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

Solid Tumors Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02650713
• Other study ID #: WP29945
• Secondary ID: RG78022015-00377
• Status: Completed
• Phase: Phase 1
• Start date: January 7, 2016
• Est. completion date: January 13, 2020

Study information

• Verified date: February 2020
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 228
• Est. completion date: January 13, 2020
• Est. primary completion date: January 13, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Neoplasms
• Solid Tumors

Intervention

Drug:
• Atezolizumab
Atezolizumab will be administered at a fixed dose of 1200 milligrams (mg) by intravenous (IV) infusion.
• RO6958688
RO6958688 is administered by IV infusion In Part IA: RO6958688 is administered weekly (QW) on days 1,8 and 15 of each 21-day cycle. In Part 1b: RO6958688 is administered weekly (QW) or every 3 weeks (Q3W). Cohort A: RO6958688 starting dose will be 100 mg either QW or Q3W. Step Up dose cohorts: RO6958688 starting dose will be 40mg and increase with each administration up to the MTD or 1200 mg whichever is lower.

Locations

Country	Name	City	State
Canada	Princess Margaret Cancer Center	Toronto	Ontario
Denmark	Rigshospitalet; Onkologisk Klinik	København Ø
France	Centre Leon Berard; Departement Oncologie Medicale	Lyon
France	Institut Gustave Roussy	Villejuif
Italy	IRCCS IST. Tumori Fondaz. Pascale; S.C. Oncologia Medica,Melanoma,Immunoterapia E Terapie Innovative	Napoli	Campania
Italy	Azienda Ospedaliera Universitaria Senese, U.O.C. Immunoterapia Oncologica	Siena	Toscana
Netherlands	Antoni Van Leeuwenhoek Ziekenhuis; Gastro-Enterologie	Amsterdam
Spain	Hospital del Mar; Servicio de Oncologia	Barcelona
Spain	Hospital Univ Vall d'Hebron; Servicio de Oncologia	Barcelona
Spain	Hospital Universitario 12 de Octubre; Servicio de Oncologia	Madrid
Spain	START Madrid-FJD, Hospital Fundacion Jimenez Diaz	Madrid
Spain	START Madrid. Centro Integral Oncologico Clara Campal; CIOCC	Madrid
Spain	Clinica Universitaria de Navarra; Servicio de Oncologia	Pamplona	Navarra
United States	University Of Colorado	Aurora	Colorado
United States	Dana Farber Can Ins	Boston	Massachusetts
United States	Medical University of South Carolina	Charleston	South Carolina
United States	Duke Cancer Center	Durham	North Carolina
United States	Sarah Cannon Cancer Center	Germantown	Tennessee
United States	MD Anderson Cancer Center	Houston	Texas
United States	Smilow Cancer Hospital at Yale- New Haven Oncology Investigational Drug Pharmacy	New Haven	Connecticut
United States	Columbia Univ Med Ctr	New York	New York
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	UCLA Cancer Center	Santa Monica	California
United States	Stanford Comprehensive Cancer Center	Stanford	California

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Countries where clinical trial is conducted

United States,  Canada,  Denmark,  France,  Italy,  Netherlands,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants with Adverse Events (AEs)		Baseline up to 60 months
Primary	Percentage of Participants with Dose-Limiting Toxicities (DLTs)		Day 1 up to Day 21
Primary	Maximum-Tolerated Dose (MTD) of RO6958688		Part IA: Day 1 up to Day 21; Part IB Step-up Cohorts: Day 1 up to Day 7 after each dose escalation
Primary	Recommended Phase II Dose (RP2D) of RO6958688		Day 1 up to 60 months
Secondary	Pharmacokinetic (PK): Area Under the Concentration-Time Curve (AUC) of RO6958688		Baseline up to 60 months
Secondary	PK: Volume of Distribution at Steady State (Vss) of RO6958688		Baseline up to 60 months
Secondary	PK: Maximum Serum Concentration (Cmax) of RO6958688		Baseline up to 60 months
Secondary	PK: Clearance (CL) of RO6958688		Baseline up to 60 months
Secondary	PK: AUC of Atezolizumab		Baseline up to 60 months
Secondary	PK: Vss of Atezolizumab		Baseline up to 60 months
Secondary	PK: Cmax of Atezolizumab		Baseline up to 60 months
Secondary	PK: CL of Atezolizumab		Baseline up to 60 months
Secondary	Pharmacodynamics: Immune Cell Numbers as Assessed using Flow Cytometry		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)
Secondary	Percentage of Participants with Objective Response (Partial Response [PR] or Complete Response [CR] as Assessed Using Response Evaluation Criteria in Solid Tumors [RECIST])	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.	Baseline up to 60 months
Secondary	Percentage of Participants with Disease Control (PR, CR, or Stable Disease [SD]) as Assessed Using RECIST	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.	Baseline up to 60 months
Secondary	Percentage of Participants with Stable Disease (SD) as Assessed Using RECIST	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.	Baseline up to 60 months
Secondary	Duration of Response (DOR) as Assessed Using RECIST	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.	From initial objective response (PR or CR to the first disease progression or death from any cause (up to 60 months)
Secondary	Progression-Free Survival (PFS) according to RECIST V1.1	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.	From first study treatment to the first occurrence of objective disease progression or death from any cause (up to 60 months)
Secondary	Overall Survival (OS)	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.	From first study treatment to death from any cause (up to 60 months)
Secondary	Best Overall Response (BOR)	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.	Baseline up to 60 months