Drug Combination for Advanced Cancer

Age: Any Age

Sex: Any

Trial Phase: Phase 1

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Phenytoin, Carbamazepine, Barbiturates, others

Disqualifiers: Myocardial infarction, Pregnancy, 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a mix of drugs to determine the highest safe dose for people with advanced cancer, emphasizing safety and effectiveness. It combines drugs—vorinostat (a type of cancer treatment), sirolimus, everolimus, and temsirolimus—known to slow or stop cancer cell growth. The trial targets those whose cancer hasn't responded to standard treatments or for whom such treatments don't exist. Participants must have measurable or noticeable disease and be able to swallow pills. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the chance to contribute to groundbreaking cancer research.

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.

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

Research has shown that the drugs in this study have been used before, either alone or in different combinations, and some safety information is available. The FDA has approved vorinostat for treating cutaneous T-cell lymphoma, a type of skin cancer. Temsirolimus, everolimus, and sirolimus are also approved for other conditions, such as preventing kidney rejection and treating certain cancers, indicating they have been tested and found safe for those uses.

In studies where vorinostat was combined with either sirolimus or everolimus, some patients experienced side effects. The most common were low blood cell counts, such as thrombocytopenia, which means low platelet levels and can affect blood clotting. Another study found that the combination of everolimus with other drugs was generally safe, but some patients experienced myelosuppression, a drop in blood cell production.

Since this trial is in its early stages (Phase 1), the main goal is to find the highest dose that patients can handle without too many side effects. The treatment is still being tested for safety and effectiveness in this specific combination.

Overall, while the individual drugs have been used safely in other treatments, combining them is new. This trial aims to ensure that together, they are safe and tolerable for people with advanced cancer. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they combine drugs that target cancer in unique ways. Vorinostat, an HDAC inhibitor, disrupts cancer cell growth, while Temsirolimus, Sirolimus, and Everolimus are mTOR inhibitors that block signals cancer cells need to grow. This combination approach can potentially enhance treatment effectiveness by attacking cancer from multiple angles. Unlike standard chemotherapy, which often has widespread effects, these combinations aim to be more targeted, potentially leading to fewer side effects and improved outcomes for patients with advanced cancer.

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

This trial will evaluate different combinations of vorinostat with other drugs to treat advanced cancer. Research has shown that combining vorinostat with temsirolimus, which participants in Arm C of this trial may receive, enhances their ability to fight cancer. In studies, this combination has shown promise in slowing tumor growth in kidney cancer models. Participants in Arm A will receive the combination of vorinostat and sirolimus, which early data suggests is well-tolerated and may benefit patients with advanced Hodgkin lymphoma. Meanwhile, Arm B will test vorinostat with everolimus, a combination that has demonstrated effectiveness in early studies, particularly for Hodgkin lymphoma. These drug combinations target the pathways that help cancer cells grow. Vorinostat blocks certain proteins, while the other drugs inhibit mTOR, a protein linked to cancer growth. ^{1 4 6 7 8}

Who Is on the Research Team?

Filip Janku, MD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT01087554

Sirolimus or Everolimus or Temsirolimus and Vorinostat in ... The goal of this clinical research study is to find the highest tolerable dose of the combination vorinostat given in combination with either sirolimus, ...

2. ecancer.org ecancer.org/en/news/18842-inhibition-of-hdac-and-mtor-may-improve-outcomes-for-relapsed-refractory-hodgkin-lymphoma

Inhibition of HDAC and mTOR may improve outcomes for ... In this study, Janku and colleagues examined the clinical efficacy of vorinostat in combination with either sirolimus or everolimus in a larger ...

3. cancernetwork.com cancernetwork.com/view/combined-hdac-mtor-inhibition-shows-clinical-efficacy-in-relapsed-refractory-hodgkin-lymphoma

Combined HDAC, mTOR Inhibition Shows Clinical Efficacy ... This phase 1 study found that vorinostat (Zolinza) in combination with either sirolimus (Rapamune) or everolimus (Afinitor) demonstrated ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5341894/

Phase I dose-escalation study of the mTOR inhibitor ... Phase I dose-escalation study of the mTOR inhibitor sirolimus and the HDAC inhibitor vorinostat in patients with advanced malignancy · Abstract.

5. aacrjournals.org aacrjournals.org/clincancerres/article/doi/10.1158/1078-0432.CCR-20-1215/56623/p/Safety-and-Efficacy-of-Vorinostat-Plus-Sirolimus

Safety and Efficacy of Vorinostat Plus Sirolimus or Everolimus ... Preclinical and early clinical data suggested that combining histone deacetylase (HDAC) and mTOR inhibitors can synergistically inhibit Hodgkin lymphoma.

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/33055173/

Safety and Efficacy of Vorinostat Plus Sirolimus or Everolimus ... Combined HDAC and mTOR inhibition has salutary activity in patients with relapsed refractory Hodgkin lymphoma and warrants further investigation.

7. researchgate.net researchgate.net/publication/346231151_Safety_and_Efficacy_of_Vorinostat_Plus_Sirolimus_or_Everolimus_in_Patients_with_Relapsed_Refractory_Hodgkin_Lymphoma

Safety and Efficacy of Vorinostat Plus Sirolimus or ... Complete response was reported in 6 (27%) patients treated with V+S and 2 (11%) patients treated with V+E, and PR was reported in 6 patients (27 ...

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7182475/

Phase I study of the mTOR inhibitor everolimus in ... A safe and tolerable dosing regimen was established for combination everolimus/panobinostat therapy with myelosuppression as the major DLT. This therapeutic ...