Clinical Trials /

Pilot Study of Durvalumab and Vigil in Advanced Women's Cancers

NCT02725489

Description:

In this study, the researchers want to learn more about Vigil and durvalumab in advanced women's cancers: 1) how much of Vigil in combination with durvalumab (MEDI4736) can be given with an acceptable level of side effects, 2) the effects of Vigil and durvalumab in combination (good and bad), 3) if Vigil will cause changes in cancer cells that may help durvalumab attack the cancer, and 4) whether or not Vigil and durvalumab will slow your cancer or stop your cancer from getting worse. Combining Vigil with durvalumab will allow the former to induce (or increase) the infiltration of activated T cells into tumors, and in addition, to enhance PD-L1 (programmed cell death ligand 1) expression. Consequently, the response rate of historically low or un-responsive cancer will be increased with the combination of Vigil and anti PD-L1.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Pilot Study of <span class="go-doc-concept go-doc-intervention">Durvalumab (MEDI4736)</span> in Combination With Vigil in Advanced Breast Cancer

Title

  • Brief Title: Pilot Study of Durvalumab (MEDI4736) in Combination With Vigil in Advanced Breast Cancer
  • Official Title: Pilot Study of Durvalumab (MEDI4736) in Combination With Vigil in Advanced Breast Cancer
  • Clinical Trial IDs

    NCT ID: NCT02725489

    ORG ID: 16-06

    NCI ID: CL-PTL 124

    Trial Conditions

    Triple Negative Breast Cancer

    Trial Interventions

    Drug Synonyms Arms
    Durvalumab (MEDI4736) Part 1 - Cohort 1 - 3 to 6 patients, low dose of Vigil, Part 1 - Cohort 2 - 3 to 6 patients, higher dose of Vigil, Part 1 - Cohort -1, if needed - lowest dose of Vigil, Part 2 - remaining patients, Part 1 determined dose of Vigil

    Trial Purpose

    Combining Vigil with Durvalumab (MEDI4736) will allow Vigil to increase the infiltration
    of activated T cells into tumors, and in addition, to enhance PD-L1 (programmed cell death
    ligand 1) expression. Consequently, the response rate of historically unresponsive PD-L1
    negative cancer to Durvalumab (MEDI4736) will reach a level similar to that achieved in
    PD-L1 positive cancer.

    Detailed Description

    This is an open label pilot study to evaluate the safety, tolerability, and efficacy of the
    combination of Vigil autologous tumor cell immunotherapy and Durvalumab (programmed cell
    death ligand 1) inhibitor in patients with PD-L1 negative locally advanced or metastatic
    triple negative breast cancer (TNBC), regardless of the number of prior therapies. PD-L1
    negative tumor status is defined as < 1% membranous PD-L1 staining with antihuman PDL1
    rabbit monoclonal antibody SP263 (Ventana, Tucson, AZ) of neoplastic cells.

    Patients undergoing a standard surgical procedure (e.g., tumor biopsy, palliative resection,
    thoracentesis of malignant pleural effusion) will have tumor tissue procured for manufacture
    of Vigil vaccine. This will be a 2 part study. The first part will be a safety run-in
    comprised of 2 cohorts that will use a 3 + 3 design to determine the Vigil dose in Part 2.
    Cohort 1 will receive a low dose of Vigil (1x10^6 cells/intradermal (ID) injection) in
    combination with Durvalumab (1500 mg (if > 30 kg) IV over 60 minutes) every 4 weeks. Cohort
    2 will receive Vigil at 1x10^7 cells/ID injection and Durvalumab (1500mg (if > 30 kg) IV
    over 60 minutes) every 4 weeks. If needed, Cohort -1 will be used which will receive Vigil
    at 1x10^5 cells/ID injection and Durvalumab (1500mg (if > 30 kg) IV over 60 minutes) every 4
    weeks. The enrollment of the first two patients in each Cohort of Part 1 will be staggered
    by 2 weeks, In Part 2 of the study, patients meeting study eligibility criteria will receive
    Vigilat the dose determined in Part 1 and Durvalumab (1500mg (if > 30 kg) IV over 60
    minutes) every 4 weeks.

    Three to six weeks after tissue procurement has occurred eligibility will be reconfirmed by
    the study site. Subjects must begin the study regimen within 6 weeks of tissue procurement.
    Radiological assessment of tumor response should be performed at screening, Cycle 3 and
    every 2nd cycle thereafter, and end of treatment (EOT) using RECIST 1.1 and investigator
    assessment. Tumor biopsy for correlative studies including scoring of tumor infiltrating
    lymphocyte (TIL) and PD-1 and PD-L1 expression analysis should be obtained at tissue
    procurement and at Cycle 3. Peripheral blood mononuclear cells (PBMC) for correlative
    studies should be obtained at pre-procurement, and prior to study regimen administration at
    Cycle 1, Cycle 3, Cycle 5 and EOT. Patient survival will be followed for 1 year after
    treatment initiation.

    Trial Arms

    Name Type Description Interventions
    Part 1 - Cohort 1 - 3 to 6 patients, low dose of Vigil Experimental The first part will be a safety run-in comprised of 2 cohorts that will use a 3 + 3 design to determine the Vigil dose in Part 2. Cohort 1 will receive a low dose of Vigil (1x10^6 cells/intradermal (ID) injection) in combination with Durvalumab (1500 mg (if > 30 kg) IV over 60 minutes) every 4 weeks. Durvalumab (MEDI4736)
    Part 1 - Cohort 2 - 3 to 6 patients, higher dose of Vigil Active Comparator Cohort 2 will receive Vigil at 1x10^7 cells/ID injection and Durvalumab (1500mg (if > 30 kg) IV over 60 minutes) every 4 weeks. Durvalumab (MEDI4736)
    Part 1 - Cohort -1, if needed - lowest dose of Vigil Active Comparator If needed, Cohort -1 will be used which will receive Vigil at 1x10^5 cells/ID injection and Durvalumab (1500mg (if > 30 kg) IV over 60 minutes) every 4 weeks. Durvalumab (MEDI4736)
    Part 2 - remaining patients, Part 1 determined dose of Vigil Active Comparator In Part 2 of the study, patients meeting study eligibility criteria will receive Vigil at the dose determined in Part 1 and Durvalumab (1500mg (if > 30 kg) IV over 60 minutes) every 4 weeks. Durvalumab (MEDI4736)

    Eligibility Criteria

    Inclusion Criteria:

    Tissue Procurement Inclusion Criteria:

    - Ability to understand and the willingness to sign a written informed consent document
    for tissue harvest

    - Willing and able to comply with the protocol for the duration of the study including
    undergoing treatment and scheduled visits and examinations including follow up.

    - Histologically or cytologically confirmed diagnosis of triple negative breast cancer
    (TNBC) that is locally advanced or metastatic for which the projected response rate
    to Durvalumab is 10% or less.

    - Female patients age 18 years

    - No prior Vigil immunotherapy

    - No prior PD-1 or PD-L1 inhibitor therapy including Durvalumab

    - ECOG Performance Status 1

    - Estimated survival 6 months

    - Planned standard of care surgical procedure (e.g., tumor biopsy or palliative
    resection or thoracentesis) and expected availability of a cumulative mass of ~10-30
    grams tissue ("golf-ball" size) or pleural fluid estimated volume 500mL (must be
    primary tap) for immunotherapy manufacture.

    - One lesion not previously irradiated nor intended for vaccine manufacture, which can
    be biopsied with minimal invasion and measurable at baseline as per RECIST 1.1
    guidelines (performed prior to biopsy) or 2 lesions not previously irradiated nor
    intended for vaccine manufacture, one of which can be biopsied with minimal invasion
    and the other of which is measurable at baseline as per RECIST 1.1 guidelines. If the
    only such target lesion has previously been irradiated it must have shown unequivocal
    evidence of disease progression following completion of radiation therapy.

    - Provision of tumor tissue sample (archived or fresh) to allow for PD-L1 expression
    analysis

    Study Enrollment Inclusion Criteria:

    - Successful manufacturing of at least 4 vials of Vigil.

    - Ability to understand and the willingness to sign a written informed consent document

    - Willing and able to comply with the protocol for the duration of the study including
    undergoing treatment and scheduled visits and examinations including follow up.

    - Estimated survival of 6 months

    - If female of childbearing potential, has a negative urine or serum pregnancy test. If
    the urine test is positive or cannot be confirmed as negative, a negative serum test
    will be required for study entry. Females of childbearing potential are defined as
    those who are not surgically sterile (ie, bilateral tubal ligation, bilateral
    oophorectomy, or complete hysterectomy) or postmenopausal (defined as 12 months with
    no menses without an alternative medical cause)

    - Adequate organ and bone marrow function as defined below:

    1. Absolute neutrophil count (ANC) > 1.5 10^9/L (1500 per mm3)

    2. Platelets > 100 10^9/L (100,000 per mm3)

    3. Hemoglobin 9.0 g/dL (5.59 mmol/L)

    4. Creatinine clearance (CrCL) > 50 mL/min by the Cockcroft-Gault formula or by
    24-hour urine collection for determination of creatinine clearance:

    Females: CrCL (mL/min) = Weight (kg) (140 - Age) 0.85 / 72 serum creatinine
    (mg/dL)

    5. Serum bilirubin 1.5 upper limit of normal (ULN). This will not apply to
    patients with confirmed Gilbert's syndrome (persistent or recurrent
    hyperbilirubinemia that is predominantly unconjugated in the absence of evidence
    of hemolysis or hepatic pathology) who will be allowed in consultation with
    their physician.

    6. AST and ALT 2.5 ULN in patients with no liver metastasis

    7. AST or ALT 5 ULN in patients with liver metastasis

    - Subject has recovered to CTCAE Grade 1 or better from all adverse events associated
    with prior therapy or surgery

    1. Pre-existing motor or sensory neurologic pathology or symptoms must be recovered
    to CTCAE Grade > 2 or better

    2. Patients with irreversible toxicity that is not reasonably expected to be
    exacerbated by the IPs may be included (e.g., hearing loss) after consultation
    with the Medical Monitor

    - Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy,
    endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal
    antibodies, other investigational agent) prior to tissue procurement and at least 21
    days prior to the first dose of study drug (at least 21 days prior to the first dose
    of study drug for subjects who have received prior TKIs [e.g., erlotinib, gefitinib
    and crizotinib] and within 6 week for nitrosourea or mitomycin C). (If sufficient
    wash-out time has not occurred due to the schedule or PK properties of an agent, a
    longer wash-out period may be required.)

    Exclusion Criteria:

    Tissue Procurement Exclusion Criteria:

    - Concurrent enrollment in another clinical study, unless it is an observational
    (noninterventional) clinical study or the follow-up period of an interventional
    study.

    - Medical condition requiring any form of chronic systemic immunosuppressive therapy
    (steroid or other) except physiologic replacement doses of hydrocortisone or
    equivalent (no more than 30 mg hydrocortisone or 10 mg prednisone equivalent daily
    for < 30 days duration.

    - Any prior Grade 3 immune-related adverse event (irAE) while receiving any previous
    immunotherapy agent.

    - Known history of other malignancy unless having undergone curative intent therapy
    without evidence of that disease for 5 years except cutaneous squamous cell and
    basal cell skin cancer, superficial bladder cancer, in situ cervical cancer or other
    in situ cancers are allowed if definitively resected.

    - History of brain metastases unless treated with curative intent (gamma knife or
    surgical resection) and without evidence of progression for 4 months.

    - Any documented history of autoimmune disease with exception of Type 1 diabetes on
    stable insulin regimen, hypothyroidism on stable dose of replacement thyroid
    medication, vitiligo, or asthma not requiring systemic steroids (unless within the
    protocol allowed doses).

    - Known history of allergies or sensitivities to gentamicin, Durvalumab, or any
    excipient.

    - History of or current evidence of any condition (including medical, psychiatric or
    substance abuse disorder), therapy, or laboratory abnormality that might confound the
    results of the study, interfere with the patient's participation for the full
    duration of the study, or is not in the best interest of the patient to participate,
    in the opinion of the treating Investigator.

    - Known HIV or acute or chronic Hepatitis B or C infection.

    - History of pneumonitis or interstitial lung disease.

    - History of organ transplant that requires therapeutic immunosuppression

    - Active or prior documented inflammatory bowel disease (e.g., Crohn's disease,
    ulcerative colitis)

    - History of Peptic Ulcer Disease or gastritis

    - History of primary immunodeficiency

    - History of leptomeningeal carcinomatosis

    - Known history of previous clinical diagnosis of tuberculosis

    - Previous allogeneic bone marrow transplant

    - Involvement in the planning and/or conduct of the study (applies to both AstraZeneca
    staff and/or staff at the study site)

    - Previous enrollment in the present study

    Study Enrollment Exclusion Criteria:

    - Any anti-neoplastic therapy between tissue procurement for vaccine manufacture and
    start of study therapy. Limited field of radiation for palliation greater than 3
    weeks prior of the first dose of study treatment is allowed:

    1. Provided the lung is not in the radiation field

    2. Provided irradiated lesion(s) cannot be used as target lesions

    - Receipt of live, attenuated vaccine within 30 days prior to the first dose of Vigil
    Durvalumab. NOTE: Subjects, if enrolled, should not receive live vaccine during the
    study and 180 days after the last dose of both drugs.

    - Post-surgery complication that in the opinion of the treating investigator would
    interfere with the patient's study participation or make it not in the best interest
    of the patient to participate

    - Participation in another clinical study with an investigational product during the
    last 3 weeks

    - Mean QT interval corrected for heart rate (QTc) 470 ms calculated from 3
    electrocardiograms (ECGs) using Frediricia's Correction

    - Female subjects who are pregnant, breast-feeding or of reproductive potential who are
    not employing an effective method of birth control defined in the protocol (section
    7.6)

    - Any condition that, in the opinion of the investigator, would interfere with
    evaluation of study treatment or interpretation of patient safety or study results

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Female

    Primary Outcome Measures

    Number of patients who tolerate and experience adverse events with Vigil combined with Durvalumab.

    Secondary Outcome Measures

    Overall response rate in patients with PD-L1 negative triple negative breast cancer who are treated with Vigil and Durvalumab.

    Number of patients who's IFN-ELISPOT was negative who conversely became IFN-ELISPOT positive following treatment with Vigil and Durvalumab.

    Trial Keywords

    Vigil, Durvalumab (MEDI4736), Triple Negative Breast Cancer, PD-L1