naive): Participants with histologically confirmed incurable, advanced RCC with component of clear cell histology and/or component of sarcomatoid histology not previously treated with anti-PD-L1/PD-1 and/or anti-CTLA-4 (investigational or approved)
Melanoma Cohort (CIT-Naive in metastatic setting): Participants with histologically confirmed incurable, advanced melanoma not previously treated with anti-PD-L1/PD-1 and/or anti-CTLA-4 (investigational or approved) in the metastatic setting
Melanoma Cohort (CIT-Treated): Participants with histologically confirmed incurable, advanced melanoma previously treated with anti-PD-L1/ or PD-1 with or without CTLA-4 (investigational or approved)

Additional Inclusion Criteria for Participants in the Serial-Biopsy Expansion Cohort of

Phase 1b:

Participants must have one of the locally advanced or metastatic solid tumor types specified in the protocol.
Participants must have accessible lesion(s) that permit a total of two to three biopsies (pretreatment and on-treatment) or one biopsy (on-treatment, if archival tissue can be submitted in place of a pre-treatment biopsy) without unacceptable risk of a significant procedural complication. RECIST lesions should not be biopsied.

Exclusion Criteria:

Known clinically significant liver disease, including active viral, alcoholic, or other hepatitis, cirrhosis, and inherited liver disease or current alcohol abuse
Major surgical procedure within 28 days prior to Cycle 1, Day 1, or anticipation of need for a major surgical procedure during the course of the study
Any other diseases, metabolic dysfunction, physical examination finding, and/or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or may render the participant at high risk from treatment complications
Previous splenectomy
Known primary immunodeficiencies, either cellular (e.g., DiGeorge syndrome, T-negative severe combined immunodeficiency [SCID]) or combined T- and B-cell immunodeficiencies (e.g., T- and B-negative SCID, Wiskott Aldrich syndrome, ataxia telangiectasia, common variable immunodeficiency)
Any medical condition or abnormality in clinical laboratory tests that, in the investigator's judgment, precludes the participant's safe participation in and completion of the study Cancer-Specific Exclusion Criteria
Any anti-cancer therapy, whether investigational or approved, including chemotherapy, hormonal therapy, and/or radiotherapy, within 3 weeks prior to initiation of study treatment, with the exceptions as mentioned in the protocol
Eligibility based on prior treatment with CIT depends on the mechanistic class of the drug and the cohort for which the participant is being considered, as described below. In addition, all criteria pertaining to adverse events attributed to prior cancer therapies must be met

All Cohorts (Dose-Escalation in Phase 1a and Dose-Escalation, Backfill, and Expansion in

Phase 1b):

Prior neoantigen-specific or whole-tumor cancer vaccines are not allowed, with the exception as specified in protocol
Prior treatment with cytokines is allowed provided that at least 6 weeks or 5 half-lives of the drug, whichever is shorter, have elapsed between the last dose and the proposed Cycle 1, Day 1
Prior treatment with immune checkpoint inhibitors, immunomodulatory monoclonal antibody (mAbs), and/or mAb-derived therapies is allowed provided that at least 6 weeks (Phase 1a) or 3 weeks (Phase 1b) have elapsed between the last dose and the proposed Cycle 1, Day 1, with the exceptions as specified in protocol Phase Ib Dose-Exploration/Expansion Group Only Cohorts
In the non-melanoma CIT-Naive expansion cohort in Phase Ib, prior treatment with anti-PD-L1/PD-1 and/or anti-CTLA-4 (investigational or approved), is not allowed.
In the melanoma CIT-naive in metastatic setting expansion cohort in Phase Ib, prior treatment with anti-PD- L1/PD-1 and/or anti-CTLA-4 (investigational or approved) is not allowed. Prior anti-PD-L1/PD-1 and/or anti-CTLA-4 therapy in the adjuvant setting is allowed provided that there is at least a 6-month treatment-free interval between completion of adjuvant therapy and Cycle 1, Day 1.
Prior treatment with immunomodulators, including toll-like receptor (TLR) agonists, inhibitors of indoleamine 2,3-dioxygenase (IDO)/ tryptophan-2,3-dioxygenase (TDO), or agonists of OX40, is allowed provided that at least 5 half-lives of the drug or a minimum of 3 weeks have elapsed between the last dose of the prior treatment and the proposed Cycle 1, Day 1, with the exception as specified in protocol
Any history of an immune-mediated Grade 4 adverse event attributed to prior CIT (other than endocrinopathy managed with replacement therapy or asymptomatic elevation of serum amylase or lipase)
Any history of an immune-mediated Grade 3 adverse event attributed to prior CIT (other than hypothyroidism managed with replacement therapy) that resulted in permanent discontinuation of the prior immunotherapeutic agent and/or occurred less than or equal to (<=) 6 months prior to Cycle 1 Day 1
Adverse events from prior anti-cancer therapy that have not resolved to Grade <=1 except for alopecia, vitiligo, or endocrinopathy managed with replacement therapy
All immune-mediated adverse events related to prior CIT (other than endocrinopathy managed with replacement therapy or stable vitiligo) must have resolved completely to baseline
Primary central nervous system (CNS) malignancy, untreated CNS metastases, or active CNS metastases (progressing or requiring corticosteroids for symptomatic control)
Leptomeningeal disease
Uncontrolled tumor-related pain
Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures
Malignancies other than disease under study within 5 years prior to Cycle 1, Day 1, with the exception of those with a negligible risk of metastasis or death
Uncontrolled hypercalcemia
Participant has spinal cord compression not definitively treated with surgery and/or radiation or previously diagnosed and treated spinal cord compression without evidence that disease has been clinically stable for >=2 weeks prior to screening

Treatment-Specific Exclusion Criteria:

History of autoimmune disease with caveats as specified in protocol
Treatment with monoamine oxidase inhibitors (MAOIs) within 3 weeks prior to Cycle 1, Day 1
Treatment with systemic immunosuppressive medications within 2 weeks prior to Cycle 1, Day 1
History of idiopathic pulmonary fibrosis, pneumonitis, organizing pneumonia, or evidence of active pneumonitis on screening chest computed tomography (CT) scan
Positive test for human immunodeficiency virus (HIV) infection
Active hepatitis B, hepatitis C
Known active or latent tuberculosis infection
Severe infections within 4 weeks prior to Cycle 1, Day 1
Recent infections not meeting the criteria for severe infections within 2 weeks prior to Cycle 1, Day 1
Prior allogeneic bone marrow transplantation or prior solid organ transplantation
Administration of a live, attenuated vaccine within 4 weeks before Cycle 1, Day 1 or anticipation that such a live attenuated vaccine will be required during the study
Known hypersensitivity to the active substance or to any of the excipients in the vaccine
Phase 1b and crossover only: History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins; Known hypersensitivity to Chinese Hamster Ovary (CHO)-cell products; Allergy or hypersensitivity to components of the atezolizumab formulation

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	HonorHealth Research Institute - Bisgrove	Scottsdale	Arizona	United States	85258
2	The Los Angeles Clinic	Los Angeles	California	United States	90025
3	UCSF Comprehensive Cancer Ctr	San Francisco	California	United States	94158
4	Stanford Cancer Center	Stanford	California	United States	94305-5820
5	University of Colorado	Aurora	Colorado	United States	80045-2517
6	Yale University Cancer Center, Smilow Cancer Hospital; Medical Oncology	New Haven	Connecticut	United States	06511
7	Georgetown University	Washington	District of Columbia	United States	20007
8	Massachusetts General Hospital.	Boston	Massachusetts	United States	02114
9	Dana Farber Can Ins	Boston	Massachusetts	United States	02215
10	Comprehensive Cancer Centers of Nevada (CCCN) - Central Valley	Las Vegas	Nevada	United States	89169
11	Columbia University Medical Center; Clinical Research Management Office	New York	New York	United States	10032
12	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065
13	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma	United States	73104
14	Providence Oncology and Hematology Care Eastside	Portland	Oregon	United States	97213
15	University of Pittsburgh Medical Center	Pittsburgh	Pennsylvania	United States	15213
16	Sarah Cannon Res Inst; TN Onc	Nashville	Tennessee	United States	37203
17	Seattle Cancer Care Alliance	Seattle	Washington	United States	98109
18	UZ Gent	Gent		Belgium	9000
19	CHU Sart-Tilman	Liège		Belgium	4000
20	Sint Augustinus Wilrijk	Wilrijk		Belgium	2610
21	The Ottawa Hospital Cancer Centre; Oncology	Ottawa	Ontario	Canada	K1H 8L6
22	Princess Margaret Cancer Center	Toronto	Ontario	Canada	M5G 2M9
23	Universitätsklinikum Essen; Innere Klinik und Poliklinik für Tumorforschung	Essen		Germany	45122
24	LungenClinic Großhansdorf GmbH	Großhansdorf		Germany	22927
25	Nationales Centrum für Tumorerkrankungen Heidelberg (NCT); Thoraxklinik Heidelberg	Heidelberg		Germany	69120
26	Fachklinik für Lungenerkrankungen	Immenhausen		Germany	34376
27	Universitaetsmedizin der Johannes Gutenberg-Universitaet Mainz	Mainz		Germany	55101
28	Antoni van Leeuwenhoek Ziekenhuis	Amsterdam		Netherlands	1066 CX
29	LUMC	Leiden		Netherlands	2333 ZA
30	Universitair Medisch Centrum Utrecht	Utrecht		Netherlands	3584 CX
31	Clinica Universitaria de Navarra; Servicio de oncología	Pamplona	Navarra	Spain	31008
32	Vall d´Hebron Institute of Oncology (VHIO), Barcelona	Barcelona		Spain	08035
33	Karolinska Hospital; Oncology - Radiumhemmet	Stockholm		Sweden	171 76
34	Akademiska sjukhuset, Onkologkliniken	Uppsala		Sweden	751 85
35	Barts & London School of Med; Medical Oncology	London		United Kingdom	EC1A 7BE
36	Southampton General Hospital; Medical Oncology	Southampton		United Kingdom	SO16 6YD
37	The Royal Marsden Hospital	Sutton		United Kingdom	SM2 5PT