Drug Combination for Advanced Cancer

Age: Any Age

Sex: Any

Trial Phase: Phase 1

Sponsor: M.D. Anderson Cancer Center

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

249 Participants Needed

Trial Summary

What is the purpose of this trial?

The goal of this clinical research study is to find the highest tolerable dose of the combination vorinostat given in combination with either sirolimus, everolimus or temsirolimus that can be given to patients with advanced cancer. The safety of this drug combination will also be studied. The Study Drugs: Vorinostat is designed to prevent or slow down the growth of cancer cells by blocking proteins. Everolimus is designed to stop cells from dividing. This may stop or slow the growth or spread of cancer cells. Temsirolimus is designed to block a protein called mTOR (a protein that is thought to cause cancer cells to grow) inside the cancer cell. This may interfere with the growth or spread of cancer cells or possibly kill them. Sirolimus is designed to block a protein called mTOR inside the cancer cell. This may interfere with the growth or spread of cancer cells or possibly kill the cancer cells. This is an investigational study. Sirolimus is FDA approved and commercially available as an anti-rejection drug for kidney transplant recipients. Everolimus is FDA-approved and commercially available for the treatment of pancreatic neuroendocrine tumor, subependymal giant cell astrocytoma, and renal cell carcinoma. Temsirolimus is FDA approved and commercially available for the treatment of renal cell carcinoma. Vorinostat is FDA approved and commercially available for the treatment of cutaneous T-cell lymphoma. The combination of these drugs is investigational. Up to 249 patients will take part in this study. All will be enrolled at MD Anderson.

Do I need to stop taking my current medications to join the trial?

You may need to stop taking certain medications, especially if you are using drugs like phenytoin, carbamazepine, barbiturates, rifampin, phenobarbital, St. John's wort, cyclosporine, diltiazem, or ketoconazole. It's best to discuss your current medications with the trial team to see if any changes are needed.

What data supports the effectiveness of this drug combination for advanced cancer?

Everolimus, one of the drugs in the combination, has been shown to be effective in treating advanced renal cell carcinoma, with a study showing it increased progression-free survival from 1.9 to 4.9 months in patients whose disease had progressed on other treatments. ^{1 2 3 4 5}

Is the drug combination for advanced cancer safe for humans?

Everolimus, also known as Afinitor, has been tested in patients with advanced renal cell carcinoma and was generally well tolerated, with most side effects being mild to moderate. The most common serious side effects were mouth sores, tiredness, lung inflammation, and infections. ^{1 2 5 6 7}

What makes the drug combination Everolimus, Sirolimus, Temsirolimus, and Vorinostat unique for advanced cancer?

This drug combination is unique because it includes Everolimus, an oral inhibitor of the mTOR pathway, which has shown effectiveness in treating advanced cancers like renal cell carcinoma by preventing cancer cell growth and blood vessel formation. Everolimus is often used when other treatments have failed, and its combination with other drugs like Sirolimus, Temsirolimus, and Vorinostat may enhance its anti-cancer effects. ^{1 2 4 5 8}

Research Team

Filip Janku, MD

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

This trial is for adults with advanced cancers that haven't responded to standard treatments or have no standard treatment improving survival by three months. Participants need measurable disease, must not have had recent chemotherapy, and should have proper organ function. They must use effective contraception and cannot be pregnant or nursing.

Inclusion Criteria

I can care for myself but may not be able to do heavy physical work.

I haven't had chemotherapy or targeted therapy for at least three weeks.

I can have radiation for symptom relief and still join the trial if I have untreated cancer areas.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive vorinostat in combination with either sirolimus, everolimus, or temsirolimus in 28-day cycles to determine the maximum tolerated dose

28 days per cycle

Weekly visits for drug administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Expansion Phase

Participants with the tumor type most likely to respond receive the study drugs at the maximum tolerated dose

As long as benefitting

Treatment Details

Interventions

• Everolimus
• Sirolimus
• Temsirolimus
• Vorinostat

Trial Overview Researchers are testing the highest dose of Vorinostat combined with either Sirolimus, Everolimus, or Temsirolimus that patients can tolerate without severe side effects. These drugs aim to slow cancer growth by targeting specific proteins in cancer cells.

Participant Groups

Group I: Arm C: Vorinostat + Temsirolimus Experimental Treatment 2 Interventions

Escalation and Expansion Phase: Vorinostat dose 300 mg by mouth on Days 7 - 28. Rest of cycles: 300 mg by mouth on Days 1 - 28. Escalation Phase: Temsirolimus starting dose 12.5 mg by vein on Days 1, 8, 15, 22. Expansion Phase: MTD from Escalation Phase.

Group II: Arm B: Vorinostat + Everolimus Experimental Treatment 2 Interventions

Escalation and Expansion Phase: Vorinostat dose 300 mg by mouth on Days 7 - 28. Rest of cycles: 300 mg by mouth on Days 1 - 28. Escalation Phase: Everolimus starting dose 5 mg by mouth on Days 1 - 28. Expansion Phase: MTD from Escalation Phase.

Group III: Arm A: Vorinostat + Sirolimus Experimental Treatment 2 Interventions

Escalation Phase: Vorinostat starting dose 100 mg by mouth on Days 7 - 28 of Cycle 1; For all other cycles, dose of 100 mg Days 1-28. Expansion Phase starting dose: MTD from Escalation Phase. Escalation Phase: Sirolimus starting dose1 mg by mouth on Days 1 - 28. Expansion Phase starting dose: MTD from Escalation Phase.

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+

Findings from Research

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]

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]

Sirolimus is a powerful immunosuppressant used in kidney transplantation that works by inhibiting the mTOR pathway, which is crucial for cell growth and proliferation, leading to reduced rates of acute rejection episodes to less than 10% when combined with cyclosporin A (CsA).

In clinical trials, using sirolimus at doses of 2 or 5 mg/day alongside CsA and steroids resulted in acute rejection rates of only 19% and 14% within 12 months, while also potentially reducing the need for nephrotoxic calcineurin inhibitors, although it may cause side effects like myelosuppression and increased lipid levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sirolimus: a comprehensive review. Kahan, BD.[2019]

In a phase I study involving 23 advanced-stage cancer patients, vorinostat was found to be safe and tolerable, with common side effects including mild to moderate nausea and fatigue.

The study revealed that a high-fat meal slightly increased the absorption of vorinostat but did not significantly impact its overall effectiveness, suggesting that vorinostat can be administered with or without food in future studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A study to determine the effects of food and multiple dosing on the pharmacokinetics of vorinostat given orally to patients with advanced cancer. Rubin, EH., Agrawal, NG., Friedman, EJ., et al.[2018]

References

1. Spain pubmed.ncbi.nlm.nih.gov

Everolimus in renal cell carcinoma. [2021]

2. England pubmed.ncbi.nlm.nih.gov

Everolimus for the treatment of advanced renal cell carcinoma. [2021]

3. England pubmed.ncbi.nlm.nih.gov

Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. [2022]

4. Germany pubmed.ncbi.nlm.nih.gov

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

5. 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]

6. England pubmed.ncbi.nlm.nih.gov

Sirolimus: a comprehensive review. [2019]

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

A study to determine the effects of food and multiple dosing on the pharmacokinetics of vorinostat given orally to patients with advanced cancer. [2018]

8. England pubmed.ncbi.nlm.nih.gov

Safety and pharmacokinetics of paclitaxel and the oral mTOR inhibitor everolimus in advanced solid tumours. [2021]