Vorinostat + Chemotherapy for Advanced Cancer

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

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

20 Participants Needed

Trial Summary

What is the purpose of this trial?

This randomized pilot clinical trial studies high-dose or low-dose vorinostat in combination with carboplatin or paclitaxel in treating patients with advanced solid tumors. Vorinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as carboplatin and paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving different doses of vorinostat together with carboplatin or paclitaxel may kill more tumor cells.

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.

What data supports the effectiveness of the drug Vorinostat (SAHA) in combination with chemotherapy for advanced cancer?

Vorinostat (SAHA) has shown potential effectiveness in treating T-cell lymphoma and possibly breast cancer, as well as having antiproliferative effects in non-small cell lung cancer with specific mutations. It is also being evaluated in combination with other drugs for acute leukemias, suggesting its potential as part of a combination therapy for various cancers. ^{1 2 3 4 5}

Is the combination of Vorinostat and chemotherapy safe for humans?

Vorinostat, when used with chemotherapy drugs like carboplatin and paclitaxel, has been studied for safety in humans. Common side effects include fatigue, nausea, vomiting, diarrhea, and low platelet counts, with some serious cases of blood clots. However, no drug-related deaths were reported in the studies. ^{1 6 7 8 9}

What makes the drug Vorinostat combined with Carboplatin and Paclitaxel unique for treating advanced cancer?

The combination of Vorinostat with Carboplatin and Paclitaxel is unique because Vorinostat is a histone deacetylase inhibitor, which can modify gene expression and potentially enhance the effectiveness of chemotherapy. This combination aims to improve treatment outcomes by targeting cancer cells more effectively than standard chemotherapy alone. ^{10 11 12 13 14}

Research Team

Michael L Maitland

Principal Investigator

University of Chicago Comprehensive Cancer Center

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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/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, 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, 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, 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]

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]

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]

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]

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]

References

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

Redox-Mediated Suberoylanilide Hydroxamic Acid Sensitivity in Breast Cancer. [2018]

2. Ireland 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. [2022]

3. Netherlands 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. [2018]

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

Preclinical studies of vorinostat (suberoylanilide hydroxamic acid) combined with cytosine arabinoside and etoposide for treatment of acute leukemias. [2018]

5. England pubmed.ncbi.nlm.nih.gov

Chemosensitivity enhancement toward arsenic trioxide by inhibition of histone deacetylase in NB4 cell line. [2018]

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

Vorinostat: a new oral histone deacetylase inhibitor approved for cutaneous T-cell lymphoma. [2022]

7. United States 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. [2021]

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

Carboplatin and Paclitaxel in combination with either vorinostat or placebo for first-line therapy of advanced non-small-cell lung cancer. [2021]

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

Assessment of developmental toxicity of vorinostat, a histone deacetylase inhibitor, in Sprague-Dawley rats and Dutch Belted rabbits. [2018]

10. Switzerland pubmed.ncbi.nlm.nih.gov

[Therapeutic experiences using the new podophyllotoxin derivative VP 16-213 in malignant human tumors]. [2013]

11. Germany pubmed.ncbi.nlm.nih.gov

Podophyllotoxin derivative VP 16-213. [2019]

12. United States 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. [2015]

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

Optimizing primary chemotherapy in ovarian cancer. [2019]

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

VP-16-213 salvage therapy for refractory germinal neoplasms. [2019]