Clinical Trials /

A Phase 2 Trial for Men With Metastatic Prostatic Adenocarcinoma

NCT04090775

Description:

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.

Related Conditions:
  • Prostate Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Phase 2 Trial for Men With Metastatic Prostatic Adenocarcinoma
  • Official Title: A Phase 2 Trial of Cryosurgical Freezing and Intratumoral Combination Immunotherapy in Men With Metastatic Prostatic Adenocarcinoma

Clinical Trial IDs

  • ORG STUDY ID: ABSCOPAL 1001
  • NCT ID: NCT04090775

Conditions

  • Metastatic Prostatic Adenocarcinoma

Interventions

DrugSynonymsArms
Opdivo Injectable ProductnivolumabSingle arm. Subjects receiving treatment.
Yervoy Injectable ProductipilimumabSingle arm. Subjects receiving treatment.
CytoxanCyclophosphamideSingle arm. Subjects receiving treatment.

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Single arm. Subjects receiving treatment.OtherCryosurgical freezing and intratumoral combination immunotherapy as determined by the proportion of patients achieving serum PSA decline from baseline of at least 50%.
  • Opdivo Injectable Product
  • Yervoy Injectable Product
  • Cytoxan

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.

          -  Distant metastatic lymph node disease defined by imaging. A lymph node ≥1 cm in
             shortest dimension will be noted as involved with disease. Distant metastatic lymph
             nodes will be determined as any lymph nodes outside the confines of the true pelvis.
             For patients undergoing PSMA PET, only PSMA avid lesions that are consistent with
             metastasis will be counted as a site of metastasis.

          -  Any other soft tissue lesion defined by imaging deemed by the physician to be
             consistent with distant metastatic disease. For patients undergoing PSMA PET, only
             PSMA avid lesions that have a CT or MRI correlate consistent with metastasis will be
             counted as a site of metastasis.

        5.3.10 The effects of the medications in this protocol on the developing human fetus are
        unknown. Men treated or enrolled on this protocol must agree to use adequate contraception
        prior to the first dose of study therapy, for the duration of the study participation, and
        for 120 days after the last dose of study therapy.

        5.3.11 Their partners should be encouraged to use proper method of contraception.

        5.3.12 Acceptable initial laboratory values within 14 days of treatment initiation
        according to the following: ANC ≥ 1500/µl; Hemoglobin ≥ 9.0 g/dL(prior transfusion
        permitted); Platelet count ≥ 100,000/µl; Creatinine ≤ 2.0 x the institutional upper limit
        of normal (ULN) OR creatinine clearance >30 ml/min; Potassium ≥ 3.5 mmol/L (within
        institutional normal range); Bilirubin ≤ 1.5 x ULN (unless documented Gilbert's disease);
        SGOT (AST) ≤ 2.5x ULN, or <5x ULN in patients with documented liver metastases; SGPT (ALT)
        ≤ 2.5x ULN or <5x ULN in patients with documented liver metastases; Albumin >2.5 mg/dL;
        Activated Partial Thromboplastin Time (aPTT) ≤1.5 X ULN unless subject is receiving
        anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of
        anticoagulants ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT
        or PTT is within therapeutic range of intended use of anticoagulants. Deviation from these
        values is allowed at the discretion of the treating investigator.

        5.3.13 No active major medical or psychological problems that could be complicated by study
        participation.

        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.

        5.4.11 Has active autoimmune disease that has required systemic treatment in the past 2
        years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive
        drugs), including but not limited to systemic or cutaneous lupus erythematosus, cutaneous
        psoriasis, psoriatic arthritis, rheumatoid arthritis, scleroderma, sicca syndrome,
        polymyalgia rheumatica, polyarteritis nodosa, granulomatous polyangiitis, microscopic
        polyangiitis, polyarteritis nodosa, temporal arteritis, giant cell arteritis,
        dermatomyositis, Kawasaki disease. Replacement therapy (e.g., thyroxine, insulin, or
        physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency,
        hydroxychloroquine, etc.) is not considered a form of systemic treatment.

        5.4.12 Has known history of, or any evidence of active, non-infectious pneumonitis.

        5.4.13 Has an active infection requiring systemic therapy.

        5.4.14 Has a history or current evidence of any condition, therapy, or laboratory
        abnormality that might confound the results of the trial, interfere with the subject's
        participation for the full duration of the trial, or is not in the best interest of the
        subject to participate, in the opinion of the treating investigator.

        5.4.15 Has known psychiatric or substance abuse disorder or any other condition that would
        interfere with cooperation with the requirements of the trial in the opinion of the
        Physician-investigator.

        5.4.16 Expecting to father children within the projected duration of the trial, starting
        with the pre-screening or screening visit through 120 days after the last dose of trial
        treatment.

        5.4.17 Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).

        5.4.18 Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA
        [qualitative] is detected).

        5.4.19 Has received a live vaccine within 30 days of planned start of study therapy.

        Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and
        are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated
        vaccines, and are not allowed within 30 days.

        5.4.20 Personal representative (family member or friend) withholds consent for any reason.

        5.4.21 Unable for any reason to understand the consent form and other written information
        and freely give written informed consent.

        5.4.22 Scores less than 14.5 (out of possible maximum of 20) on the UBACC Capacity to
        Consent Assessment Instrument.

        5.4.23 Does not re-sign the consent form a second time at least 24 hours after initial
        consent but before the treatment procedure.

        5.4.24 Hypersensitivity to Cyclophosphamide.

        5.4.25 Urinary outflow obstruction.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Male
Healthy Volunteers:No

Primary Outcome Measures

Measure:Primary endpoint: PSA decline
Time Frame:baseline to 8 weeks after end of treatment (approximately 6 months)
Safety Issue:
Description: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 Outcome Measures

Measure:Efficacy of cryosurgical freezing and intratumoral combination immunotherapy iRECIST criteria
Time Frame:baseline to 8 weeks after end of treatment (approximately 6 months)
Safety Issue:
Description:Efficacy of cryosurgical freezing and intratumoral combination immunotherapy as determined by iRECIST criteria. Overall response rate as determined by PCWG3 using iRECIST radiographic response.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Rampart Health, L.L.C.

Last Updated