| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic colorectal cancer (CRC) |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10052362 |
| E.1.2 | Term | Metastatic colorectal cancer |
| E.1.2 | System Organ Class | 100000004864 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
• Efficacy
Primary: efficacy in RAS wild type (WT) subjects
Other: efficacy in all subjects, efficacy in RAS mutant subjects
• Safety: safety and tolerability
• Other: characterize PK, immunogenicity of atezolizumab, quality of life, biomarkers, and healthcare utilization
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| E.2.2 | Secondary objectives of the trial |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 complying with the protocol requirements and must have signed the informed consent document.
10. Sexually active fertile subjects and their partners must agree to use highly effective methods of contraception during the course of the study and for the following durations after the last dose of treatment (whichever is later):
• Through 186 days after the last dose of XL092 for women of childbearing potential (WOCBP) or through 96 days after the last dose of XL092 for men,
• Through 5 months after the last dose of atezolizumab (for both WOCBP and men), or
• Through 2 months after the last dose of regorafenib (for both WOCBP and men).
An additional contraceptive method, such as a barrier method (eg, condom), is required.
11. Female subjects of childbearing potential must not be pregnant at screening. Female subjects are considered to be of childbearing potential unless one of the following criteria is met: permanent sterilization (hysterectomy, bilateral salpingectomy, or bilateral oophorectomy) or documented postmenopausal status (defined as 12 months of amenorrhea in a woman > 45 years-of-age in the absence of other biological or physiological causes. In addition, females < 55 years-of-age must have a serum follicle stimulating hormone [FSH] level > 40 mIU/mL to confirm menopause).
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| E.4 | Principal 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 within 10 days before randomization per electrocardiogram (ECG) before randomization (see Section 5.6.4 for Fridericia formula).
10. History of psychiatric illness likely to interfere with ability to comply with protocol requirements or give informed consent.
11. Pregnant or lactating females.
12. Inability to swallow study treatment formulation, inability to receive IV administration. or presence of GI condition that might affect the absorption of study drug (eg, PEG tube).
13. Previously identified allergy or hypersensitivity to components of the study treatment
formulations.
14. Any other active malignancy or diagnosis of another malignancy within 2 years before randomization, except for superficial skin cancers, or localized, low-grade tumors deemed cured and not treated with systemic therapy. Incidentally diagnosed prostate cancer is allowed if assessed as stage ≤ T2N0M0 and Gleason score ≤ 6.
15. Administration of a live, attenuated vaccine within 30 days before randomization. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The time from randomization to death due to any cause, in RAS WT subjects. |
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| E.5.2 | Secondary end point(s) |
Additional Efficacy Endpoints
• Duration of progression-free survival (PFS) as assessed by the Investigator per RECIST 1.1
• Objective response rate (ORR) as assessed by the Investigator per RECIST 1.1
• Duration of response (DOR) as assessed by the Investigator per RECIST 1.1
• Change in tumor markers from baseline
2.1.2. Endpoints Supporting Safety Objectives
• Evaluation of AEs, including adverse events of special interest (AESIs) and SAEs
• Change in laboratory parameters and vital signs
2.1.3. Endpoints Supporting Other Objectives
• Change in mobility, self-care, usual activities, pain/discomfort, and anxiety/depression, and global health as assessed by the European Organization for the Research and Treatment of Cancer (EORTC) QLQ-C30, EORTC QLQ-CR29, and EQ-5D-5L measures
• Change in tumor status by circulating tumor DNA (ctDNA)
• Correlation of biomarker analyses with clinical outcomes
• Plasma concentration of XL092 given in combination with atezolizumab
• Serum concentration of atezolizumab given in combination with XL092
• The incidence of antidrug antibody (ADA) response against atezolizumab given in combination with XL092
• Hospital ER visits, hospital admissions, and/or ICU admissions
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 49 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Canada |
| Hong Kong |
| Korea, Republic of |
| New Zealand |
| Singapore |
| Taiwan |
| Thailand |
| United States |
| France |
| Poland |
| Spain |
| Czechia |
| Germany |
| Belgium |
| Hungary |
| Portugal |
| United Kingdom |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| End of trial is defined as the later of two dates: the date of the last visit or procedure for the last subject remaining on treatment or the date at which the last data point required for follow-up for the last subject is obtained. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 11 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
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