Vorinostat + Isotretinoin + Temozolomide for Glioblastoma

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: M.D. Anderson Cancer Center

Must be taking: Isotretinoin, Temozolomide

Must not be taking: Valproic acid, Bevacizumab

Disqualifiers: Other cancer, Active infection, Liver disease, others

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

Compensation: Varies

Number of Visits: 4

Duration: Up to 12 months

55 Participants Needed

Trial Summary

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 valproic acid (an anticonvulsant) unless switched to another drug before starting the trial. Also, if you are on enzyme-inducing anti-epileptic drugs, your doctor might need to monitor your drug levels.

Is the combination of Vorinostat, Isotretinoin, and Temozolomide safe for humans?

The combination of Vorinostat and Temozolomide has been studied for safety in patients with high-grade gliomas, and Temozolomide alone has been evaluated for safety in various cancer patients. Common side effects include fatigue, nausea, vomiting, and low platelet counts (thrombocytopenia), which can be managed. Vorinostat and Temozolomide are generally well-tolerated, but close monitoring is necessary. ^{1 2 3 4 5}

What makes the drug combination of Vorinostat, Isotretinoin, and Temozolomide unique for treating glioblastoma?

This drug combination is unique because it combines Temozolomide, a standard treatment for glioblastoma, with Vorinostat and Isotretinoin, which may enhance the effectiveness of Temozolomide by targeting different pathways and potentially overcoming resistance that can develop with Temozolomide alone. ^{2 6 7 8 9}

What is the purpose of this trial?

This study is evaluating whether a drug combination can help control glioblastoma or gliosarcoma.

Research Team

Vinay Puduvalli, MD

Principal Investigator

Brain Tumor Trials Collaborative (BTTC), and Ohio State University

Marta Penas-Prado, MD

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

Adults over 18 with recurrent WHO grade IV glioma (glioblastoma or gliosarcoma) who've failed radiation therapy can join. They must be able to sign consent, have a Karnofsky performance status >=60, stable health post-prior treatments, and agree to contraception. Exclusions include other cancers within 3 years (except certain types), prior bevacizumab treatment, valproic acid use without switching drugs first, inability to tolerate study procedures or swallow tablets.

Inclusion Criteria

My recent MRI was done within the last 17 days and I've been on a stable or decreasing dose of steroids for at least 5 days.

I can care for myself but may need occasional help.

I have recovered from side effects of my previous cancer treatments.

Exclusion Criteria

Patient must be able to tolerate study procedures and comply with protocol

I do not have an active infection, serious illness, or have been treated with HDAC inhibitors.

I am not currently taking valproic acid, or I have switched to another medication.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive vorinostat, isotretinoin, and temozolomide in 28-day cycles

Up to 12 months

Weekly visits for blood tests and monitoring, with additional visits every 2 cycles for MRI and exams

Follow-up

Participants are monitored for safety and effectiveness after treatment

Every 2 months

Phone calls every 2 months, clinic visits if stopped due to side effects

Treatment Details

Interventions

• Isotretinoin
• Temozolomide
• Vorinostat

Trial Overview The trial tests if vorinostat combined with isotretinoin and temozolomide can control recurrent brain tumors in adults and assesses the safety of this drug combination. Participants will undergo surgical resection as needed and receive these medications under careful monitoring for effectiveness and adverse reactions.

Participant Groups

Group I: Ph II: Arm 2 Experimental Treatment 1 Intervention

Surgical Arm

Group II: Ph I: Arm 3 Experimental Treatment 3 Interventions

Vorinostat plus isotretinoin plus temozolomide

Group III: Ph I: Arm 2 Experimental Treatment 2 Interventions

Temozolomide plus isotretinoin

Group IV: Ph I: Arm 1 Experimental Treatment 2 Interventions

Vorinostat plus isotretinoin

Group V: Ph II: Arm 1 Active Control 1 Intervention

Non-Surgical

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Merck Sharp & Dohme LLC

Industry Sponsor

Trials

4,096

Recruited

5,232,000+

Chirfi Guindo

Merck Sharp & Dohme LLC

Chief Marketing Officer since 2022

Degree in Engineering from Ecole Centrale de Paris, MBA from New York University Stern School of Business

Robert M. Davis

Merck Sharp & Dohme LLC

Chief Executive Officer since 2021

JD from Northwestern University Pritzker School of Law, MBA from Northwestern University Kellogg Graduate School of Management, Bachelor's in Finance from Miami University

Findings from Research

The maximum tolerated dose (MTD) of vorinostat when combined with temozolomide (TMZ) was determined to be 500 mg daily in the first part of the study, with dose-limiting toxicities including severe anorexia and thrombocytopenia.

Vorinostat was found to be well tolerated in patients with high-grade glioma, showing no significant pharmacokinetic interactions with TMZ, and it effectively caused hyperacetylation of histones, indicating its mechanism of action.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of vorinostat in combination with temozolomide in patients with high-grade gliomas: North American Brain Tumor Consortium Study 04-03. Lee, EQ., Puduvalli, VK., Reid, JM., et al.[2021]

In a phase II trial involving 46 patients with progressive low-grade glioma, Temozolomide (Temodar) demonstrated a 61% objective response rate, with 24% achieving complete response and 37% achieving partial response.

The treatment showed promising safety, with limited toxicity observed; however, one patient experienced severe complications, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of temozolomide in patients with progressive low-grade glioma. Quinn, JA., Reardon, DA., Friedman, AH., et al.[2022]

In a phase II trial involving 88 patients with recurrent malignant gliomas, the combination of temozolomide (TMZ) and 13-cis-retinoic acid (cRA) demonstrated a progression-free survival (PFS) rate of 43% at 6 months, indicating significant efficacy in this difficult-to-treat population.

The treatment was generally well-tolerated, with low rates of severe side effects, such as granulocytopenia (1.8%) and thrombocytopenia (1.4%), suggesting that the combination therapy is a viable option for patients with recurrent malignant gliomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II evaluation of temozolomide and 13-cis-retinoic acid for the treatment of recurrent and progressive malignant glioma: a North American Brain Tumor Consortium study. Jaeckle, KA., Hess, KR., Yung, WK., et al.[2022]

Temozolomide (TMZ) is well tolerated in patients with glioma and melanoma, with dose-limiting toxicity primarily being thrombocytopenia, observed at maximum tolerated doses of 150 mg/m2/day for patients with prior nitrosourea exposure and 250 mg/m2/day for those without.

The study showed promising antitumor activity, with two complete responses in patients without prior nitrosourea treatment, suggesting that TMZ could be an effective treatment option for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I trial of temozolomide (NSC 362856) in patients with advanced cancer. Dhodapkar, M., Rubin, J., Reid, JM., et al.[2018]

The study confirmed that the generic temozolomide capsules (TOZ039) are bioequivalent to the brand Temodal® capsules, with pharmacokinetic parameters falling within the acceptable range for both 20-mg and 100-mg doses in 29 patients with brain tumors.

The treatment was found to be safe, with no treatment-related severe adverse events or mortality reported, although 82.8% of patients experienced some adverse effects, highlighting the importance of monitoring patient responses during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bioequivalence study of 20-mg and 100-mg temozolomide capsules (TOZ309 and Temodal®) in glioma patients in China. Hu, C., Lin, Q., Liu, C., et al.[2021]

Naringenin (NGEN) significantly reduces the migration and invasion of drug-resistant glioma cells, suggesting it can enhance the effectiveness of temozolomide (TMZ) treatment.

The study provides evidence that NGEN can overcome TMZ resistance by modifying protein levels related to cell migration and invasion, making it a promising adjunct therapy for glioma patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Naringenin Sensitizes Resistant C6 Glioma Cells with a Repressive Impact on the Migrating Ability. J, J., Vanisree, AJ.[2022]

The TMZ-resistant glioma cell line SF188/TR showed a 6-fold resistance to temozolomide and cross-resistance to various other anticancer agents, indicating a significant challenge in treating resistant tumors.

Increased activity of the enzyme alkylguanine alkyltransferase (AGT) was identified as a primary mechanism of resistance to TMZ, while changes in the balance of pro-apoptotic and anti-apoptotic proteins contributed to broader cross-resistance to other drugs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biochemical changes associated with a multidrug-resistant phenotype of a human glioma cell line with temozolomide-acquired resistance. Ma, J., Murphy, M., O'Dwyer, PJ., et al.[2022]

References

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

Phase I study of vorinostat in combination with temozolomide in patients with high-grade gliomas: North American Brain Tumor Consortium Study 04-03. [2021]

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

Phase II trial of temozolomide in patients with progressive low-grade glioma. [2022]

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

Phase II evaluation of temozolomide and 13-cis-retinoic acid for the treatment of recurrent and progressive malignant glioma: a North American Brain Tumor Consortium study. [2022]

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

Phase I trial of temozolomide (NSC 362856) in patients with advanced cancer. [2018]

5. Germany pubmed.ncbi.nlm.nih.gov

Bioequivalence study of 20-mg and 100-mg temozolomide capsules (TOZ309 and Temodal®) in glioma patients in China. [2021]

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

A phase I factorial design study of dose-dense temozolomide alone and in combination with thalidomide, isotretinoin, and/or celecoxib as postchemoradiation adjuvant therapy for newly diagnosed glioblastoma. [2022]

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

Naringenin Sensitizes Resistant C6 Glioma Cells with a Repressive Impact on the Migrating Ability. [2022]

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

Biochemical changes associated with a multidrug-resistant phenotype of a human glioma cell line with temozolomide-acquired resistance. [2022]

9. Germany pubmed.ncbi.nlm.nih.gov

Honokiol enhances temozolomide-induced apoptotic insults to malignant glioma cells via an intrinsic mitochondrion-dependent pathway. [2019]