COAST Therapy for Prostate Cancer

(COAST Trial)

Overseen By Jasmin Brooks

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Medical University of South Carolina

Must not be taking: Coumadin, Apixaban, others

Disqualifiers: Cardiac disease, Psychiatric disorder, others

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

76 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this Phase I/II study is to determine the safety and effectiveness of up to 5 study drugs used together for the treatment of solid tumor cancers. The drugs are hydroxychloroquine, metformin, sirolimus, dasatinib and nelfinavir and are given orally.

Will I have to stop taking my current medications?

The trial requires that patients stop using statins (cholesterol-lowering drugs) within 48 hours before starting the study treatment if they are taking nelfinavir mesylate. Other medications are not specifically mentioned, so it's best to discuss your current medications with the study team.

What data supports the effectiveness of the COAST Therapy drugs for prostate cancer?

Research suggests that metformin, one of the drugs in the COAST Therapy, may improve survival in prostate cancer patients and has potential anticancer effects. It is also being tested in combination with standard treatments for high-risk prostate cancer. ^{1 2 3 4 5}

Is Metformin safe for use in humans?

Metformin is considered a safe and well-tolerated treatment, commonly used for type 2 diabetes and being explored for prostate cancer treatment. ^{2 3 4 6 7}

What makes the COAST Therapy drug unique for prostate cancer?

The COAST Therapy drug is unique because it combines multiple agents like Hydroxychloroquine, Metformin, Sirolimus, Dasatinib, and Nelfinavir, which are not typically used together for prostate cancer. This combination targets different pathways in cancer cells, potentially offering a novel approach compared to standard treatments like docetaxel-based therapies. ^{8 9 10 11 12}

Eligibility Criteria

Adults with advanced solid tumors or prostate cancer, who have tried standard treatments without success. They must be relatively healthy, with stable vital signs and organ function, not on certain blood thinners or statins, and willing to use contraception if they can have children.

Inclusion Criteria

Platelet count ≥ 75,000 cells / mm3

I can take care of myself and am up and about more than half of the day.

Serum creatinine ≤ 1.5 times ULN

Exclusion Criteria

I haven't had radiation, surgery, or experimental treatments in the last 28 days.

I am currently taking blood thinners like coumadin or apixaban.

I have a serious health condition that might affect the study's goals.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment Phase I

Phase I cohort receives increasing components of the COAST regimen following a traditional 3+3 escalation design to determine the maximum tolerated dose.

Minimum of 3 months

Regular visits for dose escalation and monitoring

Treatment Phase II

Phase II evaluates the anti-tumor activity of the COAST RP2D combination in patients with advanced prostate cancer.

16 weeks

Regular visits for treatment and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessment of PSA progression-free rate.

4 weeks

Treatment Details

Interventions

• Hydroxychloroquine, Metformin, Sirolimus
• Hydroxychloroquine, Metformin, Sirolimus, Dasatanib
• Hydroxychloroquine, Metformin, Sirolimus, Nelfinavir
• Hydroxychloroquine, Metformin, Sirolimus, Nelfinavir, Dasatinib

Trial Overview The trial is testing a combination of five drugs: hydroxychloroquine, nelfinavir, metformin, dasatinib, and sirolimus for their safety and effectiveness in treating solid tumor cancers including advanced prostate cancer.

Participant Groups

Group I: Dose level 4 Experimental Treatment 1 Intervention

Group II: Dose level 3b Experimental Treatment 1 Intervention

Group III: Dose level 3a Experimental Treatment 1 Intervention

Group IV: Dose level 2b Experimental Treatment 1 Intervention

Group V: Dose level 2a Experimental Treatment 1 Intervention

Group VI: Dose level 1 Experimental Treatment 1 Intervention

Who Is Running the Clinical Trial?

Medical University of South Carolina

Lead Sponsor

Trials

994

Recruited

7,408,000+

Findings from Research

In a study of 551 patients diagnosed with high-grade prostatic intraepithelial neoplasia (HGPIN), metformin use in diabetic patients was linked to a significantly lower risk of developing prostate cancer compared to those who did not use metformin.

Longer durations of metformin treatment (≥2 years) were associated with a reduced incidence of prostate cancer and lower Gleason scores, suggesting that metformin may have protective effects in diabetic patients with HGPIN.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The impact of metformin use on the risk of prostate cancer after prostate biopsy in patients with high grade intraepithelial neoplasia. Dell'Atti, L., Galosi, AB.[2018]

Metformin is a safe and well-tolerated medication that can be used alongside standard treatments for prostate cancer, potentially reducing side effects from castration.

The STAMPEDE trial, starting in summer 2016, will evaluate the effectiveness of metformin as a repurposed treatment for men with high-risk prostate cancer, aiming to confirm its additional anticancer benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Repurposing Metformin as Therapy for Prostate Cancer within the STAMPEDE Trial Platform. Gillessen, S., Gilson, C., James, N., et al.[2021]

In a study of 25,695 male patients with type 2 diabetes, metformin users had a 20% lower risk of developing new-onset prostate cancer compared to those using sulfonylureas, indicating a potential protective effect of metformin.

Metformin was also associated with a 11% reduction in all-cause mortality compared to sulfonylurea users, suggesting that it may offer additional health benefits beyond blood sugar control.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Risk of New-Onset Prostate Cancer for Metformin Versus Sulfonylurea Use in Type 2 Diabetes Mellitus: A Propensity Score-Matched Study. Lee, YHA., Zhou, J., Hui, JMH., et al.[2022]

The novel biguanide derivative IM176 significantly reduced the viability of prostate cancer cell lines and patient-derived castration-resistant prostate cancer (CRPC) cells, showing lower IC50 values than metformin and phenformin, indicating it may be more effective in treating these cancers.

IM176 activates AMP-activated protein kinase, inhibits the mammalian target of rapamycin (mTOR), and induces apoptosis in prostate cancer cells, suggesting a strong mechanism of action that could make it a promising candidate for prostate cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A novel biguanide derivative, IM176, induces prostate cancer cell death by modulating the AMPK-mTOR and androgen receptor signaling pathways. Kim, Y., Yoo, S., Lim, B., et al.[2023]

In a study of 14,424 men who underwent radical prostatectomy, pre- and postdiagnostic use of metformin was linked to a significantly reduced risk of prostate cancer death (HR 0.47) and initiation of androgen deprivation therapy (ADT), suggesting it may improve survival outcomes for diabetic prostate cancer patients.

In contrast, high-dose insulin use was associated with an increased risk of ADT initiation and poorer survival, indicating that not all antidiabetic medications are beneficial for men with prostate cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prostate Cancer-specific Survival After Radical Prostatectomy Is Improved Among Metformin Users but Not Among Other Antidiabetic Drug Users. Joentausta, RM., Rannikko, A., Murtola, TJ.[2022]

A frequent co-deletion of the PTEN and STAT3 genes was found in liquid biopsies from patients with metastatic prostate cancer (mPCa), indicating a potential genetic marker for understanding the disease's progression.

Metformin, a diabetes medication, showed promise in reducing tumor growth in prostate cancer models by inhibiting the mTORC1/CREB pathway, suggesting that targeting the STAT3 signaling pathway could be an effective strategy for treating lethal mPCa.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

STAT3/LKB1 controls metastatic prostate cancer by regulating mTORC1/CREB pathway. Pencik, J., Philippe, C., Schlederer, M., et al.[2023]

In a study involving 11 patients with metastatic castration-resistant prostate cancer, the combination of ridaforolimus and bicalutamide showed no significant drug-drug interaction, indicating that ridaforolimus's effectiveness is not altered by bicalutamide.

However, the treatment resulted in dose-limiting toxicities in 3 out of 11 patients, including serious side effects like Grade 3 hyperglycemia, suggesting that this combination may not be safe or suitable for patients with asymptomatic or minimally symptomatic prostate cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tolerability, safety and pharmacokinetics of ridaforolimus in combination with bicalutamide in patients with asymptomatic, metastatic castration-resistant prostate cancer (CRPC). Meulenbeld, HJ., de Bono, JS., Tagawa, ST., et al.[2021]

The combination of docetaxel, estramustine, and imatinib in treating metastatic hormone-refractory prostate cancer resulted in a high incidence of serious thromboembolic events, including two deaths, leading to the early closure of the study.

Despite the potential for synergy between imatinib and taxanes, the safety concerns, particularly the interactions causing elevated prothrombin time and other severe toxicities, make this regimen unsuitable for further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I trial of docetaxel/estramustine/imatinib in patients with hormone-refractory prostate cancer. Lin, AM., Rini, BI., Derynck, MK., et al.[2018]

In a Phase II trial involving 34 patients with hormone-refractory prostate cancer, the combination therapy of dexamethasone, calcitriol, and carboplatin resulted in a prostate-specific antigen (PSA) response in 38.2% of patients, indicating potential efficacy in this difficult-to-treat population.

The median overall survival for patients receiving this combination therapy was 97.7 weeks, and while there were significant adverse events, the side-effect profile was considered acceptable for the treatment context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II trial of dexamethasone, vitamin D, and carboplatin in patients with hormone-refractory prostate cancer. Flaig, TW., Barqawi, A., Miller, G., et al.[2013]

In patients with colorectal cancer (CC) and type 2 diabetes, those taking metformin had significantly better outcomes, including fewer deaths (48% vs. 76%), lower recurrence rates (4% vs. 19%), and improved 5-year survival rates (57% vs. 37%).

For lung cancer (LC) patients with type 2 diabetes, metformin also improved survival, with a 5-year survival rate of 29% compared to 15% in controls, indicating that metformin may enhance prognosis in both cancer types, albeit through different metabolic pathways.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metformin Has Positive Therapeutic Effects in Colon Cancer and Lung Cancer. Henderson, D., Frieson, D., Zuber, J., et al.[2018]

Docetaxel-based therapy has been shown to provide a survival benefit for men with metastatic prostate cancer, marking a significant advancement beyond palliative care options.

Ongoing trials are exploring various combination therapies with docetaxel, but the best timing for initiating treatment remains unclear due to a lack of prospective clinical trial data.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The current role of chemotherapy in metastatic hormone-refractory prostate cancer. Petrylak, DP.[2022]

The combination of docetaxel and zoledronic acid in treating 14 patients with metastatic hormone-refractory prostate cancer was found to be safe, with no reported drug-related toxicity and minimal need for blood transfusions.

More than half of the patients experienced a significant reduction in prostate-specific antigen (PSA) levels by over 50% after 2 months, indicating potential efficacy, although further randomized trials are necessary to confirm these findings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Docetaxel and zoledronic acid in patients with metastatic hormone-refractory prostate cancer. Vordos, D., Paule, B., Vacherot, F., et al.[2018]

References

1. Brazil pubmed.ncbi.nlm.nih.gov

The impact of metformin use on the risk of prostate cancer after prostate biopsy in patients with high grade intraepithelial neoplasia. [2018]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Repurposing Metformin as Therapy for Prostate Cancer within the STAMPEDE Trial Platform. [2021]

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

Risk of New-Onset Prostate Cancer for Metformin Versus Sulfonylurea Use in Type 2 Diabetes Mellitus: A Propensity Score-Matched Study. [2022]

4. Korea (South) pubmed.ncbi.nlm.nih.gov

A novel biguanide derivative, IM176, induces prostate cancer cell death by modulating the AMPK-mTOR and androgen receptor signaling pathways. [2023]

5. Netherlands pubmed.ncbi.nlm.nih.gov

Prostate Cancer-specific Survival After Radical Prostatectomy Is Improved Among Metformin Users but Not Among Other Antidiabetic Drug Users. [2022]

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

STAT3/LKB1 controls metastatic prostate cancer by regulating mTORC1/CREB pathway. [2023]

7. Germany pubmed.ncbi.nlm.nih.gov

Tolerability, safety and pharmacokinetics of ridaforolimus in combination with bicalutamide in patients with asymptomatic, metastatic castration-resistant prostate cancer (CRPC). [2021]

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

A phase I trial of docetaxel/estramustine/imatinib in patients with hormone-refractory prostate cancer. [2018]

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

A phase II trial of dexamethasone, vitamin D, and carboplatin in patients with hormone-refractory prostate cancer. [2013]

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

Metformin Has Positive Therapeutic Effects in Colon Cancer and Lung Cancer. [2018]

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

The current role of chemotherapy in metastatic hormone-refractory prostate cancer. [2022]

12. England pubmed.ncbi.nlm.nih.gov

Docetaxel and zoledronic acid in patients with metastatic hormone-refractory prostate cancer. [2018]