Efficacy and Safety of Standard of Care Plus Durvalumab in Patients With Limited Disease Small Cell Lung Cancer (DOLPHIN)

The trial is subdivided in a safety run-in phase and a randomized part with the induction phase (Radiochemotherapy ± Durvalumab and including prophylactic cranial irradiation (PCI; if clinically indicated and according to local standard)) followed by the maintenance phase. The trial starts with the safety run-in phase of 6 patients in Durvalumab group. After the completion of the first cycle of all 6 patients a safety interim analysis will be performed. Study should be discontinued if ≥ 2 out of 6 patients within safety run-in phase (first cycle):

• show more than 2 AEs CTCAE grade ≥3 related to study drug Durvalumab
• or develop pneumonitis (CTCAE grade ≥2)
• or drop out, Otherwise, the trial can continue with randomization. Eligible patients will be randomized to Durvalumab group or standard of care group 2:1.

The safety interim analysis was performed in Q4 2021. The independent DMC has recommended the continuation of the trial.

Induction phase:

Durvalumab group: Cisplatin (75 mg/m² (BSA) D1#) or alternatively Carboplatin (AUC 5 D1) and Etoposide (100 mg/m² (BSA) D1-3) once every 3 weeks for 4-6 cycles and concomitant Radiotherapy (60±6 Gy, 1.8-2 Gy/d or 45±1.5 Gy (1.5 Gy per fraction twice daily, with 4 hours or more between fractions) with start at latest at beginning of cycle 3, ideally during cycle 1) and additional Durvalumab (1500 mg once every 3 weeks) for 4-6 cycles according to randomization followed by prophylactic cranial irradiation (PCI, if clinically indicated and according to local standard at any time after completion of radio-chemotherapy))

Control group: Cisplatin (75 mg/m² (BSA) D1#) or alternatively Carboplatin (AUC 5 D1) and Etoposide (100 mg/m² (BSA) D1-3) once every 3 weeks for 4-6 cycles and concomitant Radiotherapy (60±6 Gy, 1.8-2 Gy/d or 45±1.5 Gy (1.5 Gy per fraction twice daily, with 4 hours or more between fractions with start at latest at beginning of cycle 3, ideally during cycle 1) followed by prophylactic cranial irradiation (PCI, if clinically indicated and according to local standard at any time after completion of radio-chemotherapy)

# Due to the potential toxicity of Cisplatin 75 mg/m² D1, a Cisplatin split dose with 40 mg/m² on D1 and D8 is alternatively allowed. A switch from Cisplatin to Carboplatin AUC 5 D1 (due to new contraindication to Cisplatin) or split dose Carboplatin (AUC 2.5 D1 and D8) is also allowed. In case of initial contraindication to Cisplatin (i.e. renal dysfuction) at baseline, treatment can be started with Carboplatin once every 3 weeks (q21) AUC 5 D1, or split dose AUC 2.5 D1 and D8. A simultaneous administration of platinum-based chemotherapy (preferred Cisplatin) and radiotherapy for at least 2 cycles should be performed.

Maintenance phase:

In Durvalumab group patients will be treated with Durvalumab once every 4 weeks until disease progression (radiologic or clinical progression) or unacceptable toxicities, if patients show at least stable disease after induction phase. Patients with PD after induction phase will have EoT visit and will be followed up until death.

Patients in control group will have EoT visit and will receive standard of care treatment until PD and thereafter will be followed up until death.

Inclusion criteria

• Signed and dated informed consent of the subject must be available before start of any specific trial procedures
• Male or female ≥ 18 years
• Histological confirmed limited disease small cell lung cancer (stage 2 and 3; T1a-4, N1-3, M0 according UICC8 criteria; if primarius is not eligible as RECIST1.1 target lesion (in cases with T1a and T1b) at least one lymph node must meet RECIST1.1 criteria for target lesion (≥15 mm short axis))
• Availability of tumor tissue or fresh tumor material for translational research by central lab testing
• ECOG PS 0 - 1
• At least one measurable lesion according RECIST 1.1
• Body weight > 30 kg
• Adequate normal organ function

• Hemoglobin ≥ 9.0 g/dL
• Absolute neutrophil count (ANC) ≥ 1.5 x109/L
• Platelet count ≥ 100 x109/L
• AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional upper limit of normal
• Serum Bilirubin ≤ 1.5 x institutional upper limit of normal
• Estimated glomerular filtration rate (eGFR) ≥ 30 mL/min for Carboplatin, ≥ 60 mL/min for Cisplatin, calculated by the Cockcroft-Gault formula
• Life expectancy of at least 12 weeks in the discretion of the investigator
• Ability of subject to understand nature, importance and individual consequences of clinical trial

Exclusion criteria

• Extensive disease small cell lung cancer (Tx, Nx, M1; stage IV)
• Major surgical process within 28 day prior first dose of IMP and/or Radiochemotherapy
• History of allogenic organ transplantation
• Active or prior documented autoimmune or inflammatory disorder (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) stable on hormone replacement
• Patients with any chronic skin condition that not required 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
• Uncontrolled intercurrent illness (i.e. active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, interstitial lung disease, serious chronic gastrointestinal conditions (i.e. diarrhea), psychiatric illness)
• History of another primary malignancy in the last 5 years, except adequately treated nonmelanoma skin cancer, adequately treated carcinoma in situ (without evidence of disease)
• History of leptomeningeal carcinomatosis, or brain metastases
• Known HIV positive and/or 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. 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.
• Current or prior use of immunosuppressive medication within 14 days before the first dose.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 exceeding 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 IMP
• Participation in another clinical trial with an investigational product within the last 30 days (unless during follow-up period of an interventional study)
• Known hypersensitivity to one of the ingredients
• Medical or psychological conditions that would jeopardize an adequate and orderly completion of the trial
• Pregnancy, lactation and contraception

• Women who are pregnant, nursing or who plan to become pregnant while in the trial
• Women of child-bearing potential (WOCBP) and men who are able to father a child, unwilling to be abstinent or use highly effective methods of birth control that result in a low failure rate of less than 1% per year when used consistently and correctly beginning at informed consent, for the duration of drug treatment and for the drug out washout period (90 days after last dose of Durvalumab and/or 6 months after last dose of cisplatin/carboplatin and etoposide).
• Patients who are legally institutionalized