Vorinostat + Chemotherapy for Advanced Cancer

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must not be taking: Valproic acid, Antiretrovirals

Disqualifiers: Brain metastases, Allergic reactions, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 21 days per course

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of treatments for individuals with advanced cancers that cannot be surgically removed or have metastasized. The study examines various doses of vorinostat (a histone deacetylase inhibitor) alongside two chemotherapy drugs, carboplatin and paclitaxel, to determine their effectiveness in stopping or slowing cancer cells. Participants will receive different combinations of these drugs to identify the most effective method for shrinking or controlling tumors. Those with difficult-to-treat cancer who have not recently undergone chemotherapy or radiation may be suitable candidates. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new combination therapy.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but you cannot be on other investigational drugs or have used valproic acid. You also need to have stopped chemotherapy or radiotherapy at least 4 weeks before joining the study.

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

Research shows that vorinostat, whether used alone or with other drugs, is generally well tolerated by cancer patients. Studies have found that combining vorinostat with paclitaxel or carboplatin is usually safe for patients, allowing most to undergo treatment without serious side effects.

Safety data for the combination of vorinostat and paclitaxel indicates that patients manage the treatment well. Similarly, previous trials have shown a good safety record for the combination of vorinostat and carboplatin.

This trial is in its early phase, which primarily focuses on safety. While the results so far appear promising, the researchers are still gathering complete safety information. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of vorinostat with chemotherapy agents like carboplatin and paclitaxel because it introduces a novel approach to treating cancer. Vorinostat is a histone deacetylase (HDAC) inhibitor, which works by altering the way cancer cells use their genes, potentially stopping their growth. This is different from standard chemotherapy treatments, which typically target rapidly dividing cells without affecting gene expression. By pairing vorinostat with traditional chemotherapy, there's hope to enhance the effectiveness of treatment, potentially leading to better outcomes for patients with advanced cancer.

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

Research has shown that vorinostat, one of the treatments in this trial, can enhance the effectiveness of chemotherapy drugs like carboplatin and paclitaxel for advanced cancers. In studies with patients who have non-small cell lung cancer (NSCLC), vorinostat increased the success rate of these chemotherapy drugs, with a significant 53% response rate observed. Vorinostat blocks certain enzymes that cancer cells need to grow, potentially stopping tumor growth. This trial will explore different dosing combinations of vorinostat with either carboplatin or paclitaxel, offering hope to patients with advanced cancers. ^{1 2 4 6 7}

Who Is on the Research Team?

Michael L Maitland

Principal Investigator

University of Chicago Comprehensive Cancer Center

Are You a Good Fit for This Trial?

This trial is for patients with advanced solid tumors that can't be removed by surgery or have spread, and who haven't had chemotherapy or radiation in the last 4-6 weeks. They should have a life expectancy over 3 months, adequate organ function, and no severe illnesses that would limit study participation. Pregnant or breastfeeding women are excluded.

Inclusion Criteria

Platelets > 100,000/mcL

My cancer is advanced, cannot be surgically removed, and has no better treatment options.

Potassium < institutional upper limits of normal

Exclusion Criteria

Patients may not be receiving any other investigational agents

I am allergic to medications similar to paclitaxel, vorinostat, or carboplatin.

I cannot swallow pills.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive varying doses of vorinostat in combination with carboplatin or paclitaxel, with courses repeating every 21 days

21 days per course

Multiple visits per course for drug administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Carboplatin
• Paclitaxel
• Vorinostat

Trial Overview The trial tests high-dose versus low-dose Vorinostat combined with Carboplatin or Paclitaxel to see which dosage is more effective at stopping tumor growth. The enzymes blocked by Vorinostat could help kill more cancer cells when used with these chemotherapy drugs.

How Is the Trial Designed?

Group I: Arm VI (mid- and low-dose vorinostat and paclitaxel) Experimental Treatment 4 Interventions

Patients receive mid-dose vorinostat PO QD on days 1-3 and low-dose vorinostat PO QD on days 8-10. After 5 days, patients receive vorinostat and paclitaxel as in Arm V.

Group II: Arm V (low- and mid-dose vorinostat and paclitaxel) Experimental Treatment 4 Interventions

Patients receive low-dose vorinostat PO QD on days 1-3 and mid-dose vorinostat PO QD on days 8-10 (course 0). After 5 days, patients receive mid-dose vorinostat PO QD on days 1-3 and paclitaxel IV over 3 hours on day 3.

Group III: Arm IV (low- and high-dose vorinostat and carboplatin) Experimental Treatment 4 Interventions

Patients receive low-dose vorinostat and high-dose vorinostat as in Arm III. After 5 days, patients receive vorinostat and carboplatin as in Arm II.

Group IV: Arm III (low- and high-dose vorinostat and carboplatin) Experimental Treatment 4 Interventions

Patients receive low-dose vorinostat PO QD on days 1-3 and high-dose vorinostat PO QD on days 8-10 (course 0). After 5 days, patients receive vorinostat and carboplatin as in Arm I.

Group V: Arm II (high- and low-dose vorinostat and carboplatin) Experimental Treatment 4 Interventions

Patients receive high-dose vorinostat and low-dose vorinostat as in Arm I. After 5 days, patients receive lower-dose vorinostat PO QD on days 1-3 and carboplatin IV over 30 minutes on day 3.

Group VI: Arm I (high- and low-dose vorinostat and carboplatin) Experimental Treatment 4 Interventions

Patients receive high-dose vorinostat PO QD on days 1-3 and low-dose vorinostat PO QD on days 8-10 (course 0). After 5 days, patients receive high-dose vorinostat PO QD on days 1-3 and carboplatin IV over 30 minutes on day 3 of all subsequent courses.

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

Approved in United States as Paraplatin for:

• Ovarian cancer
• Testicular cancer
• Lung cancer
• Head and neck cancer
• Brain cancer

Approved in European Union as Carboplatin for:

• Ovarian cancer
• Small cell lung cancer

Approved in Canada as Carboplatin for:

• Ovarian cancer
• Small cell lung cancer
• Testicular cancer

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

VP 16-213, a new semisynthetic epipodophyllotoxin, demonstrated clinically valuable antitumor activity in a phase II trial involving 33 patients with solid tumors and acute leukemias, particularly showing promising results in patients with oat cell carcinoma of the lung.

The drug was generally well tolerated, but it commonly caused side effects like leukothrombopenia and hair loss, indicating a need for further studies to optimize its dosage and explore its use in combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Therapeutic experiences using the new podophyllotoxin derivative VP 16-213 in malignant human tumors]. Jungi, WF., Senn, HJ., Beckmann, C., et al.[2013]

In a multicenter phase II study involving 50 patients with advanced ovarian cancer who had previously undergone platinum-based chemotherapy, the combination of paclitaxel and carboplatin showed an overall response rate of 43%, indicating its efficacy in this patient population.

The treatment was generally safe, with myelosuppression being the most common severe side effect, but only one case of neutropenic fever was reported, suggesting that this regimen can be administered safely to outpatients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of the combination paclitaxel/carboplatin in patients with previously treated advanced ovarian carcinoma: a multicenter French Groupe des Investigateurs Nationaux pour l'Etude des Cancers Ovariens phase II study. Pujade-Lauraine, E., Guastalla, JP., Weber, B., et al.[2015]

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]

Primary chemotherapy for advanced ovarian cancer typically involves a combination of platinum agents (like carboplatin or cisplatin) and taxanes (such as paclitaxel or docetaxel), leading to a favorable response in 60% to 80% of patients.

Future research aims to integrate new cancer-fighting drugs into standard treatments to improve effectiveness, enhance quality of life, and extend survival for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Optimizing primary chemotherapy in ovarian cancer. Markman, M.[2019]

VP 16-213, a new drug derived from podophyllotoxin, shows significant effectiveness against small-cell bronchial carcinoma and may also be beneficial for other lung tumors, testicular teratomas, and certain leukemias, making it a promising treatment option.

The drug's mechanism of action is not fully understood, but it appears to cause the most damage to cancer cells during specific phases of the cell cycle, and prolonged administration may enhance its effectiveness compared to single doses, with no long-term toxicity reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Podophyllotoxin derivative VP 16-213. Arnold, AM.[2019]

Vorinostat, the first FDA-approved HDAC inhibitor, has shown safety and efficacy in treating cutaneous T-cell lymphoma (CTCL) with an overall response rate of 24-30% in advanced, refractory cases during Phase II trials.

Common side effects of vorinostat include gastrointestinal issues, fatigue, and thrombocytopenia, with thrombosis being the most serious adverse event reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vorinostat: a new oral histone deacetylase inhibitor approved for cutaneous T-cell lymphoma. Duvic, M., Vu, J.[2022]

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]

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]

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]

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, 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. clinicaltrials.gov clinicaltrials.gov/ct2/show/NCT00481078?term=PHII+82&rank=1

Vorinostat, Carboplatin, and Paclitaxel in Treating Patients ... This randomized phase II trial is studying carboplatin, paclitaxel, and vorinostat to see how well they work compared with carboplatin, paclitaxel, ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC2799233/

Carboplatin and Paclitaxel in Combination With Either ... Conclusion. Vorinostat enhances the efficacy of carboplatin and paclitaxel in patients with advanced NSCLC. HDAC inhibition is a promising therapeutic strategy ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC2795066/

Vorinostat increases carboplatin and paclitaxel activity in non ... We observed a 53% response rate in non-small cell lung cancer (NSCLC) patients treated with vorinostat plus paclitaxel/carboplatin in a Phase I trial.

4. clinicaltrials.gov clinicaltrials.gov/study/NCT00976183

Paclitaxel, Carboplatin and Vorinostat for the Treatment of ... There have been recent data suggesting that weekly chemotherapy regimens may significantly benefit cancer patients' prognosis [4, 5]. Non-small cell lung cancer ...

5. ascopubs.org ascopubs.org/doi/abs/10.1200/JCO.2009.24.9094

Carboplatin and Paclitaxel in Combination With Either ... This phase II randomized, double-blinded, placebo-controlled study evaluated the efficacy of vorinostat in combination with carboplatin and ...

6. sciencedirect.com sciencedirect.com/science/article/pii/S0006497119545232

The Combined Safety and Tolerability Profile of Vorinostat ... Vorinostat is generally well tolerated when administered as monotherapy or in a combination regimen in cancer patients.

7. jhoonline.biomedcentral.com jhoonline.biomedcentral.com/articles/10.1186/1756-8722-2-31

Vorinostat in solid and hematologic malignancies Overall, these studies showed that vorinostat as monotherapy was effective in advanced CTCL and had an acceptable safety profile. Vorinostat is ...