Clinical trial NCT02650713: A Study of the Safety, Pharmacokinetics, and Therapeutic Activity of RO6958688 in Combination With Atezolizumab in Participants With Locally Advanced and/or Metastatic Carcinoembryonic Antigen (CEA)-Positive Solid Tumors
Official title: An Open-Label, Multicenter, Dose Escalation and Expansion Phase Ib Study to Evaluate the Safety, Pharmacokinetics, and Therapeutic Activity of RO6958688 in Combination With Atezolizumab in Patients With Locally Advanced and/or Metastatic CEA-Positive Solid Tumors
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Solid Tumors
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2016-01-08
Enrollment: 228
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: This is an open-label, multicenter, dose-escalation and expansion Phase Ib clinical study of RO6958688 in combination with atezolizumab. 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 RO6958688 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 RO6958688 in combination with atezolizumab. Part IB is a dose/schedule finding part that will explore different administration schedules of RO6958688 in combination with atezolizumab (1200 mg Q3W) to establish the appropriate dose/schedule of RO6958688 in combination with atezolizumab.


Eligibility criteria: Inclusion Criteria

* 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
* Radiologically measurable and clinically evaluable disease (as per RECIST v1.1)
* 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)
* Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0-1
* 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
* Adequate hematological, liver, and renal function
* 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)
* Participants must agree to remain abstinent or be willing to use effective methods of contraception as defined in the protocol
* 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

Exclusion Criteria

* 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
* 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
* Leptomeningeal disease
* Participants with paraspinal, paratracheal, and mediastinal pathological lesions larger than 2 cm unless they are previously irradiated
* 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
* Significant, uncontrolled concomitant diseases which could affect compliance with the protocol or interpretation of results
* Uncontrolled hypertension, unstable angina, congestive heart failure (CHF), serious cardiac arrhythmia requiring treatment history of myocardial infarction within 6 months of enrollment
* 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
* Human Inmmunodeficiency Virus (HIV), active Hepatitis B or Hepatitis C (HCV)
* 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
* Received oral or intravenous (IV) antibiotics within 14 days prior to Day 1
* 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
* 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
* Known history of autoimmune disease as defined in the protocol
* 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
* 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
* Pregnant or breast-feeding
* Known hypersensitivity to any of the components of RO6958688 and atezolizumab; hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies
* 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
* Last dose of any approved anti-cancer therapy within 28 days prior to the first RO6958688 infusion
* Prior systemic corticosteroids greater than 10mg prednisone (or equivalent) within 14 days of Cycle 1 Day 1. Inhaled and/or topical steroids are permitted
* Expected need for regular immunosuppressive therapy
* Radiotherapy within the last 28 days before Cycle 1 Day 1 with the exception of limited-field palliative radiotherapy

Primary outcomes:
measure: Number of Participants with Adverse Events (AEs)
timeFrame: Baseline up to 60 months
measure: Percentage of Participants with Dose-Limiting Toxicities (DLTs)
timeFrame: Day 1 up to Day 21
measure: Maximum-Tolerated Dose (MTD) of RO6958688
timeFrame: Part IA: Day 1 up to Day 21; Part IB Step-up Cohorts: Day 1 up to Day 7 after each dose escalation
measure: Recommended Phase II Dose (RP2D) of RO6958688
timeFrame: Day 1 up to 60 months
Secondary outcomes:
measure: Pharmacokinetic (PK): Area Under the Concentration-Time Curve (AUC) of RO6958688
timeFrame: Baseline up to 60 months
measure: PK: Volume of Distribution at Steady State (Vss) of RO6958688
timeFrame: Baseline up to 60 months
measure: PK: Maximum Serum Concentration (Cmax) of RO6958688
timeFrame: Baseline up to 60 months
measure: PK: Clearance (CL) of RO6958688
timeFrame: Baseline up to 60 months
measure: PK: AUC of Atezolizumab
timeFrame: Baseline up to 60 months
measure: PK: Vss of Atezolizumab
timeFrame: Baseline up to 60 months
measure: PK: Cmax of Atezolizumab
timeFrame: Baseline up to 60 months
measure: PK: CL of Atezolizumab
timeFrame: Baseline up to 60 months
measure: Pharmacodynamics: Immune Cell Numbers as Assessed using Flow Cytometry
timeFrame: 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)
measure: Percentage of Participants with Objective Response (Partial Response [PR] or Complete Response [CR] as Assessed Using Response Evaluation Criteria in Solid Tumors [RECIST])
timeFrame: Baseline up to 60 months
measure: Percentage of Participants with Disease Control (PR, CR, or Stable Disease [SD]) as Assessed Using RECIST
timeFrame: Baseline up to 60 months
measure: Percentage of Participants with Stable Disease (SD) as Assessed Using RECIST
timeFrame: Baseline up to 60 months
measure: Duration of Response (DOR) as Assessed Using RECIST
timeFrame: From initial objective response (PR or CR to the first disease progression or death from any cause (up to 60 months)
measure: Progression-Free Survival (PFS) according to RECIST V1.1
timeFrame: From first study treatment to the first occurrence of objective disease progression or death from any cause (up to 60 months)
measure: Overall Survival (OS)
timeFrame: From first study treatment to death from any cause (up to 60 months)
measure: Best Overall Response (BOR)
timeFrame: Baseline up to 60 months
Other outcomes:
Locations:
city: Santa Monica
country: United States
facility: UCLA Cancer Center
state: California
city: Stanford
country: United States
facility: Stanford Comprehensive Cancer Center
state: California
city: Aurora
country: United States
facility: University Of Colorado
state: Colorado
city: New Haven
country: United States
facility: Smilow Cancer Hospital at Yale- New Haven Oncology Investigational Drug Pharmacy
state: Connecticut
city: Boston
country: United States
facility: Dana Farber Can Ins
state: Massachusetts
city: New York
country: United States
facility: Columbia Univ Med Ctr
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Durham
country: United States
facility: Duke Cancer Center
state: North Carolina
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Germantown
country: United States
facility: Sarah Cannon Cancer Center
state: Tennessee
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Toronto
country: Canada
facility: Princess Margaret Cancer Center
state: Ontario
city: København Ø
country: Denmark
facility: Rigshospitalet; Onkologisk Klinik
city: Lyon
country: France
facility: Centre Leon Berard; Departement Oncologie Medicale
city: Villejuif
country: France
facility: Institut Gustave Roussy
city: Napoli
country: Italy
facility: IRCCS IST. Tumori Fondaz. Pascale; S.C. Oncologia Medica,Melanoma,Immunoterapia E Terapie Innovative
state: Campania
city: Siena
country: Italy
facility: Azienda Ospedaliera Universitaria Senese, U.O.C. Immunoterapia Oncologica
state: Toscana
city: Amsterdam
country: Netherlands
facility: Antoni Van Leeuwenhoek Ziekenhuis; Gastro-Enterologie
city: Pamplona
country: Spain
facility: Clinica Universitaria de Navarra; Servicio de Oncologia
state: Navarra
city: Barcelona
country: Spain
facility: Hospital del Mar; Servicio de Oncologia
city: Barcelona
country: Spain
facility: Hospital Univ Vall d'Hebron; Servicio de Oncologia
city: Madrid
country: Spain
facility: START Madrid-FJD, Hospital Fundacion Jimenez Diaz
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre; Servicio de Oncologia
city: Madrid
country: Spain
facility: START Madrid. Centro Integral Oncologico Clara Campal; CIOCC
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Martinez-Sabadell A, Morancho B, Rius Ruiz I, Roman Alonso M, Ovejero Romero P, Escorihuela M, Chicote I, Palmer HG, Nonell L, Alemany-Chavarria M, Klein C, Bacac M, Arribas J, Arenas EJ. The target antigen determines the mechanism of acquired resistance to T cell-based therapies. Cell Rep. 2022 Oct 18;41(3):111430. doi: 10.1016/j.celrep.2022.111430.