Drug Combinations for Kidney Cancer

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must be taking: Lipid lowering

Must not be taking: Rifampin, St. John's wort

Disqualifiers: Active malignancy, Brain metastases, Cardiovascular disease, others

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

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: 4

Duration: Variable, as long as the doctor thinks it is in the participant's best interest

180 Participants Needed

Trial Summary

What is the purpose of this trial?

The goal of this clinical research study is to compare 6 different 2-drug "sequences" of everolimus, bevacizumab, or pazopanib to learn how they may affect metastatic kidney cancer. For the 2-drug sequence, participants will receive 1 of these drugs and may start taking another of these drugs after that. Researchers will also study the safety of these 2-drug sequences.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot take certain drugs like rifampin, St. John's wort, or specific antiepileptic drugs during the study. It's best to discuss your current medications with the trial team.

What data supports the effectiveness of the drug combinations for kidney cancer?

Research shows that pazopanib, a drug used in the combination, is effective in treating advanced kidney cancer by targeting specific proteins involved in cancer growth. Additionally, everolimus, another drug in the combination, has shown benefits in patients with advanced kidney cancer. ^{1 2 3 4 5}

Is the drug combination including Pazopanib safe for humans?

Pazopanib, also known as Votrient, is generally well tolerated in humans, but it can cause side effects like abnormal liver function tests and potential drug interactions. It is important to monitor for these side effects during treatment. ^{1 3 6 7 8}

How is the drug combination of Bevacizumab, Everolimus, and Pazopanib unique for kidney cancer?

This drug combination is unique because it combines Bevacizumab, which inhibits blood vessel growth in tumors, with Everolimus, an mTOR inhibitor that blocks cancer cell growth, and Pazopanib, a multikinase inhibitor targeting several pathways involved in cancer progression. This multi-targeted approach may offer a broader attack on kidney cancer compared to single-agent therapies. ^{1 4 9 10 11}

Research Team

Amado Zurita, MD

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

Adults with metastatic renal cell carcinoma (RCC) that includes a clear cell component, who have had surgery or certain other treatments for their primary tumor. They must be able to swallow pills, not have received targeted therapy or chemotherapy for mRCC (though prior immunotherapy is okay), and agree to use birth control. People with active infections, another cancer treatment ongoing, significant heart issues, uncontrolled hypertension or diabetes, severe liver disease, brain metastases (except controlled solitary ones), coagulation disorders on certain anticoagulants are excluded.

Inclusion Criteria

Patients must give written informed consent prior to initiation of study-related procedures. Patients with a history of major psychiatric illness must be judged able to fully understand the investigational nature of the study and the risks associated with the therapy

I can swallow pills.

Patients of child fathering or childbearing potential must agree to practice a form of medically acceptable birth control while on study

Exclusion Criteria

Your diabetes is not well managed, as shown by high fasting blood sugar levels.

I am not allergic to bevacizumab, pazopanib, or everolimus.

I am not planning to take any experimental drugs but can take bisphosphonates while in this study.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive one of the study drugs (everolimus, bevacizumab, or pazopanib) and may switch to another drug if the disease progresses.

Variable, as long as the doctor thinks it is in the participant's best interest

Weekly visits for the first 4 weeks, then every 4 weeks, with additional tests every 8 weeks

End-of-Treatment

Participants undergo a final assessment after completing the study drug regimen.

Long-Term Follow-Up

Participants are monitored for safety and effectiveness after treatment completion, with follow-ups every 3 months for the first 2 years, every 6 months for the third year, and annually thereafter.

5 years

Treatment Details

Interventions

• Bevacizumab
• Everolimus
• Pazopanib

Trial Overview The START trial is testing six different combinations of the drugs everolimus, bevacizumab, and pazopanib in sequences to see which works best against metastatic kidney cancer. Participants will start with one drug and may switch to another as part of the sequence while researchers monitor safety and effectiveness.

Participant Groups

Group I: Group 6 Experimental Treatment 2 Interventions

Bevacizumab + possible Everolimus

Group II: Group 5 Experimental Treatment 1 Intervention

Bevacizumab + possible Pazopanib

Group III: Group 4 Experimental Treatment 2 Interventions

Everolimus + possible Pazopanib

Group IV: Group 3 Experimental Treatment 2 Interventions

Everolimus + possible Bevacizumab

Group V: Group 2 Experimental Treatment 2 Interventions

Pazopanib + possible Everolimus

Group VI: Group 1 Experimental Treatment 2 Interventions

Pazopanib + possible Bevacizumab

Bevacizumab is already approved in European Union, United States, Japan, Canada for the following indications:

Approved in European Union as Avastin for:

• Colorectal cancer
• Breast cancer
• Non-small cell lung cancer
• Renal cell carcinoma
• Ovarian cancer

Approved in United States as Avastin for:

• Colorectal cancer
• Non-small cell lung cancer
• Glioblastoma
• Renal cell carcinoma
• Cervical cancer
• Ovarian cancer

Approved in Japan as Avastin for:

• Colorectal cancer
• Non-small cell lung cancer
• Breast cancer
• Renal cell carcinoma
• Ovarian cancer

Approved in Canada as Avastin for:

• Colorectal cancer
• Non-small cell lung cancer
• Breast cancer
• Renal cell carcinoma
• Ovarian cancer

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Novartis

Industry Sponsor

Trials

1,646

Recruited

2,778,000+

Vasant Narasimhan

Novartis

Chief Executive Officer since 2018

MD from Harvard Medical School, Bachelor's in Biological Sciences from University of Chicago, Master's in Public Policy from John F. Kennedy School of Government

Shreeram Aradhye

Novartis

Chief Medical Officer since 2022

MD from Yale University, MSc in Clinical Epidemiology from University of Pennsylvania

Findings from Research

Pazopanib, a multikinase inhibitor, was approved by the US FDA in October 2009 for treating advanced renal cell carcinoma, highlighting its significance in cancer therapy.

The drug targets vascular endothelial growth factor receptors, which play a crucial role in tumor growth and blood vessel formation, making it an effective option for managing this type of kidney cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pazopanib. Bukowski, RM., Yasothan, U., Kirkpatrick, P.[2021]

In a study of 143 patients with advanced renal cell carcinoma (RCC), over 50% of patients remained on pazopanib therapy for nearly 4 months, demonstrating high persistence and compliance across both treatment-naïve and previously treated groups.

Younger age and higher comorbidity were identified as strong predictors of better persistence and compliance with pazopanib treatment, suggesting that these factors may influence treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Persistence and compliance with pazopanib in patients with advanced renal cell carcinoma within a U.S. administrative claims database. Hackshaw, MD., Nagar, SP., Parks, DC., et al.[2023]

Pazopanib is an FDA-approved multi-kinase inhibitor effective in treating advanced renal cell carcinoma (RCC), showing significant clinical activity in metastatic cases.

The drug not only targets VEGF receptors but also affects other receptors, which contributes to its side-effect profile, indicating a broader mechanism of action beyond just inhibiting VEGF.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pazopanib and anti-VEGF therapy. Drabkin, HA.[2021]

Axitinib demonstrated superior progression-free survival (PFS) compared to pazopanib and sorafenib in patients with metastatic renal cell carcinoma (mRCC), based on an analysis of four randomized controlled trials involving second-line therapies.

While axitinib was more effective in prolonging PFS, it also carried a higher risk of side effects such as fatigue and stomatitis, highlighting the need to balance efficacy with safety in treatment choices.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Small molecule targeted therapies for the second-line treatment for metastatic renal cell carcinoma: a systematic review and indirect comparison of safety and efficacy. Dranitsaris, G., Schmitz, S., Broom, RJ.[2021]

Pazopanib is a potent pan-VEGF inhibitor that has shown clinical efficacy in treating metastatic renal cell carcinoma, leading to its recent FDA approval.

In a Phase III clinical trial, pazopanib demonstrated similar effectiveness to other approved treatments but exhibited different toxicity profiles, which may help differentiate it from other VEGFR inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pazopanib: therapeutic developments. Limvorasak, S., Posadas, EM.[2021]

Pazopanib is an effective treatment for advanced renal cell carcinoma, showing significantly better progression-free survival and objective response rates compared to placebo, and is noninferior to sunitinib in terms of efficacy.

Patients preferred pazopanib over sunitinib primarily due to its better tolerability and quality of life outcomes, despite pazopanib causing more abnormal liver function tests.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pazopanib: a review of its use in the management of advanced renal cell carcinoma. McCormack, PL.[2021]

References

1. England pubmed.ncbi.nlm.nih.gov

Pazopanib. [2021]

2. United States pubmed.ncbi.nlm.nih.gov

Persistence and compliance with pazopanib in patients with advanced renal cell carcinoma within a U.S. administrative claims database. [2023]

3. New Zealand pubmed.ncbi.nlm.nih.gov

Pazopanib and anti-VEGF therapy. [2021]

4. United States pubmed.ncbi.nlm.nih.gov

A Single-Arm Phase 1b Study of Everolimus and Sunitinib in Patients With Advanced Renal Cell Carcinoma. [2020]

5. Germany pubmed.ncbi.nlm.nih.gov

Small molecule targeted therapies for the second-line treatment for metastatic renal cell carcinoma: a systematic review and indirect comparison of safety and efficacy. [2021]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Pazopanib and Statin-Induced Rhabdomyolysis. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Pazopanib: therapeutic developments. [2021]

8. New Zealand pubmed.ncbi.nlm.nih.gov

Pazopanib: a review of its use in the management of advanced renal cell carcinoma. [2021]

9. England pubmed.ncbi.nlm.nih.gov

Bevacizumab in combination with IFN-α in metastatic renal cell carcinoma: the AVOREN trial. [2015]

10. Netherlands pubmed.ncbi.nlm.nih.gov

First-line antiangiogenics for metastatic renal cell carcinoma: A systematic review and network meta-analysis. [2022]

11. New Zealand pubmed.ncbi.nlm.nih.gov

Indirect treatment comparison of bevacizumab + interferon-α-2a vs tyrosine kinase inhibitors in first-line metastatic renal cell carcinoma therapy. [2023]