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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the safety and effectiveness of a combination of up to five study drugs for treating solid tumor cancers, with a specific focus on prostate cancer. The drugs being tested—hydroxychloroquine, metformin, sirolimus, dasatinib, and nelfinavir—are all taken orally. The study seeks participants with advanced prostate cancer who have experienced disease progression despite standard treatments and have a PSA level of at least 0.1 ng/mL. Participants should have shown progression during or after treatments such as chemotherapy or hormone therapy. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to contribute to groundbreaking research.

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.

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

Research has shown that the combination of hydroxychloroquine, metformin, sirolimus, nelfinavir, and dasatinib has been studied for safety in treating certain cancers. One study found that metformin, typically used for diabetes, might improve survival rates in prostate cancer patients and could have cancer-fighting effects. However, another study found that combining metformin with statins, which lower cholesterol, was linked to higher death rates in prostate cancer patients.

Trials have been conducted to determine the best dose and monitor side effects of these drug combinations. These trials aim to assess how well patients tolerate the drugs when used together. It is important to note that this study is in its early stages, with researchers still gathering information on the safety of these combinations. This phase of research typically focuses on ensuring the treatments are safe for people and identifying the correct doses. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for prostate cancer because they combine well-known drugs like hydroxychloroquine, metformin, sirolimus, dasatinib, and nelfinavir in innovative ways to potentially enhance effectiveness. Unlike standard treatments that often focus on hormone therapy or chemotherapy, these combinations aim to target cancer cells through multiple pathways, potentially reducing resistance. Specifically, dasatinib works by inhibiting cancer cell growth, while metformin and hydroxychloroquine may disrupt cancer cell metabolism. This multi-pronged approach could lead to more effective treatments with fewer side effects, offering hope for improved patient outcomes.

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

Research has shown that metformin, a drug used in COAST Therapy, may lower the risk of prostate cancer. In one study involving over 25,000 men with type 2 diabetes, those who took metformin had a 20% lower chance of developing prostate cancer. Hydroxychloroquine, another drug in the therapy, might enhance cancer treatment by increasing a protein that helps stop tumors. Early results suggest that using these drugs together, along with Sirolimus and potentially Dasatinib or Nelfinavir, could be especially effective against prostate cancer by targeting how cancer cells survive. Researchers are investigating whether this combination can fight cancer more effectively and prevent resistance to treatment. Participants in this trial will receive different combinations of these drugs at various dose levels to evaluate their effectiveness. ^{1 2 3 5 6}

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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]

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]

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 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]

Citations

1. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2022-03007

Autophagy Therapeutics (Hydroxychloroquine, Nelfinavir ... This phase I/II trial studies the side effects and best dose of a hydroxychloroquine, nelfinavir, sirolimus, metformin, and dasatinib combination (COAST)

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4006350/

Impact Of Metformin On Prostate Cancer Outcomes After ... Recent studies have shown a relative risk reduction in the incidence of prostate cancer in patients taking metformin. However there are conflicting findings ...

3. withpower.com withpower.com/trial/phase-2-prostatic-neoplasms-9-2021-78808

COAST Therapy for Prostate Cancer (COAST Trial) 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 ...

4. hollingscancercenter.musc.edu hollingscancercenter.musc.edu/news/archive/2022/07/14/researchers-test-drug-combination-as-means-to-prevent-drug-resistance-in-cancer-cells

Researchers test drug combination as means to prevent ... Lilly said early indications are that these drugs might be particularly effective against ovarian and prostate cancers. Lilly, who treats ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT04011410

Hydroxychloroquine to Increase Tumor Suppressor PAR-4 ... Treatment of recurrent oligometastatic prostate cancer may be enhanced by the addition of Hydroxychloroquine to the current treatment regimens.

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40348654/

Eliciting the Impact of Metformin and Statins on Prostate ... The highest mortality was observed in PC patients exposed to both statins and metformin (hazard ratio [HR] 2.29, 95% confidence interval [CI] 2.25-2.33).