Vandetanib + Everolimus for Advanced Cancer

Overseen By Vivek Subbiah, MD

Age: Any Age

Sex: Any

Trial Phase: Phase 1

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Antihistamines, Immunosuppressants

Disqualifiers: Uncontrolled illness, Pregnancy, Cardiac disease, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 28 days per cycle

153 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase I trial studies the side effects and best dose of vandetanib and everolimus when given together in treating patients with cancer that has spread to other places in the body. Vandetanib and everolimus may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you must be at least 3 weeks past your last chemotherapy and radiation treatments, and 5 half-lives or 3 weeks past any targeted or biologic therapy.

What data supports the effectiveness of the drug combination Vandetanib and Everolimus for advanced cancer?

Research suggests that combining Vandetanib, which targets specific proteins involved in cancer growth, with Everolimus, which blocks a pathway important for cancer cell survival, may enhance their ability to fight tumors. Additionally, Everolimus has shown benefits in treating advanced kidney cancer, providing a basis for its potential effectiveness in other advanced cancers. ^{1 2 3 4 5}

Is the combination of Vandetanib and Everolimus safe for humans?

The combination of Vandetanib and Everolimus has been studied for safety in patients with advanced solid tumors. Some patients experienced dose-limiting toxicities, which are side effects that prevent further dose increases, but the study determined a maximum tolerated dose and a recommended dose for further trials. ^{1 3 6 7 8}

How is the drug combination of Vandetanib and Everolimus unique for treating advanced cancer?

This drug combination is unique because Vandetanib targets multiple pathways involved in cancer growth, including VEGFR, EGFR, and RET, while Everolimus inhibits the mTOR pathway, potentially enhancing antitumor activity by affecting cancer cell growth and survival through different mechanisms. ^{1 3 8 9 10}

Research Team

Sarina Piha-Paul, MD

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

This trial is for patients with advanced or metastatic cancer that's resistant to standard therapy, relapsed, or without a survival-improving standard option. They must be weeks past prior treatments, have adequate organ/marrow function and agree to use contraception. Exclusions include certain heart conditions, uncontrolled illnesses, pregnancy/lactation, and hypersensitivity to the drugs tested.

Inclusion Criteria

It has been over 3 weeks since my last chemotherapy.

I agree to use effective birth control or practice abstinence.

My cancer does not respond to standard treatments, has come back, or there are no treatments that could extend my life by at least three months.

Exclusion Criteria

I have a slow heartbeat or heart failure that affects my daily life.

History of hypersensitivity to vandetanib, lactose, murine products, or any component of the formulation

Pregnant or lactating women

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive vandetanib and everolimus orally once daily on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

28 days per cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment completion.

14-28 days

Treatment Details

Interventions

• Everolimus
• Vandetanib

Trial Overview The study tests combining vandetanib and everolimus in patients with widespread cancer. It aims to find the safest dose while observing how these drugs might halt cancer cell growth by inhibiting key enzymes necessary for their proliferation.

Participant Groups

Group I: Treatment (vandetanib, everolimus) Experimental Treatment 4 Interventions

Patients receive vandetanib PO QD and everolimus PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

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

Approved in United States as Afinitor for:

• Advanced renal cell carcinoma
• Subependymal giant cell astrocytoma
• Progressive neuroendocrine tumors of pancreatic origin
• Advanced hormone receptor-positive, HER2-negative breast cancer
• Tuberous sclerosis complex-associated partial-onset seizures

Approved in European Union as Votubia for:

• Subependymal giant cell astrocytoma
• Renal angiomyolipoma
• Tuberous sclerosis complex-associated partial-onset seizures

Approved in United States as Zortress for:

• Prevention of organ rejection in kidney transplant patients

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

The combination of vandetanib (VAN) and everolimus (EV) was found to be safe and showed promising antitumor activity in a phase I trial involving 80 patients with advanced solid tumors, with a maximum tolerated dose of 300 mg for VAN and 10 mg for EV.

Out of the evaluable patients, 10% achieved a partial response and 51% had stable disease, with a median overall survival of 10.5 months, indicating that this combination therapy could be effective for patients with refractory solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and activity of vandetanib in combination with everolimus in patients with advanced solid tumors: a phase I study. Cascone, T., Sacks, RL., Subbiah, IM., et al.[2022]

Patients with advanced renal cell carcinoma treated with the combination of lenvatinib (LEN) and everolimus (EVE) experienced a significant improvement in quality-adjusted time without symptoms of disease progression or toxicity (Q-TWiST), gaining an average of 3.7 months compared to those receiving EVE alone.

The LEN+EVE combination resulted in a 24% relative gain in Q-TWiST, indicating a clinically important benefit in quality survival time for patients who had previously undergone antiangiogenic therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Quality-adjusted Time Without Symptoms or Toxicity (Q-TWiST) for Lenvatinib plus Everolimus Versus Everolimus Monotherapy in Patients with Advanced Renal Cell Carcinoma. Lee, CH., Wan, Y., Smith, A., et al.[2022]

The combination of everolimus and vatalanib (PTK/ZK) showed at least additive and potentially synergistic anti-tumor effects in a mouse model of melanoma, enhancing efficacy without increasing toxicity compared to either drug alone.

Pharmacokinetic studies revealed that vatalanib increased the plasma concentration of everolimus, but this interaction did not fully explain the enhanced anti-tumor activity, suggesting that the two drugs may work together through distinct mechanisms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Everolimus and PTK/ZK show synergistic growth inhibition in the orthotopic BL16/BL6 murine melanoma model. O'Reilly, T., Lane, HA., Wood, JM., et al.[2021]

In a study of 78 patients with metastatic renal cell carcinoma (mRCC) treated with everolimus, the median progression-free survival was 7 months, indicating a significant clinical benefit for patients who had previously failed VEGF-targeted therapies.

The treatment was generally well-tolerated, with serious adverse events occurring in only 6% of patients, primarily respiratory toxicity, suggesting that everolimus has a manageable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Metastatic renal cell carcinoma treated with everolimus--data from the RENIS Clinical Registry]. Büchler, T., Dusek, L., Fínek, J., et al.[2021]

Everolimus, an oral mTOR inhibitor, significantly improves progression-free survival in patients with clear cell renal cancer, increasing it from a median of 1.9 months to 4.9 months in a phase III trial with a hazard ratio of 0.33 (P < 0.001).

The treatment is generally well-tolerated, with mild to moderate side effects that can be managed, and it has been approved as a validated option for patients who have progressed on VEGFR inhibitors, with ongoing trials exploring its use in combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Everolimus: the first approved product for patients with advanced renal cell cancer after sunitinib and/or sorafenib. Coppin, C.[2021]

References

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

Safety and activity of vandetanib in combination with everolimus in patients with advanced solid tumors: a phase I study. [2022]

2. Netherlands pubmed.ncbi.nlm.nih.gov

Quality-adjusted Time Without Symptoms or Toxicity (Q-TWiST) for Lenvatinib plus Everolimus Versus Everolimus Monotherapy in Patients with Advanced Renal Cell Carcinoma. [2022]

3. Germany pubmed.ncbi.nlm.nih.gov

Everolimus and PTK/ZK show synergistic growth inhibition in the orthotopic BL16/BL6 murine melanoma model. [2021]

4. Czech Republic pubmed.ncbi.nlm.nih.gov

[Metastatic renal cell carcinoma treated with everolimus--data from the RENIS Clinical Registry]. [2021]

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

A Phase I Study of Safety, Pharmacokinetics, and Pharmacodynamics of Concurrent Everolimus and Buparlisib Treatment in Advanced Solid Tumors. [2021]

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

Risk of rash associated with vandetanib treatment in non-small-cell lung cancer patients: A meta-analysis of 9 randomized controlled trials. [2022]

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

Everolimus: the first approved product for patients with advanced renal cell cancer after sunitinib and/or sorafenib. [2021]

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

Phase I trial of vandetanib in combination with gemcitabine and capecitabine in patients with advanced solid tumors with an expanded cohort in pancreatic and biliary cancers. [2022]

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

Open-label phase I trial of vandetanib in combination with mFOLFOX6 in patients with advanced colorectal cancer. [2022]

10. England pubmed.ncbi.nlm.nih.gov

An open-label study of vandetanib with pemetrexed in patients with previously treated non-small-cell lung cancer. [2022]