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

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ClinicalTrials.gov Identifier: NCT03386721
Recruitment Status : Recruiting
First Posted : December 29, 2017
Last Update Posted : July 10, 2019
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Advanced/Metastatic Head and Neck, Oesophageal and Cervical Cancers Drug: RO6874281 Drug: Atezolizumab (MPDL3280A), an Engineered Anti-PD-L1 Antibody Drug: Gemcitabine Drug: Vinorelbine Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 280 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : February 19, 2018
Estimated Primary Completion Date : January 28, 2022
Estimated Study Completion Date : January 28, 2022

Arm Intervention/treatment
Experimental: Cohort A in Part I- arm is now closed to recruitment
Checkpoint 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.
Drug: RO6874281
RO6874281 will be administered as per the dosage regimen mentioned in arm descriptions.

Drug: Atezolizumab (MPDL3280A), an Engineered Anti-PD-L1 Antibody
Atezolizumab will be administered as per the dosage regimen mentioned in arm descriptions.

Experimental: Cohort B in Part I- arm is now closed to recruitment

CPI-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.

Drug: RO6874281
RO6874281 will be administered as per the dosage regimen mentioned in arm descriptions.

Drug: Atezolizumab (MPDL3280A), an Engineered Anti-PD-L1 Antibody
Atezolizumab will be administered as per the dosage regimen mentioned in arm descriptions.

Experimental: Cohort C in Part I- arm has not been opened to recruitment

This 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.

Drug: RO6874281
RO6874281 will be administered as per the dosage regimen mentioned in arm descriptions.

Drug: Atezolizumab (MPDL3280A), an Engineered Anti-PD-L1 Antibody
Atezolizumab will be administered as per the dosage regimen mentioned in arm descriptions.

Experimental: Cohort D Arm I in Part I- arm is now closed to recruitment

CPI 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.

Drug: RO6874281
RO6874281 will be administered as per the dosage regimen mentioned in arm descriptions.

Drug: Atezolizumab (MPDL3280A), an Engineered Anti-PD-L1 Antibody
Atezolizumab will be administered as per the dosage regimen mentioned in arm descriptions.

Experimental: Cohort D Arm 2 in Part I- arm is now closed to recruitment

CPI 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.

Drug: RO6874281
RO6874281 will be administered as per the dosage regimen mentioned in arm descriptions.

Drug: Atezolizumab (MPDL3280A), an Engineered Anti-PD-L1 Antibody
Atezolizumab will be administered as per the dosage regimen mentioned in arm descriptions.

Experimental: Cohort D Arm 3 in Part I- arm is now closed to recruitment

CPI 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.

Drug: Gemcitabine
Single-agent treatment administered as per approved protocol.

Drug: Vinorelbine
Single-agent treatment administered as per approved protocol.

Experimental: Cohort E Arm I in Part II- arm is now closed to recruitment

This 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.

Drug: RO6874281
RO6874281 will be administered as per the dosage regimen mentioned in arm descriptions.

Drug: Atezolizumab (MPDL3280A), an Engineered Anti-PD-L1 Antibody
Atezolizumab will be administered as per the dosage regimen mentioned in arm descriptions.

Experimental: Cohort E Arm 2 in Part II- arm is now closed to recruitment

This 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.

Drug: RO6874281
RO6874281 will be administered as per the dosage regimen mentioned in arm descriptions.

Drug: Atezolizumab (MPDL3280A), an Engineered Anti-PD-L1 Antibody
Atezolizumab will be administered as per the dosage regimen mentioned in arm descriptions.

Experimental: Cohort G in Part III

CPI-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.

Drug: RO6874281
RO6874281 will be administered as per the dosage regimen mentioned in arm descriptions.

Drug: Atezolizumab (MPDL3280A), an Engineered Anti-PD-L1 Antibody
Atezolizumab will be administered as per the dosage regimen mentioned in arm descriptions.

Experimental: Cohort H in Part III

Previously 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.

Drug: RO6874281
RO6874281 will be administered as per the dosage regimen mentioned in arm descriptions.

Drug: Atezolizumab (MPDL3280A), an Engineered Anti-PD-L1 Antibody
Atezolizumab will be administered as per the dosage regimen mentioned in arm descriptions.

Experimental: Cohort I in Part III

Previously 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.

Drug: RO6874281
RO6874281 will be administered as per the dosage regimen mentioned in arm descriptions.

Drug: Atezolizumab (MPDL3280A), an Engineered Anti-PD-L1 Antibody
Atezolizumab will be administered as per the dosage regimen mentioned in arm descriptions.

Experimental: Cohort J in Part III

Previously 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.

Drug: RO6874281
RO6874281 will be administered as per the dosage regimen mentioned in arm descriptions.

Experimental: Cohort F in Part I- this arm is now closed to recruitment
CPI-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.
Drug: RO6874281
RO6874281 will be administered as per the dosage regimen mentioned in arm descriptions.

Drug: Atezolizumab (MPDL3280A), an Engineered Anti-PD-L1 Antibody
Atezolizumab will be administered as per the dosage regimen mentioned in arm descriptions.

Experimental: Cohort K in Part III

CPI-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.

Drug: RO6874281
RO6874281 will be administered as per the dosage regimen mentioned in arm descriptions.

Drug: Atezolizumab (MPDL3280A), an Engineered Anti-PD-L1 Antibody
Atezolizumab will be administered as per the dosage regimen mentioned in arm descriptions.

Experimental: Cohort L in Part III

Previously 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.

Drug: RO6874281
RO6874281 will be administered as per the dosage regimen mentioned in arm descriptions.

Drug: Atezolizumab (MPDL3280A), an Engineered Anti-PD-L1 Antibody
Atezolizumab will be administered as per the dosage regimen mentioned in arm descriptions.

Experimental: Cohort M in Part III

Esophageal 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

Drug: RO6874281
RO6874281 will be administered as per the dosage regimen mentioned in arm descriptions.

Drug: Atezolizumab (MPDL3280A), an Engineered Anti-PD-L1 Antibody
Atezolizumab will be administered as per the dosage regimen mentioned in arm descriptions.

Experimental: Cohort N in Part III

Cervical 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

Drug: RO6874281
RO6874281 will be administered as per the dosage regimen mentioned in arm descriptions.

Drug: Atezolizumab (MPDL3280A), an Engineered Anti-PD-L1 Antibody
Atezolizumab will be administered as per the dosage regimen mentioned in arm descriptions.




Primary Outcome Measures :
  1. 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) ]

Secondary Outcome Measures :
  1. 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) ]
  2. 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) ]
  3. 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) ]
  4. Overall Survival (OS) [ Time Frame: Baseline up to death due to any cause (up to approximately 3 years) ]
  5. Percentage of Participants with Adverse Events (AEs) [ Time Frame: Baseline up to end of the study (up to approximately 3 years) ]
  6. 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) ]
  7. 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) ]
  8. 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) ]
  9. 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) ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03386721


Contacts
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Contact: Reference Study ID Number: BP40234 www.roche.com/about_roche/roche_worldwide.htm 888-662-6728 (U.S. and Canada) global-roche-genentech-trials@gene.com

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Sponsors and Collaborators
Hoffmann-La Roche
Investigators
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Study Director: Clinical Trials Hoffmann-La Roche

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Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT03386721     History of Changes
Other Study ID Numbers: BP40234
2017-003182-94 ( EudraCT Number )
First Posted: December 29, 2017    Key Record Dates
Last Update Posted: July 10, 2019
Last Verified: July 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Uterine Cervical Neoplasms
Uterine Neoplasms
Genital Neoplasms, Female
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Uterine Cervical Diseases
Uterine Diseases
Genital Diseases, Female
Gemcitabine
Atezolizumab
Vinorelbine
Antibodies
Antibodies, Monoclonal
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents, Phytogenic
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators