Study of XL092 + Atezolizumab vs Regorafenib in Subjects With Metastatic Colorectal Cancer (STELLAR-303)

Phase 1

Conditions: Metastatic colorectal cancer (CRC)
MedDRA version: 21.0Level: LLTClassification code 10052362Term: Metastatic colorectal cancerSystem Organ Class: 100000004864
Therapeutic area: Diseases [C] - Cancer [C04]

Registration Number: EUCTR2021-003243-21-PT

Lead Sponsor: Exelixis, Inc.

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 600

Inclusion Criteria

1. Subjects with histologically or cytologically confirmed adenocarcinoma of the colon or rectum
a. Documented RAS status (mutant or wild-type [WT]), by tissue-based analysis
Note: Local RAS testing is permitted but must include testing for KRAS/NRAS exons 2, 3, and 4. After randomization of 400 subjects with RAS WT disease, subjects with RAS WT disease will not be eligible. After randomization of 200 subjects with RAS mutant disease, subjects with RAS mutant disease will not be eligible.
b.Documented NOT to have microsatellite instability-high (MSI-high) or mismatch repair deficient (dMMR) CRC by tissue-based analysis by an accredited laboratory
2.Has received the following SOC anticancer therapies as prior therapy for metastatic CRC and has radiographically progressed, is refractory or intolerant to these therapies.
a. Systemic SOC anticancer therapy must include ALL of the following agents if approved and available in the country where the subject is randomized:
i. Fluoropyrimidine, irinotecan and oxaliplatin, with or without an anti-vascular endothelial growth factor (VEGF) monoclonal antibody (eg, bevacizumab)
ii. Anti-epidermal growth factor receptor (EGFR) monoclonal antibody (eg, cetuximab or panitumumab) for RAS WT subjects
iii. BRAF inhibitor for subjects with known BRAF V600E mutations
b. Radiographic progression during treatment with or within 3 months following the last dose of the most recent approved SOC chemotherapy regimen
3. Measurable disease according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1; ) as determined by the Investigator.
4. Available archival tumor biopsy material. If archival tissue is unavailable, must provide fresh tumor tissue biopsy prior to randomization.
5. Recovery to baseline or = Grade 1 severity (CTCAE v5) from AEs related to any prior treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive therapy.
6. Age 18 years or older on the day of consent.
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
8. Adequate organ and marrow function, based upon meeting all of the following laboratory criteria within 10 days before randomization:
a. Absolute neutrophil count (ANC) = 1500/mm3 (= 1.5 109/L) without granulocyte colony-stimulating factor support within 2 weeks before screening laboratory sample collection.
b. Platelets = 100,000/mm3 (= 100 109/L) without transfusion within 2 weeks before screening laboratory sample collection.
c. Hemoglobin = 9 g/dL (= 90 g/L) without transfusion within 2 weeks prior to screening laboratory sample collection.
d. International Normalized Ratio (INR) = 1.5 and activated partial thromboplastin time (aPTT) = 1.2 × upper limit of normal (ULN).
e. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) = 3 × ULN.
f. Albumin = 3.0 g/dL.
g. Lipase and amylase = 1.5 × ULN.
h. Total bilirubin = 1.5 × ULN (for subjects with Gilbert’s disease = 3 × ULN).
i. Calculated creatinine clearance = 40 mL/min (= 0.67 mL/sec) using the Cockcroft-Gault equation.
j. Urine protein-to-creatinine ratio (UPCR) = 1 mg/mg (=113.1 mg/mmol).
k. Negative hepatitis B surface antigen (HBsAg) test.
l. Negative hepatitis C virus (HCV) antibody test, or positive HCV antibody test followed by a negative HCV RNA test and no ongoing anti-HCV therapy.
Note: The HCV RNA test will be performed only for subjects who have a positive HCV antibody test.
9. Capable of understanding and comply

Exclusion Criteria

1. Prior treatment with XL092, regorafenib, trifluridine/tipiracil, or PD-L1/PD-1 targeting immune checkpoint inhibitors (ICIs).
2. Receipt of a small molecule kinase inhibitor (including investigational agents) within 2 weeks before randomization.
3. Receipt of any type of anticancer antibody therapy, systemic chemotherapy, or hormonal anti-cancer therapy within 3 weeks (or bevacizumab within 4 weeks) before randomization.
4. Radiation therapy for bone metastasis within 2 weeks, any other radiation therapy within 4 weeks before randomization. Subjects with clinically relevant ongoing complications from prior radiation therapy are not eligible.
5. Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks before randomization.
6. Concomitant anticoagulation with oral anticoagulants (eg, warfarin, direct thrombin and Factor Xa inhibitors) and platelet inhibitors (eg, clopidogrel).
7. The subject has uncontrolled, significant intercurrent or recent illness including, but not
limited to, the following conditions:
a. Cardiovascular disorders:
i. Congestive heart failure New York Heart Association class 2 or higher, unstable angina pectoris, new-onset angina, unstable angina pectoris, serious cardiac arrhythmias (eg, ventricular flutter, ventricular fibrillation, Torsades de pointes).
ii. Uncontrolled hypertension defined as sustained blood pressure (BP) > 140 mm Hg systolic or 90 mm Hg diastolic despite optimal antihypertensive treatment.
iii. Stroke (including transient ischemic attack [TIA]), myocardial infarction, pulmonary embolism (PE), prior clinically significant venous or other arterial ischemic event within 6 months before randomization.
iv. Deep vein thrombosis (DVT) within 3 months prior to randomization unless stable, asymptomatic, and treated with therapeutic anticoagulation for at least 4 weeks before randomization.
b. Gastrointestinal (GI) disorders including those associated with a high risk of perforation or fistula formation:
i. Tumors invading the GI-tract from external viscera.
ii. Active peptic ulcer disease, inflammatory bowel disease, diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, or acute pancreatitis.
iii. Acute obstruction of the bowel, gastric outlet, or pancreatic or biliary duct within 6 months before randomization unless cause of obstruction is definitively managed and subject is asymptomatic.
iv. Abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months before randomization.
v. Ascites, pleural effusion or pericardial fluid requiring drainage in last 4 weeks.
c. Clinically significant hematuria, hematemesis, or hemoptysis of > 0.5 teaspoon (2.5 mL) of red blood, or other history of significant bleeding (eg, gastrointestinal or pulmonary hemorrhage) within 12 weeks before randomization.
d. Cavitating pulmonary lesion(s) or known endobronchial disease manifestation.
e. Lesions invading major blood vessels including, but not limited to, inferior vena cava, pulmonary artery, or aorta.
f. Other clinically significant disorders, see protocol
8. Major surgery (eg, GI surgery, removal or biopsy of brain metastasis) within 4 weeks prior to randomization. Complete wound healing from major or minor surgery must have occurred at least prior to randomization.
9. Corrected QT interval calculated by the Fridericia formula (QTcF) > 460 ms

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: • Efficacy<br>Primary: efficacy in RAS wild type (WT) subjects<br>Other: efficacy in all subjects, efficacy in RAS mutant subjects<br>• Safety: safety and tolerability<br>• Other: characterize PK, immunogenicity of atezolizumab, quality of life, biomarkers, and healthcare utilization<br>;Secondary Objective: None;Primary end point(s): Duration of OS ;Timepoint(s) of evaluation of this end point: The time from randomization to death due to any cause, in RAS WT subjects.

Secondary Outcome Measures

Name	Time	Method

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