Neoadjuvant Hiltonol® (PolyICLC) for Prostate Cancer
Study Details
Study Description
Brief Summary
The purpose of this study is to test an approach of stimulating the body's immune system to attack prostate cancer. This study will test injection of a substance polylysine and carboxymethylcellulose (Poly-ICLC, Hiltonol®)through a needle guided by MRI (magnetic resonance imaging) ultrasound fusion technology into the prostate gland. Poly ICLC has been used to help the body in its fight against cancer. The first aim of the study is to determine the highest dose of a substance Poly-ICLC (Hiltonol®) that can be safely tolerated by the study participants. The second aim of the study is to find out the toxicity or side effects of poly-ICLC.
Condition or Disease | Intervention/Treatment | Phase |
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|
Phase 1 |
Detailed Description
This is a pilot dose escalation study of IT/IM Poly-ICLC in patients with high risk clinically localized prostate cancer. The dose and frequency of IT injections will be increased in successive cohorts to define a safe dose and schedule for further testing.
Intratumoral + intramuscular poly-ICLC in patients with clinical localized prostate cancer. In the current pilot clinical trial, poly-ICLC will be administered intratumorally (Artemis guided) and intramuscularly (e.g., deltoid muscle) prior to prostatectomy in patients with clinically localized prostate cancer. Based on the available preclinical data exploring intratumoral administration of PAMPs described above, we expect this approach will result in three immunomodulatory steps26:
Immunomodulatory Step 1: Innate immune local tumor killing induced by intratumoral poly-ICLC
- the initial intratumoral injections are expected to induce activation/recruitment of IL-12, TNF-α, and other cytokines and NK cells, resulting in early tumor killing and antigen release.9-11 Poly-ICLC may also have a direct antiproliferative effect on tumor cells mediated by interferon-inducible nuclear enzyme systems.
Immunomodulatory Step 2: Th1 and cytotoxic T lymphocyte priming as a result of the repeated in-situ poly-ICLC 'danger signal' combined with the tumor antigens released in step 1 and further processed and cross-presented by poly-ICLC-activated myeloid dendritic cells.7,8 Poly-ICLC is expected to recruit myeloid dendritic cells and macrophages to the tumor site where they can load with antigens being released through the innate mechanisms, present them Th1 cells, and cross-present them to CD8 T cells in the tumor or in the regional lymph nodes, thus generating antigen specific cytotoxic T lymphocytes.
Immunomodulatory Step 3 (or "Boost" phase): Maintenance of the systemic anti-tumor immune response and migration of cytotoxic T lymphocytes to remote metastases, through repeated intramuscular poly-ICLC induction of chemokines, other costimulatory factors, and inflammasome activation.23-25 The rationale for followup with intramuscular maintenance is that as part of the comprehensive response, dsRNAs such as poly-ICLC induce various chemokines and costimulatory factors that help target the response to tumor. For example, one of these costimulatory factors is OX40, which belongs to the tumor necrosis factor family of cytokines, and helps maintain cytotoxic lymphocyte longevity and action at the tumor and metastatic sites.
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
---|---|
Experimental: Cohort 1 Intratumoral (IT) Poly ICLC 0.5 mg IT once/week (week 1) Intramuscular (IM) Poly ICLC 1 mg IM twice weekly (weeks 3-6) Followed by Radical Prostatectomy at Week 10 |
Biological: Intratumoral (IT) Poly ICLC 0.5 mg
0.5 mg IT once/week (week 1)
Biological: Intramuscular (IM) Poly ICLC
1 mg IM twice weekly (weeks 3-6)
Other Names:
Procedure: Radical Prostatectomy
as per standard care
|
Experimental: Cohort 2 Intratumoral (IT) Poly ICLC 0.5 mg IT once/week (week 1+2) Intramuscular (IM) Poly ICLC 1 mg IM twice weekly (weeks 3-6) Followed by Radical Prostatectomy at Week 10 |
Biological: Intratumoral (IT) Poly ICLC 0.5 mg
0.5 mg IT once/week (week 1)
Biological: Intramuscular (IM) Poly ICLC
1 mg IM twice weekly (weeks 3-6)
Other Names:
Procedure: Radical Prostatectomy
as per standard care
|
Experimental: Cohort 3 Intratumoral (IT) Poly ICLC 1.0 mg IT once/week (week 1) Intramuscular (IM) Poly ICLC 1 mg IM twice weekly (weeks 3-6) Followed by Radical Prostatectomy at Week 10 |
Biological: Intratumoral (IT) Poly ICLC 1.0 mg
1.0 mg IT once/week (week 1)
Other Names:
Biological: Intramuscular (IM) Poly ICLC
1 mg IM twice weekly (weeks 3-6)
Other Names:
Procedure: Radical Prostatectomy
as per standard care
|
Experimental: Cohort 4 Intratumoral (IT) Poly ICLC 1.0 mg IT once/week (week 1+2) Intramuscular (IM) Poly ICLC 1 mg IM twice weekly (weeks 3-6) Followed by Radical Prostatectomy at Week 10 |
Biological: Intratumoral (IT) Poly ICLC 1.0 mg
1.0 mg IT once/week (week 1)
Other Names:
Biological: Intramuscular (IM) Poly ICLC
1 mg IM twice weekly (weeks 3-6)
Other Names:
Procedure: Radical Prostatectomy
as per standard care
|
Outcome Measures
Primary Outcome Measures
- Dose-Limiting Toxicity level [Week 6]
3+3 dose escalation rules to define a safe dose of preoperative intratumoral (IT) plus intramuscular (IM) Polyinosinic-polycytidylic acid stabilized with polylysine and carboxymethylcellulose (poly-ICLC, Hiltonol®) prior to radical prostatectomy
Secondary Outcome Measures
- Number of adverse events [Week 6]
Safety as determined by the frequency of adverse events as per the Common Terminology for Adverse Events (CTCAE) version 4.0.
- Time to PSA progression [up to Week 12]
The time to prostate-specific antigen (PSA) progression will be defined as the time to PSA > 0.2 ng/mL
Eligibility Criteria
Criteria
Inclusion Criteria:
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Written informed consent and HIPAA authorization for release of personal health information.
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Age > 18 years at the time of consent.
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ECOG Performance Status of 0-1 within 14 days prior to being registered for protocol therapy (Study Procedure Manual).
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Histologically confirmed adenocarcinoma of the prostate (with previous diagnostic tissue available for tumor marker analysis).
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Gleason 7 - 10, cT2a - cT3b adenocarcinoma of the prostate with plans for radical prostatectomy
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PSA ≥ 4 ng/ml
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Tumor visible on multiparametric MRI
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Tolerated previous transrectal ultrasound guided biopsy procedure under local anesthetic
- Uncomplicated previous TRUS biopsy procedure (i.e., no prior hospitalization due to sepsis, prostatic abscess or severe hemorrhage following TRUS prostate biopsy)
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Willing to undergo the intra-tumoral (IT) injection of the Poly-ICLC into the prostatic tumor as per the protocol
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No prior hormonal therapy with the exception of oral 5-alpha-reductase inhibitors (finasteride, dutasteride, etc.). Patients who have received prior oral anti-androgen therapies (bicalutamide, flutamide, nilutamide, etc.) must be off treatment for at least 6 weeks prior to enrollment. Patients who have received prior LHRH agonist or antagonist therapy (leuprolide, goserelin acetate, etc.) are eligible provided serum testosterone is > 50 mg/dl.
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No prior radiation therapy (external beam or brachytherapy) to the pelvis or prostate.
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No clinically significant infections as judged by the treating investigator.
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No characteristics suggesting a potential higher risk of infection with intraprostatic injections:
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Recurrent urinary tract infections or history of prostatitis within 3 months prior to enrollment into the study.
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Urine analysis positive for nitrites and leucocyte esterase. Such patients could be considered for the study after treatment and resolution of the infection.
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Active proctitis
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History of prostatic abscess
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Taking immunosuppressive medication including systemic corticosteroids
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Active hematologic malignancy
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No uncontrolled angina, congestive heart failure or MI within 6 months.
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Patients with history of HIV (if CD4+ T cell counts are ≥350 cells/µL on established ART therapy), Hepatitis B (with viral load below limits of quantification) or Hepatitis C (who have completed a curative therapy and have a viral load below the limit of quantification) are eligible for this study.
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No treatment with any investigational agent for any medical condition within 28 days prior to being registered for protocol therapy.
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Adequate end organ function as determined by the following laboratory values:
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White blood cell count (WBC) > 2.5 k/mm3
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Absolute neutrophil count (ANC) > 1.5 k/mm3
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Hemoglobin (Hgb) > 8.0 g/dL
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Platelets > 100 k/mm3
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Calculated creatinine clearance of > 60 cc/min using the Cockcroft-Gault formula:
Males: (140 - Age in years) × Actual Body Weight in kg 72 × Serum Creatinine (mg/dL)
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Bilirubin < 2.0 x ULN
-
Aspartate aminotransferase (AST) < 2.5 x ULN
-
Alanine aminotransferase (ALT) < 2.5 x ULN
- Able to speak, read and write in English.
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
---|---|---|---|---|---|
1 | Icahn School of Medicine at Mount Sinai | New York | New York | United States | 10029 |
Sponsors and Collaborators
- Ashutosh Kumar Tewari
- Oncovir, Inc.
Investigators
- Principal Investigator: Ashutosh K. Tewari, MD, Icahn School of Medicine at Mount Sinai
Study Documents (Full-Text)
None provided.More Information
Publications
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- GCO 15-2081