SHetA2 for Gynecologic Cancers

(Okgyn1 Trial)

Overseen By Ingrid Block

Age: 18+

Sex: Female

Trial Phase: Phase 1

Sponsor: University of Oklahoma

Must not be taking: Immunosuppressants, Steroids, Chemotherapy, others

Disqualifiers: Pregnancy, Autoimmune disease, Hepatitis, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: up to three years

50 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this research is to test the safety of the study drug (OK-1) and see what effects (good and bad) this drug has on patients with recurrent solid tumors.

Will I have to stop taking my current medications?

The trial requires that any hormonal therapy directed at the malignant tumor be stopped at least one week before joining. Other medications, like those for autoimmune diseases or certain investigational therapies, may also need to be stopped, but the protocol does not specify all medications that must be discontinued.

What evidence supports the effectiveness of the drug SHetA2 for gynecologic cancers?

Research shows that SHetA2 is effective against uterine cancer cell lines, reducing their survival, and it selectively targets cancer cells over normal cells. Additionally, in ovarian cancer models, SHetA2 has shown potential in preventing tumor development when used alone or in combination with another drug, without observed toxicity. ^{1 2 3 4 5}

Is SHetA2 safe for use in humans?

Studies in mice have shown that SHetA2, when administered vaginally, did not cause any adverse effects, suggesting it may be safe. Additionally, SHetA2 is noted for its low toxicity in preclinical studies, indicating a high safety profile. ^{1 2 6 7 8}

What makes the drug SHetA2 unique for treating gynecologic cancers?

SHetA2 is a novel drug that selectively targets cancer cells over normal cells and works by inhibiting specific proteins involved in cancer cell growth and survival. It is unique because it can be administered orally or vaginally, with the vaginal route significantly increasing its absorption in the cervix, making it potentially more effective for certain gynecologic cancers compared to traditional oral administration. ^{1 2 6 8 9}

Research Team

Debra L. Richardson

Principal Investigator

Stephenson Cancer Center

Eligibility Criteria

This trial is for adults with advanced or recurrent ovarian, cervical, and endometrial cancers resistant to platinum therapy or other treatments. Participants must have good organ function, no severe infections like HIV with a positive viral load, no recent major surgeries, and not be on certain medications that could affect the study results. They should be able to take oral meds and agree to use contraception if applicable.

Inclusion Criteria

I am 18 years old or older.

Patients must have satisfactory results for the baseline laboratory analyses and diagnostic procedures as specified in the protocol.

I am willing to undergo a biopsy after the first treatment cycle.

Exclusion Criteria

I have had a transplant of an organ, bone marrow, or stem cells.

I have not taken steroids or immunosuppressants in the last 7 days.

I do not have another cancer that could affect this treatment's safety or results.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive OK-1 capsules twice a day in 21-day cycles

up to three years

Regular lab tests and examinations

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• SHetA2

Trial Overview The trial is testing SHetA2's safety and effectiveness in patients with specific types of cancer that have come back after treatment. It involves taking this investigational drug to see both its positive effects (like shrinking tumors) and any negative ones (side effects).

Participant Groups

Group I: OK-1 capsule Experimental Treatment 1 Intervention

OK-1 (oral, BID) within a 21-days cycle

Who Is Running the Clinical Trial?

University of Oklahoma

Lead Sponsor

Trials

484

Recruited

95,900+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

Doxorubicin was found to be particularly effective against uterine sarcoma cell lines, while it showed little to no activity against endometrial adenocarcinoma and mixed Mullerian tumor cell lines, indicating a potential need for tailored treatment approaches based on cancer type.

The novel compound SHetA2 demonstrated cytotoxic effects on various uterine cancer cell lines, but it did not enhance the effectiveness of standard chemotherapeutic agents like cisplatin or paclitaxel, suggesting it may be useful as a standalone treatment rather than a combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sensitivities of Uterine Adenocarcinoma, Mixed Mullerian Tumor (MMT) and Sarcoma Cell Lines to Chemotherapeutic Agents and a Flex-Het Drug. Hyde, J., Benbrook, DM.[2021]

SHetA2, a novel anticancer drug, shows selective inhibition of cancer cells over normal cells and has a half-life of 4.5 hours, indicating its potential effectiveness in cancer treatment.

The study developed a physiologically based pharmacokinetic (PBPK) model that revealed SHetA2 has rapid and extensive tissue distribution, with oral bioavailability estimated at 22.3%, which is crucial for predicting its efficacy in tumor treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Physiologically Based Pharmacokinetic Modeling and Tissue Distribution Characteristics of SHetA2 in Tumor-Bearing Mice. Sharma, A., Li, M., Thavathiru, E., et al.[2021]

A screening of 7914 approved drugs revealed that two HDAC inhibitors, mocetinostat and entinostat, effectively suppress various gynecologic cancers, showing promising IC50 values close to their human plasma concentrations.

The study highlights the potential of both known and non-anticancer drugs to inhibit the growth of gynecologic cancer cell lines, suggesting new avenues for therapeutic development and personalized treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Quantitative Chemotherapeutic Profiling of Gynecologic Cancer Cell Lines Using Approved Drugs and Bioactive Compounds. Gorshkov, K., Sima, N., Sun, W., et al.[2023]

The combination of SHetA2 and PRIMA-1MET significantly inhibited tumor growth in ovarian cancer models, achieving a 67% tumor-free rate in mice, compared to 0% in controls, indicating a promising maintenance therapy strategy.

This combination therapy specifically targets mutant p53, showing no toxicity in healthy cells, which suggests a safer treatment option for patients with ovarian cancer who have missense mutations in the TP53 gene.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel ovarian cancer maintenance therapy targeted at mortalin and mutant p53. Ramraj, SK., Elayapillai, SP., Pelikan, RC., et al.[2021]

Patient Derived Xenografts (PDXs) from chemotherapy-naïve high-grade serous epithelial ovarian cancer (HGS-EOC) showed responsiveness to drugs like carboplatin, trabectedin, and gemcitabine, indicating potential effectiveness of these agents in untreated cancers.

After initial platinum-based chemotherapy, PDXs from the same patients lost responsiveness to trabectedin and gemcitabine, highlighting the need for personalized treatment strategies as tumor responses can vary significantly post-chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Xenopatients show the need for precision medicine approach to chemotherapy in ovarian cancer. Erriquez, J., Olivero, M., Mittica, G., et al.[2022]

Vaginal administration of SHetA2 results in significantly higher absorption into the cervix (23.9%) compared to oral administration (0.02%), making it a more effective delivery method for treating cervical dysplasia.

Daily vaginal doses of SHetA2 maintained therapeutic drug levels in the cervix for 65 hours and effectively reduced cyclin D1 levels by approximately 45%, indicating both efficacy and safety, as no adverse effects were observed in the study.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vaginal Suppositories Containing SHetA2 to Treat Cervical Dysplasia: Pharmacokinetics of Daily Doses and Preliminary Safety Profile. Mahjabeen, S., Hatipoglu, MK., Kosanke, SD., et al.[2021]

SHetA2 shows a promising safety profile and potential for cancer prevention and treatment, with pharmacokinetic modeling conducted on data from mice, rats, and dogs to predict human absorption and disposition.

The study found that SHetA2's oral bioavailability varies significantly across species and doses, leading to a recommended first-in-human dose that is lower than what toxicology studies suggested, ensuring safety in initial human trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and interspecies scaling of a novel, orally-bioavailable anti-cancer drug, SHetA2. Sharma, A., Benbrook, DM., Woo, S.[2021]

Vaginal administration of SHetA2 at a 15 mg/kg dose resulted in cervix concentrations that were about 120 times higher than those achieved with a 60 mg/kg oral dose, indicating a much more effective delivery method for this compound.

The 30 mg/kg vaginal dose not only provided the highest cervix concentration but also significantly reduced cyclin D1 levels, making it the chosen dose for future studies on its efficacy in treating cervical neoplasia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and Pharmacodynamics of Escalating Doses of SHetA2 After Vaginal Administration to Mice. Mahjabeen, S., Hatipoglu, MK., Benbrook, DM., et al.[2023]

SHetA2 effectively inhibits key cancer behaviors such as growth, migration, and invasion in endometrial cancer cell lines, while also inducing cell death through mitochondrial damage and apoptosis mechanisms.

When combined with paclitaxel, SHetA2 shows a synergistic effect, leading to greater tumor growth inhibition in xenograft models than either drug used alone, suggesting a promising new treatment strategy for advanced endometrial cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Utility and Mechanism of SHetA2 and Paclitaxel for Treatment of Endometrial Cancer. Chandra, V., Rai, R., Benbrook, DM.[2021]

References

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

Sensitivities of Uterine Adenocarcinoma, Mixed Mullerian Tumor (MMT) and Sarcoma Cell Lines to Chemotherapeutic Agents and a Flex-Het Drug. [2021]

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

Physiologically Based Pharmacokinetic Modeling and Tissue Distribution Characteristics of SHetA2 in Tumor-Bearing Mice. [2021]

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

Quantitative Chemotherapeutic Profiling of Gynecologic Cancer Cell Lines Using Approved Drugs and Bioactive Compounds. [2023]

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

Novel ovarian cancer maintenance therapy targeted at mortalin and mutant p53. [2021]

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

Xenopatients show the need for precision medicine approach to chemotherapy in ovarian cancer. [2022]

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

Vaginal Suppositories Containing SHetA2 to Treat Cervical Dysplasia: Pharmacokinetics of Daily Doses and Preliminary Safety Profile. [2021]

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

Pharmacokinetics and interspecies scaling of a novel, orally-bioavailable anti-cancer drug, SHetA2. [2021]

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

Pharmacokinetics and Pharmacodynamics of Escalating Doses of SHetA2 After Vaginal Administration to Mice. [2023]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Utility and Mechanism of SHetA2 and Paclitaxel for Treatment of Endometrial Cancer. [2021]