Trial Information
Status:
Open
Specialty:
Renal
Date Opened:
23/04/2026
Planned Close date:
31/10/2027
Sponsors:
Arcus Biosciences
Site Recruitment:
0 /
5
Principal Investigator:
Dr Natalie Charnley
Study Title:
Randomized Phase 3 Trial of Casdatifa n & Cabozantinib Vs Placebo & Cabozantinib
Contacts
Research Nurse / Study Coordinator:
Rashmi Madan
Administrator:
Aaisha Khan
A Randomized, Double-Blind, Active-Control, Multicenter Phase 3 Trial of Casdatifan and Cabozantinib Versus Placebo and Cabozantinib in Patients With Advanced Clear Cell Renal Cell Carcinoma
This is a Phase 3, randomized, placebo-controlled, double-blind, 2-arm, global, multicenter study to evaluate the PFS of casdatifan versus placebo when each is given in combination with cabozantinib in patients with confirmed advanced or metastatic ccRCC following progression on prior anti-PD-1 immunotherapy.
Patients are eligible for study inclusion if all the following criteria apply:
1. Age ≥ 18 years (or age ≥ regionally approved age of consent for participation in
investigational clinical studies) at the time of signing the informed consent form (ICF).
2. Capable of giving signed informed consent, which includes compliance with the
requirements and restrictions listed in the ICF and in this protocol.
3. Unresectable locally advanced or metastatic renal cell carcinoma with a primary clear cell
component.
4. Must have received anti-PD-1 or anti-PD-L1 therapy as part of the most recent regimen
(either adjuvant monotherapy or first-line in combination with anti-CTLA-4 or
VEGFR-TKI), with no more than 1 prior regimen in the metastatic setting.
a. Patients must have received at least 2 doses of anti-PD-1 or anti-PD-L1 therapy.
b. For patients who received anti-PD-1 in adjuvant setting, radiographic progression
must have occurred on or within 12 months of last dose.
5. A Karnofsky Performance Status (KPS) score ≥ 80%.
6. At least 1 target lesion measurable by computed tomography/magnetic resonance
imaging per RECIST 1.1, not within a field of prior radiation therapy.
7. Adequate organ and marrow function, as defined by the following laboratory values
≤ 72 hours prior to randomization, except as noted below:
a. Neutrophils: ≥ 1500 cells/μL (without granulocyte colony-stimulating factor
support within the last 2 weeks).
b. Platelets: ≥ 100 × 103
cells/μL (without thrombopoietic stimulating agents or
transfusion within the last 7 days).
c. White blood cell counts ≥ 2500 cells/μL.
d. Hemoglobin: ≥ 10.0 g/dL (without erythropoietin or erythropoietin-stimulating
agents or transfusion within the last 7 days).
e. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT): ≤ 2.5 ×
upper limit of normal (ULN) without hepatic metastasis; ≤ 5 × ULN with hepatic
metastasis
f. Total bilirubin: ≤ 1.5 × ULN, with the exception:
• Patients with known Gilbert disease: total bilirubin ≤ 3 × ULN.
g. Creatinine clearance: ≥ 30 mL/min (calculated using the Cockcroft-Gault formula
or based on 24-hour urine collection).
h. A partial thromboplastin time: ≤ 1.5 × ULN.
i. Albumin ≥ 2.5 g/dL.
8. Acceptable coagulation status as indicated by an international normalized ratio (INR)
≤ 1.5 × ULN obtained ≤ 14 days prior to randomization.
9. A 6-minute walk test (according to the guidelines published by the American Thoracic
Society [American Thoracic Society, 2002]) that does not demonstrate exercise-induced
oxygen desaturation, defined as a blood oxygen saturation by pulse oximetry < 88%.
10. A left ventricular ejection fraction within the normal range per the American Society of
Echocardiography and the European Association of Cardiovascular Imaging.
11. Patients with a history of hepatitis B, hepatitis C, or human immunodeficiency virus
(HIV) must:
a. For hepatitis B, demonstrate resolution of infection or be on adequate suppressive
antiviral therapy and not at risk for hepatic decompensation.
b. For hepatitis C, demonstrate resolution of infection or be on adequate suppressive
antiviral therapy and not at risk for hepatic decompensation.
c. For HIV, demonstrate cluster of differentiation 4 positive T cell count of at least
350 cells/microliter and be on adequate suppressive antiviral therapy.
Note: No hepatitis or HIV testing is required unless mandated by local health
authority or patient has a history of such infection(s).
12. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test.
13. Female patients must not be breastfeeding at the time of providing informed consent and
throughout the study.
14. Male and female patients must agree to follow contraception guidelines
Please refer to the protocol for the section references.
1. Age ≥ 18 years (or age ≥ regionally approved age of consent for participation in
investigational clinical studies) at the time of signing the informed consent form (ICF).
2. Capable of giving signed informed consent, which includes compliance with the
requirements and restrictions listed in the ICF and in this protocol.
3. Unresectable locally advanced or metastatic renal cell carcinoma with a primary clear cell
component.
4. Must have received anti-PD-1 or anti-PD-L1 therapy as part of the most recent regimen
(either adjuvant monotherapy or first-line in combination with anti-CTLA-4 or
VEGFR-TKI), with no more than 1 prior regimen in the metastatic setting.
a. Patients must have received at least 2 doses of anti-PD-1 or anti-PD-L1 therapy.
b. For patients who received anti-PD-1 in adjuvant setting, radiographic progression
must have occurred on or within 12 months of last dose.
5. A Karnofsky Performance Status (KPS) score ≥ 80%.
6. At least 1 target lesion measurable by computed tomography/magnetic resonance
imaging per RECIST 1.1, not within a field of prior radiation therapy.
7. Adequate organ and marrow function, as defined by the following laboratory values
≤ 72 hours prior to randomization, except as noted below:
a. Neutrophils: ≥ 1500 cells/μL (without granulocyte colony-stimulating factor
support within the last 2 weeks).
b. Platelets: ≥ 100 × 103
cells/μL (without thrombopoietic stimulating agents or
transfusion within the last 7 days).
c. White blood cell counts ≥ 2500 cells/μL.
d. Hemoglobin: ≥ 10.0 g/dL (without erythropoietin or erythropoietin-stimulating
agents or transfusion within the last 7 days).
e. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT): ≤ 2.5 ×
upper limit of normal (ULN) without hepatic metastasis; ≤ 5 × ULN with hepatic
metastasis
f. Total bilirubin: ≤ 1.5 × ULN, with the exception:
• Patients with known Gilbert disease: total bilirubin ≤ 3 × ULN.
g. Creatinine clearance: ≥ 30 mL/min (calculated using the Cockcroft-Gault formula
or based on 24-hour urine collection).
h. A partial thromboplastin time: ≤ 1.5 × ULN.
i. Albumin ≥ 2.5 g/dL.
8. Acceptable coagulation status as indicated by an international normalized ratio (INR)
≤ 1.5 × ULN obtained ≤ 14 days prior to randomization.
9. A 6-minute walk test (according to the guidelines published by the American Thoracic
Society [American Thoracic Society, 2002]) that does not demonstrate exercise-induced
oxygen desaturation, defined as a blood oxygen saturation by pulse oximetry < 88%.
10. A left ventricular ejection fraction within the normal range per the American Society of
Echocardiography and the European Association of Cardiovascular Imaging.
11. Patients with a history of hepatitis B, hepatitis C, or human immunodeficiency virus
(HIV) must:
a. For hepatitis B, demonstrate resolution of infection or be on adequate suppressive
antiviral therapy and not at risk for hepatic decompensation.
b. For hepatitis C, demonstrate resolution of infection or be on adequate suppressive
antiviral therapy and not at risk for hepatic decompensation.
c. For HIV, demonstrate cluster of differentiation 4 positive T cell count of at least
350 cells/microliter and be on adequate suppressive antiviral therapy.
Note: No hepatitis or HIV testing is required unless mandated by local health
authority or patient has a history of such infection(s).
12. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test.
13. Female patients must not be breastfeeding at the time of providing informed consent and
throughout the study.
14. Male and female patients must agree to follow contraception guidelines
Please refer to the protocol for the section references.
Patients are excluded from the study if any of the following criteria apply:
1. Unwilling or unable to comply with study procedures and/or study visits, including
subsequent treatment data collection for the progression-free survival-2 (PFS-2) endpoint,
safety follow-up, and long-term follow-up for survival.
2. Received prior treatment with a HIF-2α inhibitor.
3. Received prior treatment with cabozantinib.
4. Receiving ongoing concomitant treatment with moderate or strong CYP3A4 inducers, or
moderate or strong CYP3A4 inhibitors within 5 half-lives of the concomitant treatment,
(Section 7.3.2) or up to 28 days, whichever is longer, prior to randomization.
5. Receiving ongoing concomitant treatment with sensitive substrates of CYP3A4,
CYP2C8, CYP2C9, or CYP2C19 with narrow therapeutic indices within 5 half-lives of
the concomitant treatment (Section 7.3.2) or up to 28 days, whichever is longer, prior to
randomization.
6. History of leptomeningeal disease or spinal cord compression.
7. Patients with previously treated brain metastases are eligible provided they do not
demonstrate any neurologic symptoms and do not require > 10 mg prednisone (or
equivalent dose) 14 days prior to randomization.
8. Underlying medical conditions that, in the investigator’s or sponsor’s opinion, will make
the administration of study-specified therapy hazardous or any of the following:
a. Medical history of severe (ie, Global Initiative for Chronic Obstructive Lung
Disease grade 3; GOLD 3) or very severe (ie, GOLD 4) chronic obstructive
pulmonary disease (COPD) per Appendix 5 and/or use of continuous or
intermittent supplemental oxygen.
b. Active viral, bacterial, or fungal infections requiring systemic treatment within
14 days of randomization.
Note: Prophylactic antibiotic treatment (eg, to prevent a urinary tract infection)
is allowed; however, exclusion criteria numbers 4 and 5 above still apply.
c. Clinically significant cardiovascular disease, such as New York Heart Association
Class III or greater cardiac disease or cerebrovascular accident within 3 months
prior to randomization, unstable angina or new onset angina within 3 months prior
to randomization, myocardial infarction within 6 months prior to randomization,
or unstable arrhythmia within 3 months prior to randomization.
9. History of trauma or major surgery within 28 days prior to randomization. Patients who
undergo locoregional therapy or radiation therapy should have completed treatment
without residual symptoms at least 14 days prior to randomization.
Note: Placement of central venous access catheter (eg, port or similar) or biliary or
urinary stent is not considered a major surgical procedure.
10. Corrected QT interval (QTc) ≥ 450 ms in males and QTc ≥ 470 ms in females using
Fredericia’s QT correction formula (based on an average of triplicate recordings) within
28 days prior to randomization.
11. Other prior malignancy active within the previous year except for locally curable cancers
that have been apparently cured, such as basal or squamous cell skin cancer, superficial
bladder cancer, or carcinoma in situ of the cervix, breast, or prostate cancer. Also,
indolent malignancies, including but not limited to early-stage chronic lymphocytic
leukemia and follicular lymphoma or watch-and-wait eligible prostate cancer, that don’t
require anticancer treatment could be allowed after discussion with the medical monitor.
12. Known hypersensitivity to any of the components in the investigational product or
cabozantinib formulations.
13. Inability to swallow study treatment.
14. Malabsorption condition that would alter the absorption of orally administered
medications.
15. Concomitant treatment with therapeutic doses of anticoagulants such as heparin,
warfarin, thrombin, or Factor Xa inhibitors, or antiplatelet agents (eg, clopidogrel).
Note: Low-dose aspirin for cardioprotection (per local applicable guidelines) and
prophylactic low molecular weight heparin (LMWH) are permitted. Anticoagulation with
therapeutic doses of LMWH is allowed in patients who are on a stable dose of LMWH for
at least 1 week before administration of the first dose of study treatment, and who have
had no complications from a thromboembolic event or the anticoagulation regimen.
16. Uncontrolled or poorly controlled hypertension, as defined by a sustained blood pressure
> 140/90 mm Hg on more than three antihypertensives.
Note: Blood pressure medication may not be started nor changed within the 14 days
prior to randomization.
17. Stroke (including transient ischemic attack), myocardial infarction, or other ischemic
event or thromboembolic event (eg, deep venous thrombosis, pulmonary embolism
[DVT/PE]) within 6 months before randomization. Patients with a diagnosis of DVT/PE
within 6 months are allowed if stable and treated with LMWH for at least 3 weeks before
randomization.
18. Gastrointestinal (GI) disorders, including those associated with a high risk of perforation
or fistula formation:
a. 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.
b. Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal abscess
within 6 months before administration of the first dose of study treatment.
Note: Complete healing of an intra-abdominal abscess must be confirmed before
administration of the first dose of study treatment.
19. 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 administration of the first dose of study treatment.
20. Tumor invading or encasing any major blood vessels.
21. Other clinically significant disorders such as:
a. Serious non-healing wound/ulcer/bone fracture.
22. Moderate to severe hepatic impairment (Child-Pugh B or C).
23. Requirement for hemodialysis or peritoneal dialysis
24. History of solid organ transplantation.
25. History of osteonecrosis of the jaw (ONJ).
Note: Caution should be used in patients receiving agents associated with ONJ, such as
bisphosphonates.
26. History of aneurysm bleeds.
27. Clinically significant toxicities related to any prior anticancer treatment, or toxicities
Grade ≥ 3 per National Cancer Institute Common Terminology Criteria for Adverse
Events, version 5.0 (NCI CTCAE v5.0) regardless of relatedness to prior anticancer
therapies. Clinically nonsignificant toxicities are allowed if a patient’s AE(s) are stable
on supportive therapy (excluding prohibited therapies; Section 7.3.2), or they have
resolved to baseline or Grade ≤ 2.
28. Any condition(s), disease(s), clinical examination or laboratory finding(s) not previously
mentioned that would contraindicate the study treatments, impose a high risk of treatment
complications for the patient, or obscure the interpretation of toxicity attribution of AEs
to the study drugs.
29. Received any of the prohibited therapies (Section 7.3.2) within the last 14 days, or within
the time specified in Section 7.3.2, prior to randomization
Please refer to the protocol for the section references.
1. Unwilling or unable to comply with study procedures and/or study visits, including
subsequent treatment data collection for the progression-free survival-2 (PFS-2) endpoint,
safety follow-up, and long-term follow-up for survival.
2. Received prior treatment with a HIF-2α inhibitor.
3. Received prior treatment with cabozantinib.
4. Receiving ongoing concomitant treatment with moderate or strong CYP3A4 inducers, or
moderate or strong CYP3A4 inhibitors within 5 half-lives of the concomitant treatment,
(Section 7.3.2) or up to 28 days, whichever is longer, prior to randomization.
5. Receiving ongoing concomitant treatment with sensitive substrates of CYP3A4,
CYP2C8, CYP2C9, or CYP2C19 with narrow therapeutic indices within 5 half-lives of
the concomitant treatment (Section 7.3.2) or up to 28 days, whichever is longer, prior to
randomization.
6. History of leptomeningeal disease or spinal cord compression.
7. Patients with previously treated brain metastases are eligible provided they do not
demonstrate any neurologic symptoms and do not require > 10 mg prednisone (or
equivalent dose) 14 days prior to randomization.
8. Underlying medical conditions that, in the investigator’s or sponsor’s opinion, will make
the administration of study-specified therapy hazardous or any of the following:
a. Medical history of severe (ie, Global Initiative for Chronic Obstructive Lung
Disease grade 3; GOLD 3) or very severe (ie, GOLD 4) chronic obstructive
pulmonary disease (COPD) per Appendix 5 and/or use of continuous or
intermittent supplemental oxygen.
b. Active viral, bacterial, or fungal infections requiring systemic treatment within
14 days of randomization.
Note: Prophylactic antibiotic treatment (eg, to prevent a urinary tract infection)
is allowed; however, exclusion criteria numbers 4 and 5 above still apply.
c. Clinically significant cardiovascular disease, such as New York Heart Association
Class III or greater cardiac disease or cerebrovascular accident within 3 months
prior to randomization, unstable angina or new onset angina within 3 months prior
to randomization, myocardial infarction within 6 months prior to randomization,
or unstable arrhythmia within 3 months prior to randomization.
9. History of trauma or major surgery within 28 days prior to randomization. Patients who
undergo locoregional therapy or radiation therapy should have completed treatment
without residual symptoms at least 14 days prior to randomization.
Note: Placement of central venous access catheter (eg, port or similar) or biliary or
urinary stent is not considered a major surgical procedure.
10. Corrected QT interval (QTc) ≥ 450 ms in males and QTc ≥ 470 ms in females using
Fredericia’s QT correction formula (based on an average of triplicate recordings) within
28 days prior to randomization.
11. Other prior malignancy active within the previous year except for locally curable cancers
that have been apparently cured, such as basal or squamous cell skin cancer, superficial
bladder cancer, or carcinoma in situ of the cervix, breast, or prostate cancer. Also,
indolent malignancies, including but not limited to early-stage chronic lymphocytic
leukemia and follicular lymphoma or watch-and-wait eligible prostate cancer, that don’t
require anticancer treatment could be allowed after discussion with the medical monitor.
12. Known hypersensitivity to any of the components in the investigational product or
cabozantinib formulations.
13. Inability to swallow study treatment.
14. Malabsorption condition that would alter the absorption of orally administered
medications.
15. Concomitant treatment with therapeutic doses of anticoagulants such as heparin,
warfarin, thrombin, or Factor Xa inhibitors, or antiplatelet agents (eg, clopidogrel).
Note: Low-dose aspirin for cardioprotection (per local applicable guidelines) and
prophylactic low molecular weight heparin (LMWH) are permitted. Anticoagulation with
therapeutic doses of LMWH is allowed in patients who are on a stable dose of LMWH for
at least 1 week before administration of the first dose of study treatment, and who have
had no complications from a thromboembolic event or the anticoagulation regimen.
16. Uncontrolled or poorly controlled hypertension, as defined by a sustained blood pressure
> 140/90 mm Hg on more than three antihypertensives.
Note: Blood pressure medication may not be started nor changed within the 14 days
prior to randomization.
17. Stroke (including transient ischemic attack), myocardial infarction, or other ischemic
event or thromboembolic event (eg, deep venous thrombosis, pulmonary embolism
[DVT/PE]) within 6 months before randomization. Patients with a diagnosis of DVT/PE
within 6 months are allowed if stable and treated with LMWH for at least 3 weeks before
randomization.
18. Gastrointestinal (GI) disorders, including those associated with a high risk of perforation
or fistula formation:
a. 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.
b. Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal abscess
within 6 months before administration of the first dose of study treatment.
Note: Complete healing of an intra-abdominal abscess must be confirmed before
administration of the first dose of study treatment.
19. 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 administration of the first dose of study treatment.
20. Tumor invading or encasing any major blood vessels.
21. Other clinically significant disorders such as:
a. Serious non-healing wound/ulcer/bone fracture.
22. Moderate to severe hepatic impairment (Child-Pugh B or C).
23. Requirement for hemodialysis or peritoneal dialysis
24. History of solid organ transplantation.
25. History of osteonecrosis of the jaw (ONJ).
Note: Caution should be used in patients receiving agents associated with ONJ, such as
bisphosphonates.
26. History of aneurysm bleeds.
27. Clinically significant toxicities related to any prior anticancer treatment, or toxicities
Grade ≥ 3 per National Cancer Institute Common Terminology Criteria for Adverse
Events, version 5.0 (NCI CTCAE v5.0) regardless of relatedness to prior anticancer
therapies. Clinically nonsignificant toxicities are allowed if a patient’s AE(s) are stable
on supportive therapy (excluding prohibited therapies; Section 7.3.2), or they have
resolved to baseline or Grade ≤ 2.
28. Any condition(s), disease(s), clinical examination or laboratory finding(s) not previously
mentioned that would contraindicate the study treatments, impose a high risk of treatment
complications for the patient, or obscure the interpretation of toxicity attribution of AEs
to the study drugs.
29. Received any of the prohibited therapies (Section 7.3.2) within the last 14 days, or within
the time specified in Section 7.3.2, prior to randomization
Please refer to the protocol for the section references.