| Eligibility |
Inclusion Criteria:
1. Locally-advanced, unresectable, stage III NSCLC (including PET-CT and MRI-brain in the
diagnostic work-up).
2. Capable of giving signed informed consent which includes 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 (European
Union [EU] Data Privacy Directive in the EU) obtained from the patient/legal
representative prior to performing any protocol-related procedures, including
screening evaluations.
3. Diagnostic biopsy with PD-L1 <1% in 50 patients PD-L1 =1% in 50 patients
4. Adequate core or excisional biopsy for tumor assessment
5. Age > 18 years at time of study entry
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
7. Life expectancy of at least 12 weeks
8. Body weight >30 kg
9. Adequate normal organ and marrow function as defined below:
- Haemoglobin =9.0 g/dL
- Absolute neutrophil count (ANC) 1.5 x (> 1500 per mm3)
- Platelet count =100 x 109/L (>75,000 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 unless liver
metastases are present, in which case it must be =5x ULN
- Measured creatinine clearance (CL) >40 mL/min or Calculated creatinine CL>40
mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour
urine collection for determination of creatinine clearance:
Males:
- Creatinine CL (mL/min) = Weight (kg) x (140 - Age) 72 x serum creatinine (mg/dL)
Females:
- Creatinine CL (mL/min) = Weight (kg) x (140 - Age) x 0.85 72 x serum creatinine
(mg/dL)
10. Evidence of post-menopausal status or negative urinary or 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.
11. Women of childbearing potential (WOCBP) should have a negative urine or serum
pregnancy within 7 days prior to receiving the firs dose of study medication. If the
urine test is positive or cannot be confirmed as negative, a serum pregnancy test will
be required. A woman is considered as WOCBP, i.e. fertile, following menarche and
until becoming post-menopausal unless permanently sterile. Permanent sterilisation
methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.
12. WOCBP should use an adequate method to avoid pregnancy
13. males who are sexually active with women of childbearing potential must agree to
follow instructions for method(s) of contraception for a period of 90 days (duration
of sperm turnover) / the time required for the investigational drug to undergo five
half-lives
14. 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. Non-small cell lung cancer disease suitable for curative surgery
2. Significant cardiac, pulmonary or other medical illness that would limit activity or
survival
3. 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 during the last 2 weeks.
4. Any concurrent chemotherapy, Investigational Product (IP), biologic, or hormonal
therapy for cancer treatment. Concurrent use of hormonal therapy for
non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable.
5. Major surgical procedure (as defined by the Investigator) within 28 days prior to the
first dose of IP. Note: Local surgery of isolated lesions for palliative intent is
acceptable.
6. History of allogenic organ transplantation.
7. 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) stableon
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
i. 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 j. History of
another primary malignancy except for
- Malignancy treated with curative intent and with no known active disease =5 years
before the first dose of IP and of low potential risk for recurrence
- Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of
disease
- Adequately treated carcinoma in situ without evidence of disease k. History of active
primary immunodeficiency or medical condition requiring high doses (>30 mg
prednisolone daily) of systemic steroids or other forms of immunosuppressive therapy
l. Active infection 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), and
hepatitis C. 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.
m. 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)
- 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.
n. 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 monotherapy.
o. Known allergy or hypersensitivity to any of the study drugs or any of the study
drug excipients.
p. Prior randomisation or treatment in a previous durvalumab clinical study regardless
of treatment arm assignment.
q. Judgement by the investigator that the patient is unsuitable to participate in the
study and the patient is unlikely to comply with study procedures, restrictions and
requirements.
r. Patients with grade =2 neuropathy will be evaluated on a case-by-case basis after
consultation with the Study physician.
s. Patients with irreverible toxicity not reasonably expected to be exacerbated by
treatment with durvalumab may be included only after consulation with the Study
Physician.
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