Overview

This this study is for individuals who have treatment-naïve extensive-stage small cell lung cancer (small cell lung cancer that wont respond to treatment). Doctors leading this study hope to learn if combining durvalumab, carboplatin and etoposide with hyofractionated ablative radiation therapy (radiation focused on certain parts of the body) will help treat your cancer and improve how long you can live with extensive-stage small cell cancer without it getting worse (progression-free survival). Your participation in this research will last about 48 months.

Durvalumab along with chemotherapy has been approved by the Food and Drug Administration (FDA) for the treatment of small cell lung cancer along with chemotherapy. This study is testing the addition of radiation to durvalumab and chemotherapy.

Eligibility

Inclusion Criteria:

For inclusion in the study patients must fulfill all of the following criteria:

1. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in the study protocol.
2. Age > 18 years at time of study entry.
3. Have a histologic/clinically confirmed diagnosis of small cell lung cancer with known metastatic disease.
4. Patient is suitable to receive a platinum-based chemotherapy regimen as first line treatment for extensive stage small cell lung cancer.
5. Brain metastases must be asymptomatic or treated and stable off steroids and anti-convulsant for at least 2 weeks prior to study treatment.
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
7. Life expectancy of at least 12 weeks
8. Body weight >30 kg
9. Adequate normal organ and marrow function as defined by lab values the study doctor will review.
10. 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.
11. Have measurable disease based on Response Evaluation Criteria in Solid Tumor (RECIST 1.1) including at least ONE lesion that meets criteria for ablative radiation, including 0.25 cc to 65 cc of viable tumor (i.e. primary disease or metastases) approximately 5cm in maximal dimension. Tumors larger than 65 cc can be partially treated.
12. Female subject of childbearing potential should have a negative urine or serum pregnancy within 24 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
13. Female subjects of childbearing potential should 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 120 days after the last dose of study medication. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year.
14. Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy.

Exclusion Criteria:

        Patients should not enter the study if any of the following exclusion criteria are
        fulfilled:
          1. Participation in another clinical study with an investigational product during the
             last 2 weeks.
          2. Concurrent enrollment in another clinical study, unless it is an observational
             (non-interventional) clinical study or during the follow-up period of an
             interventional study
          3. 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.
          4. Any concurrent chemotherapy, investigational product (IP), biologic, or hormonal
             therapy for cancer treatment, outside of those specified as part of this clinical
             trial. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g.,
             hormone replacement therapy) is acceptable.
          5. Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of
             radiation within 4 weeks of the first dose of study drug
          6. 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.
          7. History of allogenic organ transplantation.
          8. 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
          9. 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
         10. 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
         11. History of leptomeningeal carcinomatosis
         12. Has a paraneoplastic syndrome (PNS) of autoimmune nature, requiring systemic treatment
             (systemic steroids or immunosuppressive agents) or has a clinical symptomatology
             suggesting worsening of PNS.
         13. All patients at screening should have an MRI (preferred) or CT each preferably with IV
             contrast of the brain prior to study entry. Patients whose brain metastases have been
             treated may participate provided they show radiographic stability (defined as 2 brain
             images, both of which are obtained after treatment to the brain metastases. These
             imaging scans should both be obtained at least two weeks apart and show no evidence of
             intracranial progression). In addition, any neurologic symptoms that developed either
             as a result of the brain metastases or their treatment must have resolved or be stable
             either, without the use of steroids, or are stable on a steroid dose of ≤10mg/day of
             prednisone or its equivalent for at least 14 days prior to the start of treatment.
             Brain metastases will not be recorded as RECIST Target Lesions at baseline.
         14. History of active primary immunodeficiency
         15. Active infection including tuberculosis (clinical evaluation that includes clinical
             history, physical examination and radiographic findings, and tuberculosis (TB) testing
             in line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg)
             result), hepatitis C, or HIV. 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 hepatitis C (HCV) ribonucleic acid (RNA).
         16. 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)
         17. 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.
         18. 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.
         19. Known allergy or hypersensitivity to any of the study drugs or any of the study drug
             excipients.
         20. Prior randomisation or treatment in a previous durvalumab clinical study regardless of
             treatment arm assignment.
         21. Has received prior chemotherapy, immunotherapy or thoracic radiation for small cell
             lung cancer.
         22. Has prior exposure to anti-PD (Programmed death-ligand 1) 1/PD-L1 or anti- cytotoxic T
             lymphocyte-associated antigen (CTLA4) therapy.
         23. Has had prior radiation therapy (defined as >10% of prior prescription dose) to the
             area planning to be treated with trial RT.
        Procedures for withdrawal of incorrectly enrolled patients are presented in Section 4.3