CHIO3 Trial: Chemotherapy Combined with Immune Checkpoint Inhibitor for Operable Stage IIIA/B Non-Small Cell Lung Cancer

This is a single arm, phase II trial of combined neoadjuvant platinum doublet chemotherapy
plus durvalumab followed by surgery, postoperative radiation and adjuvant durvalumab for 13
cycles for patients with potentially resectable stage IIIA and IIIB (T1-3, N2) NSCLC (per the
8th International Association for the Study of Lung Cancer classification). The primary
objective of this study is to increase N2 nodal clearance (N2NC) to 50% or greater for
combined platinum doublet chemotherapy with durvalumab induction therapy from historical rate
of 30% for platinum doublet chemotherapy alone in patients with potentially resectable stage
IIIA/B (N2) NSCLC.

Operability Criteria:

1. ECOG Performance Status 0-1.

2. Absence of major associated comorbidities that increase the surgery risk to an
unacceptable level.

3. Pulmonary function capacity capable of tolerating the proposed lung resection. FEV1 at
least 2 L. If less than 2 L, the predicted postoperative forced expiratory volume in 1
second (FEV1) must be >0.8 L or be >35% of the predicted value. Postoperative
predicted DLCO ≥35% is required.

Inclusion Criteria:

1. Patients who are at least 18 years of age.

2. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1.

3. Life expectancy of at least 12 weeks.

4. Patients with potentially resectable IIIA/B (T1-3, N2) NSCLC (per the 8th
International Association for the Study of Lung Cancer classification) who are
candidates for surgery with intent of R0 resection. Invasive T3 disease (eg, phrenic
nerve, pericardium, chest wall other than Pancoast superior sulcus) may be included if
the surgeon and study team deem it to be resectable. T4 disease per AJCC 8th edition
staging system is excluded given the lack of benefit of surgery in T4N2.

5. Patients must be evaluated by a thoracic surgeon within 4 weeks of registration.

6. Operability is defined as having adequate pulmonary, cardiac, renal, nutritional,
musculoskeletal, neurologic, and cognitive capacity to undergo major pulmonary
resection with acceptable morbidity and mortality.

7. N2 nodes must be discrete (ie, not invading surrounding structures) and less than 3 cm
in maximum diameter.

8. Measurable disease according to Response Evaluation Criteria in Solid Tumors version
1.1 (RECIST v1.1).

9. Pathologically proven N2 disease within 4 weeks of registration. PET/CT positivity in
the ipsilateral mediastinal nodes will not be sufficient to establish N2 nodal status.
Mediastinal lymph node sampling biopsy is required pre-operatively by at least one of
the following:

- Endobronchial Ultrasound Transbronchial Needle Aspiration (EBUS-TBNA);

- Mediastinoscopy;

- Mediastinotomy (Chamberlain procedure);

- Endoscopic ultrasound guided node aspiration (EUS);

- Video-assisted thoracoscopy; OR

- Fine needle aspiration by image guidance.

- Endobronchial ultrasound (EBUS) or mediastinoscopy or other tissue sampling (at
least 2 stations must be biopsied, with at least one station positive for N2
disease). If there are any mediastinal nodes suspicious by CT (>1.5 cm) or PET in
N3 stations, they must be biopsied. If biopsy proven involvement in an N3
station, the patient is excluded.

10. Mediastinal nodal biopsy or aspiration can only be omitted in the special circumstance
in which ALL of the following are true:

- The tumor is left sided;

- The only mediastinal nodal involvement is a node visible in the AP (level 5)
region on CT scan;

- Distinct primary tumor separate from the nodes; AND

- Biopsy proven non-small cell histology from the primary tumor.

11. No prior history of thoracic radiation.

12. Organ and marrow function definitions (example below)

- leukocytes ≥3,000/mcL

- absolute neutrophil count ≥1,500/mcL

- platelets ≥100,000/mcL

- Hemoglobin >9.0 g/dL

- total bilirubin within normal institutional limits

- AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal

- creatinine within normal institutional limits OR

- creatinine clearance ≥60 mL/min/1.73 m2 for participants with creatinine levels
above institutional normal.

13. Patients are capable of giving informed consent and/or have an acceptable surrogate
capable of giving consent on the subject's behalf.

14. Nonpregnant and non-nursing. The effect of durvalumab on the fetus is unknown.

15. Women of childbearing potential (WOCBP) must be willing to use 2 methods of birth
control or be surgically sterile, or abstain from heterosexual activity for the course
of the study through 3 months after the last dose of study medication. Patients of
childbearing potential are those who have not been surgically sterilized or have not
been free of menses >1 year.

16. Evidence of postmenopausal status or negative urinary or serum pregnancy test for
female premenopausal patients. Women will be considered postmenopausal if they have
been amenorrheic for 12 months without an alternative medical cause. The following
age-specific requirements apply:

- Women <50 years of age would be considered postmenopausal if they have been
amenorrheic for 12 months or more following cessation of exogenous hormonal
treatments and if they have luteinizing hormone and follicle-stimulating hormone
levels in the postmenopausal range for the institution or underwent surgical
sterilization (bilateral oophorectomy or hysterectomy).

- Women ≥50 years of age would be considered postmenopausal if they have been
amenorrheic for 12 months or more following cessation of all exogenous hormonal
treatments, had radiation-induced menopause with last menses >1 year ago, had
chemotherapy-induced menopause with last menses >1 year ago, or underwent
surgical sterilization (bilateral oophorectomy, bilateral salpingectomy, or
hysterectomy).

17. Patient is willing and able to comply with the protocol for the duration of the study
including undergoing treatment and scheduled visits and examinations including follow
up.

18. Male patients must agree to use an adequate method of contraception starting with the
first dose of study therapy through 12 weeks after the last dose of study therapy.

Exclusion Criteria:

1. Any prior treatment for NSCLC.

2. Prior thoracic radiation.

3. Patients with ≥Grade 2 peripheral neuropathy.

4. Any active or history of autoimmune disease (including any history of inflammatory
bowel disease) or history of a syndrome that required systemic steroids or
immunosuppressive medications, except for patients with vitiligo or resolved childhood
asthma/atopy.

5. Patients requiring systemic treatment with either corticosteroids (>10 mg daily
prednisone equivalents) or other immunosuppressive medications within 14 days of study
drug administration. Inhaled or topical steroids and adrenal replacement doses <10 mg
daily prednisone equivalents are permitted in the absence of active autoimmune
disease.

6. Patients with previous malignancies (except nonmelanoma skin cancers, in situ bladder,
gastric, breast, colon or cervical cancers/dysplasia) are excluded unless a complete
remission was achieved at least 2 years prior to study entry and no additional therapy
is required or anticipated to be required during the study period.

7. History of solid organ transplant.

8. N3 nodal disease.

9. Mixed small cell/NSCLC will be excluded.

10. Pregnant or breastfeeding.

11. History of allogenic organ transplantation.

12. Active or prior documented autoimmune or inflammatory disorders (including
inflammatory bowel disease [eg, colitis or Crohn's disease], active 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 (eg, 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.

13. Uncontrolled intercurrent illness, including but not limited to, ongoing or active
infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable
angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic
gastrointestinal conditions associated with diarrhea, or psychiatric illness/social
situations that would limit compliance with study requirement, substantially increase
risk of incurring AEs or compromise the ability of the patient to give written
informed consent.

14. Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥470 ms
calculated.