A Phase 2 Trial of Cryosurgical Freezing and Intratumoral Combination Immunotherapy in Men With Metastatic Prostatic Adenocarcinoma
Overview
- Phase
- Phase 2
- Intervention
- Opdivo Injectable Product
- Conditions
- Metastatic Prostatic Adenocarcinoma
- Sponsor
- Rampart Health, L.L.C.
- Enrollment
- 12
- Locations
- 2
- Primary Endpoint
- Primary endpoint: PSA decline
- Status
- Completed
- Last Updated
- 3 years ago
Overview
Brief Summary
This study seeks to estimate the occurrence of adverse events related to the study treatment (Cryosurgical freezing and Intratumoral Combination Immunotherapy), as well as determine the potential efficacy.
Detailed Description
Cryosurgical freezing will release intact antigens to prime the immune system. The study treatment immunotherapeutic drugs (PD-1 inhibitor monoclonal antibody nivolumab and anti-CTLA-4 monoclonal antibody ipilimumab, and cyclophosphamide) will then be sequentially injected directly into the cancer immediately following cryosurgical freezing. Oral low-dose cyclophosphamide will also be administered subsequently. It is speculated that neoantigens released from the cryoablated necrotic cancer will be available in the vicinity of the cryosurgical freezing field immediately following the procedure. Immature dendritic cells attracted to the injection site will internalize neoantigens to become activated to recognize cancer-specific antigenic proteins. The activated dendritic cells will recruit killer T-cells to the injection site to attack cancer cells, and then migrate through the lymphatic system to sites of metastases, targeting cancer-specific neoantigens and recruiting more killer T-lymphocytes to destroy other cancer cells harboring the precise antigenic epitopes (abscopal (bystander) effect). In this way, dendritic cells are capable of initiating cell-mediated systemic immune response in combination with cytotoxic killer T-cells. Regulatory T lymphocytes, which have been implicated in dampening or halting cell-mediated, antigen-specific immune responses, will be selectively depleted by anti-CTLA-4 monoclonal antibodies and low-dose cyclophosphamide. Intratumoral injection of the immunotherapeutic medications assists in stimulating and harnessing the local and systemic immune response. Oral cyclophosphamide prolongs the immune response. Using this combination of therapies, referred to as AbscopalRx1001, it is thought that a clinically significant systemic anti-cancer immune response might be elicited. Intratumoral injection of drugs will likely offer fewer side effects than systemic therapy.
Investigators
Eligibility Criteria
Inclusion Criteria
- •5.3.1 Be willing and able to provide written informed consent/assent for the trial.
- •5.3.2 Be ≥18 years of age on day of signing informed consent.
- •5.3.3 Have a performance status of 0-3 on the ECOG Performance Scale.
- •5.3.4 Have a life expectancy of 6 months or more as determined by treating physician.
- •5.3.5 Not a candidate for or refuses chemotherapy; or failure of prior chemotherapy.
- •5.3.6 PSA \>2 ng/mL at baseline.
- •5.3.7 Available archival tumor tissue for correlative studies. Submission of archival TRUS prostate biopsy tissue is required if available, in the form of representative formalin-fixed paraffin-embedded (FFPE) tumor specimens in paraffin blocks (preferred) or at least 15 slides, with an associated pathology report. If archival prostate tissues are unavailable or cannot be obtained, a repeat TRUS prostate biopsy is not required for eligibility.
- •5.3.8 Histologically-documented adenocarcinoma or mixed adenocarcinoma-neuroendocrine carcinoma of the prostate. All subjects must submit their primary tumor or metastatic biopsy pathology specimens and laboratory and imaging reports to Rampart Health where they will be centrally reviewed. Central Rampart Health pathologic review is not required for screening but rather for confirmation of diagnosis and histologic subtype of cancer. Local pathologic review is sufficient for eligibility determination.
- •5.3.9 Measurable disease as defined by PCWG3 using iRECIST criteria and identified by radiographic imaging. In order to be eligible, the patient must have at least one metastatic bone and/or metastatic lymph node site(s) with cancer mass measuring 1 cm or more in diameter based on bone and/or soft tissue lesions as defined by any of the following:
- •Bone metastases defined by bone imaging. If the patient has technetium bone scan, and/or NaF PET performed, either study may be used for documenting metastases; both scans do not need to show the number of metastases required for study entry. For patients undergoing PSMA PET, only PSMA avid lesions that are consistent with metastasis will be counted as a site of metastasis.
Exclusion Criteria
- •5.4.1 Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment.
- •5.4.2 Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of systemic immunosuppressive therapy within 7 days prior to the first dose of trial treatment, with the exception of steroids for adrenal insufficiency in which case prednisone \<10mg/day or its equivalent is allowed.
- •5.4.3 Has a performance status of 4-5 on the ECOG Performance Scale.
- •5.4.4 Has a known history of active TB (Bacillus Tuberculosis).
- •5.4.5 Hypersensitivity to monoclonal antibodies such as nivolumab or any of its excipients.
- •5.4.6 Has had a prior anti-cancer monoclonal antibody within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
- •5.4.7 Clinically significant (i.e. active) cardiovascular disease: cerebral vascular accident (\<6 months prior to enrollment), myocardial infarction (\<6 months prior to enrollment), unstable angina, congestive heart failure (≥ New York Heart Association Classification Class II), or serious cardiac arrhythmia requiring medication.
- •5.4.8 Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent. Persisting toxicity related to prior therapy (NCI CTCAE v.5 Grade \> 1); however, alopecia, sensory neuropathy Grade ≤ 2, Grade 2 anemia, or other Grade ≤ 2 not constituting a safety risk based on investigator's judgment are acceptable.
- •5.4.9 Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting.
- •5.4.10 Has a known additional malignancy that is progressing or requires active treatment. Exceptions include carcinoid, basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.
Arms & Interventions
Single arm. Subjects receiving treatment.
Cryosurgical freezing and intratumoral combination immunotherapy as determined by the proportion of patients achieving serum PSA decline from baseline of at least 50%.
Intervention: Opdivo Injectable Product
Single arm. Subjects receiving treatment.
Cryosurgical freezing and intratumoral combination immunotherapy as determined by the proportion of patients achieving serum PSA decline from baseline of at least 50%.
Intervention: Yervoy Injectable Product
Single arm. Subjects receiving treatment.
Cryosurgical freezing and intratumoral combination immunotherapy as determined by the proportion of patients achieving serum PSA decline from baseline of at least 50%.
Intervention: Cytoxan
Single arm. Subjects receiving treatment.
Cryosurgical freezing and intratumoral combination immunotherapy as determined by the proportion of patients achieving serum PSA decline from baseline of at least 50%.
Intervention: Cryosurgical freezing (cryosurgery)
Outcomes
Primary Outcomes
Primary endpoint: PSA decline
Time Frame: baseline to 8 weeks after end of treatment (approximately 6 months)
Primary Endpoint: Efficacy of cryosurgical freezing and intratumoral combination immunotherapy as determined by the proportion of patients achieving serum PSA decline from baseline of at least 50%.
Secondary Outcomes
- Efficacy of cryosurgical freezing and intratumoral combination immunotherapy iRECIST criteria(baseline to 8 weeks after end of treatment (approximately 6 months))