Clinical Trials /

A Pilot Study of MPDL3280A and HIGRT in Metastatic NSCLC

NCT02463994

Description:

The purpose of this study is to find out whether a brief course of radiation therapy given to one area affected by the cancer will improve the chances of responding to immuno-therapy in the form of a medicine called MPDL3280A, an antibody against PD-L1. PD-L1 is expressed on lung cancers and is known to block the effects of the body's immune system in attacking the cancer. Blocking this PD-L1 has been shown to improve the body's immune cells to attack and kill the cancer cells in non-small cell lung cancer. The goal of this study is to see if prior treatment with radiation will allow improved recognition of the cancer by the body's immune cells in the presence of MPDL3280A.

Related Conditions:
  • Lung Adenocarcinoma
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Completed

Phase:

Early Phase 1

Trial Eligibility

Document

Title

  • Brief Title: A Pilot Study of MPDL3280A and HIGRT in Metastatic NSCLC
  • Official Title: A Pilot Study of MPDL3280A (PD-L1) Antibody Therapy and Hypofractionated Image-guided Radiotherapy (HIGRT) in Patients With Metastatic Non-Small Cell Lung Cancer

Clinical Trial IDs

  • ORG STUDY ID: UMCC 2015.005
  • SECONDARY ID: HUM00100387
  • NCT ID: NCT02463994

Conditions

  • Non-small Cell Lung Cancer

Interventions

DrugSynonymsArms
MPDL3280AMPDL3280A + HIGRT

Purpose

The purpose of this study is to find out whether a brief course of radiation therapy given to one area affected by the cancer will improve the chances of responding to immuno-therapy in the form of a medicine called MPDL3280A, an antibody against PD-L1. PD-L1 is expressed on lung cancers and is known to block the effects of the body's immune system in attacking the cancer. Blocking this PD-L1 has been shown to improve the body's immune cells to attack and kill the cancer cells in non-small cell lung cancer. The goal of this study is to see if prior treatment with radiation will allow improved recognition of the cancer by the body's immune cells in the presence of MPDL3280A.

Trial Arms

NameTypeDescriptionInterventions
MPDL3280A + HIGRTExperimental
  • MPDL3280A

Eligibility Criteria

        Inclusion Criteria:

          -  Signed Informed Consent Form (ICF)

          -  Ability and willingness to comply with the requirements of the study protocol

          -  Age ≥18 years old

          -  ECOG (Eastern Cooperative Oncology Group) performance status (PS) of 0 or 1 (scores
             run from 0 to 5 where 0 denotes perfect health and 5 death).

          -  Patients with ECOG PS of 2, secondary to the underlying disease, may be enrolled.

          -  Patients with Stage IIIB (not eligible for definitive chemo-radiotherapy), Stage IV,
             or recurrent non-small cell lung cancer (NSCLC); patients with Stage IV NSCLC should
             have previously received platinum based doublet chemotherapy. Patients with a new
             diagnosis of Stage IV NSCLC are eligible if they have an initial requirement for
             palliative XRT for symptomatic lesion (example: painful bone lesion or obstructive
             airway).

          -  Patients must be candidates for palliative radiation.

          -  Measurable disease per mRECIST v1.1 Patients must have at least 1 distinct site of
             measurable disease, ≥ 1 cm in its largest diameter, in addition to the site that is
             being irradiated.

          -  Patients may have additional measurable and/or non-measurable but radiographically
             visible metastatic lesions (e.g. bone metastases).

          -  Patients with treated brain metastasis as long as neurologically stable and not on
             steroids for at least 12 weeks (see Exclusion criteria below for details).

          -  Patients must be candidates for PD-L1 Ab as determined by the treating physician

          -  At least 3 weeks must have elapsed from any prior chemotherapy, and the patient must
             have recovered from side effects to ≤ grade 1 toxicities.

          -  Adequate hematologic and end organ function, defined by the following laboratory
             results obtained within 14 days prior to the first study treatment (Cycle 1, Day 1):

               -  ANC (Absolute Neutrophil Count) ≥ 1500 cells/µL

               -  WBC (White Blood Cell) counts > 2500/µL

               -  Lymphocyte count ≥ 500/µL

               -  Platelet count ≥ 100,000/µL; for patients with hematologic malignancies, platelet
                  count ≥ 75,000/µL

               -  Hemoglobin ≥ 9.0 g/dL

               -  Total bilirubin ≤ 1.5 x ULN with the following exception:

               -  Patients with known Gilbert disease who have serum bilirubin level ≤ 3 x ULN may
                  be enrolled.

               -  AST (Aspartate Aminotransferase) and ALT (Alanine Aminotransferase) ≤ 3.0 x ULN
                  with the following exception: Patients with liver involvement: AST and/or ALT ≤ 5
                  x ULN

               -  Alkaline phosphatase ≤ 2.5 x ULN with the following exception: Patients with
                  documented liver involvement or bone metastases: alkaline phosphatase ≤ 5 x ULN

               -  Serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 50 mL/min on the basis of
                  the Cockcroft-Gault glomerular filtration rate estimation: (140 - age) x (weight
                  in kg) x (0.85 if female) 72 x (serum creatinine in mg/dL)

               -  INR (International Normalized Ratio) and aPTT ≤1.5 x ULN

               -  This applies only to patients who do not receive therapeutic anticoagulation;
                  patients receiving therapeutic anticoagulation (such as low molecular weight
                  heparin or warfarin) should be on a stable dose.

          -  For female patients of childbearing potential and male patients with partners of
             childbearing potential, agreement (by patient and/or partner) to use 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

          -  Representative tumor specimens in paraffin blocks (preferred) or at least 15 unstained
             slides, with an associated pathology report, requested at any time prior to study
             entry. Only tissue from core needle, punch, or excisional biopsy sample collection
             will be accepted. Fine-needle aspiration, brushing, and lavage samples are not
             acceptable. For all biopsy types, submitted blocks should have sufficient tissue to
             generate at least 15 sections, and tissue for which the pathology report specifies
             that the overall tumor content is low (e.g., "sparse" or "scant") is not acceptable.
             Tissue from separate time points (such as time of initial diagnosis and time of
             metastatic diagnosis) or from the multiple metastatic tumors may also be collected for
             a given patient, on the basis of availability.

          -  If archival tissue is either insufficient or unavailable, the patient may still be
             eligible if the patient can provide at least five unstained, serial slides or is
             willing to consent to and undergo a pre-treatment core or excisional biopsy sample
             collection of the tumor. Fine-needle aspiration, brushing, and lavage samples are not
             acceptable.

        Exclusion Criteria:

          -  Any approved anticancer therapy, including chemotherapy, hormonal therapy, or
             radiotherapy, within 3 weeks prior to initiation of study treatment; however, the
             following are allowed:

          -  Hormone-replacement therapy or oral contraceptives.

          -  Herbal therapy > 1 week prior to Cycle 1, Day 1 (herbal therapy intended as anticancer
             therapy must be discontinued at least 1 week prior to Cycle 1, Day 1).

          -  Palliative radiotherapy for bone metastases < 2 weeks prior to Cycle 1, Day 1

          -  AEs from prior anticancer therapy that have not resolved to Grade ≤ 1 except for
             alopecia.

          -  Bisphosphonate therapy for symptomatic hypercalcemia.

          -  Use of bisphosphonate therapy for other reasons (e.g., bone metastasis or
             osteoporosis) is allowed.

          -  Known clinically significant liver disease, including active viral, alcoholic, or
             other hepatitis, cirrhosis, fatty liver, and inherited liver disease.

          -  Patients with acute leukemias, accelerated/blast-phase chronic myelogenous leukemia,
             chronic lymphocytic leukemia (except Rai-stage I), Burkitt lymphoma, plasma cell
             leukemia, or non-secretory myeloma

          -  Known primary CNS (Central Nervous System) malignancy or symptomatic CNS metastases

          -  Patients with asymptomatic untreated CNS disease may be enrolled after consultation,
             provided all of the following criteria are met:

          -  Evaluable or measurable disease outside the CNS

          -  No metastases to brain stem, midbrain, pons, medulla, cerebellum, or within 10 mm of
             the optic apparatus (optic nerves and chiasm)

          -  No history of intracranial hemorrhage or spinal cord hemorrhage

          -  No ongoing requirement for dexamethasone for CNS disease; patients on a stable dose of
             anticonvulsants are permitted

          -  No neurosurgical resection or brain biopsy within 28 days prior to Cycle 1, Day 1

          -  Patients with asymptomatic treated CNS metastases may be enrolled after consultation,
             provided all the criteria listed above are met as well as the following:

          -  Radiographic demonstration of improvement upon the completion of CNS-directed therapy
             and no evidence of interim progression between the completion of CNS-directed therapy
             and the screening radiographic study

          -  No stereotactic radiation or whole-brain radiation within 28 days prior to Cycle 1,
             Day 1

          -  Screening CNS radiographic study ≥ 4 weeks from completion of radiotherapy and ≥ 2
             weeks from discontinuation of corticosteroids

          -  Pregnancy, lactation, or breastfeeding

          -  Known hypersensitivity to Chinese hamster ovary cell products or other recombinant
             human antibodies

          -  Inability to comply with study and follow-up procedures

          -  History or risk of autoimmune disease, including but not limited to systemic lupus
             erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis
             associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's
             syndrome, Bell's palsy, Guillain-Barré syndrome, multiple sclerosis, autoimmune
             thyroid disease, vasculitis, or glomerulonephritis

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

          -  Patients with controlled Type 1 diabetes mellitus on a stable insulin regimen may be
             eligible.

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

          -  Patients with psoriasis must have a baseline ophthalmologic exam to rule out ocular
             manifestations

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

          -  Disease is well controlled at baseline and only requiring low potency topical steroids
             (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%, fluocinolone 0.01%, desonide
             0.05%, alclometasone dipropionate 0.05%)

          -  No acute exacerbations of underlying condition within the last 12 months (not
             requiring PUVA [Psoralen Plus Ultraviolet A Radiation], methotrexate, retinoids,
             biologic agents, oral calcineurin inhibitors, high potency or oral steroids)

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

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

          -  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

          -  History of HIV infection or active hepatitis B (chronic or acute) or hepatitis C
             infection

          -  Patients with past or resolved hepatitis B infection (defined as having a negative
             hepatitis B surface antigen [HBsAg] test and a positive anti-HBc [Antibody to
             Hepatitis B Core Antigen] antibody test) are eligible.

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

          -  Active tuberculosis

          -  Severe infections within 4 weeks prior to Cycle 1, Day 1 including but not limited to
             hospitalization for complications of infection, bacteremia, or severe pneumonia

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

          -  Received 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 chronic obstructive pulmonary disease) are eligible.

          -  Major surgical procedure within 28 days prior to Cycle 1, Day 1 or anticipation of
             need for a major surgical procedure during the course of the study

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

          -  Influenza vaccination should be given during influenza season only (approximately
             October to March). 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.

          -  Malignancies other than disease under study within 5 years prior to Cycle 1, Day 1,
             with the exception of those with a negligible risk of metastasis or death and with
             expected curative outcome (such as adequately treated carcinoma in situ of the cervix,
             basal or squamous cell skin cancer, localized prostate cancer treated surgically with
             curative intent, or ductal carcinoma in situ treated surgically with curative intent)
             or undergoing active surveillance per standard-of-care management (e.g., CLL Rai Stage
             0, prostate cancer with Gleason score ≤ 6, and PSA ≤10 mg/mL, etc.)

        Medication-Related Exclusion Criteria:

          -  Prior treatment with anti-PD-1, or anti-PD-L1 therapeutic antibody or pathway
             targeting agents

          -  Patients who have received prior treatment with anti-CTLA-4 may be enrolled, provided
             the following requirements are met:

          -  Minimum of 12 weeks from the first dose of anti-CTLA-4 and > 6 weeks from the last
             dose

          -  No history of severe immune-related adverse effects from anti-CTLA-4 (CTCAE Grade 3
             and 4)

          -  Treatment with systemic immunostimulatory agents (including but not limited to IFN,
             IL-2) within 6 weeks or five half-lives of the drug (whichever is shorter) prior to
             Cycle 1, Day 1

          -  Treatment with investigational agent within 4 weeks prior to Cycle 1, Day 1 (or within
             five half-lives of the investigational product, whichever is longer)

          -  Treatment with systemic immunosuppressive medications (including but not limited to
             prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor
             necrosis factor [TNF] 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.

          -  The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) for
             patients with orthostatic hypotension or adrenocortical insufficiency is allowed.

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

          -  Patients with prior allogeneic bone marrow transplantation or prior solid organ
             transplantation

        Specific Exclusion Criteria:

          -  Patients having no distinct measurable lesions outside of the field of radiation.

          -  Previous radiotherapy to the lesion(s) of interest.

          -  Concurrent treatment with any other anti-neoplastic drug or concurrent participation
             in another therapeutic clinical trial

          -  Patients with EGFR/ALK/ROS-1+ lung adenocarcinoma.

          -  Uncontrolled tumor-related pain.

          -  Uncontrolled hypercalcemia
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:The number of participants that respond to a combination of HIGRT and MPDL3280A (PD-L1)
Time Frame:5 years
Safety Issue:
Description:The primary outcome is overall response rate (ORR) to combination of HIGRT and MPDL3280A. The number of participants that respond to treatment will be determined. Response will be assessed by Response Evaluation Criteria in Solid Tumors (mRECIST) version 1.1, using primarily CT scans, immune response criteria and/or clinical benefit as assessed by the investigator.

Details

Phase:Early Phase 1
Primary Purpose:Interventional
Overall Status:Completed
Lead Sponsor:University of Michigan Rogel Cancer Center

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