Phase II Multicenter Single-Arm Study of Durvalumab with Carboplatin or Cisplatin and Etoposide in First-Line Treatment of Extensive Stage Extrapulmonary Small Cell Carcinoma
- Trial ID
- 2023-505078-13-00
- Protocol
- GOIRC‐01‐2021
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the preliminary efficacy of **durvalumab** in combination with **carboplatin** or **cisplatin** and **etoposide** in first-line treatment for patients with extensive stage extrapulmonary small cell carcinoma (EPSCC). The primary endpoint is the 12-month progression-free survival (PFS), which is clinically relevant as it provides insight into the duration patients remain free from disease progression, thereby assessing the potential benefit of this therapeutic regimen in a challenging cancer type.
Secondary objectives include:
- Evaluating the clinical activity in terms of Objective Response Rate (ORR).
- Measuring the Disease Control Rate (DCR).
- Assessing overall survival (OS).
- Measuring the duration of response (DOR).
- Describing changes in quality of life (QoL) of patients during the study.
- Evaluating the safety profile of durvalumab in association with carboplatin or cisplatin and etoposide.
Participants
The clinical trial involves participants diagnosed with **extensive stage extrapulmonary small cell carcinoma** (ES-EPSCC). The study population includes both male and female subjects, aged 18 years and older, with a performance status of 0 or 1 on the ECOG Performance Scale. Participants are required to have adequate organ and marrow function, with specific laboratory criteria met within 14 days of treatment initiation. The trial does not specify the total number of participants, as the sponsor has not provided this information. Participants must have a life expectancy of at least 12 weeks at enrollment and be suitable for a platinum-based chemotherapy regimen as first-line treatment. The trial includes individuals who are considered a vulnerable population. Key lifestyle considerations, such as diet and physical activity, are not detailed in the available data. The selection criteria emphasize the need for histologically or cytologically confirmed ES-EPSCC, with no prior exposure to immune-mediated therapy or chemotherapy for advanced disease. Participants must provide written informed consent and have at least one measurable lesion suitable for repeated measurements according to RECIST 1.1 criteria.
Plans and Procedures
The clinical trial is designed as a **Phase II**, multicenter, single-arm study to evaluate the preliminary efficacy of **durvalumab** in combination with **carboplatin** or **cisplatin** and **etoposide** in patients with extensive stage extrapulmonary small cell carcinoma (ES-EPSCC). The primary objective is to assess the 12-month progression-free survival (PFS) of the treatment regimen. The trial is expected to commence recruitment on December 1, 2023, and conclude by June 1, 2027. Participants will be involved in the study for a maximum treatment period of 24 months, depending on the specific treatment regimen.
The trial will include an initial screening visit to confirm eligibility based on criteria such as age, organ function, and disease status. Participants must have histologically or cytologically confirmed ES-EPSCC and meet specific laboratory and clinical criteria. Following the screening, eligible participants will undergo treatment initiation, with regular follow-up visits scheduled to monitor treatment response and safety. These visits will include assessments of disease progression, adverse events, and quality of life using the EORTC QLQ-C30 questionnaire. The end-of-study visit will occur after the completion of the treatment period or upon early termination.
Participants may be withdrawn from the study if they experience unacceptable toxicity, disease progression, or withdrawal of consent. The study will employ a rigorous methodology to ensure the reliability of results, with endpoints including overall response rate (ORR), disease control rate (DCR), overall survival (OS), and duration of response (DOR). Safety will be evaluated based on the incidence and severity of adverse events, graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The trial's design and procedures are structured to provide comprehensive data on the efficacy and safety of the treatment regimen in the target patient population.
Treatment
The clinical trial involves the administration of several **experimental medications**. **Cisplatin** is utilized in two forms: as a concentrate for solution for infusion and as a concentrate for solution for injection. Both forms are administered via **infusion**. The dosage is calculated based on body surface area, with a maximum daily and total dose of 80 mg/m². The treatment period for cisplatin is up to 18 weeks. Cisplatin functions as a neoplastic chemotherapeutic agent.
**Carboplatin** is another experimental medication used in this trial. It is provided as a concentrate for solution for infusion and administered through infusion. The maximum daily and total dose is 1000 mg, with a treatment period extending up to 18 weeks. Similar to cisplatin, carboplatin acts as a neoplastic chemotherapeutic agent.
**Etoposide** is included in the study as a concentrate for solution for infusion, administered via infusion. The dosage is determined by body surface area, with a maximum daily and total dose of 100 mg/m². The treatment duration for etoposide is up to 18 weeks. Etoposide serves as an inhibitor of the enzyme topoisomerase II.
**Durvalumab**, marketed as Imfinzi, is a monoclonal antibody provided as a 50 mg/mL concentrate for solution for infusion. It is administered through infusion with a maximum daily and total dose of 1500 mg. The treatment period for durvalumab is up to 24 weeks. Durvalumab is used in combination with the aforementioned chemotherapeutic agents to evaluate its efficacy in patients with extensive stage extrapulmonary small cell carcinoma.
Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment regimen. The trial does not include any non-experimental treatments such as placebo or comparator treatments. All medications are administered under controlled conditions to maintain the integrity of the study and ensure participant safety.
Efficacy
The efficacy of the clinical trial will be assessed primarily through the evaluation of **Progression-Free Survival (PFS)**, which is defined as the time from the initiation of study treatment to the first occurrence of disease progression or death from any cause. Secondary efficacy endpoints include **Overall Response Rate (ORR)**, which measures the percentage of patients achieving complete or partial response according to RECIST v1.1 criteria, and **Disease Control Rate (DCR)**, which includes patients with complete response, partial response, and stable disease. **Overall Survival (OS)** will also be assessed, defined as the time from the start of treatment to death from any cause. Additionally, **Duration of Response (DOR)** will be evaluated for patients who achieve a complete or partial response, measuring the time from initial response to disease progression or death.
Quality of Life (QoL) will be measured using pre-defined patient-reported outcomes (PRO) endpoints, specifically the mean change from baseline in the EORTC QLQ-C30 questionnaire, administered at baseline and after the induction phase (3±2 weeks). Safety assessments will include the incidence, nature, frequency, and severity of adverse events and laboratory abnormalities, graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v.5.0. These efficacy and safety parameters will be collected and analyzed at specified timepoints throughout the trial to determine the overall benefit-risk profile of the treatment regimen.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Age ≥ 18 years on day of signing informed consent.
- Written informed consent and any locally required authorization obtained from the patient/legal representative prior to performing any protocol‐related procedures, including screening evaluations.
- Histologically or cytologically confirmed extensive disease extrapulmonary small cell carcinoma.
- Brain metastases; must be asymptomatic or treated and stable off steroids and anti‐convulsant for at least 1 month prior to study treatment. Patients with suspected brain metastases at screening should have a CT/MRI of the brain prior to study entry.
- No prior exposure to immune‐mediated therapy, including durvalumab excluding therapeutic anticancer vaccines.
- No prior exposure to chemotherapy for advance disease.
- Performance status of 0 or 1 on the ECOG Performance Scale.
- Life expectancy ≥12 weeks at enrollment (day 1).
- Patients must be considered suitable to receive a platinum‐based chemotherapy regimen as first‐line treatment for ES‐EPSCC.
- Adequate organ and marrow function, all screening labs should be performed within 14 days of treatment initiation: a. Haemoglobin ≥9.0 g/dL b. Absolute neutrophil count (ANC) ≥1.0 × 109 /L c. Platelet count ≥75 × 109/L d. Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN). <> e. AST (SGOT)/ALT (SGPT) ≤2.5 x institutional upper limit of normal unless liver metastases are present, in which f. case it must be ≤5x ULN
- Measured creatinine clearance (CL) >40 mL/min or Calculated creatinine CL>40 mL/min by the Cockcroft‐ Gault formula.
- Availability of an archived tumor tissue block at baseline.
- Evidence of post‐menopausal status or negative urinary or serum pregnancy test for female premenopausal patients.
- At least 1 lesion, not previously irradiated, that can be accurately measured at baseline as ≥10 mm in the longest diameter (except lymph nodes, which must have a short axis ≥15 mm) with CT o MRI, suitable for repeated measurements as per RECIST 1.1 criteria.
- Body weight >30 kg
Exclusion Criteria
- Subjects with active, known or suspected autoimmune disease requiring systemic treatment (systemic steroids or immunosuppressive agents) prior 14 days before the first dose of durvalumab. The following are exceptions to this criterion: Intranasal, inhaled, topical steroids or local steroid injections (eg, intra articular injection). Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent. Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication). Premedication with steroids for chemotherapy is acceptable
- Additional malignancy in the last 5 years. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy.
- Any concurrent chemotherapy, investigational product, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non‐cancer‐related conditions (eg, hormone replacement therapy) is acceptable.
- Any history of radiotherapy prior to systemic therapy. Radiation therapy for palliative care (ie, bone metastasis) is allowed but must be completed before first dose of the study medication.
- Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [eg, 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, and uveitis, etc]). The following are exceptions to this criterion: • Patients with vitiligo or alopecia • Patients with hypothyroidism (eg, following Hashimoto syndrome) and stable on hormone replacement • Any chronic skin condition that does not require 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
- Major surgical procedure within 28 days prior to the first dose of investigational product. Local surgery of isolated lesions for palliative intent is acceptable.
- History of leptomeningeal carcinomatosis.
- History of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
- Active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
- Receipt of live, attenuated vaccine within 30 days prior to the first dose of investigational product. Patients, if enrolled, should not receive live vaccine whilst receiving the investigational product and up to 30 days after the last dose of investigational product.
- 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
- History of allogenic organ transplantation.
- 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)
- Female patients with a positive pregnancy test at enrollment or prior to administration of study medication
- 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 (for more information, refer to paragraph 10.8) .
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Italy | Recruiting | 01 Dec 2023 | 66 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
CISPLATIN | Other | — | INFUSION | 80 | 18 | SUB07483MIG |
CARBOPLATIN | Other | — | INFUSION | 1000 | 18 | SUB06614MIG |
CISPLATIN | Other | — | INFUSION | 80 | 18 | SUB07483MIG |
ETOPOSIDE | Other | — | INFUSION | 100 | 18 | SUB07337MIG |
IMFINZI 50 mg/mL concentrate for solution for infusion. | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INFUSION | 1500 | 24 | PRD6651406 |