Safety and Efficacy Study of AVB-S6-500 (Batiraxcept) in Patients With Advanced or Metastatic Clear Cell Renal Cell Carcinoma

Study Overview
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Brief Summary
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This is a Phase 1b/2 study of AVB-S6-500 designed to evaluate the safety and efficacy of AVB-S6-500 in combination with cabozantinib, AVB-S6-500 in combination with cabozantinib and nivolumab and AVB-S6-500 monotherapy in subjects with advanced or metastatic clear cell renal cell carcinoma (ccRCC). The phase 1b portion of the study is open label and patients with advanced ccRCC who had progressed on or after at least one prior line of treatment will receive AVB-S6-500 + cabozantinib. Two dose levels will be evaluated. The Phase 2 portion of the study is open-label 3-part study to evaluate efficacy and tolerability of AVB-S6-500 + cabozantinib, AVB-S6-500 + cabozantinib + nivolumab, and AVB-S6-500 alone.

Official Title
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A Phase 1b/2 Study Of AVB-S6-500 In Combination With Cabozantinib, AVB-S6-500 In Combination With Cabozantinib and Nivolumab, and AVB-S6-500 Monotherapy in Patients With Advanced or Metastatic Clear Cell Renal Cell Carcinoma

Conditions
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Clear Cell Renal Cell Carcinoma

Intervention / Treatment
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* Drug: Batiraxcept
* Drug: Cabozantinib (Cabo)
* Drug: Nivolumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18 years or older Histologically confirmed advanced or metastatic clear cell Renal Cell Carcinoma confirmed by imaging. Phase 1b and Phase 2 Part A: has progressed on/after at least one front-line of treatment; Phase 2 Part B: No prior systemic treatment; Phase 2 Part C: not amenable to curative intent therapy. Must have radiologic imaging with a computed tomography (CT) scan or magnetic resonance imaging (MRI) within 28 days of enrollment Must have at least one measurable lesion according to RECIST 1.1 ECOG performance status of 0-1 Adequate bone marrow, liver and kidney function Life expectancy of >12 weeks At least 28 days between termination of prior major surgery or anticancer therapy or 14 days from last radiation therapy and administration of AVB-S6-500 Exclusion Criteria: Received prior treatment with cabozantinib (Phase1b and Phase 2 Part A) Received prior treatment with nivolumab (Phase 2 Part B) Concurrent anti-cancer therapy or any other interventional treatment or other interventional research trial History of prior malignancy within the past 3 years except adequately treated basal or squamous cell skin cancer, superficial bladder cancer or carcinoma in situ of the prostate, cervix or breast Symptomatic CNS metastasis or metastases Active GI disease that would impact absorption of cabozantinib Nephrotic range proteinuria at screening Evidence of pleural effusion, ascites etc that requires therapeutic intervention within 28 days prior to AVB-S6-500 administration Phase 2 Part A and Part B: Has had a major bleed in the last 3 months, uncontrolled hypertension despite treatment with antihypertensives or is not appropriate for treatment with cabozantinib in the Investigator's opinion Serious active infection requiring IV antibiotics and/or hospitalization at study entry Phase 2 Part B: Has active, known or suspected autoimmune disease, defined as requiring systemic treatment Active COVID-19, HIV, Hepatitis B or Hepatitis C virus.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1b: Batiraxcept + cabozantinib<br>Two dose levels of batiraxcept administered Q2W (once every two weeks) in combination with QD (once a day) cabozantinib will be evaluated. | Drug: Batiraxcept<br>* Batiraxcept is experimental drug<br>* Other names: AVB-S6-500;Drug: Cabozantinib (Cabo)<br>* Cabozantinib is standard of care as monotherapy and in combination with nivolumab in ccRCC<br>* Other names: Cabometyx®;|
| Experimental: Phase 2 Part A: batiraxcept + cabozantinib<br>One dose level of batiraxcept administered Q2W in combination with QD cabozantinib will be evaluated. | Drug: Batiraxcept<br>* Batiraxcept is experimental drug<br>* Other names: AVB-S6-500;Drug: Cabozantinib (Cabo)<br>* Cabozantinib is standard of care as monotherapy and in combination with nivolumab in ccRCC<br>* Other names: Cabometyx®;|
| Experimental: Phase 2 Part B: batiraxcept + cabozantinib + nivolumab<br>One dose level of batiraxcept administered Q2W in combination with QD cabozantinib and nivolumab. | Drug: Batiraxcept<br>* Batiraxcept is experimental drug<br>* Other names: AVB-S6-500;Drug: Cabozantinib (Cabo)<br>* Cabozantinib is standard of care as monotherapy and in combination with nivolumab in ccRCC<br>* Other names: Cabometyx®;Drug: Nivolumab<br>* Nivolumab is standard of care in the first line treatment of ccRCC<br>* Other names: Opdivo®;|
| Experimental: Phase 2 Part C: batiraxcept alone<br>One dose level of batiraxcept administered Q2W will be evaluated. | Drug: Batiraxcept<br>* Batiraxcept is experimental drug<br>* Other names: AVB-S6-500;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events in Phase 1b as graded by NCI-CTCAE version 5.0 | Safety and tolerability of AVB-S6-500 in combination with cabozantinib. | 10 months | 
| Identify the recommended Phase 2 dose of AVB-S6-500 in combination with cabozantinib | Measured by dose limiting toxicities experienced in Phase 1b | 10 months | 
| Anti-tumor activity of AVB-S6-500 in combination with cabozantinib (ORR) | Measured by objective response rate (ORR) in patients receiving AVB-S6-500 + cabozantinib in Phase 1b and Phase 2 Part A. ORR is proportion of subjects who have a partial or complete confirmed response to therapy relative to baseline as assessed per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. | 30 months | 
| Anti-tumor activity of AVB-S6-500 in combination with cabozantinib and nivolumab (ORR) | Measured by objective response rate (ORR) in patients receiving AVB-S6-500 + cabozantinib + nivolumab in Phase 2 Part B. ORR is proportion of subjects who have a partial or complete confirmed response to therapy relative to baseline as assessed per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. | 30 months | 
| Anti-tumor activity of AVB-S6-500 alone (ORR) | Measured by objective response rate (ORR) in patients receiving AVB-S6-500 in Phase 2 Part C. ORR is proportion of subjects who have a partial or complete confirmed response to therapy relative to baseline as assessed per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. | 30 months | 
| Anti-tumor activity of AVB-S6-500 alone (DOR) | Measured by duration of response (DOR) in patients receiving AVB-S6-500 in Phase 2 Part C. DOR is measured from the date of partial or complete response to therapy until the cancer progresses. | 30 months | 
| Anti-tumor activity of AVB-S6-500 alone (CBR) | Measured by clinical benefit rate (CBR) in patients receiving AVB-S6-500 in Phase 2 Part C. CBR is the proportion of subjects who have a complete or partial response to therapy or maintain stable disease. | 30 months | 
| Anti-tumor activity of AVB-S6-500 alone (PFS) | Measured by progression-free survival (PFS) in patients receiving AVB-S6-500 in Phase 2 Part C. PFS is the time from treatment until radiological disease progression or death. | 30 months | 
| Anti-tumor activity of AVB-S6-500 alone (OS) | Measured by overall survival (OS) in patients receiving AVB-S6-500 in Phase 2 Part C. OS is the time from the start of the treatment until death. | 60 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics: AUC | Area under the AVB-S6-500 concentration-time curve. | 30 months | 
| Pharmacokinetics: Cmax | Maximum observed AVB-S6-500 concentration. | 30 months | 
| Pharmacokinetics: Tmax | Time of maximum observed AVB-S6-500 concentration. | 30 months | 
| Pharmacokinetics: t1/2 | Apparent terminal half-life of AVB-S6-500. | 30 months | 
| Pharmacodynamic marker assessment | Change from the baseline in GAS6 serum levels. | 30 months | 
| Anti-drug antibody (ADA) titers | Change from baseline in ADA titer. | 30 months | 
| Anti-tumor activity of AVB-S6-500 in combination with cabozantinib (CBR) | Measured by clinical benefit rate (CBR) in patients receiving AVB-S6-500 + cabozantinib in Phase 1b and Phase 2 Part A. CBR is the proportion of subjects who have a complete or partial response to therapy or maintain stable disease. | 30 months | 
| Anti-tumor activity of AVB-S6-500 in combination with cabozantinib (DOR) | Measured by duration of response (DOR) in patients receiving AVB-S6-500 in Phase 1b and Phase 2 Part A. DOR is measured from the date of partial or complete response to therapy until the cancer progresses. | 30 months | 
| Anti-tumor activity of AVB-S6-500 in combination with cabozantinib (OS) | Measured by overall survival (OS) in patients receiving AVB-S6-500 in Phase 1b and Phase 2 Part A. OS is the time from the start of the treatment until death. | 60 months | 
| Anti-tumor activity of AVB-S6-500 in combination with cabozantinib (PFS) | Measured by progression-free survival (PFS) in patients receiving AVB-S6-500 in Phase 1b and Phase 2 Part A, PFS is the time from treatment until radiological disease progression or death. | 30 months | 
| Anti-tumor activity of AVB-S6-500 in combination with cabozantinib and nivolumab (DOR) | Measured by duration of response (DOR) in patients receiving AVB-S6-500, cabozantinib and nivolumab in Phase 2 Part B. DOR is measured from the date of partial or complete response to therapy until the cancer progresses. | 30 months | 
| Anti-tumor activity of AVB-S6-500 in combination with cabozantinib and nivolumab (CBR) | Measured by clinical benefit rate (CBR) in patients receiving AVB-S6-500, cabozantinib and nivolumab in Phase 2 Part B. CBR is the proportion of subjects who have a complete or partial response to therapy or maintain stable disease. | 30 months | 
| Anti-tumor activity of AVB-S6-500 in combination with cabozantinib and nivolumab (PFS) | Measured by progression-free survival (PFS) in patients receiving AVB-S6-500, cabozantinib and nivolumab in Phase 2 Part B. PFS is the time from treatment until radiological disease progression or death. | 30 months | 
| Anti-tumor activity of AVB-S6-500 in combination with cabozantinib and nivolumab (OS) | Measured by overall survival (OS) in patients receiving AVB-S6-500, cabozantinib and nivolumab in Phase 2 Part B. OS is the time from the start of the treatment until death. | 60 months | 
| Incidence of adverse events in Phase 2 Part C as graded by NCI-CTCAE version 5.0 | Safety and tolerability of AVB-S6-500 alone | 30 months | 
| Incidence of adverse events in Phase 2 Part B as graded by NCI-CTCAE version 5.0 | Safety and tolerability of AVB-S6-500 in combination with cabozantinib and nivolumab | 30 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Clear cell renal cell carcinoma, Renal cell carcinoma, Recurrent renal cell carcinoma, Kidney cancer, Kidney Neoplasms, Kidney Diseases, Urologic Neoplasms