Renal Carcinoma MetastaticPhase 2TIDE-ANCT04698213
Avelumab Plus Intermittent Axitinib in Previously Untreated Patients With Metastatic Renal Cell Carcinoma
A Phase 2 study testing Axitinib Oral Tablet and Avelumab in people with Renal Carcinoma Metastatic, run by Consorzio Oncotech at 20 sites in Italy.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Renal Carcinoma Metastatic
- What is being tested?
- Axitinib Oral Tablet and Avelumab
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 75 participants
- Where
- 20 sitesItaly
- Study dates
- 7 Oct 2020to Oct 2024
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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:
Show all 13Show fewer
- 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.
- Total bilirubin ≤ 1.5 × the upper limit of normal. For subjects with Gilbert's disease ≤ 3 mg/dL (≤ 51.3 µmol/L).
- 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.
Who cannot join
- 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
Show all 42Show fewer
- 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:
- Cardiovascular disorders:
- Symptomatic congestive heart failure, unstable angina pectoris, serious cardiac arrhythmias.
- Uncontrolled hypertension defined as sustained BP > 150 mm Hg systolic or > 100 mm Hg diastolic despite optimal antihypertensive treatment.
- Stroke (including TIA), myocardial infarction, or other ischemic event, or thromboembolic event (eg, pulmonary embolism) within 6 months before the start of treatment.
- Gastrointestinal (GI) disorders including those associated with a high risk of perforation or fistula formation:
- 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.
- 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.
- 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.
- Cavitating pulmonary lesion(s) or known endobronchial disease manifestation.
- Lesions invading major pulmonary blood vessels.
- Other clinically significant disorders such as:
- 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]).
- Serious non-healing wound/ulcer/bone fracture.
- Malabsorption syndrome.
- Uncompensated/symptomatic hypothyroidism.
- Moderate to severe hepatic impairment (Child-Pugh B or C).
- Requirement for hemodialysis or peritoneal dialysis.
- History of solid organ transplantation including allogenic stem-cell transplantation.
- In past 6 months: pulmonary embolism.
- 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.
- 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.
- Vaccination within 4 weeks of the first dose of avelumab and while on trials is prohibited except for administration of inactivated vaccines.
- 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.
- 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).
- 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.
- Has illness or medical conditions that are unstable or could jeopardize the safety of the patient and his or her compliance in the study.
- Pregnant or lactating females.
- Inability to swallow tablets or capsules.
- 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).
Trial locations and contacts
20 sites in 1 country.
Tide- A Service contact
20 sites in 1 country
Italy20 sites, 16 recruiting
- Not yet recruiting
ASL CN2 Alba-Bra
Alba
Cinzia Ortega, MD, cinzia.ortega@gmail.com
- Not yet recruiting
Irccs Oncologico Istituto Tumori Giovanni Paolo Ii
Bari
Emanuele Naghieri, MD, emanuele.naglieri@gmail.com
- Not yet recruiting
ASST Papa Giovanni XXIII
Bergamo
Lucia Bonomi, MD, lbonomi@asst-pg23.it
- Not yet recruiting
Azienda Ospedaliero-Universitaria Di Bologna Suor Orsola Malpighi
Bologna
Francesco Massari, MD, francesco.massari@aosp.bo.it
- Not yet recruiting
Ospedale Policlinico San Martino
Genova
Giuseppe Fornarini, MD, giuseppe.fornarini@hsanmartino.it
- Not yet recruiting
OSPEDALE di LECCE "VITO FAZZI"
Lecce
Vincenzo Emanuele Chiuri, MD, chiuriv@yahoo.it
- Recruiting
Istituto Clinico Humanitas
Milan
Paolo Andrea Zucali, MD, paolo.zucali@cancercenter.humanitas.it
- Not yet recruiting
Fondazione IRCCS Istituto Nazionale dei Tumori
Milan
Giuseppe Procopio, MD, giuseppe.procopio@istitutotumori.mi.it
- Not yet recruiting
Azienda Ospedaliero-Universitaria di Modena
Modena
Roberto Sabbatini, MD, sabbatini@unimore.it,
- Active, not recruiting
Azienda Ospedaliera Universitaria di Cagliari- P.O. Duilio Casula Monserrato
Monserrato, Cagliari
- Not yet recruiting
Istituto Oncologico Veneto
Padova
Marco Maruzzo, MD, umberto.basso@iov.veneto.it
- Recruiting
Azienda Ospedaliero-Universitaria di Parma
Parma
Melissa Bersanelli, MD, bersamel@libero.it
- Not yet recruiting
Istituti Clinici Scientifici Maugeri
Pavia
Mimma Rizzo, MD
- Not yet recruiting
Presidio Ospedaliero Unico Av3 - Ospedale Generale Provinciale - Macerata
Province of Macerata
Nicola Battelli, MD, battellin@gmail.com
- Active, not recruiting
Irccs Istituto in Tecnologie Avanzate E Modelli Assistenziali in Oncologia Di Reggio Emilia
Reggio Emilia
- Not yet recruiting
Azienda Ospedaliera San Camillo-Forlanini
Roma
Fabio Calabro, MD, fabiocalabro1@alice.it
- Recruiting
Fondazione Policlinico Universitario A. Gemelli IRCCS
Rome
Roberto Iacovelli, +393339516295, roberto.iacovelli@policlinicogemelli.it
- Not yet recruiting
Azienda Ospedaliera Santa Maria Terni
Terni
Sergio Bracarda, MD, sergiobracarda@gmail.com
- Active, not recruiting
Azienda Ospedaliero-Universitaria S. Luigi Gonzaga
Torino
- Active, not recruiting
Azienda Ospedaliero-Universitaria Integrata Verona - Borgo Roma
Verona
About this study
Official title: Phase II Study of Avelumab Plus Intermittent Axitinib in Previously Untreated Patients With Metastatic Renal Cell Carcinoma (Tide-A Study)
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.
Read the detailed description
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.
- Conditions
- Renal Carcinoma Metastatic
- Being tested
- Axitinib Oral Tablet, Avelumab
- Keywords
- metastatic, renal, carcinoma, avelumab, axitinib
- Medical subject headings
- Neoplasm Metastasis, Carcinoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Axitinib Oral TabletDrug
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.
AvelumabDrug
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.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: Drug: Axitinib Oral Tablet; Drug: Avelumab |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: From the date of the first study drugs administration until week 44
Secondary outcomes (7)
Progression free survival (PFS)
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.
Measured: 2 years from the last patient first visit (LPFV)
Overall Response Rate (ORR)
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.
Measured: 2 years from the last patient first visit (LPFV)
Disease Control (DC)
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.
Measured: 2 years from the last patient first visit (LPFV)
Overall Survival (OS)
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.
Measured: 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
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.
Measured: From the date of the first study drugs administration up to 90 days after the last dose of study drugs administration
Patient reported outcome (PRO) - Health status
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.
Measured: From the enrollment date until the date of first documented progression (that per protocol causes the end of treatment), assessed up to 4 years
Patient reported outcome (PRO) - Life Status
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.
Measured: From the enrollment date until the date of first documented progression (that per protocol causes the end of treatment), assessed up to 4 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted6 Jan 2021
- Study start7 Oct 2020
- Primary completionSep 2023 (estimated)
- Study completionOct 2024 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Renal Carcinoma MetastaticStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Model description
- 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.
- Masking
- None (open label)
- Enrolment
- 75 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Consorzio Oncotech
- Sponsor type
- University, hospital or other
- Collaborators
- Clinical Research Technology S.r.l.
- Responsible party
- Sponsor
- Investigators
- Roberto Iacovelli, Principal investigator, Fondazione Policlinico Universitario Agostino Gemelli IRCCS
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04698213
- Sponsor's protocol ID
- TIDE-A
- Acronym
- TIDE-A
- Status last verified
- Jan 2021
- First submitted
- 15 Oct 2019
- Last updated
- 6 Jan 2021
- Results posted
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 6 Jan 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase II Study of Avelumab Plus Intermittent Axitinib in Previously Untreated Patients With Metastatic Renal Cell Carcinoma (Tide-A Study)
- ClinicalTrials.gov ID
- NCT04698213
- Acronym / sponsor ID
- TIDE-A / TIDE-A
- Conditions
- Renal Carcinoma Metastatic
- Keywords
- metastatic, renal, carcinoma, avelumab, axitinib
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 75 participants (estimated)
- Lead sponsor
- Consorzio OncotechUniversity, hospital or other
- Collaborators
- Clinical Research Technology S.r.l.
- Study start
- 7 Oct 2020 (actual)
- Primary completion
- Sep 2023 (estimated)
- Study completion
- Oct 2024 (estimated)
- First posted
- 6 Jan 2021 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
- Model description
- 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.
| Arm | Type | Receives |
|---|---|---|
| intermittent axitinib plus Avelumab | Experimental | Drug: Axitinib Oral Tablet, Drug: AvelumabAll 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (13 listed)
- 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.
Key exclusion criteria (42 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Axitinib Oral TabletAxitinib 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. | Drug | intermittent axitinib plus Avelumab |
| AvelumabAvelumab 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. | Drug | intermittent axitinib plus Avelumab |
Primary outcome
Overall response rate (ORR)
Time frame: From the date of the first study drugs administration until week 44
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.
7 secondary outcomes
Progression free survival (PFS)
Time frame: 2 years from the last patient first visit (LPFV)
Overall Response Rate (ORR)
Time frame: 2 years from the last patient first visit (LPFV)
Disease Control (DC)
Time frame: 2 years from the last patient first visit (LPFV)
Overall Survival (OS)
Time frame: 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
Time frame: From the date of the first study drugs administration up to 90 days after the last dose of study drugs administration
Patient reported outcome (PRO) - Health status
Time frame: From the enrollment date until the date of first documented progression (that per protocol causes the end of treatment), assessed up to 4 years
Patient reported outcome (PRO) - Life Status
Time frame: From the enrollment date until the date of first documented progression (that per protocol causes the end of treatment), assessed up to 4 years
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 6 Jan 2021.
- Individual participant dataSharing planned: No
Related trials for Renal Carcinoma Metastatic
RecruitingPhase 1/2
Study of INBRX-106 and INBRX-106 in Combination With Pembrolizumab (Keytruda®) in Subjects With Locally Advanced or Metastatic Solid Tumors (Hexavalent OX40 Agonist)
Solid Tumor, Non-Small Cell Lung Cancer
Active, not recruitingPhase 1/2
Pazopanib Hydrochloride and Bevacizumab in Treating Patients With Previously Untreated Metastatic Kidney Cancer
Clear Cell Renal Cell Carcinoma, Stage IV Renal Cell Cancer
RecruitingPhase 2
Phase II Trial of Combination Anti-PD-1 and Aldesleukin for Metastatic Melanoma and Renal Cell Carcinoma
Metastatic Melanoma, Advanced Locoregional Melanoma
Active, not recruitingPhase 1
P-MUC1C-ALLO1 Allogeneic CAR-T Cells in the Treatment of Subjects With Advanced or Metastatic Solid Tumors
Breast Cancer, Ovarian Cancer
RecruitingPhase 1
Open-Label Phase 1/2 Study of NEO-811 in Subjects With Locally Advanced or Metastatic Non-Resectable Clear Cell Renal Cell Carcinoma
Clear Cell Renal Cell Carcinoma, Renal Cell Carcinoma
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Tide- A Service contact
Roberto Iacovelli principal investigator
Fondazione Policlinico Universitario Agostino Gemelli IRCCS
20 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Axitinib Oral Tablet and Avelumab in people with Renal Carcinoma Metastatic, run by Consorzio Oncotech at 20 sites in Italy.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 13 inclusion and 42 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 6 Jan 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 20 sites in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Roberto Iacovelli (+393339516295, roberto.iacovelli@policlinicogemelli.it), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Overall response rate (ORR) (time frame: From the date of the first study drugs administration until week 44). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 6 Jan 2021.