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

• ClinicalTrials.gov Identifier: NCT02650713
• Recruitment Status: Completed
• First Posted: January 8, 2016
• Last Update Posted: February 12, 2020
• Sponsor: Hoffmann-La Roche
• Information provided by (Responsible Party): Hoffmann-La Roche

Tracking Information

• First Submitted Date: January 6, 2016
• First Posted Date: January 8, 2016
• Last Update Posted Date: February 12, 2020
• Actual Study Start Date: January 7, 2016
• Actual Primary Completion Date: January 13, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 8, 2019)

• Number of Participants with Adverse Events (AEs) [ Time Frame: Baseline up to 60 months ]
• Percentage of Participants with Dose-Limiting Toxicities (DLTs) [ Time Frame: Day 1 up to Day 21 ]
• Maximum-Tolerated Dose (MTD) of RO6958688 [ Time Frame: Part IA: Day 1 up to Day 21; Part IB Step-up Cohorts: Day 1 up to Day 7 after each dose escalation ]
• Recommended Phase II Dose (RP2D) of RO6958688 [ Time Frame: Day 1 up to 60 months ]

• Original Primary Outcome Measures (submitted: January 6, 2016): Number of Participants with Adverse Events [ Time Frame: Up to approximately 2.5 years ]

Current Secondary Outcome Measures (submitted: December 4, 2019)

• Pharmacokinetic (PK): Area Under the Concentration-Time Curve (AUC) of RO6958688 [ Time Frame: Baseline up to 60 months ]
• PK: Volume of Distribution at Steady State (Vss) of RO6958688 [ Time Frame: Baseline up to 60 months ]
• PK: Maximum Serum Concentration (Cmax) of RO6958688 [ Time Frame: Baseline up to 60 months ]
• PK: Clearance (CL) of RO6958688 [ Time Frame: Baseline up to 60 months ]
• PK: AUC of Atezolizumab [ Time Frame: Baseline up to 60 months ]
• PK: Vss of Atezolizumab [ Time Frame: Baseline up to 60 months ]
• PK: Cmax of Atezolizumab [ Time Frame: Baseline up to 60 months ]
• PK: CL of Atezolizumab [ Time Frame: Baseline up to 60 months ]
• Pharmacodynamics: Immune Cell Numbers as Assessed using Flow Cytometry [ Time Frame: 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) ]
• Percentage of Participants with Objective Response (Partial Response [PR] or Complete Response [CR] as Assessed Using Response Evaluation Criteria in Solid Tumors [RECIST]) [ Time Frame: 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.
• Percentage of Participants with Disease Control (PR, CR, or Stable Disease [SD]) as Assessed Using RECIST [ Time Frame: 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.
• Percentage of Participants with Stable Disease (SD) as Assessed Using RECIST [ Time Frame: 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.
• Duration of Response (DOR) as Assessed Using RECIST [ Time Frame: 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.
• Progression-Free Survival (PFS) according to RECIST V1.1 [ Time Frame: 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.
• Overall Survival (OS) [ Time Frame: From first study treatment to 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.
• Best Overall Response (BOR) [ Time Frame: 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.

Original Secondary Outcome Measures (submitted: January 6, 2016)

• Pharmacokinetic Assessment: Area Under the Concentration Curve (AUC) [ Time Frame: Up to approximately 2.5 years ]
• Pharmacokinetic Assessment: Volume of Distribution at Steady State (Vss) [ Time Frame: Up to approximately 2.5 years ]
• Pharmacokinetic Assessment: Minimum Serum Concentration (Cmin) [ Time Frame: Up to approximately 2.5 years ]
• Pharmacokinetic Assessment: Maximum serum concentration (Cmax) [ Time Frame: Up to approximately 2.5 years ]
• Pharmacokinetic Assessment: Time to Cmax (Tmax) [ Time Frame: Up to approximately 2.5 years ]
• Pharmacokinetic Assessment: Clearance (CL) [ Time Frame: Up to approximately 2.5 years ]
• Pharmacokinetic Assessment: Half-life (t1/2) [ Time Frame: Up to approximately 2.5 years ]
• Objective Overall Response Rate (ORR) [ Time Frame: Week 24 ]
• Disease Control Rate (DCR) [ Time Frame: Week 24 ]
• Progression-Free Survival (PFS) [ Time Frame: Up to approximately 2.5 years ]
• Overall Survival (OS) [ Time Frame: Up to approximately 2.5 years ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Randomized; Intervention Model: Sequential Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Solid Tumors

Intervention

• Drug: Atezolizumab
  Atezolizumab will be administered at a fixed dose of 1200 milligrams (mg) by intravenous (IV) infusion.
  Other Name: Tecentriq
• Drug: 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.

Study Arms

• Experimental: Dose-Escalation (Part IA): RO6958688 + Atezolizumab
  Participants will receive RO6958688 weekly (QW) at escalating doses starting at 5 mg, in combination with a fixed dose (1200 mg) of atezolizumab every 3 weeks (Q3W). RO6958688 dosage will not exceed the MTD if defined in the BP29541 study.
  Interventions:

  • Drug: Atezolizumab
  • Drug: RO6958688
• Experimental: Dose/Schedule Finding (Part IB): RO6958688 + Atezolizumab

  Part IB will explore different RO6958688 administration schedules in combination with atezolizumab, consisting of:

  Cohort A: will compare the QW vs Q3W dosing schedules at a flat dose of RO6958688.

  Step Up dosing schedules: RO6958688 dose will start at 40 mg and increase with each administration up to the MTD or 1200 mg, whichever occurs first.

  Interventions:

  • Drug: Atezolizumab
  • Drug: RO6958688

• Publications *: 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: February 8, 2019): 228
• Original Estimated Enrollment (submitted: January 6, 2016): 100
• Actual Study Completion Date: January 13, 2020
• Actual Primary Completion Date: January 13, 2020 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Canada, Denmark, France, Italy, Netherlands, Spain, United States
• Removed Location Countries: Sweden

Administrative Information

• NCT Number: NCT02650713
• Other Study ID Numbers: WP29945; RG7802 ( Other Identifier: Roche ); 2015-003771-30 ( EudraCT Number )
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Hoffmann-La Roche
• Original Responsible Party: Same as current
• Current Study Sponsor: Hoffmann-La Roche
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Clinical Trials; Hoffmann-La Roche

• PRS Account: Hoffmann-La Roche
• Verification Date: February 2020