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.

Inclusion Criteria:

Each patient must meet the following criteria to be enrolled in this study.

1. Histologically or cytologically confirmed advanced RCC with predominantly clear-cell subtype with primary tumor resected.

2. Male or female subjects aged ≥ 18 years

3. At least one measurable lesion as defined by Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1.

4. Eastern Cooperative Oncology Group performance status 0 or 1.

5. Adequate organ and bone marrow function based upon meeting all of the following laboratory criteria within 10 days before the start of treatment:

   I. Absolute neutrophil count (ANC) ≥ 1500/mm3 (≥ 1.5 GI/L). II. Platelets ≥ 100,000/mm3 (≥ 100 GI/L). III. Hemoglobin ≥ 9 g/dL (≥ 90 g/L). IV. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2.5 × upper limit of normal.

   V. Total bilirubin ≤ 1.5 × the upper limit of normal. For subjects with Gilbert's disease ≤ 3 mg/dL (≤ 51.3 µmol/L).

   VI. Serum creatinine ≤ 2.0 × upper limit of normal or calculated creatinine clearance ≥ 30 mL/min (≥ 0.5 mL/sec) using the Cockroft-Gault.

6. Capable of understanding and complying with the protocol requirements and must have signed the informed consent document.

7. Sexually active fertile subjects and their partners must agree to use medically accepted methods of contraception (eg, barrier methods, including male condom, female condom, or diaphragm with spermicidal gel) during the course of the study and for at least 30 days after the last dose of study treatment.

8. Negative serum or urine pregnancy test at screening for women of childbearing potential.

Female subjects of childbearing potential must not be pregnant at screening. Females of childbearing potential are defined as premenopausal females capable of becoming pregnant (ie, females who have had any evidence of menses in the past 12 months, with the exception of those who had prior hysterectomy). However, women who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, antiestrogens, low body weight, ovarian suppression or other reasons. A lactating woman should be advised to not to breastfeed during treatment and for at least one month after the last dose of avelumab.

Exclusion Criteria:

Patients who meet any of the following criteria will be excluded from the study:

1. Prior treatment with systemic therapy for advanced RCC

2. Prior adjuvant or neoadjuvant therapy

3. Bulky or symptomatic disease or hepatic metastases.

4. Prior treatment with any agent specifically targeting T-cell co-stimulation or checkpoint pathways

5. Active seizure disorder or evidence of brain metastases, spinal cord compression, or carcinomatous meningitis

6. Diagnosis of any non-RCC malignancy occurring within 2 years prior to the date of the start of treatment except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the breast or of the cervix or low-grade prostate cancer (≤pT2,N0; Gleason 6) with no plans for treatment intervention.

7. Radiation therapy for bone metastasis within 2 weeks, any other external radiation therapy within 4 weeks before the start of treatment. Systemic treatment with radionuclides within 6 weeks before the start of treatment. Subjects with clinically relevant ongoing complications from prior radiation therapy are not eligible.

8. Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 3 months before the start of treatment. Eligible subjects must be neurologically asymptomatic and without corticosteroid treatment at the time of the start of treatment.

9. Concomitant anticoagulation at therapeutic doses with oral anticoagulants (eg, warfarin, direct thrombin and Factor Xa inhibitors).

10. In past 6 months: myocardial infarction, uncontrolled angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident, or transient ischemic attack.

11. Chronic treatment with corticosteroids or other immunosuppressive agents (with the exception of inhaled or topical corticosteroids or corticosteroids with a daily dosage equivalent ≤ 10 mg prednisone if given for disorders other than renal cell cancer). Subjects with brain metastases requiring systemic corticosteroid are not eligible.

12. The subject has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions:

    I. Cardiovascular disorders:

    1. Symptomatic congestive heart failure, unstable angina pectoris, serious cardiac arrhythmias.
    2. Uncontrolled hypertension defined as sustained BP > 150 mm Hg systolic or > 100 mm Hg diastolic despite optimal antihypertensive treatment.
    3. Stroke (including TIA), myocardial infarction, or other ischemic event, or thromboembolic event (eg, pulmonary embolism) within 6 months before the start of treatment.

    II. Gastrointestinal (GI) disorders including those associated with a high risk of perforation or fistula formation:

    1. Tumors invading the GI-tract, active peptic ulcer disease, inflammatory bowel disease, diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis or acute obstruction of the pancreatic or biliary duct, or gastric outlet obstruction.
    2. Abdominal fistula, gastrointestinal perforation, bowel obstruction, or intra-abdominal abscess within 6 months before the start of treatment. Note: Complete healing of an intra-abdominal abscess must be confirmed before the start of treatment.

    III. Clinically significant hematuria, hematemesis, or hemoptysis of > 0.5 teaspoon (2.5 ml) of red blood, or other history of significant bleeding (eg, pulmonary hemorrhage) within 3 months before the start of treatment.

    IV. Cavitating pulmonary lesion(s) or known endobronchial disease manifestation.

    V. Lesions invading major pulmonary blood vessels.

    VI. Other clinically significant disorders such as:

    1. Active infection requiring systemic treatment, infection with human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)- related illness, or chronic hepatitis B or C infection (Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening [positive HBV surface antigen or HCV RNA if anti-HCV antibody screening test positive]).
    2. Serious non-healing wound/ulcer/bone fracture.
    3. Malabsorption syndrome.
    4. Uncompensated/symptomatic hypothyroidism.
    5. Moderate to severe hepatic impairment (Child-Pugh B or C).
    6. Requirement for hemodialysis or peritoneal dialysis.
    7. History of solid organ transplantation including allogenic stem-cell transplantation.
    8. In past 6 months: pulmonary embolism.

13. Major surgery (eg, GI surgery, removal or biopsy of brain metastasis) within 3 months before the start of treatment. Complete wound healing from major surgery must have occurred 1 month before the start of treatment and from minor surgery (eg, simple excision, tooth extraction) at least 10 days before the start of treatment. Subjects with clinically relevant ongoing complications from prior surgery are not eligible.

14. Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 msec within 1 month before the start of treatment (see Section 5.5.4 for Fridericia formula). Three ECGs must be performed. If the average of these three consecutive results for QTcF is ≤ 500 msec, the subject meets eligibility in this regard.

15. Vaccination within 4 weeks of the first dose of avelumab and while on trials is prohibited except for administration of inactivated vaccines.

16. Active autoimmune disease that might deteriorate when receiving an immuno-stimulatory agent. Patients with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid diseases not requiring immunosuppressive treatment are eligible.

17. Current use of immunosuppressive medication, EXCEPT for the following: a. intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular injection); b. Systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisone or equivalent; c. Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication).

18. Has a history of substance abuse or medical, psychological, or social conditions that may interfere with the patient's participation in the study or evaluation of the study results.

19. Has illness or medical conditions that are unstable or could jeopardize the safety of the patient and his or her compliance in the study.

20. Pregnant or lactating females.

21. Inability to swallow tablets or capsules.

22. Known prior severe hypersensitivity to investigational product or any component in its formulations, including known severe hypersensitivity reactions to monoclonal antibodies (NCI CTCAE Grade ≥ 3).