COAST Therapy in Advanced Solid Tumors and Prostate Cancer

Study Overview
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Brief Summary
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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, nelfinavir, metformin, dasatinib and sirolimus.

Official Title
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Combination of Autophagy Selective Therapeutics (COAST) in Advanced Solid Tumors or Relapsed Prostate Cancer, A Phase I/II Trial

Conditions
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Prostate Cancer Recurrent, Solid Tumor, Adult

Intervention / Treatment
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* Combination Product: Hydroxychloroquine, Metformin, Sirolimus
* Combination Product: Hydroxychloroquine, Metformin, Sirolimus, Dasatanib
* Combination Product: Hydroxychloroquine, Metformin, Sirolimus, Nelfinavir
* Combination Product: Hydroxychloroquine, Metformin, Sirolimus, Nelfinavir, Dasatinib
* Combination Product: Hydroxychloroquine, Metformin, Sirolimus, Nelfinavir
* Combination Product: Hydroxychloroquine, Metformin, Sirolimus, Nelfinavir, Dasatinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient must have advanced solid tumor cancer of any type (Phase I) or advanced prostate cancer (Phase II). Tissue diagnosis documented by pathology report, or clinic note attesting to same. Measurable / evaluable tumor by RECIST, quantitative blood biomarker, or radionuclide imaging Voluntary, signed and dated, Institutional Review Board (IRB) approved consent form in accordance with regulatory and institutional guidelines. Documented progression of disease during treatment with one or more standard systemic regimens. Single or multiple regimens of chemotherapy, hormone suppression therapy, radiation therapy, surgery, immunotherapy, or adoptive cell therapy are allowed. 18 years of age or older. ECOG performance status of 0-2. Bilirubin ≤ 1.5 times upper limit of normal (ULN) and AST / ALT ≤ 3 times ULN. Subjects with Gilbert's syndrome may be included if the total bilirubin is < 3 times ULN and the direct bilirubin is within normal limits. Serum creatinine ≤ 1.5 times ULN. Absolute neutrophil count (ANC) ≥ 1,000 cells / mm3 Platelet count ≥ 75,000 cells / mm3 Hemoglobin ≥ 9 g/ dL. Fasting glucose ≤ 160 mg/dL or non-fasting glucose ≤ 200 mg/dL. Urinalysis with no clinically significant abnormalities. Adequately controlled blood pressure as determined by the treating investigator. Subjects with the potential to produce children must agree to effective contraceptive method use during study participation. Patients requiring narcotic analgesics must be on stable doses for at least 2 weeks prior to study entry. Patients being considered for a dose level containing nelfinavir mesylate must discontinue any statin use within 48 hours of beginning study treatment. Exclusion Criteria: New York Heart Association Class III or IV, cardiac disease, myocardial infarction within the past 6 months, unstable arrhythmia, or history of ischemia on ECG. Underlying psychiatric disorder requiring hospitalization within the last two years. Clinically significant neurological disorder (Parkinson's disease, dementia, multiple sclerosis), as determined by the enrolling investigator. Active, uncontrolled bacterial, viral, or fungal infection, requiring systemic therapy. Treatment with local or systemic radiation therapy, surgery, or investigational therapy within 28 days prior to registration. Unwillingness or inability to comply with procedures required in this protocol. Serious nonmalignant disease that could compromise protocol objectives in the opinion of the Investigator. Patients who are receiving, coumadin, apixaban, argatroban or rivaroxaban. Patients who are currently participating in any other clinical trial of an investigational product. Any other mental incapacitation or psychiatric illness that would preclude study participation, as determined by the enrolling investigator. Prisoners or patients who are compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical (e.g., infectious disease) illness must not be enrolled into this study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose level 1<br> | Combination Product: Hydroxychloroquine, Metformin, Sirolimus<br>* Hydroxychloroquine 600mg twice daily Metformin 500mg daily for 7 days, then increase to 1000mg daily Sirolimus 0.5mg daily<br>|
| Experimental: Dose level 2a<br> | Combination Product: Hydroxychloroquine, Metformin, Sirolimus, Dasatanib<br>* Hydroxychloroquine 600mg twice daily Metformin 500mg daily for 7 days, then increase to 1000mg daily Sirolimus 0.5mg daily Dasatinib 20mg daily<br>|
| Experimental: Dose level 2b<br> | Combination Product: Hydroxychloroquine, Metformin, Sirolimus, Nelfinavir<br>* Hydroxychloroquine 600mg twice daily Metformin 500mg daily for 7 days, then increase to 1000mg daily Sirolimus 0.5mg daily Nelfinavir 1250mg twice daily<br>|
| Experimental: Dose level 3a<br> | Combination Product: Hydroxychloroquine, Metformin, Sirolimus, Nelfinavir, Dasatinib<br>* Hydroxychloroquine 600mg twice daily Metformin 500mg daily for 7 days, then increase to 1000mg daily Sirolimus 0.5mg daily Nelfinavir 1250mg twice daily Dasatanib 20mg daily<br>|
| Experimental: Dose level 3b<br> | Combination Product: Hydroxychloroquine, Metformin, Sirolimus, Nelfinavir<br>* Hydroxychloroquine 600mg twice daily Metformin 500mg daily for 7 days, then increase to 1000mg daily Sirolimus 0.5mg daily Nelfinavir 2500mg twice daily<br>|
| Experimental: Dose level 4<br> | Combination Product: Hydroxychloroquine, Metformin, Sirolimus, Nelfinavir, Dasatinib<br>* Hydroxychloroquine 600mg twice daily Metformin 500mg daily for 7 days, then increase to 1000mg daily Sirolimus 0.5mg daily Nelfinavir 2500mg twice daily Dasatanib 20mg daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) - Phase I | Maximum dose achievable without dose limiting toxicities (DLT's) | Minimum of 3 months after start of treatment on each dose level | 
| Measure of proportion of patients with disease control - Phase II | Stable disease by RECIST or PCWG3 criteria after 16 weeks of treatment on study. | Minimum of 16 weeks after start of treatment, per patient | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Quality of Life (QOL) score | To document the change in QOL (via disease-specific FACT questionnaire, composite score) in patients treated with COAST) after two and four cycles of treatment | Minimum of 16 weeks of treatment on study |