Phase II Evaluation of Axitinib Intensification Plus Standard of Care Versus Standard of Care Alone Post-Induction with Nivolumab and Ipilimumab in mRCC Patients

Trial ID: 2024-511397-70-00
Protocol: AxIn
Sponsor: Consorzio Oncotech

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Diseases & Conditions

Metastatic renal cell carcinoma

Objectives

The primary objective of this Phase II study is to investigate the **efficacy** of axitinib in patients with **metastatic renal cell carcinoma (mRCC)** who are eligible to receive the standard of care (SOC) following induction with nivolumab plus ipilimumab. This is clinically relevant as it aims to determine whether axitinib can enhance treatment outcomes in mRCC patients who have not achieved a complete response with initial therapy.

The secondary objective is to investigate the **safety** and activity of axitinib in the same patient population, providing additional insights into the therapeutic profile of axitinib when used in conjunction with SOC after initial treatment with nivolumab plus ipilimumab.

Participants

The clinical trial involves participants diagnosed with **metastatic renal cell carcinoma (mRCC)**. The study population includes both male and female subjects aged 18 years and older. Participants are required to have a histologically or cytologically confirmed advanced renal cell carcinoma with a predominantly clear-cell subtype. The trial population was selected based on their eligibility to continue the standard of care with immunotherapy after induction with nivolumab plus ipilimumab, without experiencing nivolumab-related toxicity that would prevent continuation. Participants must have completed at least two cycles of the induction therapy and should not have achieved a complete response or experienced progressive disease. The trial includes individuals with an Eastern Cooperative Oncology Group performance status of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Adequate organ and bone marrow function is required, as defined by specific laboratory criteria. The sponsor has not provided information regarding the total number of participants. The trial also considers lifestyle factors, requiring sexually active fertile subjects and their partners to use medically accepted methods of contraception during the study and for five months after the last dose of treatment. Female participants of childbearing potential must not be pregnant at screening. The trial includes a vulnerable population, ensuring that participants are capable of understanding and complying with protocol requirements and have signed informed consent documents.

Plans and Procedures

The clinical trial is designed to evaluate the efficacy of **axitinib** in combination with the standard of care (SOC) compared to SOC alone in patients with **metastatic renal cell carcinoma (mRCC)**. This is a Phase II, randomized, double-blind, controlled trial. The trial aims to assess the overall response rate, progression-free survival, overall survival, depth and duration of response, quality of life, and safety of axitinib when added to SOC. The trial is expected to conclude by December 31, 2026, with recruitment having commenced on April 18, 2023.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically or cytologically confirmed advanced RCC, completion of at least two cycles of induction with nivolumab plus ipilimumab, and adequate organ and bone marrow function. Following the screening, participants will be randomized to receive either axitinib plus SOC or SOC alone. The treatment period will last up to 12 months, with regular follow-up visits to monitor efficacy and safety outcomes. The end-of-study visit will occur after the completion of the treatment period or upon early termination.

Participant involvement is expected to last for the duration of the treatment period, with additional follow-up as required. Conditions that may lead to early termination from the study include the occurrence of unacceptable toxicity, disease progression, or withdrawal of consent. The trial is conducted under strict adherence to protocol requirements, ensuring that all participants are capable of understanding and complying with the study procedures. The trial's primary and secondary endpoints will be evaluated to determine the added benefit of axitinib in the treatment regimen for mRCC patients.

Treatment

The clinical trial involves the administration of **axitinib**, a chemical substance classified as an antineoplastic agent and protein kinase inhibitor. Axitinib is provided in an oral pharmaceutical form, designated as PHF00082MIG. The maximum daily dose of axitinib is 10 mg, with a total maximum dose of 3600 mg over the course of the treatment. The treatment period is limited to a maximum of 12 months. Axitinib is administered orally, and the dosing schedule is designed to ensure optimal therapeutic efficacy while monitoring for potential adverse effects. Participant compliance with the dosing regimen is monitored throughout the study to ensure adherence to the protocol.

In addition to the experimental treatment with axitinib, the study includes a standard-of-care (SOC) therapy, which consists of the administration of nivolumab plus ipilimumab. This SOC therapy is provided to patients as part of the induction phase prior to the introduction of axitinib. The SOC therapy serves as a comparator treatment to evaluate the efficacy of axitinib intensification in patients with metastatic renal cell carcinoma (mRCC) who have not achieved a complete response. The trial aims to assess the potential benefits of axitinib when added to the existing SOC regimen.

Efficacy

The efficacy of the clinical trial will be assessed by evaluating the overall response rate in patients treated with **axitinib** in addition to the standard of care (SOC) compared to SOC alone. The primary endpoint focuses on the overall response rate, while secondary endpoints include progression-free survival, overall survival, depth of response, duration of response, and quality of life. These parameters will be measured using established clinical criteria and validated scales, such as the Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1, to ensure consistency and reliability in the assessment of tumor response.

Data collection will occur at specified intervals throughout the trial, with assessments scheduled to align with the treatment cycles and follow-up periods. The analysis will involve comparing the efficacy outcomes between the two treatment groups to determine the added benefit of axitinib when combined with SOC. The trial is designed to provide robust data on the efficacy of axitinib in patients with metastatic renal cell carcinoma (mRCC) who have not achieved a complete response following induction therapy with nivolumab plus ipilimumab.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Histologically or cytologically confirmed advanced RCC with predominantly clear-cell subtype and candidate to continue the standard of care with immunotherapy after nivolumab plus ipilimumab induction as per standard clinical practice. 2. Completion of at least 2 cycles of the induction of nivolumab and ipilimumab without nivolumab-related toxicity that cannot allow the continuation of nivolumab and no complete response or progressive disease. Treatment with SOC ± axitinib should be started within 12 weeks from last dose of nivolumab/ipilimumab.3. Male or female subjects aged = 18 years 4. Available tumor tissue sample. 5. At least one measurable lesion as defined by Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1. 6. Eastern Cooperative Oncology Group performance status 0 or 1. 7. Adequate organ and bone marrow function based upon meeting all of the following laboratory criteria within 10 days before the start of treatment: a) Absolute neutrophil count (ANC) = 1500/mm3 (= 1.5 GI/L) b) Platelets = 100,000/mm3 (= 100 GI/L). c) Haemoglobin = 9 g/dL (= 90 g/L). d) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 3.0 × upper limit of normal. e) Total bilirubin = 1.5 × the upper limit of normal. For subjects with Gilbert’s disease = 3 mg/dL (= 51.3 µmol/L). f) Serum creatinine = 2.0 × upper limit of normal or calculated creatinine clearance = 30 mL/min (= 0.5 mL/sec) using the Cockroft-Gault. 8. Capable of understanding and complying with the protocol requirements and must have signed the informed consent document. 9. Sexually active fertile subjects and their partners must agree to use medically accepted methods of contraception (e.g., barrier methods, including male condom, female condom, or diaphragm with spermicidal gel) during the course of the study and for 5 months after the last dose of study treatment. 10. Female subjects of childbearing potential must not be pregnant at screening. Females of childbearing potential are defined as premenopausal females capable of becoming pregnant (i.e., 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 amenorrhoeic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, antioestrogens, low body weight, ovarian suppression or other reasons.

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Exclusion Criteria

Prior treatment with systemic therapy for advanced RCC with the exclusion of the induction of nivolumab and ipilimumab. 2. Prior adjuvant or neoadjuvant therapy 3. Active seizure disorder or evidence of brain metastases, spinal cord compression, or carcinomatous meningitis 4. 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 with no plans for treatment intervention. 5. 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. 6. 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. 7. Concomitant anticoagulation at therapeutic doses with oral anticoagulants (e.g., warfarin, direct thrombin and Factor Xa inhibitors) or platelet inhibitors (e.g., clopidogrel). These are not allowed in case of randomization in the experimental arm, enrollment is allowed if clinician and patient agree to switch to low-molecular-weight heparin (LMWH) in case of randomization to axitinib + SOC arm. No restrictions to anticoagulants is applied for patients randomized in the SOC arm alone.8. In past 6 months: myocardial infarction, uncontrolled angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident, or transient ischemic attack. 9. 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. 10. The subject has uncontrolled, significant intercurrent or recent illness i 11. Major surgery (e.g., 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 (e.g., 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. 12. Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 msec within 1 month before the start of treatment . 13. Vaccination within 4 weeks of the first dose of axitinib and while on trials is prohibited except for administration of inactivated vaccines. 14. Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent. Patients with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid diseases not requiring immunosuppressive treatment are eligible. 15. Current use of immunosuppressive medication, 16. 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. 17. Has illness or medical conditions that are unstable or could jeopardize the safety of the patient and his or her compliance in the study. 18. Pregnant or lactating females. 19. Inability to swallow tablets or capsules. 20. Previously identified allergy or hypersensitivity to components of the study treatment formulations. 21. Rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption.