Neoadjuvant MPDL3280A, Nab-paclitaxel and Carboplatin (MAC) in NSCLC
Condition: Carcinoma, Non-Small-Cell Lung
MeSH terms: Carcinoma, Non-Small-Cell Lung
Intervention: MPDL3280A; Carboplatin; Nab-paclitaxel
Intervention description: MPDL3280A is a human, Fc optimized, monoclonal antibody directed against the protein ligand programmed cell death-1 ligand 1 (PD-L1), with potential immune checkpoint inhibitory and antineoplastic activities. Atezolizumab binds to PD-L1, blocking its binding to and activation of its receptor programmed death 1 (PD-1) expressed on activated T-cells, which may enhance the T-cell-mediated immune response to neoplasms and reverse T-cell inactivation. MPDL3280A 1200 mg will be administered as a 60 minute IV infusion on first administration, then over 30 minutes subsequently if tolerated.; Carboplatin is a second-generation platinum compound with a broad spectrum of antineoplastic properties. Carboplatin contains a platinum atom complexed with two ammonia groups and a cyclobutane-dicarboxyl residue. This agent is activated intracellularly to form reactive platinum complexes that bind to nucleophilic groups, thereby inducing intrastrand and interstrand DNA cross-links, as well as DNA-protein cross-links. These carboplatin-induced DNA and protein effects result in apoptosis and cell growth inhibition. Carboplatin area under the curve (AUC)=6 will be administered as a 30 minute IV infusion immediately after nab-paclitaxel.; Nab-paclitaxel is an albumin-stabilized nanoparticle formulation of the natural taxane paclitaxel with antineoplastic activity. Nab-paclitaxel binds to and stabilizes microtubules, preventing their depolymerization and so inhibiting cellular motility, mitosis, and replication. Nab-paclitaxel 100 mg/m2 will be administered as a 30 minute IV infusion.
Intervention MeSH terms: Paclitaxel; Carboplatin; Atezolizumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 39.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Non-Small Cell Lung Cancer; Non-Small-Cell Lung Carcinoma; Nonsmall Cell Lung Cancer; NSCLC

Summary:

      This is a research study to test the effectiveness of nab-paclitaxel + carboplatin +
      MPDL3280A for treatment of non-small-cell lung carcinoma (NSCLC), which is a type of lung
      cancer. The study aims to determine if chemotherapy combined with immune-based therapy can
      lead to improvement in tumor response rates over historical response rates with chemotherapy
      alone.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Patients must have pathologically confirmed non-small cell lung cancer, of either
             squamous or non-squamous histology.

          -  Stage 1B-3A

          -  Deemed surgically resectable by a thoracic surgeon

          -  Age ≥ 18 years

          -  Radiologically measurable disease, as defined by response evaluation criteria in solid
             tumours (RECIST) v1.1

          -  Ability to understand and the willingness to sign a written informed consent document

          -  Females of child-bearing potential must:

               -  Either commit to true abstinence from heterosexual contact, or agree to use, and
                  be able to comply with, effective contraception (</=1% failure rate annually)
                  without interruption, 28 days prior to starting therapy (including dose
                  interruptions), and while on study medication or for a period of 90 days
                  following treatment completion.

               -  Have a negative serum pregnancy test (β -hCG) result at screening and agree to
                  ongoing pregnancy testing during the course of the study, and after the end of
                  study therapy.

          -  Male subjects must practice true abstinence or agree to use a condom during sexual
             contact with a pregnant female or a female of childbearing potential while
             participating in the study, during dose interruptions and for 6 months following
             treatment discontinuation, even if he has undergone a successful vasectomy.

          -  Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1

          -  Representative formalin-fixed paraffin-embedded (FFPE) tumor specimens in paraffin
             blocks (blocks are preferred) or at least 10 unstained slides, with an associated
             pathology report, for central testing of tumor PD-L1 expression

               -  Tumor tissue should be of good quality based on total and viable tumor content.

               -  Patients who do not have tissue specimens meeting eligibility requirements may
                  undergo a biopsy during the screening period.

          -  Adequate organ and marrow function as defined below:

               -  Lymphocyte count ≥300/microliter (mcL)

               -  Neutrophil count ≥1,500/mcL

               -  Hemoglobin ≥9.0g/dl

               -  Platelets ≥100,000/mcL

               -  Total bilirubin ≤1.5 x institutional upper limit of normal (ULN) (*Patients with
                  Gilbert's disease: ≤3 x ULN)

               -  Aspartate aminotransferase (AST)(SGOT)/alanine aminotransferase (ALT)(SGPT) ≤2.5
                  × ULN

               -  Alkaline phosphatase ≤2.5 x ULN

               -  International normalized ratio (INR) and activated partial thromboplastin time
                  (aPTT) ≤ 1.5 x ULN (*Unless the patient is on therapeutic anticoagulation)

               -  Serum creatinine ≤1.5 x ULN or

               -  Creatinine clearance ≥50 mL/min/1.73 m2 by Cockcroft-Gault estimation

        Exclusion Criteria:

          -  Any approved anticancer therapy, including chemotherapy, hormonal therapy, or
             radiotherapy, within 5 years 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)

          -  Malignancies other than the 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 or undergoing active surveillance per standard-of-care
             management (e.g., chronic lymphocytic leukemia Rai Stage 0, prostate cancer with
             Gleason score ≤ 6, and prostate-specific antigen (PSA) ≤ 10 mg/mL, etc.)

          -  Patients who are receiving any other investigational agents concurrently.

          -  Patients with no smoking history

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to MPDL3280A, carboplatin, or paclitaxel.

          -  Patients with active hepatitis B or C infections or a history of HIV infection.

               -  Patients with past or resolved hepatitis B infection (defined as having a
                  negative hepatitis B surface antigen (HBsAg) test and a positive for the antibody
                  test to detect antibodies to hepatitis B core antigen (anti-HBc) are eligible.

               -  Patients positive for hepatitis C virus (HCV) antibody are eligible only if
                  polymerase chain reaction (PCR) is negative for HCV RNA.

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection including tuberculosis (TB), symptomatic congestive heart failure, unstable
             angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that
             would limit compliance with study requirements.

          -  Known clinically significant liver disease, including active viral, alcoholic, or
             other hepatitis; cirrhosis; fatty liver; and inherited liver disease

          -  Known hypersensitivity to Chinese hamster ovary cell products or other recombinant
             human antibodies

          -  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 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

                    -  No acute exacerbations of underlying condition within the last 12 months
                       (not requiring psoralen plus ultraviolet A radiation (PUVA), methotrexate,
                       retinoids, biologic agents, oral calcineurin inhibitors; high potency or
                       oral steroids)

          -  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

          -  Patients must not have >/= Grade 2 pre-existing peripheral neuropathy (per CTCAE)

          -  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

          -  Pregnant women

          -  History of interstitial lung disease or pneumonitis of any cause

        Immunotherapy-Related Exclusion Criteria:

          -  Prior treatment with anti-PD-1, anti-CTLA-4 (cytotoxic T lymphocyte-associated antigen
             (CTLA-4)), or anti-PD-L1 therapeutic antibody or pathway-targeting agents

          -  Treatment with systemic immunosuppressive medications (including but not limited to
             prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor
             necrosis factor (anti-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.