A study of the safety, pharmacokinetics, and therapeutic activity of cibisatamab in combination with atezolizumab in participants with locally advanced and/or metastatic carcinoembryonic antigen (CEA)-positive solid tumors

ISRCTN	ISRCTN16358704
DOI	https://doi.org/10.1186/ISRCTN16358704
EudraCT/CTIS number	2015-003771-30
ClinicalTrials.gov number	NCT02650713
Secondary identifying numbers	WP29945

Submission date: 23/02/2021
Registration date: 22/06/2021
Last edited: 23/06/2021

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Cancer

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Plain English Summary

Background and study aims
This is a study to evaluate the safety, tolerability (side effects) and effectiveness of cibisatamab in combination with atezolizumab in patients with locally advanced and/or metastatic carcinoembryonic antigen (CEA)-positive solid tumors. Locally advanced cancer is cancer that has spread only to nearby tissues or lymph nodes, while metastatic cancer is cancer that has spread to other parts of the body. CEAs are substances (usually proteins) that are produced by some types of cancer.

Who can participate?
Patients with locally advanced and/or metastatic CEA-positive solid tumors

What does the study involve?
Part I of the study is subdivided into parts IA and IB. In Part IA participants receive increasing doses with a starting dose of 5 mg of cibisatamab given once a week and a fixed, flat dose of 1200 mg of atezolizumab given every 3 weeks, to evaluate the safety and determine the highest tolerated dose of cibisatamab in combination with atezolizumab. Part IB is a dose/schedule finding part that will test different schedules of cibisatamab in combination with atezolizumab.

What are the possible benefits and risks of participating?
Data from previous studies suggest that cibisatamab and atezolizumab could act together in their anti-cancer properties and their combination could provide a meaningful clinical benefit in patients with cancer. Potential side effects for cibisatamab and atezolizumab include gastrointestinal (GI) side effects (diarrhea), breathing side effects (shortness of breath and lack of oxygen), and blood side effects (low white blood cell count and low red blood cell count).

Where is the study run from?
Hospitals in the United States, Canada, Denmark, France, Italy, Netherlands and Spain

When is the study starting and how long is it expected to run for?
May 2015 to January 2020

Who is funding the study?
Genentech (USA)

Who is the main contact?
global-roche-genentech-trials@gene.com

Study website

Contact information

Miss Clinical Trials
Public

1 DNA Way
South San Francisco
94080
United States of America

Phone	+1 (0)888 662 6728
Email	global-roche-genentech-trials@gene.com

Study information

Study design	Open-label multicenter dose-escalation and expansion Phase Ib clinical study
Primary study design	Interventional
Secondary study design	Non randomised study
Study setting(s)	Hospital
Study type	Treatment
Participant information sheet	No participant information sheet available
Scientific title	An open-label, multicenter, dose-escalation and expansion Phase Ib study to evaluate the safety, pharmacokinetics, and therapeutic activity of cibisatamab in combination with atezolizumab in patients with locally advanced and/or metastatic CEA-positive solid tumors
Study hypothesis	To evaluate the safety, tolerability and clinical activity of cibisatamab in combination with atezolizumab in patients with locally advanced and/or metastatic CEA-positive solid tumors. Part I of the study is subdivided into parts IA and IB. Part IA is dose escalation with a starting dose of 5 mg of cibisatamab given QW (once a week) and a fixed, flat dose of 1200 mg given Q3W (every 3 weeks) of atezolizumab, to evaluate the safety and determine the MTD of cibisatamab in combination with atezolizumab. Part IB is a dose/schedule finding part that will explore different administration schedules of cibisatamab in combination with atezolizumab (1200 mg Q3W) to establish the appropriate dose/schedule of cibisatamab in combination with atezolizumab.
Ethics approval(s)	Approved 15/12/2015, Ethics Committee for Clinical Investigation of Navarra (Departamento de Salud, Pabellon de Docencia, C/ Irunlarrea, 3, 31008 Pamplona, Navarra, Spain; +34 (0)848422495; ceic@cfnavarra.es), ref: 84/15
Condition	Solid tumors
Intervention	Dose-Escalation (Part IA): Participants will receive cibisatamab weekly (QW) at escalating doses starting at 5 mg, in combination with a fixed dose (1200 mg) of atezolizumab every 3 weeks (Q3W). Cibisatamab dosage will not exceed the MTD if defined in the BP29541 study. Atezolizumab will be administered at a fixed dose of 1200 milligrams (mg) by intravenous (IV) infusion. Cibisatamab is administered by IV infusion weekly (QW) on days 1,8 and 15 of each 21-day cycle. Step up dose cohorts: cibisatamab starting dose will be 40 mg and increase with each administration up to the MTD or 1200 mg, whichever is lower. Tocilizumab will be administered as an IV infusion as necessary to treat adverse events. Dose/Schedule Finding (Part IB): Part IB will explore different cibisatamab administration schedules in combination with atezolizumab: Cohort A: will compare the QW vs Q3W dosing schedules at a flat dose of cibisatamab. Step up dosing schedules: cibisatamab dose will start at 40 mg and increase with each administration up to the MTD or 1200 mg, whichever occurs first. Atezolizumab will be administered at a fixed dose of 1200 milligrams (mg) by intravenous (IV) infusion. Cibisatamab is administered by IV infusion weekly (QW) or every 3 weeks (Q3W). Cohort A: cibisatamab starting dose will be 100 mg either QW or Q3W. Step up dose cohorts: cibisatamab starting dose will be 40 mg and increase with each administration up to the MTD or 1200 mg whichever is lower. Tocilizumab will be administered as an IV infusion as necessary to treat adverse events.
Intervention type	Drug
Pharmaceutical study type(s)
Phase	Phase I
Drug / device / biological / vaccine name(s)	Cibisatamab, atezolizumab, tocilizumab
Primary outcome measure	1. Number of participants with adverse events (AEs) measured using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03 (NCI CTCAE v5 was used for CRS) at baseline up to 60 months 2. Percentage of participants with dose-limiting toxicities (DLTs) measured using NCI CTCAE v4.03 (NCI CTCAE v5 was used for CRS) at Day 1 up to Day 21 3. Maximum-tolerated dose (MTD) of cibisatamab in combination with atezolizumab measured using NCI CTCAE v4.03 (NCI CTCAE v5 was used for CRS) Part IA: Day 1 up to Day 21; Part IB Step-up Cohorts: Day 1 up to Day 7 after each dose escalation 4. Recommended Phase II Dose (RP2D) of cibisatamab in combination with atezolizumab measured using NCI CTCAE v4.03 (NCI CTCAE v5 was used for CRS) at Day 1 up to 60 months
Secondary outcome measures	1. Pharmacokinetics (PK): area under the concentration-time curve (AUC) of cibisatamab measured using a validated bi-functional PK assay at baseline up to 60 months 2. PK: volume of distribution at steady state (Vss) of cibisatamab measured using a validated bi-functional PK assay at baseline up to 60 months 3. PK: maximum serum concentration (Cmax) of cibisatamab measured using a validated bi-functional PK assay at baseline up to 60 months 4. PK: clearance (CL) of cibisatamab measured using a validated bi-functional PK assay at baseline up to 60 months 5. Pharmacodynamics: immune cell numbers measured using immunohistochemistry (IHC), gene expression and fluorescence-activated cell sorting (FACS) at pre-infusion (1 hour before infusion start) on Day 1 of Cycles 1, 2, 3, 6; Cycle 1 Days 2 and 8 (cycle length = 21 days) 6. Percentage of participants with objective response (partial response [PR] or complete response [CR] measured using Response Evaluation Criteria in Solid Tumors [RECIST]) at baseline up to 60 months. Assessed at screening and after the start of treatment every 8 weeks for the first year, then every 12 weeks thereafter until disease progression or treatment discontinuation. 7. Percentage of participants with disease control (PR, CR or stable disease [SD]) measured using RECIST at baseline up to 60 months. Assessed at screening and after the start of treatment every 8 weeks for the first year, then every 12 weeks thereafter until disease progression or treatment discontinuation. 8. Percentage of participants with stable disease (SD) measured using RECIST at baseline up to 60 months. Assessed at screening and after the start of treatment every 8 weeks for the first year, then every 12 weeks thereafter until disease progression or treatment discontinuation. 9. Duration of response (DOR) measured using RECIST from initial objective response (PR or CR to the first disease progression or death from any cause (up to 60 months). Assessed at screening and after the start of treatment every 8 weeks for the first year, then every 12 weeks thereafter until disease progression or treatment discontinuation. 10. Progression-free survival (PFS) measured using RECIST V1.1 from first study treatment to the first occurrence of objective disease progression or death from any cause (up to 60 months). Assessed at screening and after the start of treatment every 8 weeks for the first year, then every 12 weeks thereafter until disease progression or treatment discontinuation. 11. Overall survival (OS) measured using the date of death from first study treatment to death from any cause (up to 60 months) 12. Best overall response (BOR) measured using RECIST v1.1 at baseline up to 60 months. Assessed at screening and after the start of treatment every 8 weeks for the first year, then every 12 weeks thereafter until disease progression or treatment discontinuation.
Overall study start date	27/05/2015
Overall study end date	13/01/2020

Eligibility

Participant type(s)	Patient
Age group	Mixed
Sex	Both
Target number of participants	228
Total final enrolment	228
Participant inclusion criteria	1. Confirmed locally advanced and/or metastatic solid tumor, with at least one tumor lesion of accessible non-critical location to biopsy, in participants who have progressed on a standard therapy, are intolerant to standard therapy, and/or are non-amenable to standard therapy 2. Radiologically measurable and clinically evaluable disease (as per RECIST v1.1) 3. Life expectancy (in the opinion of the investigator) of at least 12 weeks and lactate dehydrogenase (LDH) levels </= 2.5 ULN (upper limit of normal) 4. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0-1 5. All acute toxic effects of any prior radiotherapy, chemotherapy, or surgical procedure must have resolved to Grade </= 1 or returned to baseline except alopecia (any grade) and Grade 2 peripheral neuropathy 6. Adequate hematological, liver, and renal function 7. Negative serum pregnancy test within 7 days prior to study treatment in premenopausal women and women </= 2 years after start of menopause (menopause is defined as amenorrhea for more than 2 years) 8. Participants must agree to remain abstinent or be willing to use effective methods of contraception as defined in the protocol 9. Participants with non-colorectal cancer should have confirmed CEA expression in tumor tissue. For colorectal cancer (CRC), the CEA assessment should be performed but the result is not required for participant selection
Participant exclusion criteria	1. Active or untreated central nervous system (CNS) metastases as determined by computed tomography (CT) or magnetic resonance imaging (MRI) evaluation during screening and prior radiographic assessments 2. 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 at least 2 weeks prior to enrollment 3. Leptomeningeal disease 4. Participants with paraspinal, paratracheal, and mediastinal pathological lesions larger than 2 cm unless they are previously irradiated 5. Malignancies within 5 years prior to enrollment, with the exception of those with a negligible risk of metastasis or death and treated with expected curative outcome 6. Significant, uncontrolled concomitant diseases which could affect compliance with the protocol or interpretation of results 7. Uncontrolled hypertension, unstable angina, congestive heart failure (CHF), serious cardiac arrhythmia requiring treatment history of myocardial infarction within 6 months of enrollment 8. Administration of a live, attenuated vaccine within 28 days before Cycle 1 Day 1 or anticipation that such a live attenuated vaccine will be required during the study 9. Human Immunodeficiency Virus (HIV), active Hepatitis B or Hepatitis C (HCV) 10. Severe infections within 28 days prior to Cycle 1 Day 1, including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia or active tuberculosis 11. Received oral or intravenous (IV) antibiotics within 14 days prior to Day 1 12. 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 13. Major surgery or significant traumatic injury less than 28 days prior to Cycle 1 Day 1 (excluding biopsies) or anticipation of the need for major surgery during study treatment 14. Known history of autoimmune disease as defined in the protocol 15. History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced), organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia, etc.), or evidence of active pneumonitis (including drug induced) on screening chest CT scan. History of radiation pneumonitis in the radiation field (fibrosis) is permitted 16. Participants with bilateral lung lesions and dyspnea and/or oxygen saturation level (SaO2) less than 92% (at rest, room air and exertion) or participants with lobectomy or pneumonectomy with lung metastases in the remaining lung and either dyspnea or SaO2 less than 92% (at rest, room air and exertion) at baseline 17. Pregnant or breastfeeding 18. Known hypersensitivity to any of the components of cibisatamab and atezolizumab; hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies 19. Investigational therapy (defined as treatment for which there is no regulatory authority approved indication) or last dose of prior immunotherapies within 28 days prior to Cycle 1 Day 1. Participants previously treated with anti-programmed death-ligand 1 (PD-L1), or anti-PD-1 are excluded 20. Last dose of any approved anti-cancer therapy within 28 days prior to the first cibisatamab infusion 21. Prior systemic corticosteroids greater than 10mg prednisone (or equivalent) within 14 days of Cycle 1 Day 1. Inhaled and/or topical steroids are permitted 22. Expected need for regular immunosuppressive therapy 23. Radiotherapy within the last 28 days before Cycle 1 Day 1 with the exception of limited-field palliative radiotherapy
Recruitment start date	07/01/2016
Recruitment end date	14/05/2018

Locations

Countries of recruitment

Canada
Denmark
France
Italy
Netherlands
Spain
United States of America

Study participating centres

UCLA Cancer Center

10945 Le Conte Ave, Suite 3360
Los Angeles
90095
United States of America

Princess Margaret Cancer Center

700 University Avenue 7th Floor, Room 7‐723
Toronto
M5G 1Z6
Canada

Rigshospitalet; Onkologisk Klinik

Blegdamsvej 9
København
2100
Denmark

Institut Gustave Roussy

114 Rue Edouard Vaillant, Cedex
Villejuif
94805
France

Centre Leon Berard

Departement Oncologie Medicale
28 Rue Laennec, CEDEX 08
Lyon
69373
France

Azienda Ospedaliera Universitaria Senese, U.O.C.

Immunoterapia Oncologica
Viale Bracci 16
Siena
53100
Italy

IRCCS IST. Tumori Fondaz. Pascale

S.C. Oncologia Medica, Melanoma, Immunoterapia E Terapie Innovative
Via Mariano Sammola, 3
Napoli
80131
Italy

Antoni van Leeuwenhoek Ziekenhuis

Gastro-Enterologie
Plesmanlaan 121
Amsterdam
1066 CX
Netherlands

Clinica Universitaria De Navarra

Servicio de Oncologia
Avenida Pio Xii N0. 36
Pamplona
31008
Spain

Hospital Univ Vall d'Hebron

Servicio de Oncologia
Passeig De La Vall D'hebron 119-129
Barcelona
08035
Spain

Hospital Universitario 12 de Octubre

Servicio de Oncologia
Avenida Cordoba Km 5.4
Madrid
28041
Spain

Hospital del Mar

Servicio de Oncologia
Passeig Maritim 25-29, Planta Baja
Barcelona
08003
Spain

START Madrid

Centro Integral Oncologico Clara Campal (CIOCC)
Oña, 10
Madrid
28050
Spain

START Madrid-FJD, Hospital Fundacion Jimenez Diaz

Avenida Reyes Catolicos 2, Floor 1
Madrid
28040
Spain

Memorial Sloan Kettering Cancer Center

300 E 66th Street
New York
10065
United States of America

Smilow Cancer Hospital at Yale

25 York Street
New Haven
CT, 06510
United States of America

Duke Cancer Center

Morris Cancer Clinic
15110 Morris Building
Trent Drive
Durham
NC, 27710
United States of America

Stanford Comprehensive Cancer Center

875 Blake Wilbur Dr.
Palo Alto
CA, 94305
United States of America

Medical University of South Carolina

86 Jonathan Lucas St
Rm 380 MSC 955
Charleston
SC, 29425
United States of America

Columbia University Medical Center

161 Fort Washington Ave, 9th Floor
New York
NY, 10032
United States of America

University Of Colorado

12801 E. 17th Ave, Rm L18-8126
Mail Stop 8117
Aurora
CO, 80045
United States of America

MD Anderson Cancer Center

1515 Holcombe Boulevard, Unit 426
Houston
TX, 77030
United States of America

Sarah Cannon Cancer Center

250 25th Avenue North, Suite 110
Germantown
TN, 38138
United States of America

Sponsor information

Genentech, Inc
Industry

1 DNA Way
South San Francisco
94080
United States of America

Phone	+1 (0)888 662 6728
Email	global-roche-genentech-trials@gene.com
Website	https://www.roche.com/about_roche/roche_worldwide.htm

Funders

Funder type

Industry

Genentech
Private sector organisation / For-profit companies (industry)

Alternative name(s): Genentech, Inc., Genentech USA, Inc., Genentech USA
Location: United States of America

Results and Publications

Intention to publish date	30/11/2021
Individual participant data (IPD) Intention to share	No
IPD sharing plan summary	Not expected to be made available
Publication and dissemination plan	Planned publication in a high-impact peer-reviewed journal. No protocol or other study documents are available.
IPD sharing plan	The datasets generated during and/or analysed during the current study are not expected to be made available due to participant-level data not being a regulatory requirement for Phase I studies.

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Basic results		19/01/2021	23/06/2021	No	No

Additional files

ISRCTN16358704 _BasicResults_19Jan21.pdf: Uploaded 23/06/2021

Editorial Notes

23/06/2021: The basic results of this trial have been uploaded as an additional file.
02/03/2021: Trial's existence confirmed by the Ethics Committee for Clinical Investigation of Navarra.