Overview

Open-label, single-arm, prospective multicenter phase II clinical trial to determine the efficacy of immunotherapy with durvalumab concomitant with radiochemotherapy, followed by durvalumab maintenance therapy in combination with stereotactic radiotherapy in extensive stage SCLC

Eligibility

Inclusion Criteria:

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

1. Histologically confirmed first diagnosis of ES-SCLC according to the Veterans Administration Lung Study Group (VALG) Staging System for SCLC1 (disease extension that cannot be treated within one radiation field).
2. Oligometastatic disease defined as follows:
   • Primary tumor with or without mediastinal or supraclavicular lymph node metastases (counts as one lesion if it can be treated within one radiation field).
   • Up to four distant tumor lesions/metastases that can be treated with stereotactic radiotherapy (stereotactic radiotherapy of lung metastases in addition to radiochemotherapy of primary tumor should previously be discussed with the principal investigator).
   • No cytologically confirmed malignant pleural effusion (in case of suspected malignant pleural effusion in imaging, pleurocentesis for cytological assessment is required).
3. Stable disease (SD) or partial response (PR) according to RECIST 1.1 criteria after

   previous treatment with two cycles of platinum/etoposide/durvalumab.

4. Adequate lung function defined as forced expiratory volume in the first second (FEV1) ≥1.3 liter in spirometry.
5. 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 including European Union Data Privacy Directive obtained from the patient prior to performing any protocol-related procedures, including screening evaluations.
6. Age > 18 years at time of study entry.
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
8. Body weight >30 kg.
9. Adequate normal organ and marrow function as defined below:
   • Hemoglobin ≥9.0 g/dL
   • White Blood Cells (WBC) ≥ 3,000 per mm3
   • Platelet count >100,000 per mm3
   • Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN). This will not apply to patients with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology), who will be allowed only in consultation with their physician.
   • 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
   • Calculated creatinine CL>40 mL/min by the Cockcroft-Gault formula
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. Must have a life expectancy of at least 12 weeks.

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 4 weeks.
          2. 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.
          3. Prior systemic anticancer therapy (chemotherapy, immunotherapy, targeted therapy),
             apart from two cycles of etoposide/platinum + durvalumab (prior chemotherapy/
             immunotherapy/ targeted therapy for other malignancy treated with curative intent ≥5
             years ago is no exclusion criterion).
          4. Any unresolved toxicity NCI CTCAE Grade ≥2 from previous chemo-immunotherapy (2 cycles
             of platinum/etoposide + durvalumab) 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.
          5. 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.
          6. 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.
          7. 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.
          8. History of allogenic organ transplantation.
          9. 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
         10. Uncontrolled intercurrent illness, including but not limited to, ongoing or active
             symptomatic infection, symptomatic congestive heart failure, uncontrolled
             hypertension, unstable angina pectoris, cardiac arrhythmia, QTcF (QT interval on ECG
             corrected using the Frederica's formula) >470 ms, 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.
         11. 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
         12. History of leptomeningeal carcinomatosis.
         13. History of active primary immunodeficiency.
         14. Known active hepatitis infection, positive hepatitis C virus (HCV) antibody, hepatitis
             B virus (HBV) surface antigen (HBsAg) or HBV core antibody (anti-HBc), at screening.
             Participants with a past or resolved HBV infection (defined as the presence of anti
             HBc and absence of HBsAg) are eligible. Participants positive for HCV antibody are
             eligible only if polymerase chain reaction is negative for HCV RNA.
         15. Known to have tested positive for human immunodeficiency virus (HIV) (positive HIV 1/2
             antibodies) or active tuberculosis infection (clinical evaluation that may include
             clinical history, physical examination and radiographic findings).
         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 randomization or treatment in a previous durvalumab clinical study regardless of
             treatment arm assignment.
         21. 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.
         22. Known allergy or hypersensitivity to IP or any excipient.