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All patients enrolled in the trail will receive axitinib at 5 mg BID plus avelumab at 10 mg/Kg every two weeks.

Treatment will be continued until progression of disease during the first 36 weeks of therapy. At week 36, patients achieving a tumor decrease ≥ 30% will discontinue axitinib and continue avelumab until progression of disease defined as ≥ 20% increase compared to the tumor burden measured at week 36. At disease progression, axitinib will be restarted at the same dosage used before discontinuation for at least 24 weeks if progression did not occur before. Patients who achieved again tumor decrease of ≥ 30% after 24 weeks of therapy rechallenge with axitinib and avelumab may discontinue axitinib and maintain avelumab until progression of disease in an intermittent manner.

Axitinib is an orally bioavailable tyrosine kinase inhibitor currently approved in EU for treatment of patients affected by metastatic renal cell carcinoma (mRCC) progressed after another anti VEGFR-tyrosine kinase inhibitor (TKI).

Axitinib inhibits the proangiogenic cytokines vascular endothelial growth factor (VEGF) and platelet-derived growth factor receptor (PDGF), thereby exerting an anti-angiogenic effect.

Axitinib Oral Tablet

Avelumab is a human immunoglobulin G1 (IgG1) monoclonal antibody directed against the human immunosuppressive ligand programmed death-ligand 1 (PD-L1) protein, with potential immune checkpoint inhibitory and antineoplastic activities. Upon administration, avelumab binds to PD-L1 and prevents the interaction of PD-L1 with its receptor programmed cell death protein 1 (PD-1). This inhibits the activation of PD-1 and its downstream signaling pathways. This may restore immune function through the activation of cytotoxic T lymphocytes (CTLs) targeted to PD-L1-overexpressing tumor cells. In addition, avelumab induces an antibody-dependent cellular cytotoxic (ADCC) response against PD-L1-expressing tumor cells. PD-1, a cell surface receptor belonging to the immunoglobulin superfamily expressed on T cells, negatively regulates T-cell activation and effector function when activated by its ligand, and plays an important role in tumor evasion from host immunity.

Roberto Iacovelli

Tide- A Service

Cinzia Ortega, MD

Emanuele Naghieri, MD

Lucia Bonomi, MD

Francesco Massari, MD

Giuseppe Fornarini, MD

Vincenzo Emanuele Chiuri, MD

Nicola Battelli, MD

Giuseppe Procopio, MD

Paolo Andrea Zucali, MD

Roberto Sabbatini, MD

Marco Maruzzo, MD

Melissa Bersanelli, MD

Mimma Rizzo, MD

Fabio Calabro, MD

Sergio Bracarda, MD

This study aims to test if patients achieving a tumor response with the combination of axitinib plus avelumab, can discontinued the axitinib in order to delay the resistance to the anti VEGFR-TKI and decrease the related toxicity of the combination therapy.

Axitinib is an orally bioavailable tyrosine kinase inhibitor currently approved in EU for treatment of patients affected by metastatic renal cell carcinoma (mRCC) progressed after another anti VEGFR-tyrosine kinase inhibitor (TKI).

Axitinib inhibits the proangiogenic cytokines vascular endothelial growth factor (VEGF) and platelet-derived growth factor receptor (PDGF), thereby exerting an anti-angiogenic effect.

Avelumab is a human immunoglobulin G1 (IgG1) monoclonal antibody directed against the human immunosuppressive ligand programmed death-ligand 1 (PD-L1) protein, with potential immune checkpoint inhibitory and antineoplastic activities. Upon administration, avelumab binds to PD-L1 and prevents the interaction of PD-L1 with its receptor programmed cell death protein 1 (PD-1). This inhibits the activation of PD-1 and its downstream signaling pathways. This may restore immune function through the activation of cytotoxic T lymphocytes (CTLs) targeted to PD-L1-overexpressing tumor cells. In addition, avelumab induces an antibody-dependent cellular cytotoxic (ADCC) response against PD-L1-expressing tumor cells. PD-1, a cell surface receptor belonging to the immunoglobulin superfamily expressed on T cells, negatively regulates T-cell activation and effector function when activated by its ligand, and plays an important role in tumor evasion from host immunity. PD-L1, a transmembrane protein, is overexpressed on a variety of tumor cell types and is associated with poor prognosis.

The combination of axitinib plus avelumab has been recently reported to be better than sunitinib alone for treatment of previously untreated mRCC patients (Motzer RJ, et al. NEJM 2019). The study reported a median PFS of 13.8 for the combination of axitinib plus avelumab compared to 8.4 months for sunitinib (p\<0.001).

To improve the treatment related toxicity, a previous study suggests that the discontinuation of the TKI in patients achieving a tumor response may lead to a longer definitive progression free survival (22.4 months) and overall survival (34.8 months) with a better safety profile (Ornstein MC et al. JCO 2017). Despite the new response to TKI after its reintroduction, the majority of patients progressed after the first months of treatment discontinuation suggesting the necessity to maintain the tumor response.

This study aims to test if patients achieving a tumor response with the combination of axitinib plus avelumab, can discontinued the axitinib in order to delay the resistance to the anti VEGFR-TKI and decrease the related toxicity of the combination therapy.

This is a phase II trial with a partial treatment discontinuation design in patients who achieved tumor decrease greater than 30% compared to baseline during the first 36 weeks of therapy.

All patients enrolled in the trail will receive axitinib at 5 mg BID plus avelumab at 10 mg/Kg every two weeks.

Treatment will be continued until progression of disease during the first 36 weeks of therapy. At week 36, patients achieving a tumor decrease ≥ 30% will discontinue axitinib and continue avelumab until progression of disease defined as ≥ 20% increase compared to the tumor burden measured at week 36. At disease progression, axitinib will be restarted at the same dosage used before discontinuation for at least 24 weeks if progression did not occur before. Patients who achieved again tumor decrease of ≥ 30% after 24 weeks of therapy rechallenge with axitinib and avelumab may discontinue axitinib and maintain avelumab until progression of disease in an intermittent manner.

This is a phase II trial with a partial treatment discontinuation design in patients who achieved tumor decrease greater than 30% compared to baseline during the first 36 weeks of therapy.

All patients enrolled in the trail will receive axitinib at 5 mg BID plus avelumab at 10 mg/Kg every two weeks.

Treatment will be continued until progression of disease during the first 36 weeks of therapy. At week 36, patients achieving a tumor decrease ≥ 30% will discontinue axitinib and continue avelumab until progression of disease defined as ≥ 20% increase compared to the tumor burden measured at week 36. At disease progression, axitinib will be restarted at the same dosage used before discontinuation for at least 24 weeks if progression did not occur before. Patients who achieved again tumor decrease of ≥ 30% after 24 weeks of therapy rechallenge with axitinib and avelumab may discontinue axitinib and maintain avelumab until progression of disease in an intermittent manner.

Avelumab Plus Intermittent Axitinib in Previously Untreated Patients With Metastatic Renal Cell Carcinoma

Phase II Study of Avelumab Plus Intermittent Axitinib in Previously Untreated Patients With Metastatic Renal Cell Carcinoma (Tide-A Study)

Tumor tissue biomarker status at screening phase (ie, positive and negative) will be determined by a predictive biomarker test with an established scoring algorithm defining positive and negative that is developed by the Sponsor; additional tumor tissue biomarkers that may be analyzed include, but may not necessarily be limited to, PD-L1, PBRM1, CD31 expression and quantitation of tumor-infiltrating CD8+ T lymphocytes by IHC.

Plasma samples will be collected from enrolled patients at screening phase, after 8 weeks and at End of Treatment. All plasma specimens from each patient will be analysed for the expression of a panel of immune-related cytokines and chemokines. The panel includes interleukin (IL)1b, IL2, IL4, IL5, IL6, IL7, IL8 (CXCL8), IL9, IL10, IL-12p70, IL13, IL15, IL17a, eotaxin, IL1Ra,granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), IFNg, IP10 (CXCL10), monocyte chemoattractant protein (MCP1; CCL2), macrophage inflammatory protein 1a (MIP1a; CCL3), MIP1b (CCL4), TNFa, PDGF-BB, RANTES, tumor necrosis factor a (TNFa), fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF).

The plasma markers will be evaluated and analysed considering possible changes. compared to baseline. Each marker (baseline value or at specific timepoint) will be evaluated for a significant correlation to the outcome (i.e. ORR, PFS, OS).

Evaluate the rate of patients who have a partial response (PR) or complete response (CR) to the study treatment according to RECIST V. 1.1 criteria, as determined by investigator's assessments, at week 8 from axitinib discontinuation and avelumab maintenance, after 36 weeks of induction treatment with the combination of avelumab and axitinib.

Will be performed the analyses of Progression free survival in the overall population. PFS, determined using the Kaplan-Meier method, is defined as the time from the first study drugs administration to the date of the first documentation of objective progression of disease (PD) or death due to any cause, whichever occurs first. PFS is calculated according to the RECIST V. 1.1 criteria, as determined by investigator's assessments.

NB: as per study design, the only PD that causes EoT is the one that occurs during the combined treatment of avelumab and axitinib.

ORR defined as the rate of patients who have a partial response (PR) or complete response (CR) to the study treatment according to RECIST V. 1.1 criteria as determined by investigator's assessments. The study tumor assessment will be performed every 12 weeks during the combined administration of axitinib and avelumab; during the avelumab maintenance tumor assessment will be performed every 8 weeks for 6 months, then every 12 weeks. NB: as per study design, the only PD that causes EoT is the one that occurs during the combined treatment of avelumab and axitinib.

Disease control (DC) is defined as complete response (CR), partial response (PR), or stable disease (SD) according to the RECIST v.1.1 recorded from enrollment until disease progression assessed by BICR or death due to any cause. DC at 24 weeks is defined as CR, PR or SD ≥24 weeks after enrollment and prior to disease progression assessed by BICR or death due to any cause.

The DC rate (DCR) and DCR at 24 weeks will be estimated by dividing the number of patients with CR, PR, or SD overall or ≥24 weeks by the number of patients enrol. The corresponding exact 2-sided 95% CIs for DCR and DCR at 24 weeks will be provided.

Overall Survival (OS) is defined as the time from date of enrollment to date of death due to any cause. Patients last known to be alive will be censored at date of last contact. In addition, OS will be tested at the OS final analysis. OS time associated will be summarized using the Kaplan-Meier method and displayed graphically where appropriate. Confidence intervals (CIs) for the 25th, 50th and 75th percentiles will be reported.

The primary safety analysis will include all patients who receive at least 1 dose of study drugs and who experienced toxicities as defined by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 5.0 criteria. Safety will be assessed by quantifying the toxicities and grades experienced by subjects who have received the combination avelumab-axitinib and the avelumab alone, including serious adverse events (SAEs) and events of clinical interest (ECIs). Safety will be assessed by reported AEs, SAEs and AESIs according to NCI CTCAE version 5.0. evaluating treatment administration/compliance and safety.

To evaluate the health status of the subjects during the study treatment the "5-Level EuroQol Group's 5-Dimension" (EQ-5D-5L) questionnaire will be administered to the patients within 3 days prior the first study treatment, the first day of each odd cycle (1, 3, 5, etc.) of avelumab, prior to treatment administration, and at the end of treatment visit.

This questionnaire consists of 2 parts, the EQ-5D index (or simply EQ-5D) and EQ-VAS. The EQ-5D comprises 5 dimensions of health (mobility, self-care, usual activities, pain or discomfort, and anxiety or depression). A unique EQ-5D health state is defined by combining one level from each of the 5 dimensions and is converted to a single summary index or health utility value. The EQ-VAS is a visual analog scale where the patient indicates how good or bad his health is today by marking an appropriate point on a line between 0 to 100, which correspond to the worst and best imaginable health states.

To evaluate the quality of life of the subjects during the study treatment the "National Comprehensive Cancer Network/ Functional Assessment of Cancer Therapy (FACT)-Kidney Symptom Index 19" (NCCN-FACT FKSI-19) questionnaire will be administered to the patients within 3 days prior the first study treatment, the first day of each odd cycle (1, 3, 5, etc.) of avelumab, prior to treatment administration, and at the end of treatment visit.

In this questionnaire the score range is 0-76, a score of "0" is a severely symptomatic patient and the highest possible score is an asymptomatic patient.

Clinical Research Technology S.r.l.

Consorzio Oncotech

Spots Global Cancer Trial Database for renal carcinoma metastatic