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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how combinations of two drugs—everolimus (also known as Afinitor, Votubia, or Zortress), bevacizumab (also known as Avastin), or pazopanib (also known as Votrient or pazopanib hydrochloride)—affect metastatic kidney cancer that has spread to other parts of the body. Researchers test different pairs to determine which is most effective and safest for treating this type of cancer. This study targets individuals who have undergone kidney cancer surgery and have a clear cell type of metastatic kidney cancer. Participants should not have received certain prior cancer treatments but may have had immunotherapy, such as vaccines. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

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.

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

Research shows that the drug combinations tested in this trial have been studied for safety before. Studies indicate that the bevacizumab and everolimus combination has been used to treat kidney cancer, with some patients experiencing manageable side effects, such as tiredness and mouth sores.

Earlier studies suggest that the pazopanib and bevacizumab mix is generally well-tolerated. Patients reported side effects like high blood pressure and tiredness, but these were usually not severe.

The combination of pazopanib and everolimus has also undergone testing. Findings suggest that patients handled this combo fairly well, with common side effects like diarrhea and changes in liver function.

Overall, these treatments have shown potential for safety, but side effects are possible. It is important to consult a doctor to understand what these might mean for individual cases. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these drug combinations for kidney cancer because they explore innovative ways to inhibit tumor growth through multiple pathways. Unlike traditional treatments that often focus on a single target, these combinations, such as Bevacizumab paired with Everolimus or Pazopanib, aim to simultaneously block blood vessel formation and disrupt cancer cell proliferation and survival. This multi-targeted approach holds promise for overcoming resistance to standard therapies like sunitinib or sorafenib, potentially leading to more effective and durable responses in patients.

What evidence suggests that this trial's drug combinations could be effective for metastatic kidney cancer?

This trial will evaluate various drug combinations for treating advanced kidney cancer. Participants in different arms may receive combinations such as bevacizumab with everolimus, which research has shown to be effective and generally well-tolerated. Another arm will explore pazopanib combined with bevacizumab, which studies have shown to yield promising results, with more than half of the patients responding well and many experiencing stable disease. Pazopanib alone has proven more effective than a placebo, significantly extending the time patients live without disease progression. Additionally, the combination of pazopanib with everolimus is under investigation, as it has shown noticeable improvements in overall survival rates for patients with advanced kidney cancer. These findings highlight the potential of these drug combinations in effectively managing metastatic kidney cancer. ^{2 6 7 8 9}

Who Is on the Research Team?

Amado Zurita, MD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

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

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

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

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

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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]

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]

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, 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]

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]

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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/20368560/

Phase II trial of bevacizumab and everolimus in patients ... Conclusion: Bevacizumab/everolimus is active and well tolerated in the treatment of advanced clear cell renal cancer, either as first-line ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/32975815/

Everolimus plus bevacizumab is an effective first ... - PubMed Everolimus plus bevacizumab is an effective first-line treatment for patients with advanced papillary variant renal cell carcinoma: Final results from a phase ...

3. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1558767312002418

A Phase II Study of Bevacizumab and Everolimus as ... Lenvatinib plus everolimus and lenvatinib alone resulted in a progression-free survival benefit for patients with metastatic renal cell carcinoma who have ...

4. acsjournals.onlinelibrary.wiley.com acsjournals.onlinelibrary.wiley.com/doi/full/10.1002/cncr.33148

Everolimus plus bevacizumab is an effective first‐line ... The combination of everolimus plus bevacizumab demonstrates robust activity in patients who have papillary variant renal cell carcinoma.

5. clinicaltrials.gov clinicaltrials.gov/study/NCT00651482

Treatment of Refractory Metastatic Renal Cell Carcinoma ... To determine the safety and efficacy of the combination of bevacizumab and everolimus (RAD001) for the treatment of metastatic renal cell cancer.

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/25851632/

phase II randomized study of everolimus and bevacizumab ... The open-label, phase II RECORD-2 trial compared efficacy and safety of first-line everolimus plus bevacizumab (EVE/BEV) with interferon plus bevacizumab (IFN/ ...

7. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/25456838/

Results From the European AVATOR Study At the time of data analysis, 15 patients (36%) were still receiving everolimus, 40% had stopped because of progressive disease, and 24% had discontinued ...

8. clinicaltrials.gov clinicaltrials.gov/study/NCT00651482

Treatment of Refractory Metastatic Renal Cell Carcinoma ... To determine the safety and efficacy of the combination of bevacizumab and everolimus (RAD001) for the treatment of metastatic renal cell cancer.

9. annalsofoncology.org annalsofoncology.org/article/S0923-7534(19)34495-3/fulltext

RECORD-2: phase II randomized study of everolimus and ... The open-label, phase II RECORD-2 trial compared efficacy and safety of first-line everolimus plus bevacizumab (EVE/BEV) with interferon plus bevacizumab ...