Vorinostat + Chemotherapy for Cancer

(NYMC195 Trial)

Overseen By Lauren Harrison, MSN

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: New York Medical College

Must not be taking: Corticosteroids, Antineoplastics, Valproic acid, others

Disqualifiers: Pregnancy, Infection, Allergy, others

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new combination of drugs to treat tumors that have returned or didn't respond to standard treatment. The researchers aim to determine the safest dose of the experimental drug vorinostat (also known as Zolinza) when combined with other chemotherapy drugs and to identify potential side effects. This trial may suit patients with solid tumors or brain cancers that have relapsed or are resistant to previous treatments. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering patients a chance to be among the first to receive this new therapy.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop all current medications, but you cannot take any other cancer treatments or certain drugs like valproic acid for at least 2 weeks before joining. If you're on corticosteroids for a CNS tumor, your dose must be stable or decreasing for 7 days before starting the trial.

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

Research has shown that vorinostat has been tested in patients with certain cancers, such as cutaneous T cell lymphoma. In these studies, most patients tolerated the drug well, though some experienced side effects like low blood platelet levels, tiredness, nausea, vomiting, and loss of appetite.

The chemotherapy drugs in this trial—vincristine, irinotecan, and temozolomide—already treat cancer. Each has known side effects, but doctors can manage them. This trial is in its early stages and aims to find the safest dose of vorinostat when combined with these other drugs. Safety information is still being collected, and side effects are closely monitored.

Considering joining a trial means the treatment is still being tested for safety and effectiveness. Participants play a crucial role in helping researchers learn more about the treatment. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike standard chemotherapy options for cancer, which typically target rapidly dividing cells, vorinostat works differently by inhibiting histone deacetylase (HDAC). This action can lead to the reactivation of tumor suppressor genes and potentially slow down tumor growth. Researchers are excited about vorinostat because it represents a novel mechanism that could enhance the effectiveness of chemotherapy regimens. By combining vorinostat with traditional chemotherapy, there's potential for improved outcomes for patients who may not respond optimally to existing treatments alone.

What evidence suggests that this trial's treatments could be effective against cancer?

Research has shown that vorinostat may help treat certain cancers. In studies with patients who had diffuse large B-cell lymphoma, one patient fully recovered, and others showed some improvement. Vorinostat has also been effective for advanced cutaneous T-cell lymphoma, a type of skin cancer. In this trial, vorinostat will be combined with other drugs such as vincristine, irinotecan, and temozolomide, starting from the second cycle, to potentially enhance its effectiveness against difficult tumors. Early results suggest this combination might be more effective than using vorinostat alone. ^{4 6 7 8 9}

Who Is on the Research Team?

Jeremy Rosenblum, MD

Principal Investigator

New York Medical College

Are You a Good Fit for This Trial?

This trial is for young patients (1 to 30 years old) with relapsed or refractory solid tumors or CNS malignancies. They must have adequate organ function, not received certain treatments recently, and cannot be pregnant or breastfeeding. Those with uncontrolled infections, allergies to protocol drugs, or recent use of specific inhibitors are excluded.

Inclusion Criteria

You have enough infection-fighting white blood cells in your body.

It's been over 14 days since my last radiation therapy, or longer for specific types.

Your hemoglobin level is 8 gm/dL or higher.

Exclusion Criteria

I am not allergic to vincristine, irinotecan, temozolomide, or vorinostat.

My child has neurofibromatosis Type 1 and is being treated for a low grade brain tumor.

I haven't taken valproic acid or similar drugs in the last 2 weeks.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Initial Chemotherapy Cycle

Participants receive vincristine, temozolomide, irinotecan, and cefixime to assess tolerance without vorinostat

3 weeks

Weekly visits for drug administration

Combination Treatment Cycles

Participants receive combination therapy with vorinostat, vincristine, temozolomide, irinotecan, and cefixime

11 cycles (approximately 33 weeks)

Weekly visits for drug administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Vorinostat

Trial Overview

The study tests the highest safe dose of vorinostat combined with vincristine, irinotecan, and temozolomide in children and young adults. It aims to determine side effects, impact on tumor cell molecules, and overall treatment effectiveness against stubborn tumors.

How Is the Trial Designed?

Group I: Vorinostat Experimental Treatment 1 Intervention

The first cycle of chemotherapy will not include the experimental agent vorinostat. This first cycle will be used to determine whether the patient can tolerate the chemotherapeutic backbone without developing a DLT. Cycle 1 * Vincristine: 1.5 mg/m2/day (maximum dose 2 mg) IV Days 1 and 8 over 1-15 minutes. * Temozolomide: 125 mg/m2/day PO Days 1-5. * Irinotecan: 50 mg/m2/day IV Days 1-5 over 60 minutes. * Cefixime: 8 mg/kg/day (maximum dose 400 mg) PO. Begin 2 days prior to irinotecan therapy and continue through Day 8. Cycles 2-12 * Vincristine: 1.5 mg/m2/day (maximum dose 2 mg) IV Days 1 and 8 over 1-15 minutes. * Temozolomide: 125 mg/m2/day PO Days 1-5. * Irinotecan: 50 mg/m2/day IV Days 1-5 over 60 minutes. * Cefixime: 8 mg/kg/day (maximum dose 400 mg) PO. Begin 2 days prior to irinotecan therapy and continue through Day 8. * Vorinostat: Dose per escalation schema daily Days 1-5. * Vorinostat will not be administered during Cycle 1.

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

Approved in United States as Zolinza for:

• Cutaneous T-cell lymphoma

Approved in European Union as Zolinza for:

• Cutaneous T-cell lymphoma

Who Is Running the Clinical Trial?

New York Medical College

Lead Sponsor

Trials

73

Recruited

8,700+

Published Research Related to This Trial

In a phase I/II trial involving 33 patients with EGFR-mutated non-small cell lung cancer (NSCLC) who progressed after tyrosine kinase inhibitors, the combination of vorinostat and erlotinib was found to be safe, with a maximum tolerated dose established for the treatment regimen.

Despite the safety of the drug combination, the study reported no significant therapeutic responses, with a progression-free survival rate of only 28% at 12 weeks, indicating that this treatment may not be effective for patients who have already progressed on other therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I/II trial of vorinostat (SAHA) and erlotinib for non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations after erlotinib progression. Reguart, N., Rosell, R., Cardenal, F., et al.[2022]

A sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay was developed to accurately measure vorinostat and its metabolites in human serum, with a lower limit of quantitation of 3.0 ng/ml for each analyte.

This assay is currently being utilized in at least 12 clinical studies, highlighting its importance in evaluating the pharmacokinetics and therapeutic effects of vorinostat as an antineoplastic agent.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A liquid chromatography-electrospray ionization tandem mass spectrometric assay for quantitation of the histone deacetylase inhibitor, vorinostat (suberoylanilide hydroxamicacid, SAHA), and its metabolites in human serum. Parise, RA., Holleran, JL., Beumer, JH., et al.[2018]

Vorinostat, when used sequentially before cytosine arabinoside (ara-C), showed mostly synergistic effects in killing leukemia cells, suggesting a promising treatment strategy for acute leukemias.

The combination of vorinostat with etoposide was found to be additive to synergistic, especially when etoposide was administered after vorinostat, indicating that the timing of drug administration is crucial for maximizing therapeutic efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical studies of vorinostat (suberoylanilide hydroxamic acid) combined with cytosine arabinoside and etoposide for treatment of acute leukemias. Shiozawa, K., Nakanishi, T., Tan, M., et al.[2018]

Vorinostat (SAHA) shows varying effectiveness in treating breast cancer, with some tumors and cell lines being resistant due to differences in gene expression related to cell adhesion and glutathione metabolism.

Depleting glutathione with buthionine sulfoximine (BSO) can enhance the effectiveness of SAHA, suggesting that evaluating antioxidant gene expression may help predict which tumors will respond to this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Redox-Mediated Suberoylanilide Hydroxamic Acid Sensitivity in Breast Cancer. Chiaradonna, F., Barozzi, I., Miccolo, C., et al.[2018]

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]

Vorinostat, a histone deacetylase inhibitor, was found to be safe and tolerable in a phase 1 study involving 41 patients with various types of leukemia and myelodysplastic syndromes, with a maximum tolerated dose of 200 mg twice daily or 250 mg thrice daily.

The treatment led to hematologic improvements in 7 patients, including 2 complete responses, and increased histone acetylation was observed, suggesting its potential efficacy in treating acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1 study of the histone deacetylase inhibitor vorinostat (suberoylanilide hydroxamic acid [SAHA]) in patients with advanced leukemias and myelodysplastic syndromes. Garcia-Manero, G., Yang, H., Bueso-Ramos, C., et al.[2021]

Vorinostat's solubility was significantly enhanced when complexed with cyclodextrins, particularly with randomly methylated-β-cyclodextrin (RM-β-CD), which increased its solubility from 0.724 mm to 70.8 mm, making it nearly 100 times more soluble.

Molecular simulations supported these findings and suggested that using cyclodextrins could improve vorinostat's delivery methods, indicating potential for better oral absorption and parenteral delivery in future studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Solubilization of vorinostat by cyclodextrins. Cai, YY., Yap, CW., Wang, Z., et al.[2018]

Vorinostat, a histone deacetylase inhibitor, did not cause maternal toxicity or major fetal malformations in Sprague-Dawley rats and Dutch Belted rabbits, indicating a relatively safe profile during pregnancy at lower doses.

However, at high doses, vorinostat was associated with developmental toxicity, such as decreased fetal weight and skeletal variations, suggesting that while it is generally safe, caution is needed with higher dosages due to potential adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Assessment of developmental toxicity of vorinostat, a histone deacetylase inhibitor, in Sprague-Dawley rats and Dutch Belted rabbits. Wise, LD., Turner, KJ., Kerr, JS.[2018]

Citations

1.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC4533557/

Vorinostat—An Overview - PMC

Studies have shown that Vorinostat had shown to give a complete response in a patient with diffuse large B-cell lymphoma (DLBCL), with partial responses in ...

2.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC11159849/

Potential efficacy of the oral histone deacetylase inhibitor ...

The present study was conducted to evaluate vorinostat in Japanese patients with malignant lymphoma (ML). The primary objectives were to determine the maximum ...

3.

ascopubs.org

ascopubs.org/doi/10.1200/jco.2006.24.18_suppl.7500

Results of a phase IIb trial | Journal of Clinical Oncology

Vorinostat (suberoylanilide hydroxamic acid, SAHA) is clinically active in advanced cutaneous T-cell lymphoma (CTCL): Results of a phase IIb ...

4.

sciencedirect.com

sciencedirect.com/science/article/abs/pii/S1773224721000150

Delivery systems for vorinostat in cancer treatment

However, despite showing promising clinical effects on hematological malignancies, the therapeutic benefits of vorinostat were poor when used as a monotherapy ...

5.

nature.com

nature.com/articles/6603465

Clinical and laboratory experience of vorinostat ...

In a Phase IIa clinical trial, vorinostat therapy achieved a meaningful partial response (>50% reduction in disease burden) in eight out of 33 ( ...

6.

pubchem.ncbi.nlm.nih.gov

pubchem.ncbi.nlm.nih.gov/compound/Vorinostat

Vorinostat | C14H20N2O3 | CID 5311 - PubChem - NIH

Vorinostat (rINN) or suberoylanilide hydroxamic acid (SAHA), is a drug currently under investigation for the treatment of cutaneous T cell lymphoma (CTCL) ...

7.

cancertreatmentreviews.com

cancertreatmentreviews.com/article/S0305-7372(15)00072-9/abstract

The safety profile of vorinostat (suberoylanilide hydroxamic ...

Associated adverse events include thrombocytopenia, fatigue, nausea, vomiting, and anorexia. •. HDAC inhibitors are also associated with AEs unique to their ...

8.

ashpublications.org

ashpublications.org/blood/article/109/1/31/117140/Phase-2-trial-of-oral-vorinostat-suberoylanilide

Phase 2 trial of oral vorinostat (suberoylanilide hydroxamic ...

Vorinostat demonstrated activity in heavily pretreated patients with CTCL. The 400 mg daily regimen had the most favorable safety profile and is being further ...

9.

cancercareontario.ca

cancercareontario.ca/en/drugformulary/drugs/monograph/44221

Drug Formulary - vorinostat

No carcinogenic tests have been conducted. In vitro and animal studies suggest that vorinostat has clastogenic, mutagenic, embryotoxic, fetotoxic effects, and ...