Clinical trial NCT02716038: Neoadjuvant MPDL3280A, Nab-paclitaxel and Carboplatin (MAC) in NSCLC
Official title: A Single-arm, Phase II Study of Neoadjuvant MPDL3280A, Nab-paclitaxel and Carboplatin (MAC) in Resectable Non-small Cell Lung Cancer (NSCLC)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Carcinoma, Non-Small-Cell Lung
Keywords: Non-Small Cell Lung Cancer
Non-Small-Cell Lung Carcinoma
Nonsmall Cell Lung Cancer
NSCLC
Lead sponsor: Columbia University
Sponsor class: OTHER
Collaborators: name: Genentech, Inc.
name: Celgene Corporation
First posted: 2016-03-22
Enrollment: 39
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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.

Detailed description: Lung cancer is the most common cancer in both men and women worldwide, accounting for 13% of incident cancers. In 2015, it was estimated there would be 221,200 new lung cancers diagnosed in the United States, with 158,040 lung cancer deaths. Approximately 85% of all lung cancers are characterized as non-small cell lung cancer (NSCLC).

Repeated studies have shown neoadjuvant cytotoxic chemotherapy to be safe prior to surgical resection of NSCLC with no difference in extent of surgical procedures performed, operative morbidity and mortality. The debate remains as to whether neoadjuvant or adjuvant chemotherapy is the best approach, with advantages and disadvantages to each.

The investigators propose that new therapies such as immune checkpoint inhibitors that demonstrate promising clinical activity in the advanced disease setting must be incorporated into the neoadjuvant setting, in order to maximize benefit early in a patient's treatment course, and with a suitable surrogate endpoint that can be used to establish a preliminary efficacy signal, prior to initiation of a large confirmatory study.

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.

Primary outcomes:
measure: Number of Subjects With Major Pathologic Response (MPR)
timeFrame: 84 days
Secondary outcomes:
Other outcomes:
Locations:
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: New York
country: United States
facility: Columbia University Irving Medical Center
state: New York
Study officials:
affiliation: Columbia University
name: Catherine Shu, MD
role: PRINCIPAL_INVESTIGATOR
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