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

Sponsor

Michael Hopp (Other)

Overall Status

Recruiting

CT.gov ID

NCT04602533

Collaborator

AstraZeneca (Industry)

105

Enrollment

Locations

Arms

33.3

Anticipated Duration (Months)

10.5

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Combination of concomitant Radio-Chemotherapy showed a significant improvement (Takada) of OS and PFS in limited disease SCLC patients. This clinical trial is a prospective, multicenter, randomized, open-label, parallel group phase II investigator initiated trial (ITT) to evaluate the efficacy and safety of Durvalumab in combination with Cisplatin/Etoposide/Radiotherapy in patients with limited disease small-cell lung cancer (SCLC).

Condition or Disease	Intervention/Treatment	Phase
Small Cell Lung Cancer Limited Stage	Drug: Durvalumab Drug: standard of care	Phase 2

Detailed Description

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#) 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 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))

Control group: Cisplatin (75 mg/m² (BSA) 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 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)

Due to the toxicity of Cisplatin 75 mg/m² D1, a Cisplatin split dose with 40 mg/m² on D1

and D8 is alternatively allowed and a switch of Cisplatin to Carboplatin AUC 5 (due to new contraindication to Cisplatin) after at least 2 cycles with Cisplatin. 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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

105 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase II Randomized Study to Evaluate the Efficacy and Safety of Cisplatin / Etoposide and Concomitant Radiotherapy Combined With Durvalumab Followed by Maintenance Therapy With Durvalumab Versus Cisplatin / Etoposide and Concomitant Radiotherapy in Patients With Limited Disease Small Cell Lung Cancer

Actual Study Start Date :

Dec 21, 2020

Anticipated Primary Completion Date :

Sep 30, 2023

Anticipated Study Completion Date :

Sep 30, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Durvalumab Induction phase: Durvalumab (1500 mg once every 3 weeks) for 4-6 cycles in combination with standard of care (Radiochemotherapy) Maintenance phase: Durvalumab (1500 mg once every 4 weeks) until PD or unacceptable toxicities.	Drug: Durvalumab Induction phase: Durvalumab (1500 mg once every 3 weeks) for 4-6 cycles in combination with standard of care (Radiochemotherap) Maintenance phase: Durvalumab (1500 mg once every 4 weeks) until PD or unacceptable toxicities. Other Names: IMFINZI®
Other: standard of care Induction phase: Radiochemotherapy according to guideline Maintenance: Standard of care	Drug: standard of care Radiochemotherapy: Cisplatin (75 mg/m² (BSA) 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 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)) # Due to the toxicity of Cisplatin 75 mg/m² D1, a Cisplatin split dose with 40 mg/m² on D1 and D8 is alternatively allowed and a switch of Cisplatin to Carboplatin AUC 5 (due to new contraindication to Cisplatin) after at least 2 cycles with Cisplatin. A simultaneous administration of platinum-based chemotherapy (preferred Cisplatin) and radiotherapy for at least 2 cycles should be performed.

Arm

Intervention/Treatment

Experimental: Durvalumab

Induction phase: Durvalumab (1500 mg once every 3 weeks) for 4-6 cycles in combination with standard of care (Radiochemotherapy) Maintenance phase: Durvalumab (1500 mg once every 4 weeks) until PD or unacceptable toxicities.

Drug: Durvalumab

Induction phase: Durvalumab (1500 mg once every 3 weeks) for 4-6 cycles in combination with standard of care (Radiochemotherap) Maintenance phase: Durvalumab (1500 mg once every 4 weeks) until PD or unacceptable toxicities.

Other Names:

IMFINZI®

Other: standard of care

Induction phase: Radiochemotherapy according to guideline Maintenance: Standard of care

Drug: standard of care

Radiochemotherapy: Cisplatin (75 mg/m² (BSA) 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 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)) # Due to the toxicity of Cisplatin 75 mg/m² D1, a Cisplatin split dose with 40 mg/m² on D1 and D8 is alternatively allowed and a switch of Cisplatin to Carboplatin AUC 5 (due to new contraindication to Cisplatin) after at least 2 cycles with Cisplatin. A simultaneous administration of platinum-based chemotherapy (preferred Cisplatin) and radiotherapy for at least 2 cycles should be performed.

Outcome Measures

Primary Outcome Measures

Progression-free survival (PFS) [18 months]
Progression-free survival (PFS) after 18 months according to iRECIST

Secondary Outcome Measures

Progression-free survival (PSF) after other assessments [12 months]
Time between first application of trial medication to date of disease progression or death due to any cause
Overall survival (OS) [18 months]
Time between first application of trial medication to date of death due to any cause
Overall response rate (ORR) [18 months]
Complete Response or Partial Response according to iRECIST
Disease control rate (DCR) [18 months]
Complete Response, Partial Response or Stable Disease according to iRECIST
Quality of Life Questionnaire - Cancer 30 (QLQ-C30) [18 months]
Symptom control assessed by patient-reported quality of life (QoL) with QLQ-C30. The score ranges from 0 to 100. The higher the score the better the outcome.
Quality of Life Questionnaire - Lung Cancer 13 (QLQ-LC13) [18 months]
Symptom control assessed by patient-reported quality of life (QoL) with QLQ-LC13. The scores ranges from 0 to 100. The higher the score the better the outcome.
EuroQol five dimension scale (EQ-5D) [18 months]
Symptom control assessed by patient-reported quality of life (QoL) with EQ-5D. The score consists of 5 items on a three step scale and a VAS scale ranging from 0 to 100. The lower the score on the three step scales the better the outcome and the higher the score on the VAS scale the better the outcome.
Adverse Events [18 months]
Treatment emergent adverse events during treatment

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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; T2-4, N1-3, M0 according UICC8 criteria)
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) ≥ 60 mL/min 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Klinik Löwenstein gGmbH	Löwenstein	Baden-Würtemberg	Germany	74245
2	Klinikverbund Allgäu gGmbH	Immenstadt	Bayern	Germany	87509
3	Universitätsklinikum Gießen Marburg	Gießen	Hessen	Germany	35392
4	Klinikum Kassel GmbH-Klinik für Onkologie und Hämatologie	Kassel	Hessen	Germany	34125
5	Sana-Klinikum Offenbach	Offenbach	Hessen	Germany	63069
6	KEM GmbH	Essen	NRW	Germany	45136
7	Lungenklinik Hemer	Hemer	NRW	Germany	D 58675
8	Universitätsklinikum Aachen	Aachen		Germany	52074
9	Johannes Wesling Klinikum Minden	Minden		Germany	32429
10	Asklepios Fachkliniken Muenchen Gauting	München Gauting		Germany	82131