XL092 + Atezolizumab vs Regorafenib for Colorectal Cancer

(STELLAR-303 Trial)

Not currently recruiting at 166 trial locations

Overseen By Backup or International

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Exelixis

Must not be taking: Corticosteroids, Immunosuppressives, Kinase inhibitors, others

Disqualifiers: Brain metastases, Uncontrolled illness, Pregnancy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 36 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests new treatments for individuals with advanced colon or rectal cancer that no longer responds to standard therapies. It compares two options: a combination of XL092 (an experimental treatment) and atezolizumab (Tecentriq) versus regorafenib (Stivarga), which is already used for this cancer type. Participants should have colorectal cancer that has spread and lack certain genetic markers (MSS/MSI-low type) that respond differently to treatments. Those who have not responded to typical cancer treatments, or cannot tolerate them, might be suitable candidates. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants access to potentially groundbreaking treatments.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications before participating. Specifically, you must not have taken a small molecule kinase inhibitor within 2 weeks, anticancer antibody therapy or systemic chemotherapy within 3 weeks, or bevacizumab within 4 weeks before joining the trial.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that the combination of XL092 (zanzalintinib) and atezolizumab is generally well-tolerated by patients with advanced colorectal cancer. Studies have found that this combination can improve survival rates compared to regorafenib, another treatment option. The results regarding its efficacy and safety are encouraging. Patients experienced manageable side effects, suggesting it might be a safe choice for those who have tried other treatments.

Regorafenib, already approved for use in certain cancers, has a well-known safety profile. Common side effects include tiredness and skin reactions on the hands and feet, but these can usually be managed with proper care.

Overall, previous studies have shown that both treatment options in this trial are well-tolerated. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about XL092 combined with atezolizumab because it offers a new approach to treating metastatic colorectal cancer (mCRC). Unlike traditional treatments like regorafenib, which targets cancer growth through inhibiting certain proteins, XL092 works as a tyrosine kinase inhibitor, potentially disrupting multiple pathways that cancer cells use to grow and spread. Atezolizumab, on the other hand, is an immunotherapy that helps the immune system recognize and attack cancer cells. This combination could provide a more comprehensive attack on cancer by both directly inhibiting tumor growth and enhancing the body's natural defenses.

What evidence suggests that this trial's treatments could be effective for metastatic colorectal cancer?

Research shows that the combination of XL092 and atezolizumab, administered to participants in one arm of this trial, may effectively treat advanced colorectal cancer that has spread. Studies have found that this combination can significantly improve survival rates, particularly for patients with microsatellite stable/microsatellite instability low (MSS/MSI-low) tumors. Atezolizumab boosts the body's immune response against cancer cells, while XL092 targets the pathways cancer cells use to grow. This approach could lead to better outcomes for patients who have already tried standard treatments. Meanwhile, another arm of this trial evaluates the effectiveness of regorafenib as an active comparator. ^{2 4 5 6 7}

Who Is on the Research Team?

Medical Director

Principal Investigator

Exelixis

Are You a Good Fit for This Trial?

Adults with metastatic colorectal cancer that's not highly unstable at the genetic level (MSS/MSI-low) can join if they've had progression after standard treatments. They need a confirmed diagnosis, RAS status known, and must have recovered from previous treatment side effects to a mild level. They should be relatively fit (ECOG 0-1), have measurable disease, and provide tumor biopsy material.

Inclusion Criteria

My cancer has worsened during or within 4 months after my last standard chemotherapy.

Measurable disease according to RECIST v1.1 as determined by the Investigator

I can provide a sample of my tumor, either from previous or new biopsies.

Exclusion Criteria

I haven't taken any cancer-targeting pill treatments in the last 2 weeks.

I haven't had cancer treatments like chemotherapy or hormone therapy in the last 3 weeks.

My brain metastases have been treated and stable for over 4 weeks.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either XL092 + atezolizumab or regorafenib

Up to 36 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 36 months

What Are the Treatments Tested in This Trial?

Interventions

• Atezolizumab
• Regorafenib
• XL092

Trial Overview The trial is testing XL092 in combination with Atezolizumab against Regorafenib alone in patients whose colorectal cancer has worsened despite standard care. It's randomized and open-label, meaning participants know which treatment they're getting.

How Is the Trial Designed?

Group I: XL092 + Atezolizumab Experimental Treatment 2 Interventions

Participants with mCRC will receive XL092 + atezolizumab.

Group II: Regorafenib Active Control 1 Intervention

Participants with mCRC will receive active comparator of regorafenib.

Atezolizumab is already approved in United States, European Union for the following indications:

Approved in United States as Tecentriq for:

• Melanoma
• Hepatocellular carcinoma
• Small cell lung cancer
• Non-small cell lung cancer
• Urothelial carcinoma

Approved in European Union as Tecentriq for:

• Melanoma
• Hepatocellular carcinoma
• Small cell lung cancer
• Non-small cell lung cancer
• Urothelial carcinoma

Who Is Running the Clinical Trial?

Exelixis

Lead Sponsor

Trials

126

Recruited

20,500+

Michael M. Morrissey

Exelixis

Chief Executive Officer since 2010

PhD in Chemistry from Harvard University, BSc in Chemistry from the University of Wisconsin

Vicki L. Goodman

Exelixis

Chief Medical Officer since 2022

MD

Published Research Related to This Trial

Regorafenib significantly improves overall survival by up to 2.5 months and progression-free survival by up to 1.5 months in patients with metastatic colorectal cancer (mCRC) who have not responded to standard therapies, based on phase 3 studies.

The treatment is generally well-tolerated, with most side effects being mild to moderate, and it does not negatively impact health-related quality of life compared to placebo.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regorafenib: A Review in Metastatic Colorectal Cancer. Dhillon, S.[2019]

Regorafenib significantly improves median overall survival and progression-free survival in patients with previously treated metastatic colorectal cancer (mCRC), as shown in the CORRECT trial with a regimen of 160 mg daily for 3 weeks of each 4-week cycle.

The drug has a generally acceptable tolerability profile and does not compromise health-related quality of life, making it a valuable addition to treatment options for patients with progressive mCRC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regorafenib: a review of its use in previously treated patients with progressive metastatic colorectal cancer. Carter, NJ.[2021]

In a study involving patients with metastatic colorectal cancer, prophylactic oral dexamethasone (DEX) showed a trend towards reducing the incidence of grade ≥2 fatigue and malaise compared to placebo, with 19.4% in the DEX group versus 38.9% in the placebo group.

Although the overall incidence of fatigue and malaise was similar between the DEX and placebo groups, patient-reported outcomes indicated a significant reduction in fatigue with DEX, suggesting it may be clinically effective in managing regorafenib-related side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prophylactic Effect of Dexamethasone on Regorafenib-Related Fatigue and/or Malaise: A Randomized, Placebo-Controlled, Double-Blind Clinical Study in Patients with Unresectable Metastatic Colorectal Cancer (KSCC1402/HGCSG1402). Tanioka, H., Miyamoto, Y., Tsuji, A., et al.[2018]

Regorafenib is an FDA-approved oral medication that targets multiple kinases involved in cancer growth and has shown survival benefits in patients with metastatic colorectal cancer after standard treatments have failed.

In addition to colorectal cancer, regorafenib significantly improves progression-free survival in patients with metastatic gastrointestinal stromal tumors (GIST) and is currently being tested in various other cancers, including renal cell carcinoma and hepatocellular carcinoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regorafenib. Ettrich, TJ., Seufferlein, T.[2015]

Regorafenib is an effective oral multikinase inhibitor approved by the FDA for treating metastatic colorectal cancer in patients who have not responded to standard chemotherapy and other targeted therapies, showing significant efficacy compared to placebo in the CORRECT trial.

While regorafenib has a greater antiangiogenic effect than sorafenib, it is associated with common severe side effects such as hand-foot skin reactions, diarrhea, hypertension, and fatigue, which require careful management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management of regorafenib-related toxicities: a review. Krishnamoorthy, SK., Relias, V., Sebastian, S., et al.[2022]

A phase III study found that the combination of atezolizumab and cobimetinib did not show improved effectiveness compared to standard therapy (regorafenib) in patients with inoperable, locally advanced, or metastatic colorectal cancer.

The overall survival for patients receiving the combination treatment was 8.9 months, slightly higher than the 8.5 months for those on standard therapy, but the response rates were very similar at 2.7% for the combination versus 2.2% for regorafenib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Drug Duo Disappoints in Colorectal Cancer. [2019]

Regorafenib is an effective treatment for patients with metastatic colorectal cancer who have previously undergone multiple chemotherapy regimens, showing a significant improvement in overall survival compared to placebo (6.4 months vs 4 months).

The treatment is associated with manageable side effects, with the most common severe adverse events being hand-foot syndrome (17%) and asthenia (10%), indicating that while it is effective, monitoring for these side effects is important.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Regorafenib approved in Metastatic Colorectal cancer]. André, T., Dumont, SN.[2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05425940

NCT05425940 | Study of XL092 + Atezolizumab vs ... The primary purpose of this study is to evaluate XL092 + atezolizumab versus regorafenib in participants with microsatellite stable/microsatellite ...

2. targetedonc.com targetedonc.com/view/zanzalintinib-atezolizumab-improves-crc-survival-expands-tki-s-role-in-solid-tumors

Zanzalintinib/Atezolizumab Improves CRC Survival ... New trial results reveal zanzalintinib and atezolizumab significantly enhance survival in metastatic colorectal cancer, ...

3. onclive.com onclive.com/view/xl092-plus-atezolizumab-vs-regorafenib-under-investigation-in-mss-msi-low-mcrc

XL092 Plus Atezolizumab Vs Regorafenib Under ... The safety and efficacy of a combination regimen comprised of XL092 and atezolizumab (Tecentriq) is being compared with that of regorafenib ...

4. asco.org asco.org/abstracts-presentations/ABSTRACT391578

STELLAR-303: A phase 3 study of XL092 in combination ... Background: The prognosis of patients with mCRC is poor, with a 5-year survival rate of 14% (American Cancer Society 2020). Patients who have progressed ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11485978/

STELLAR-303: randomized phase III study of zanzalintinib ... Abstract. Most patients with metastatic colorectal cancer (mCRC) have limited treatment options following standard-of-care therapy.

6. onclive.com onclive.com/view/zanzalintinib-plus-atezolizumab-improves-os-in-previously-treated-metastatic-crc

Zanzalintinib Plus Atezolizumab Improves OS in ... - OncLive Zanzalintinib and atezolizumab combination improved OS and PFS compared to regorafenib in metastatic CRC patients, with a median OS of 10.9 ...

7. onclive.com onclive.com/view/zanzalintinib-plus-atezolizumab-boosts-os-in-previously-treated-non-msi-h-mcrc

Zanzalintinib Plus Atezolizumab Boosts OS in Previously ... Zanzalintinib and atezolizumab combination improved overall survival in non–MSI-H metastatic colorectal cancer compared to regorafenib. The ...