Clinical Trials /

MPDL3280A-treatment-IST-UMCG

NCT02478099

Description:

To be able to evaluate the investigational imaging - 89Zr-MPDL3280A-PET, 89Zr-CD8 imaging and 18F-FB-IL2-PET - as complementary tools for selection of patients to be treated with MPDL3280A, within this treatment trial the investigators will assess safety, tolerability and anti-tumor activity of MPDL3280A in cancer patients, who have undergone investigational imaging.

Related Conditions:
  • Bladder Carcinoma
  • Breast Carcinoma
  • Non-Small Cell Lung Carcinoma
  • Renal Pelvis and Ureter Carcinoma
  • Urethral Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: MPDL3280A-treatment-IST-UMCG
  • Official Title: MPDL3280A Treatment in Patients With Locally Advance or Metastatic Non-small Cell Lung, Cancer of the Urinary Tract and Triple Negative Breast Cancer After or During Investigational Imaging

Clinical Trial IDs

  • ORG STUDY ID: ML29755
  • NCT ID: NCT02478099

Conditions

  • Cancer of the Urinary Tract
  • Non Small Cell Lung Cancer
  • Breast Cancer

Interventions

DrugSynonymsArms
MPDL3280A1 Treatment with MPDL3280A

Purpose

To be able to evaluate the investigational imaging - 89Zr-MPDL3280A-PET, 89Zr-CD8 imaging and 18F-FB-IL2-PET - as complementary tools for selection of patients to be treated with MPDL3280A, within this treatment trial the investigators will assess safety, tolerability and anti-tumor activity of MPDL3280A in cancer patients, who have undergone investigational imaging.

Detailed Description

      Encouraging clinical data emerging in the field of tumor immunotherapy have demonstrated that
      therapies focused on enhancing T cell responses against cancer can result in a significant
      survival benefit in patients with Stage IV cancer. PD-L1 is an extracellular protein that
      downregulates immune responses primarily in peripheral tissues through binding to its two
      receptors PD-1 and B7-1. Interruption of the PD L1/PD-1 pathway by the PD-L1 targeting
      antibody MPDL3280A, represents an attractive strategy to reinvigorate tumor-specific T cell
      immunity. For PD1/PD-L1 pathway inhibition PD-L1 tumor surface expression was proposed as a
      potential biomarker. In early clinical trials, PD-L1 expression has been associated with
      response to PD1/PD-L1 inhibition. However, other clinical trials reported response to
      PD1/PD-L1 checkpoint inhibitors in a big patient groups who were PD-L1-negative assessed by a
      single biopsy. Another obstacle to using PD-L1 expression as predictive biomarker might be
      its potential heterogeneous expression and fast dynamics PD-L1 tumor expression and whole
      body distribution, as well as baseline activation status of the immune system are being
      assessed in three investigational imaging trials MPDL3280A-img-042015, 89Zr-CD8 imaging or
      IL2-img--UMCG-2015.

      To be able to evaluate the investigational imaging - 89Zr-MPDL3280A-PET, 89Zr-CD8 imaging and
      18F-FB-IL2-PET - as complementary tools for selection of patients to be treated with
      MPDL3280A, within this treatment trial we will assess safety, tolerability and anti-tumor
      activity of MPDL3280A in cancer patients, who have undergone investigational imaging.
      Acquired data could lead to improved, more patient friendly, more easily accessible and
      possibly less expensive procedures for patient selection. Subsequently, the efficacy of
      (combinations of) checkpoint inhibition could also be improved, thus preventing unnecessary
      toxicity and reducing health care costs.
    

Trial Arms

NameTypeDescriptionInterventions
1 Treatment with MPDL3280AExperimentalTreatment with MPDL3280A
  • MPDL3280A

Eligibility Criteria

        Inclusion Criteria:

          1. Histologically or cytologically documented solid locally advanced or metastatic NSCLC,
             cancer of the urinary tract or TNBC.

          2. Participation within the 89Zr-MPDL3280A antibody imaging trial (MPDL3280A-img-042015),
             CD8 imaging trial (ZED88082-img-UMCG-2018), 18F-IL2 imaging trial (IL2-img-UMCG-2015)
             before participation in the MPDL3280A treatment trial.

          3. Patient must have undergone a fresh tumor biopsy for PD-L1 assessment performed as
             part of one of the investigational imaging trials.

          4. Patients are eligible if disease progression during or following first-line
             chemotherapy or any subsequent treatment lines for locally advanced or metastatic
             NSCLC, TNBC or cancer of the urinary tract occurred.

               -  Additional criteria for cancer of the cancer of the urinary tract:

             oPatients with disease progression during or following platinum-based
             adjuvant/neoadjuvant chemotherapy are eligible if ≤ 12 months have elapsed between the
             last treatment administration and the date of recurrence.

             •Additional criteria for NSCLC: oPatients with disease progression during or following
             platinum-based adjuvant/neoadjuvant chemotherapy or concurrent chemoradiation for
             NSCLC are eligible if ≤ 6 months have elapsed between the last treatment
             administration and the date of recurrence.

             oPatients with a known sensitizing mutation in the epidermal growth factor receptor
             (EGFR) gene must also have experienced disease progression (during or after treatment)
             or intolerance to treatment with erlotinib, gefitinib, or another EGFR tyrosine kinase
             inhibitor (TKI).

             oPatients with a known Anaplastic Lymphoma Kinase (ALK) fusion oncogene must also have
             experienced disease progression (during or after treatment) or intolerance to
             treatment with crizotinib or another ALK inhibitor.

          5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

          6. Life expectancy ≥12 weeks.

          7. Signed Informed Consent Form.

          8. Ability to comply with protocol.

          9. Age ≥18 years.

         10. Measurable disease, as defined by standard RECIST v1.1. Previously irradiated lesions
             should not be counted as target lesions.

         11. Adequate hematologic and end organ function, defined by the following laboratory
             results obtained within ≤28days prior to the first full dose of MPDL3280A:

               -  ANC ≥1500 cells/μL (without granulocyte colony-stimulating factor support within
                  2 weeks prior to Cycle 1, Day 1)

               -  WBC counts >2500/μL

               -  Lymphocyte count ≥500/μL

               -  Platelet count ≥100,000/μL (without transfusion within 2 weeks prior to Cycle 1,
                  Day 1)

               -  Hemoglobin ≥9.0 g/dL. Patients may be transfused or receive erythropoietic
                  treatment to meet this criterion.

               -  AST, ALT, and alkaline phosphatase ≤ 2.5× the upper limit of normal (ULN), with
                  the following exceptions:

             oPatients with documented liver metastases: AST and/or ALT ≤ 5 × ULN oPatients with
             documented liver or bone metastases: alkaline phosphatase ≤ 5 × ULN

             •Serum bilirubin ≤ 1.5 × ULN. Patients with known Gilbert disease who have serum
             bilirubin level ≤ 3 × ULN may be enrolled.

               -  INR and aPTT ≤ 1.5 × ULN. This applies only to patients who are not receiving
                  therapeutic anticoagulation; patients receiving therapeutic anticoagulation
                  should be on a stable dose.

               -  Creatinine clearance ≥ 30 mL/min

         12. For female patients of childbearing potential and male patients with partners of
             childbearing potential, agreement (by patient and/or partner) to use a highly
             effective form(s) of contraception (i.e., one that results in a low failure rate [< 1%
             per year] when used consistently and correctly) and to continue its use for 6 months
             after the last dose of MPDL3280A.

        Exclusion Criteria:

          1. Any approved anti-cancer therapy, including chemotherapy or hormonal therapy within
             ≤21 days prior to the first full dose of MPDL3280A; the following exceptions are
             allowed:

               -  Hormone-replacement therapy or oral contraceptives.

               -  TKIs approved for treatment of NSCLC discontinued >7 days prior to the first full
                  dose of MPDL3280A. The baseline scan must be obtained after discontinuation of
                  prior TKIs.

          2. Treatment with any other investigational agent, other than the investigational tracer
             18F-FB-IL2 or 89Zr-MPDL3280A or 89Zr-CD8-imaging, or participation in another clinical
             trial with therapeutic intent within 28 days prior to the first full dose of
             MPDL3280A.

          3. Unstable brain metastases.

          4. Unstable leptomeningeal disease.

          5. Uncontrolled tumor-related pain.

               -  Patients requiring pain medication must be on a stable regimen at study entry.

               -  Symptomatic lesions amenable to palliative radiotherapy (e.g., bone metastases or
                  metastases causing nerve impingement) should be treated prior to enrollment.
                  Patients should be recovered from the effects of radiation. There is no required
                  minimum recovery period.

               -  Asymptomatic metastatic lesions whose further growth would likely cause
                  functional deficits or intractable pain (e.g., epidural metastasis that is not
                  currently associated with spinal cord compression) should be considered for
                  loco-regional therapy if appropriate prior to enrollment.

          6. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent
             drainage procedures (once monthly or more frequently). Patients with indwelling
             catheters (e.g., PleurX) are allowed.

          7. Uncontrolled hypercalcemia (> 1.5 mmol/L ionized calcium or calcium >12 mg/dL or
             corrected serum calcium >ULN) or symptomatic hypercalcemia requiring continued use of
             bisphosphonate therapy or denosumab.

               -  Patients, who are receiving bisphosphonate therapy or denosumab specifically to
                  prevent skeletal events and who do not have a history of clinically significant
                  hypercalcemia are eligible.

               -  Patients who are receiving denosumab prior to enrollment must be willing and
                  eligible to receive a bisphosphonate instead while on study.

          8. Malignancies other than NSCLC, cancer of the urinary tract or TNBC within 5 years
             prior to Cycle 1 Day 1, with the exception of those with a negligible risk of
             metastasis or death treated with expected curative outcome (such as adequately treated
             carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized
             prostate cancer treated with curative intent, ductal carcinoma in situ treated
             surgically with curative intent).

          9. Pregnant and lactating women.

         10. History of severe allergic, anaphylactic, or other hypersensitivity reactions to
             chimeric or humanized antibodies or fusion proteins.

         11. Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster
             ovary cell products or any component of the MPDL3280A formulation.

         12. History of autoimmune disease, including but not limited to myasthenia gravis,
             myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis,
             inflammatory bowel disease, vascular thrombosis associated with antiphospholipid
             syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome,
             multiple sclerosis, vasculitis, or glomerulonephritis.

               -  Patients with a history of autoimmune-related hypothyroidism on a stable dose of
                  thyroid replacement hormone may be eligible for this study.

               -  Patients with controlled Type I diabetes mellitus on a stable dose of insulin
                  regimen may be eligible for this study.

               -  Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with
                  dermatologic manifestations only (e.g., patients with psoriatic arthritis would
                  be excluded) are permitted provided that they meet the following conditions:

                    -  Rash must cover less than 10% of body surface area (BSA).

                    -  Disease is well controlled at baseline and only requiring low potency
                       topical steroids.

                    -  No acute exacerbation of underlying condition within the previous 12 months
                       (not requiring PUVA [psoralen plus ultraviolet A radiation], methotrexate,
                       retinoids, biologic agents, oral calcineurin inhibitors, high potency or
                       oral steroids)

         13. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis
             obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active
             pneumonitis on screening chest CT scan.

             •History of radiation pneumonitis in the radiation field (fibrosis) is permitted.

         14. Serum albumin < 2.5 g/dL.

         15. Positive test for HIV.

         16. Patients with active hepatitis B (chronic or acute; defined as having a positive
             hepatitis B surface antigen [HBsAg] test at screening) or hepatitis C.

               -  Patients with past hepatitis B virus (HBV) infection or resolved HBV infection
                  (defined as the presence of hepatitis B core antibody [HBcAb] and absence of
                  HBsAg) are eligible. HBV DNA test must be performed in these patients prior to
                  Cycle 1, Day 1.

               -  Patients positive for hepatitis C virus (HCV) antibody are eligible only if
                  polymerase chain reaction is negative for HCV RNA.

         17. Active tuberculosis.

         18. Severe infections within 4 weeks prior to the first full dose of MPDL3280A, including
             but not limited to hospitalization for complications of infection, bacteremia, or
             severe pneumonia.

         19. Signs or symptoms of infection within 2 weeks prior to Cycle 1, Day 1.

         20. Received therapeutic oral or IV antibiotics within 2 weeks prior to Cycle 1, Day 1.

             •Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract
             infection or to prevent chronic obstructive pulmonary disease exacerbation) are
             eligible.

         21. Significant cardiovascular disease, such as New York Heart Association cardiac disease
             (Class II or greater), myocardial infarction within the previous 3 months, unstable
             arrhythmias, or unstable angina.

             •Patients with known coronary artery disease, congestive heart failure not meeting the
             above criteria, or left ventricular ejection fraction <50% must be on a stable medical
             regimen that is optimized in the opinion of the treating physician, in consultation
             with a cardiologist if appropriate.

         22. Major surgical procedure other than for diagnosis within 28 days prior to Cycle 1, Day
             1 or anticipation of need for a major surgical procedure during the course of the
             study.

         23. Prior allogeneic bone marrow transplantation or solid organ transplant.

         24. Administration of a live, attenuated vaccine within 4 weeks before Cycle 1, Day 1or
             anticipation that such a live attenuated vaccine will be required during the study.

             •Influenza vaccination should be given during influenza season only (example:
             approximately October to March in the Northern Hemisphere). Patients must not receive
             live, attenuated influenza vaccine (e.g. FluMist®) within 4 weeks prior to Cycle 1,
             Day 1 or at any time during the study treatment of within 5 months after the last dose
             of MPDL3280A..

         25. Any other diseases, metabolic dysfunction, physical examination finding, or clinical
             laboratory finding giving reasonable suspicion of a disease or condition that
             contraindicates the use of an investigational drug or that may affect the
             interpretation of the results or render the patient at high risk from treatment
             complications.

         26. Prior treatment with CD137 agonists or immune checkpoint blockade therapies,
             anti−PD-1, and anti−PD-L1 therapeutic antibodies.

             •Patients who have had prior anti−CTLA-4 treatment may be enrolled, provided the
             following requirements are met: oMinimum of 6 weeks from the last dose of anti−CTLA-4
             oNo history of severe immune related adverse effects from anti−CTLA-4 (CTCAE Grade 3
             and 4)

         27. Treatment with systemic immunostimulatory agents (including but not limited to IFNs,
             IL-2) within 6 weeks or five half-lives of the drug, whichever is shorter, prior to
             the first full dose of MPDL3280A.

         28. Treatment with systemic immunosuppressive medications (including but not limited to
             prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti−tumor
             necrosis factor agents) within 2 weeks prior to Cycle 1, Day 1.

               -  Patients who have received acute, low-dose, systemic immunosuppressant
                  medications (e.g. a one-time dose of dexamethasone for nausea) may be enrolled in
                  the study after discussion with and approval by the sponsor.

               -  The use of inhaled corticosteroids for chronic obstructive pulmonary disease,
                  mineralocorticoids (e.g. fludrocortisone) for patients with orthostatic
                  hypotension, and low-dose supplemental corticosteroids for adrenocortical
                  insufficiency are allowed.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Evaluation of efficacy of MPDL3280A after investigational imaging as measured by objective response rate
Time Frame:2 years
Safety Issue:
Description:

Secondary Outcome Measures

Measure:To evaluate progression free survival (PFS) according to standard RECIST v1.1 as assessed by the investigator.
Time Frame:2 years
Safety Issue:
Description:
Measure:To evaluate duration of response (DOR) according to standard RECIST v1.1 as assessed by the investigator.
Time Frame:2 years
Safety Issue:
Description:
Measure:To evaluate DOR according to modified RECIST as assessed by the investigator.
Time Frame:2 years
Safety Issue:
Description:
Measure:To evaluate ORR according to modified RECIST as assessed by the investigator.
Time Frame:2 years
Safety Issue:
Description:
Measure:To evaluate PFS according to modified RECIST as assessed by the investigator.
Time Frame:2 years
Safety Issue:
Description:
Measure:To evaluate the safety/tolerability (by analysis of adverse events) of MPDL3280A.
Time Frame:2 years
Safety Issue:
Description:Safety assessment through: Incidence, nature and severity of adverse events, including protocol-defined events of special interest, graded according to NCI CTCAE4.0 Changes in laboratory test results, vital signs and physical findings.
Measure:To determine the number of patients with and patients without tumor tracer uptake with 89Zr-MPDL3280A,89Zr-CD8 antibody study and 18F-FB-IL2 (as assessed in the accessory imaging trials) who also demonstrate response to MPDL3280A therapy.
Time Frame:2 years
Safety Issue:
Description:
Measure:To correlate PD-L1 biopsy results as assessed in the trials MPDL3280A-img-042015, 89Zr-CD8 antibody imaging and IL2-img-UMCG-2015 to response to MPDL3280A therapy.
Time Frame:2 years
Safety Issue:
Description:
Measure:To evaluate the utility of biopsy at the time of apparent disease progression to distinguish apparent increases in tumor volume related to the immunomodulatory activity of MPDL3280A from true disease progression
Time Frame:2 years
Safety Issue:
Description:
Measure:The fecal microbiome will be analysed in related to antitumor effect. Feces sampling will be performed before treatment and at cycle three.
Time Frame:2 years
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University Medical Center Groningen

Trial Keywords

  • MPDL3280A
  • cancer of the urinary tract
  • non small cell lung cancer
  • triple negative breast cancer

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