Clinical Trials /

Basket Study to Evaluate the Therapeutic Activity of RO6874281 as a Combination Therapy in Participants With Advanced and/or Metastatic Solid Tumors

NCT03386721

Description:

This is an open-label, multicenter, basket trial Phase II study to evaluate the antitumor activity of RO6874281 in combination with atezolizumab in participants with advanced and/or metastatic solid tumors. Currently the focus is on patients with Head and Neck, oesophageal and cervical cancers with confirmed squamous cell carcinoma histology type.

Related Conditions:
  • Cervical Squamous Cell Carcinoma
  • Esophageal Squamous Cell Carcinoma
  • Head and Neck Squamous Cell Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Basket Study to Evaluate the Therapeutic Activity of RO6874281 as a Combination Therapy in Participants With Advanced and/or Metastatic Solid Tumors
  • Official Title: An Open-Label, Multicenter, Phase II Study to Evaluate the Therapeutic Activity of RO6874281, an Immunocytokine, Consisting of Interleukin-2 Variant (IL-2v) Targeting Fibroblast Activation Protein-Α (FAP), in Combination With Atezolizumab (Anti-PD-L1), Administered Intravenously, in Participants With Advanced and/or Metastatic Solid Tumors

Clinical Trial IDs

  • ORG STUDY ID: BP40234
  • SECONDARY ID: 2017-003182-94
  • NCT ID: NCT03386721

Conditions

  • Advanced/Metastatic Head and Neck, Oesophageal and Cervical Cancers

Interventions

DrugSynonymsArms
RO6874281Cohort A in Part I- arm is now closed to recruitment
Atezolizumab (MPDL3280A), an Engineered Anti-PD-L1 AntibodyCohort A in Part I- arm is now closed to recruitment
GemcitabineCohort D Arm 3 in Part I- arm is now closed to recruitment
VinorelbineCohort D Arm 3 in Part I- arm is now closed to recruitment

Purpose

This is an open-label, multicenter, basket trial Phase II study to evaluate the antitumor activity of RO6874281 in combination with atezolizumab in participants with advanced and/or metastatic solid tumors. Currently the focus is on patients with Head and Neck, oesophageal and cervical cancers with confirmed squamous cell carcinoma histology type.

Trial Arms

NameTypeDescriptionInterventions
Cohort A in Part I- arm is now closed to recruitmentExperimentalCheckpoint Inhibitor (CPI)-Naïve Participants Participants with non-small-cell lung cancer (NSCLC) who have not received CPI therapy previously will receive RO6874281 intravenous (IV) infusion once in a week (QW) for first 5 doses, and once in 2 weeks (Q2W) for remaining doses up to maximum 36 months. Starting dose will be 10 milligrams (mg), and will be up-titrated to 15 mg from second administration onwards. Atezolizumab IV infusion will be administered in combination Q2W at a dose of 840 mg. Tumor biopsies: collection of fresh tumor biopsies (at baseline and on-treatment) will be optional.
  • RO6874281
  • Atezolizumab (MPDL3280A), an Engineered Anti-PD-L1 Antibody
Cohort B in Part I- arm is now closed to recruitmentExperimentalCPI-Experienced Participants (NSCLC) who have received CPI therapy previously will receive RO6874281 intravenous (IV) infusion once in a week (QW) for first 5 doses, and once in 2 weeks (Q2W) for remaining doses up to maximum 36 months. Starting dose will be 10 milligrams (mg), and will be up-titrated to 15 mg from second administration onwards. Atezolizumab IV infusion will be administered in combination Q2W at a dose of 840 mg. Tumor biopsies: 2 mandatory fresh tumor biopsies, one at baseline and one on-treatment, will be collected. Additional on-treatment biopsies will be optional. Tumor biopsies: 2 mandatory fresh tumor biopsies, one at baseline and one on-treatment, will be collected. Additional on-treatment biopsies will be optional.
  • RO6874281
  • Atezolizumab (MPDL3280A), an Engineered Anti-PD-L1 Antibody
Cohort C in Part I- arm has not been opened to recruitmentExperimentalThis is a mandatory biopsy cohort based on the treatment's safety and preliminary activity analysis to enroll CPI-Naive Participants. Participants (NSCLC) will receive RO6874281 intravenous (IV) infusion once in a week (QW) for first 5 doses, and once in 2 weeks (Q2W) for remaining doses up to maximum 36 months. Starting dose will be 10 milligrams (mg), and will be up-titrated to 15 mg from second administration onwards. Atezolizumab IV infusion will be administered in combination Q2W at a dose of 840 mg. Tumor biopsies: collection of fresh tumor biopsies (at baseline and on-treatment) will be optional. Tumor biopsies: 2 mandatory fresh tumor biopsies, one at baseline and one on-treatment, will be collected. Additional on-treatment biopsies will be optional.
  • RO6874281
  • Atezolizumab (MPDL3280A), an Engineered Anti-PD-L1 Antibody
Cohort D Arm I in Part I- arm is now closed to recruitmentExperimentalCPI Experienced Participants (NSCLC) who were previously treated with platinum and docetaxel. Participants will receive RO6874281 intravenous (IV) infusion once in a week (QW) for first 5 doses, and once in 2 weeks (Q2W) for remaining doses up to maximum 36 months. Starting dose will be 10 milligrams (mg), and will be up-titrated to 15 mg from second administration onwards. Atezolizumab IV infusion will be administered in combination Q2W at a dose of 840 mg. Tumor biopsies: 2 mandatory fresh tumor biopsies, one at baseline and one on-treatment, will be collected. Additional on-treatment biopsies will be optional.
  • RO6874281
  • Atezolizumab (MPDL3280A), an Engineered Anti-PD-L1 Antibody
Cohort D Arm 2 in Part I- arm is now closed to recruitmentExperimentalCPI Experienced Participants (NSCLC) who were previously treated with platinum and docetaxel. Participants will receive RO6874281 intravenous (IV) infusion once in 3 weeks (Q3W) up to maximum 36 months. Dosage will be 10 milligrams (mg). Atezolizumab IV infusion will be administered in combination Q3W at a dose of 1200 mg. Tumor biopsies: 2 mandatory fresh tumor biopsies, one at baseline and one on-treatment, will be collected. Additional on-treatment biopsies will be optional. Tumor biopsies: 2 mandatory fresh tumor biopsies, one at baseline and one on-treatment, will be collected. Additional on-treatment biopsies will be optional.
  • RO6874281
  • Atezolizumab (MPDL3280A), an Engineered Anti-PD-L1 Antibody
Cohort D Arm 3 in Part I- arm is now closed to recruitmentExperimentalCPI Experienced Participants (NSCLC) who were previously treated with platinum and docetaxel will receive a single-agent gemcitabine or vinorelbine as per approved protocol. Tumor biopsies: 2 mandatory fresh tumor biopsies, one at baseline and one on-treatment, will be collected. Additional on-treatment biopsies will be optional.
  • Gemcitabine
  • Vinorelbine
Cohort E Arm I in Part II- arm is now closed to recruitmentExperimentalThis cohort will enroll participants (NSCLC) with High-Tumor PD-L1 Expression who have not received any prior systemic therapy. Participants will will receive RO6874281 intravenous (IV) infusion once in a week (QW) for first 5 doses, and once in 2 weeks (Q2W) for remaining doses up to maximum 36 months. Starting dose will be 10 milligrams (mg), and will be up-titrated to 15 mg from second administration onwards. Atezolizumab IV infusion will be administered in combination Q2W at a dose of 840 mg. Tumor biopsies: 2 mandatory fresh tumor biopsies, one at baseline and one on-treatment, will be collected. Additional on-treatment biopsies will be optional.
  • RO6874281
  • Atezolizumab (MPDL3280A), an Engineered Anti-PD-L1 Antibody
Cohort E Arm 2 in Part II- arm is now closed to recruitmentExperimentalThis cohort will enroll participants (NSCLC) with High-Tumor PD-L1 Expression who have not received any prior systemic therapy. Participants will receive RO6874281 IV infusion in combination with atezolizumab Q3W. Dosage of RO6874281 will be 10 mg. Atezolizumab IV infusion will be administered at a dose of 1200 mg. Tumor biopsies: 2 mandatory fresh tumor biopsies, one at baseline and one on-treatment, will be collected. Additional on-treatment biopsies will be optional.
  • RO6874281
  • Atezolizumab (MPDL3280A), an Engineered Anti-PD-L1 Antibody
Cohort G in Part IIIExperimentalCPI-naïve SCC of the head and neck (SCCHN) (20 response-evaluable participants), mandatory biopsies. Participants in cohort G Part III will receive RO6874281 Q3W in combination with atezolizumab Q3W. Tumor biopsies: 2 mandatory fresh tumor biopsies, one at baseline and one on-treatment, will be collected. Additional on-treatment biopsies will be optional. Biopsies are not applicable to participants presenting with a single target lesion and absence of any non-target lesion.
  • RO6874281
  • Atezolizumab (MPDL3280A), an Engineered Anti-PD-L1 Antibody
Cohort H in Part IIIExperimentalPreviously treated, CPI-experienced squamous cell carcinoma head and heck cancer (20 response evaluable participants), mandatory biopsies. Participants in cohort H Part III will receive RO6874281 Q3W in combination with atezolizumab Q3W Tumor biopsies: 2 mandatory fresh tumor biopsies, one at baseline and one on-treatment, will be collected. Additional on-treatment biopsies will be optional. Biopsies are not applicable to participants presenting with a single target lesion and absence of any non-target lesion.
  • RO6874281
  • Atezolizumab (MPDL3280A), an Engineered Anti-PD-L1 Antibody
Cohort I in Part IIIExperimentalPreviously treated, CPI-naïve squamous esophageal cancer (20 response evaluable participants), mandatory biopsies. Participants in cohort I Part III will receive RO6874281 Q3W in combination with atezolizumab Q3W. Tumor biopsies: 2 mandatory fresh tumor biopsies, one at baseline and one on-treatment, will be collected. Additional on-treatment biopsies will be optional.
  • RO6874281
  • Atezolizumab (MPDL3280A), an Engineered Anti-PD-L1 Antibody
Cohort J in Part IIIExperimentalPreviously treated, CPI-naïve squamous cervical cancer (20 response evaluable participants): mandatory biopsy. Participants in cohort J Part III will receive RO6874281 Q3W in combination with atezolizumab Q3W. Tumor biopsies: 2 mandatory fresh tumor biopsies, one at baseline and one on-treatment, will be collected. Additional on-treatment biopsies will be optional.
  • RO6874281
Cohort F in Part I- this arm is now closed to recruitmentExperimentalCPI-experienced, docetaxel naive participants (NSCLC) who experienced disease progression during or following treatment with a platinum - containing regimen. Participants will receive combination of RO6874281 and atezolizumab in a Q3W schedule. Tumor biopsies: 2 mandatory fresh tumor biopsies, one at baseline and one on-treatment, will be collected. Additional on-treatment biopsies will be optional.
  • RO6874281
  • Atezolizumab (MPDL3280A), an Engineered Anti-PD-L1 Antibody
Cohort K in Part IIIExperimentalCPI-naïve SCC of the head and neck (SCCHN) (20 response-evaluable participants), mandatory biopsies. Participants in cohort K Part III will receive RO6874281 Q2W in combination with atezolizumab Q2W. Tumor biopsies: 2 mandatory fresh tumor biopsies, one at baseline and one on-treatment, will be collected. Additional on-treatment biopsies will be optional. Biopsies are not applicable to participants presenting with a single target lesion and absence of any non-target lesion.
  • RO6874281
  • Atezolizumab (MPDL3280A), an Engineered Anti-PD-L1 Antibody
Cohort L in Part IIIExperimentalPreviously treated, CPI-experienced squamous cell carcinoma head and neck cancer (20 response evaluable participants), mandatory biopsies. Participants in cohort L Part III will receive RO6874281 QW in combination with atezolizumab Q2W for 4 weeks followed by RO6874281 in combination with atezolizumab Q2W. Tumor biopsies: 2 mandatory fresh tumor biopsies, one at baseline and one on-treatment, will be collected. Additional on-treatment biopsies will be optional. Biopsies are not applicable to participants presenting with a single target lesion and absence of any non-target lesion.
  • RO6874281
  • Atezolizumab (MPDL3280A), an Engineered Anti-PD-L1 Antibody
Cohort M in Part IIIExperimentalEsophageal SCC participants will receive RO6874281 QW in combination with atezolizumab Q2W for 4 weeks followed by RO6874281 in combination with atezolizumab Q2W. Tumor biopsies: 2 mandatory fresh tumor biopsies, one at baseline and one on-treatment, will be collected. Additional on-treatment biopsies will be optional
  • RO6874281
  • Atezolizumab (MPDL3280A), an Engineered Anti-PD-L1 Antibody
Cohort N in Part IIIExperimentalCervical SCC participants will receive RO6874281 QW in combination with atezolizumab Q2W for 4 weeks followed by RO6874281 in combination with atezolizumab Q2W. Tumor biopsies: 2 mandatory fresh tumor biopsies, one at baseline and one on-treatment, will be collected. Additional on-treatment biopsies will be optional
  • RO6874281
  • Atezolizumab (MPDL3280A), an Engineered Anti-PD-L1 Antibody

Eligibility Criteria

        Inclusion Criteria:

          -  Participants who have progressed on at least one previous regimen of anticancer
             therapy (chemotherapy, mutation targeted therapy, and/or CPI therapy)

          -  Measurable disease, as defined by RECIST Version 1.1

          -  Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1 or Karnofsky
             Performance Score greater than or equal to (>=) 70

          -  Life expectancy of >=12 weeks

          -  Confirmed at least one tumor lesion with location accessible to safely biopsy per
             clinical judgment of the treating physician.

        Biopsies are not applicable to participants in Cohorts G, H, K, and L presenting with a
        single target lesion and absence of any non-target lesion.

          -  Consent to provide an archival tumor tissue sample (if available, applicable to all
             participants)

          -  Willingness to undergo baseline and on-treatment tumor biopsies for pharmacodynamics
             (PD) biomarker analysis

          -  Adequate cardiovascular function as defined in the study protocol

          -  AEs related to any previous radiotherapy, chemotherapy, or surgical procedure must
             have resolved to Grade less than or equal to (<=) 1, except alopecia (any grade) and
             Grade 2 peripheral neuropathy

          -  Adequate haematological, liver, and renal functions.

          -  Participants with unilateral pleural effusion (indications other than NSCLC) are
             eligible if they fulfill both of the following:

               1. NYHA Class 1

               2. Forced expiratory volume 1 (FEV1) and forced vital capacity (FVC) >70% of
                  predicted value; participants with lung metastases should present with DLCO >60%
                  of predicted value.

          -  Participants with Gilbert's syndrome will be eligible for the study Participants must
             have had confirmed diagnosis of recurrent or metastatic squamous cell carcinoma head
             and neck, or esophageal cancer or metastatic, persistent or recurrent squamous
             cervical cancer.

        Exclusion Criteria:

          -  Symptomatic or untreated central nervous system (CNS) metastases

          -  History of treated asymptomatic CNS metastases as described in the protocol

          -  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 before enrollment

          -  Leptomeningeal disease

          -  An active second malignancy

          -  Penetrating tumor infiltration

          -  Evidence of significant, uncontrolled concomitant diseases that could affect
             compliance with the protocol or interpretation of results

          -  Episode of significant cardiovascular/cerebrovascular acute disease within 6 months
             before study treatment administration

          -  History of significant vascular disease (for example, aortic aneurysm, aortic
             dissection)

          -  Peripheral arterial thrombosis within 6 months before study treatment administration

          -  Active or uncontrolled infections

          -  Human immunodeficiency virus (HIV) or hepatitis B or hepatitis C virus infection

          -  Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection
             (excluding fungal infections of nail beds) or any major episode of infection requiring
             treatment with IV antibiotics or hospitalization within 4 weeks before study treatment
             administration

          -  History of chronic liver disease or evidence of hepatic cirrhosis

          -  Dementia or altered mental status that would prohibit informed consent

          -  History of, active or suspicion of autoimmune disease

          -  History of idiopathic pulmonary fibrosis, pneumonitis (including drug-induced),
             organizing pneumonia (bronchiolitis obliterans, cryptogenic organizing pneumonia,
             etc.), or evidence of active pneumonitis on screening chest computed tomography (CT)
             scan. History of radiation pneumonitis in the radiation field (fibrosis) is permitted

          -  Bilateral pleural effusion confirmed by X-ray

          -  Any other diseases, metabolic dysfunction, physical examination finding, or clinical
             laboratory finding that give reasonable suspicion of a disease or condition that would
             contraindicate the use of an investigational drug

          -  Concurrent therapy with any other investigational drug

          -  Immunomodulating agents as described in study protocol

          -  Chronic use of steroids

          -  Last dose with any cytostatic treatments < 28 days before study treatment
             administration

          -  Radiotherapy within the last 4 weeks before start of study treatment administration,
             with the exception of limited field palliative radiotherapy

          -  Administration of a live, attenuated vaccine within 4 weeks before Cycle 1 Day 1 or at
             any time during the study and 5 months after the last dose of atezolizumab

          -  Major surgery or significant traumatic injury <28 days before study treatment
             administration (excluding fine needle biopsies) or anticipation of the need for major
             surgery during study treatment

          -  Known hypersensitivity to any of the components of the RO6874281 drug product or
             atezolizumab drug product

          -  Severe dyspnea at rest or requiring supplementary oxygen therapy Locally curative
             options are available for participant's disease.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Percentage of Participants with Objective Response of Complete Response (CR) or Partial Response (PR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1
Time Frame:Baseline up to disease progression or study treatment discontinuation (assessed every 8 weeks after study treatment start, up to approximately 1 year)
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Percentage of Participants with Disease Control According to RECIST Version 1.1
Time Frame:Baseline up to disease progression or study treatment discontinuation (assessed every 8 weeks after study treatment start for the first year, and every 12 weeks thereafter, up to approximately 3 years)
Safety Issue:
Description:
Measure:Duration of Response (DoR) According to RECIST Version 1.1
Time Frame:From first occurrence of documented CR or PR up to disease progression or study treatment discontinuation (assessed every 8 weeks after study treatment start for the first year, and every 12 weeks thereafter, up to approximately 3 years)
Safety Issue:
Description:
Measure:Progression-Free Survival (PFS) According to RECIST Version 1.1
Time Frame:Baseline up to disease progression or study treatment discontinuation (assessed every 8 weeks after study treatment start for the first year, and every 12 weeks thereafter, up to approximately 3 years)
Safety Issue:
Description:
Measure:Overall Survival (OS)
Time Frame:Baseline up to death due to any cause (up to approximately 3 years)
Safety Issue:
Description:
Measure:Percentage of Participants with Adverse Events (AEs)
Time Frame:Baseline up to end of the study (up to approximately 3 years)
Safety Issue:
Description:
Measure:Percentage of Participants by Programmed Death-Ligand 1 (PD-L1) Status According to Immunohistochemical Methods
Time Frame:Baseline, Cycle 3 Day 8, Day 1 of Cycle 9 onwards up to end of the study (up to approximately 3 years) (1 cycle = 15 days)
Safety Issue:
Description:
Measure:Change from Baseline in Density of Cluster of Differentiation (CD) 8 Positive (CD8+) Cells According to Immunohistochemical Methods
Time Frame:Day1 of Cycles 1, 2, 3, 6, and 9 onwards up to end of the study (up to approximately 3 years) (1 cycle = 15 days)
Safety Issue:
Description:
Measure:Change from Baseline in Density of Cluster of Differentiation 3 Negative (CD3-) Perforin Positive Cells According to Immunohistochemical Methods
Time Frame:Day1 of Cycles 1, 2, 3, 6, and 9 onwards up to end of the study (up to approximately 3 years) (1 cycle = 15 days)
Safety Issue:
Description:
Measure:Change from Baseline in Density of PD-L1 According to Immunohistochemical Methods
Time Frame:Baseline, Cycle 3 Day 8, Day 1 of Cycle 9 onwards up to end of the study (up to approximately 3 years) (1 cycle = 15 days)
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Hoffmann-La Roche

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