Clinical Trials /

A Phase 2 Trial for Patients With Metastatic Solid Cancer

NCT04713371

Description:

This study seeks to estimate the potential efficacy of the study treatment, as well as the occurrence of adverse events.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Phase 2 Trial for Patients With Metastatic Solid Cancer
  • Official Title: A Phase 2 Trial of Cryosurgical Freezing and Multiplex Immunochemotherapy in Patients With Metastatic Solid Cancer

Clinical Trial IDs

  • ORG STUDY ID: ABSCOPAL 5001
  • NCT ID: NCT04713371

Conditions

  • Metastatic Cancer

Interventions

DrugSynonymsArms
Keytruda Injectable ProductpembrolizumabSingle arm. Subjects receiving treatment.
Yervoy Injectable ProductipilimumabSingle arm. Subjects receiving treatment.
CytoxanCyclophosphamideSingle arm. Subjects receiving treatment.
GM-CSF InjectableSargramostimSingle arm. Subjects receiving treatment.

Purpose

This study seeks to estimate the potential efficacy of the study treatment, as well as the occurrence of adverse events.

Detailed Description

      Cryosurgical freezing (limited to 1.5 cm diameter single freeze within the cancer (up to two
      cancer sites selected and treated)) will release intact antigens to prime the immune system.
      The study treatment immunotherapeutic drugs (PD-1 inhibitor monoclonal antibody nivolumab or
      pembrolizumab and anti-CTLA-4 monoclonal antibody ipilimumab, and low-dose cyclophosphamide)
      will then be sequentially injected directly into each of the treated cancer sites immediately
      following cryosurgical freezing. These injections will be performed in combination with
      collagen (Helitene) to improve drug containment at the site of injection for improved local
      effect rather than rapid disbursement and dilution throughout adjacent interstitial spaces,
      as well as sustained drug delivery over time rather than a burst-release pattern. Prior to
      study treatment, oral low dose cyclophosphamide will be given. Post-treatment, daily
      subcutaneous low-dose GM-CSF injections 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, low-dose cyclophosphamide, and metronomic GM-CSF.
      Intra-tumoral injection of the immunotherapeutic medications assists in stimulating and
      harnessing the local and systemic immune response. GM-CSF prolongs the immune response. Using
      this combination of therapies, referred to as AbscopalRx5001, it is thought that a clinically
      significant systemic anti-cancer immune response might be elicited. Intra-tumoral injection
      of drugs will likely offer fewer side effects than systemic therapy.
    

Trial Arms

NameTypeDescriptionInterventions
Single arm. Subjects receiving treatment.OtherEfficacy of Cryosurgical Freezing and Multiplex Immunochemotherapy as determined by overall response rate of radiographic changes according to iRECIST criteria.
  • Keytruda Injectable Product
  • Yervoy Injectable Product
  • Cytoxan
  • GM-CSF Injectable

Eligibility Criteria

        Inclusion Criteria:

          -  Be willing and able to provide written informed consent/assent for the trial.

          -  Be ≥18 years of age on day of signing informed consent.

          -  Have a performance status of 0-3 on the ECOG Performance Scale.

          -  Have a life expectancy of 6 months or more as determined by treating physician.

          -  Have exhausted all other standard therapies; Have failed available therapy or are not
             a candidate for, or refuse available therapy (i.e. concerned with high adverse events
             rate in available therapy or outcome worse than disease); or failure of prior
             chemotherapy.

          -  Histologically-documented solid cancer. All subjects must submit their primary tumor
             or metastatic 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.

          -  Measurable disease as defined using iRECIST criteria and identified by radiographic
             imaging (Imaging should be current within the past three months of subject entering
             the study; if not repeat imaging must be done prior to enrollment.). In order to be
             eligible, the patient must have at least one metastatic bone and/or metastatic soft
             tissue site, lymph node site, and/or bone site with cancer mass measuring 1.0 cm or
             more in diameter based on soft tissue, lymph node, and/or bone lesions as defined by
             any of the following:

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

               -  Metastatic lymph node disease defined by imaging. Any lymph node ≥ 1.5 cm in
                  shortest dimension will be noted as involved with disease.

               -  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 (prostate cancer patients only), only PSMA-avid
                  lesions that are consistent with metastasis will be counted as a site of
                  metastasis.

          -  The effects of the medications in this protocol on the developing human fetus are
             unknown. Any subject 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.

          -  Their partners will also be encouraged to use proper method of contraception.

          -  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.

          -  NOTE: Women of child-bearing potential will be tested for pregnancy (which must be
             negative) before treatment is given. Acceptable range is < 5 mIU/mL

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

        Exclusion Criteria:

          -  Is currently participating in 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.

          -  Has bone metastasis as the only site of disease.

          -  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.

          -  Has a performance status of 4-5 on the ECOG Performance Scale.

          -  Has a known history of active TB (Bacillus Tuberculosis).

          -  Hypersensitivity to monoclonal antibodies such as nivolumab (or pembrolizumab) or any
             of its excipients.

          -  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.

          -  Is taking any current medication known to interfere with serum PSA concentration or
             radiographic extent of cancer (e.g., Enzalutamide, hormonal therapy) within 30 days
             for non-depot or 90 days for depot of start of treatment.

          -  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.

          -  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.

          -  Note: If subject received major surgery, they must have recovered adequately from the
             toxicity and/or complications from the intervention prior to starting.

          -  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.

          -  Has a metastatic lesion in locations that is deemed by the investigator as high risk
             for procedure-related complications (e.g., bleeding, nerve and/or bowel damage)
             despite consideration of preventative techniques such as hydro-dissection with fluid
             to push away adjacent crucial structures.

          -  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.

          -  Has known recent (within 2 years) history of, or any evidence of active,
             non-infectious pneumonitis.

          -  Has an active infection requiring systemic therapy.

          -  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.

          -  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.

          -  Pregnant and/or expecting to bear or 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.

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

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

          -  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.

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

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

          -  Score less than 12.0 (out of possible maximum of 20) on the UBACC Capacity to Consent
             Assessment Instrument.

          -  Hypersensitivity to Cyclophosphamide.

          -  Hypersensitivity to GM-CSF.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Primary Endpoint: Efficacy
Time Frame:baseline to 8 weeks after end of treatment (approximately 5 months))
Safety Issue:
Description:Efficacy of Cryosurgical Freezing and Multiplex Immunochemotherapy as determined by overall response rate of radiographic changes according to iRECIST criteria.

Secondary Outcome Measures

Measure:Efficacy
Time Frame:baseline to 8 weeks after end of treatment (approximately 5 months);
Safety Issue:
Description:Efficacy of Cryosurgical Freezing and Multiplex Immunochemotherapy as determined by RECIST1.1 criteria

Details

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

Last Updated

January 19, 2021