This is an open label, multi-institutional, single arm Phase II trial. All patients will be
treated with Carboplatin, Paclitaxel, Durvalumab and Radiation. All patients with non-PD
after induction therapy who remain surgical candidates will undergo surgical resection 4-12
weeks following induction therapy.
After surgical resection, all patients who remain eligible will be treated with adjuvant
Durvalumab every 4 weeks for 6 cycles beginning 4-12 weeks after surgical resection.
Inclusion Criteria:
- Written informed consent and HIPAA authorization for release of personal health
information. NOTE: HIPAA authorization may be included in the informed consent or
obtained separately.
- Age ≥ 18 years at the time of consent.
- ECOG Performance Status of 0 or 1 within 28 days prior to registration.
- Histological or cytological confirmation of NSCLC (Adenocarcinoma, Squamous Cell
Carcinoma, Large Cell Carcinoma). A pathology report (from the last 6 months)
confirming the diagnosis of NSCLC must be obtained and reviewed by the treating
physician prior to registration to study.
- Must have resectable and medically operable stage III (N2) NSCLC with clinical or
biopsy-proven N2 disease. If patients have clinical N2 disease they need to be
biopsy-proven (with EBUS or mediastinoscopy) during screening and have confirmed prior
to study enrollment). Subjects must be considered resectable and medically operable
based on the judgment of the treating physician. Stage III (N2) defined as per the 7th
edition of the TNM staging system (T1a, T1b, T1c, T2a, T2b, T3, or T4)N2M0.
- Individuals cannot have contralateral neck or contralateral mediastinum nodal
involvement.
- Subjects must have a life expectancy of at least 12 weeks to qualify.
- Individuals must not have distant metastasis, defined as M0 in the TMN staging system.
- Demonstrate adequate organ function as defined in the table below; all screening labs
to be obtained within 28 days prior to registration.
- Absolute Neutrophil Count (ANC) ≥ 1.5 K/mm3
- Hemoglobin (Hgb) ≥ 9 g/dL (may be transfused)
- Platelets ≥100,000/mcl
- Serum creatinine OR Measured or calculated creatinine clearance (GFR can also be
used in place of creatinine or CrCl) ≤ 1.5 x upper limit of normal (ULN) OR ≥ 40
mL/min for subjects with creatinine levels >1.5 x institutional ULN
- Bilirubin ≤ 1.5 × ULN OR Direct bilirubin of ≤ ULN for subjects with total
bilirubin levels of >1.5x ULN
- Aspartate aminotransferase (AST) ≤ 2.5 × ULN if no liver metastases
≤ 5 x ULN if liver metastases present
- Alanine aminotransferase (ALT) ≤ 2.5 × ULN if no liver metastases ≤ 5 x ULN if
liver metastases present
- All CT or PET imaging studies must be completed within 6 weeks (42 days) prior to
registration.
- Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy
test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 7 days prior to
registration. NOTE: Women are considered of childbearing potential unless they are
surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or
bilateral oophorectomy) or are postmenopausal. Menopause is defined clinically as 12
months of amenorrhea in a woman over 45 in the absence of other biological or
physiological causes. In addition, women under the age of 62 must have a documented
serum follicle stimulating hormone (FSH) level greater than 40 mIU/mL.
- Women of childbearing potential must be willing to abstain from heterosexual activity
or use an effective method of contraception from the time of informed consent until 90
days after treatment discontinuation.
- Men who are sexually active with WOCBP must use any contraceptive method with a
failure rate of less than 1% per year. Men receiving study drug and who are sexually
active with WOCBP will be instructed to adhere to contraception for a period of 90
days after the last dose of investigational product.
- As determined by the enrolling physician or protocol designee, ability of the subject
to understand and comply with study procedures for the entire length of the study.
Exclusion Criteria:
- History of a major surgical procedure (as defined by investigator) within 28 days
prior to the first dose of study drug. NOTE: Local surgery for isolated lesions for
palliative intent is acceptable.
- History of another primary malignancy except for a) malignancy treated with curative
intent and with no known active disease ≥ 5 years before the first dose of study drug,
b) adequately treated non-melanoma skin cancer or lentigo maligna without evidence of
disease, c) adequately treated carcinoma in situ without evidence of disease.
- History of leptomeningeal disease.
- Persons who have small cell carcinoma.
- Persons who do not meet the Stage IIIA NSCLC classification criteria outlined above.
- Presence of superior vena cava syndrome.
- Pregnant, breastfeeding, or expecting to conceive or father children within the
projected duration of the trial, starting with the pre-screening or screening visit
through 90 days after the last dose of trial treatment.
- Active central nervous system (CNS) metastases. Subjects must undergo a head computed
tomography (CT) scan or brain MRI within 42 days prior to registration for protocol
therapy to exclude brain metastases if symptomatic or without prior brain imaging.
- Treatment with any investigational agent within 28 days prior to registration for
protocol therapy.
- Patients should not have received any prior therapy for the current diagnosis of
NSCLC. Treatments done for previously diagnosed malignancies are permitted. Prior
therapy with a PD-1, PD-L1 (including Durvalumab), PD-L2 or CTLA-4 inhibitor or a lung
cancer-specific vaccine therapy are not permitted.
- Presence of metastatic disease (stage IV NSCLC) is not allowed. Subjects must be
evaluated with a CT or PET scan prior to registration for protocol therapy to exclude
metastatic disease.
- Active or prior documented autoimmune or inflammatory disorders (including
inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with
the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome,
or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid
arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this
criterion:
- Patients with vitiligo or alopecia
- Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on
hormone replacement
- Any chronic skin condition that does not require systemic therapy
- Patients without active disease in the last 5 years may be included but only
after consultation with the study physician
- Patients with celiac disease controlled by diet alone
- Interstitial lung disease or history of pneumonitis requiring treatment with
corticosteroids
- Current or prior use of immunosuppressive medication within 14 days before the first
dose of durvalumab. The following are exceptions to this criterion:
- Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra
articular injection)
- Systemic corticosteroids at physiologic doses not to exceed <<10 mg/day>> of
prednisone or its equivalent
- Steroids as premedication for hypersensitivity reactions (e.g., CT scan
premedication)
- History of psychiatric illness or social situations that would limit compliance with
study requirements
- Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the
exception of alopecia, vitiligo, and the laboratory values defined in the inclusion
criteria
- Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after
consultation with the investigator.
- Patients with irreversible toxicity not reasonably expected to be exacerbated by
treatment with durvalumab may be included only after consultation with the
investigator.
- Has a history or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the trial, interfere with the subject's
participation for the full duration of the trial, or is not in the best interest of
the subject to participate, in the opinion of the site investigator.
- Clinically significant acute infection requiring systemic antibacterial, antifungal,
or antiviral therapy including tuberculosis (clinical evaluation that includes
clinical history, physical examination and radiographic findings, and TB testing in
line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg)
result), hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies).
Patients with a past or resolved HBV infection (defined as the presence of hepatitis B
core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for
hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative
for HCV RNA. Subjects with HIV/AIDS with adequate antiviral therapy to control viral
load would be allowed. Subjects with viral hepatitis with controlled viral load would
be allowed while on suppressive antiviral therapy. Testing not required.
- Has received a live vaccine within 30 days prior to planned start of study therapy.
NOTE: Seasonal influenza vaccines for injection are generally inactivated flu vaccines
and are allowed; however, intranasal influenza vaccines (e.g., Flu-Mist®) are live
attenuated vaccines, and are not allowed.
- History of allograft or allogeneic bone marrow transplant.
