For safety reasons, consolidative hfRT will start from 6.5Gy x 2 fractions and dose escalate
to 10Gy x 2 fractions in a 3+3 design. Consolidative hfRT will be delivered one to two months
after finishing definitive chemoradiation therapy (dCRT) and concurrently with adjuvant
anti-PD-L1 therapy using durvalumab in stage III non-small cell lung cancer (NSCLC).
At the final determined consolidative hfRT dose level, a total of thirty-two subjects with
pathologically documented stage III NSCLC treated with dCRT will be enrolled for data
analyses.
Follow-up assessments will occur every 3 months during durvalumab therapy for the first two
years, then every 4-6 months after 2 years from study registration until confirmed disease
progression or death. Primary endpoints include the safety of boost hfRT and concurrent
anti-PD-L1 therapy adjuvantly following dCRT, and the 12-month progression-free survival to
compare with historical results.
Inclusion Criteria:
1. Pathologically diagnosed NSCLC (squamous cell carcinoma, adenocarcinoma, large- cell
carcinoma, or non-small-cell lung cancer not otherwise specified), clinical stage III
(AJCC 8th Ed.))
2. At time of consent, potential subjects must be a candidate for dCRT OR Must have
received dCRT with at least 2 cycles of platinum-based chemotherapy concurrent with
conventional fractionated radiation therapy with a total dose of 5700 - 6300 cGy
3. Patients must be aware of the nature of his/her disease and willingly provide written,
informed consent. Including compliance with the requirements and restrictions listed
in the informed consent form (ICF) and in this protocol. Written informed consent and
any locally required authorization (e.g., Health Insurance Portability and
Accountability Act in the US) obtained from the patient/legal representative prior to
performing any protocol-related procedures, including screening evaluations.
4. Age > 19 years at time of study entry
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at time of
enrollment.
6. Life expectancy of > 12 weeks
7. Adequate normal organ and marrow function as defined below:
- Hemoglobin ≥9.0 g/dL (5.59 mmol/L) (patients can be transfused to meet this
criterion)
- Absolute neutrophil count (ANC) > 1500 per mm3
- Platelet count ≥100 x 109/L (>100,000 per mm3)
- Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN).
- AST (SGOT)/ALT (SGPT) ≤2.5 x institutional upper limit of normal.
- Calculated creatinine CL>40 mL/min by the Cockcroft-Gault formula
8. Evidence of post-menopausal status or negative serum pregnancy test for female
pre-menopausal patients. Women will be considered post-menopausal if they have been
amenorrheic for 12 months without an alternative medical cause.
9. 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
Exclusion Criteria:
1. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca
staff and/or staff at the study site)
2. Patients who have received prior anti-PD-1, anti PD-L1 or anti CTLA-4
3. Participation in another clinical study with an investigational product during the
last 4 weeks
4. Concurrent enrolment in another clinical study, unless it is an observational (non-
interventional) clinical study or during the follow-up period of an interventional
study
5. Mixed small cell and non-small cell lung cancer histology
6. Patients who receive sequential chemoradiation therapy for locally advanced NSCLC
7. Patients with locally advanced NSCLC who have progressed during definitive platinum
based, concurrent chemoradiation therapy
8. 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
9. Any concurrent chemotherapy, immunotherapy, biologic, or hormonal therapy for cancer
treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g.,
hormone replacement therapy) is acceptable.
10. Major surgical procedure (as defined by the investigator) within 28 days to the first
dose of immunotherapy (excluding the placement of vascular access) that would prevent
administration of study drug or radiation therapy.
11. History of allogenic organ transplantation.
12. Active or prior documented autoimmune or inflammatory disorders within the past 2
years (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]).
13. Known allergy or hypersensitivity to Durvalumab or any excipient.
14. 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
15. History of another primary malignancy except for
1. Malignancy treated with curative intent and with no known active disease ≥5 years
before the informed consent and of low potential risk for recurrence
2. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
of disease
3. Adequately treated carcinoma in situ without evidence of disease
16. History of primary immunodeficiency
17. Known history or active infection of tuberculosis, hepatitis B (known positive HBV
surface antigen (HBsAg) result), hepatitis C, or human immunodeficiency virus
(positive HIV 1/2 antibodies).
18. Current or prior use of immunosuppressive medication within 14 days before the first
dose of durvalumab.
19. Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note:
Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to
30 days after the last dose of IP.
20. Female patients who are pregnant or breastfeeding or male or female patients of
reproductive potential who are not willing to employ effective birth control from
screening to 90 days after the last dose of durvalumab therapy.
21. Prior randomization or treatment in a previous durvalumab and/or tremelimumab clinical
study regardless of treatment arm assignment.
22. Any prior Grade ≥3 immune-related adverse event (irAE) while receiving any previous
immunotherapy agent, or any unresolved irAE >Grade 1.
23. Previous history of RT (other than RT as part of the dCRT for the current course of
NSCLC) involving any part of lungs, chest wall, thoracic spine or breast(s).
24. Judgment by the investigator that the patient is unsuitable to participate in the
study for any condition and the patient is unlikely to comply with study procedures,
restrictions and requirements.
25. Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥470 ms
calculated from 3 ECGs (within 30 minutes at 5 minutes apart)
