| 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 |
To evaluate the OS of XL092 + atezolizumab versus regorafenib in NLM subjects with MSS/MSI -low mCRC who have progressed during, after, or are intolerant to SOC therapy.
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| E.2.2 | Secondary objectives of the trial |
- To evaluate the OS of XL092 + atezolizumab versus regorafenib in all randomized subjects with MSS/MSI-low mCRC who have progressed
during, after, or are intolerant to SOC therapy.
- To evaluate the efficacy of XL092 + atezolizumab versus regorafenib in NLM subjects with MSS/MSI-low mCRC who have progressed during,
after, or are intolerant to SOC therapy.
- To evaluate the efficacy of XL092 + atezolizumab versus regorafenib in all randomized subjects with MSS/MSI-low mCRC who have progressed
during, after, or are intolerant to SOC therapy.
- To assess safety and tolerability of XL092 + atezolizumab versus regorafenib in all randomized subjects with MSS/MSI-low mCRC who
have progressed during, after, or are intolerant to SOC therapy.
- To characterize PK of XL092, its potential metabolites, and atezolizumab, and immunogenicity of atezolizumab in all randomized subjects with MSS/MSI-low mCRC who have progressed during, after, or
are intolerant to SOC therapy. |
|
| 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 only
- After randomization of 350 subjects without liver metastases, subjects without liver metastases will not be eligible
-After randomization of 524 subjects with liver metastases, subjects with liver metastases will not be eligible
b.Documented NOT to have microsatellite instability-high (MSI-high) or mismatch repair deficient (dMMR) CRC by tissue-based analysis
Testing for all 4 MMR genes (MLH1, MSH2, MSH6, and PMS2) is required
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.Prior investigational therapies are allowed
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 AST, and alkaline phosphatase (ALP) ≤ 3 × ULN. Note: For all subjects with documented liver metastases: ALT, AST, and ALP ≤ 5 x 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 at screening
l.Positive HBsAb test at screening, or negative HBsAb at screening accompanied by either of the following:Negative total HBcAB
-Positive total HBcAB test followed by a negative (per local lab definition) hepatitis B virus (HBV) DNA test
m.Negative 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.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 at least 186 days after the last dose of XL092 or regorafenib for WOCBP or through at least 96 days after the last dose of XL092 or regorafenib for men
•Through at least 150 days after the last dose of atezolizumab (for both WOCBP and men), or an additional contraceptive method, such as a barrier method (eg, condom), may be 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 consecutive amenorrhea in a female > 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 PDL1/PD-1 targeting 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. 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.
v.Ascites, pleural effusion or pericardial fluid requiring drainage in last weeks.
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.
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
i.Any active, known or suspected autoimmune disease
ii.Any active infection requiring systemic antimicrobial treatment.
iii.Known human immunodeficiency virus (HIV) infection with the exception of subjects meeting
all of the following criteria: (1) on stable anti-retroviral therapy; (2) CD4 count≥ 200/uL; and (3) an undetectable viral load.
iv. Active tuberculosis.
v. - xi. refer to the protocol.
7.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.
8. Systemic treatment with, or any condition requiring, either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days 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.
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) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The time from randomization to death due to any cause, in nlmITT
population |
|
| E.5.2 | Secondary end point(s) |
• OS
• PFS as assessed by the Investigator per RECIST 1.1
• ORR as assessed by the Investigator per RECIST 1.1
• DOR as assessed by the Investigator per RECIST 1.1
• Incidence and severity of AEs, SAEs and adverse events of special
interest (AESIs)
• 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 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | Yes |
| 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 | 3 |
| 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 |
| New Zealand |
| Singapore |
| Hong Kong |
| Taiwan |
| Australia |
| Canada |
| Korea, Republic of |
| Thailand |
| United Kingdom |
| United States |
| Belgium |
| Czechia |
| France |
| Germany |
| Hungary |
| Poland |
| Portugal |
| Spain |
|
| 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
|
| 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 | 6 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
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