Arcus_PEAK-1

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. 

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. 

Research Nurse: Natalie Leniewska (x3921) Natalie.Leniewska@lthtr.nhs.uk

Administrator: Aaisha Khan (x8475)