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

NCT04698213 | Unknown Phase 2

• 1 other identifier: TIDE-A
• Study Type: interventional
• Target: 75
• Locations: 1 country
• Sites: 20

Brief Summary

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.

Conditions

Renal Carcinoma Metastatic

Keywords

metastatic; renal; carcinoma; avelumab; axitinib

Outcome Measures

Primary Outcomes (1)

• Overall response rate (ORR)

  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.

  From the date of the first study drugs administration until week 44

Secondary Outcomes (7)

• Progression free survival (PFS)

  2 years from the last patient first visit (LPFV)

• Overall Response Rate (ORR)

  2 years from the last patient first visit (LPFV)

• Disease Control (DC)

  2 years from the last patient first visit (LPFV)

• Overall Survival (OS)

  From enrollment date until the date of death due to any cause, assessed up to 5 years

• Incidence of Treatment-Emergent Adverse Events, Serious adverse events and events of clinical interest, as assessed by the Investigators

  From the date of the first study drugs administration up to 90 days after the last dose of study drugs administration

Other Outcomes (2)

• Immunohistochemistry expression of markers on tumor tissue

  2 years from the last patient first visit (LPFV)

• Expression of a panel of immune-related cytokines and chemokines in blood samples

  2 years from the last patient last visit (LPLV)

Study Arms (1)

intermittent axitinib plus Avelumab

EXPERIMENTAL

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.

Drug: Axitinib Oral Tablet; Drug: Avelumab

Interventions

Axitinib Oral Tablet DRUG

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.

intermittent axitinib plus Avelumab

Avelumab DRUG

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.

intermittent axitinib plus Avelumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Each patient must meet the following criteria to be enrolled in this study.
• Histologically or cytologically confirmed advanced RCC with predominantly clear-cell subtype with primary tumor resected.
• Male or female subjects aged ≥ 18 years
• At least one measurable lesion as defined by Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1.
• Eastern Cooperative Oncology Group performance status 0 or 1.
• 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.
• Capable of understanding and complying with the protocol requirements and must have signed the informed consent document.
• 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.
• 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.

You may not qualify if:

• Patients who meet any of the following criteria will be excluded from the study:
• Prior treatment with systemic therapy for advanced RCC
• Prior adjuvant or neoadjuvant therapy
• Bulky or symptomatic disease or hepatic metastases.
• Prior treatment with any agent specifically targeting T-cell co-stimulation or checkpoint pathways
• Active seizure disorder or evidence of brain metastases, spinal cord compression, or carcinomatous meningitis
• 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.
• 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.
• 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.
• Concomitant anticoagulation at therapeutic doses with oral anticoagulants (eg, warfarin, direct thrombin and Factor Xa inhibitors).
• In past 6 months: myocardial infarction, uncontrolled angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident, or transient ischemic attack.
• 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.
• The subject has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions:
• I. Cardiovascular disorders:
• Symptomatic congestive heart failure, unstable angina pectoris, serious cardiac arrhythmias.

Sponsors & Collaborators

• Consorzio Oncotech: lead
• Clinical Research Technology S.r.l.: collaborator

Study Sites (20)

Azienda Ospedaliera Universitaria di Cagliari- P.O. Duilio Casula Monserrato

Monserrato, Cagliari, Italy

ACTIVE NOT RECRUITING

ASL CN2 Alba-Bra

Alba, Italy

NOT YET RECRUITING

Irccs Oncologico Istituto Tumori Giovanni Paolo Ii

Bari, Italy

NOT YET RECRUITING

ASST Papa Giovanni XXIII

Bergamo, Italy

NOT YET RECRUITING

Azienda Ospedaliero-Universitaria Di Bologna Suor Orsola Malpighi

Bologna, Italy

NOT YET RECRUITING

Ospedale Policlinico San Martino

Genova, Italy

NOT YET RECRUITING

OSPEDALE di LECCE "VITO FAZZI"

Lecce, Italy

NOT YET RECRUITING

Presidio Ospedaliero Unico Av3 - Ospedale Generale Provinciale - Macerata

Macerata, Italy

NOT YET RECRUITING

Istituto Clinico Humanitas

Milan, Italy

RECRUITING

Fondazione IRCCS Istituto Nazionale dei Tumori

Milan, Italy

NOT YET RECRUITING

Azienda Ospedaliero-Universitaria di Modena

Modena, Italy

NOT YET RECRUITING

Istituto Oncologico Veneto

Padua, Italy

NOT YET RECRUITING

Azienda Ospedaliero-Universitaria di Parma

Parma, Italy

RECRUITING

Istituti Clinici Scientifici Maugeri

Pavia, Italy

NOT YET RECRUITING

Irccs Istituto in Tecnologie Avanzate E Modelli Assistenziali in Oncologia Di Reggio Emilia

Reggio Emilia, Italy

ACTIVE NOT RECRUITING

Azienda Ospedaliera San Camillo-Forlanini

Roma, Italy

NOT YET RECRUITING

Fondazione Policlinico Universitario A. Gemelli IRCCS

Rome, Italy

RECRUITING

Azienda Ospedaliera Santa Maria Terni

Terni, Italy

NOT YET RECRUITING

Azienda Ospedaliero-Universitaria S. Luigi Gonzaga

Torino, Italy

ACTIVE NOT RECRUITING

Azienda Ospedaliero-Universitaria Integrata Verona - Borgo Roma

Verona, Italy

ACTIVE NOT RECRUITING

MeSH Terms

Conditions

Neoplasm Metastasis; Carcinoma

Interventions

Axitinib; avelumab

Condition Hierarchy (Ancestors)

Neoplastic Processes; Neoplasms; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type

Intervention Hierarchy (Ancestors)

Benzamides; Amides; Organic Chemicals; Benzoates; Acids, Carbocyclic; Carboxylic Acids; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Indazoles; Pyrazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Study Officials

• Roberto Iacovelli

  Fondazione Policlinico Universitario Agostino Gemelli IRCCS

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Roberto Iacovelli

CONTACT

+393339516295; roberto.iacovelli@policlinicogemelli.it

Tide- A Service

CONTACT

tide-a@oncotech.org

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: October 15, 2019
• First Posted: January 6, 2021
• Study Start: October 7, 2020
• Primary Completion: September 1, 2023
• Study Completion: October 1, 2024
• Last Updated: January 6, 2021

Record last verified: 2021-01

Data Sharing

• IPD Sharing: Will not share

Locations

IT (20)