Institutional constraints due to research staffing and diminished data safety monitoring infrastructure

Elderly (age 70 years or older) or >18 years old AND poor risk (ECOG 2) newly diagnosed stage IIIA-C (AJCC 8th edition) inoperable non-small cell lung cancer (NSCLC) patients are eligible to participate in this phase II open label study of concurrent, split course chemoradiation followed by Durvalumab (MEDI4736).

The rationale for the study is to identify another cohort of stage III NSCLC for whom adjuvant Durvalumab can be safely given, expanding its utilization and benefits. With a unique, extremely well-tolerated 4-phase split course CRT regimen preceding the administration of Durvalumab, we expect to be able to offer adjuvant Durvalumab to a significant proportion of patients on study.

Patients who have completed four cycles of chemoradiation (Radiation is 60 Gy in 30 fractions administered over 12 weeks with 1-1.5 week breaks between cycles; Chemotherapy is once every 3 weeks for up to 4 cycles) will go on to receive durvalumab (MEDI4736) monotherapy as 1500mg durvalumab (MEDI4736) via IV infusion Q4W for up to a maximum of 12 months (up to 13 doses/cycles) with the last administration on week 48 until confirmed disease progression unless there is unacceptable toxicity, withdrawal of consent, or another discontinuation criterion is met.

Primary objectives are:

1. To determine the percentage of poor risk and/or elderly unresectable stage III NSCLC patients who complete split course chemoradiation
2. To determine the safety and tolerability of durvalumab (MEDI4736) after completion of chemoradiation in this group of patients.

Secondary Objectives are:

1. To determine the 1-year overall survival rate
2. To determine the 1-year progression-free survival rate
3. To determine the 1-year loco-regional progression-free survival rate
4. To determine rate of grade 3 and 4 toxicities with this regimen in the selected patient population

Inclusion Criteria:

1. Participants must have histologically or cytologically confirmed stage IIIA-C (AJCC 8th edition) non-small cell lung cancer, that will be treated with curative intent.

2. Participants must have been deemed medically inoperable by multidisciplinary team/tumor board

3. Participants must have been staged with a PET/CT within 30 days of enrollment

4. Patients must have undergone an MRI Brain w/IV contrast, or CT brain if MRI not feasible, confirming no evidence of brain metastases, within 30 days of enrollment.

5. Participants must be elderly (age 70 years or older and PS 0-1) or >18 years old AND poor risk (ECOG 2)

6. Participants ideally have endobronchial ultrasound biopsy (EBUS) or mediastinoscopy to confirm nodal status, but can be deferred if PET/CT imaging characteristics are highly suggestive of nodal metastases

7. Participants should have a life expectancy of >6 months

8. Participants must have normal organ and marrow function: Leukocytes >3000/mcL; ANC >1500/mcL; PLT>100000/mcL; Hemoglobin ≥9.0 g/dL

9. Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN)

10. AST/ALT <2.5 x institutional upper limit of normal

11. Measured creatinine clearance (CL) >40 mL/min or Calculated creatinine CL>40 mL/min by the Cockcroft-Gault formula

    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)

12. Patients must be 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 (eg, Health Insurance Portability and Accountability Act in the US, 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. If study includes Japan add (For patients aged <20 years and enrolling in Japan, a written informed consent should be obtained from the patient and his or her legally acceptable representative.)

13. Body weight >30kg

14. 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. The following age-specific requirements apply:

    Women <50 years of age would be considered post-menopausal 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 post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy).

    Women ≥50 years of age would be considered post-menopausal 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).

15. 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. History of allergic reactions attributed to compounds of similar chemical or biologic composition to carboplatin, pemetrexed (for patients with adenocarcinoma), etoposide (for patients with squamous cell carcinoma), or immunotherapy

2. Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic CHF, unstable angina pectoris, cardiac arrhythmia, or psychiatric/social situations that would limit compliance with study requirements.

3. Pregnant women

4. HIV positive patients

5. Participation in another clinical study with an investigational product during the last 6 months

6. 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

7. Receipt of the last dose of anticancer therapy (CRT) ≤7 days prior to the first dose of study drug. If sufficient wash-out time has not occurred due to the schedule or PK properties of an agent, a longer wash-out period will be required, as agreed by AstraZeneca/MedImmune and the investigator

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

   1. Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the Study Physician.
   2. Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab may be included only after consultation with the Study Physician.

9. Any concurrent chemotherapy, 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.

10. 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.

11. History of allogenic organ transplantation.

12. 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:

    1. Patients with vitiligo or alopecia
    2. Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement
    3. Any chronic skin condition that does not require systemic therapy
    4. Patients without active disease in the last 5 years may be included but only after consultation with the study physician
    5. 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. History of another primary malignancy except for

    1. 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
    2. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
    3. Adequately treated carcinoma in situ without evidence of disease

15. History of leptomeningeal carcinomatosis

16. Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥470 ms calculated from 3 ECGs (within 15 minutes at 5 minutes apart) <<for durvalumab monotherapy.

17. History of active primary immunodeficiency

18. 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), 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.

19. Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab. The following are exceptions to this criterion:

    1. Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection)
    2. Systemic corticosteroids at physiologic doses not to exceed <<10 mg/day>> of prednisone or its equivalent
    3. Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)

20. 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.

21. 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.

22. Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.

23. Prior randomisation or treatment in a previous durvalumab clinical study regardless of treatment arm assignment.

24. Patients who have received prior anti-PD-1, anti PD-L1, including durvalumab or anti CTLA-4:

    1. Must not have experienced a toxicity that led to permanent discontinuation of prior immunotherapy.
    2. All AEs while receiving prior immunotherapy must have completely resolved or resolved to baseline prior to screening for this study.
    3. Must not have experienced a ≥Grade 3 immune related AE or an immune related neurologic or ocular AE of any grade while receiving prior immunotherapy. NOTE: Patients with endocrine AE of ≤Grade 2 are permitted to enroll if they are stably maintained on appropriate replacement therapy and are asymptomatic.
    4. Must not have required the use of additional immunosuppression other than corticosteroids for the management of an AE, not have experienced recurrence of an AE if re-challenged, and not currently require maintenance doses of > 10 mg prednisone or equivalent per day.

25. Judgment 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.

Procedures for withdrawal of incorrectly enrolled patients are presented in Section 4.3 Withdrawal of patients from study treatment and/or study

1 year