| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| relapsed or refractory small cell lung cancer (SCLC) |
|
| E.1.1.1 | Medical condition in easily understood language |
| small cell lung cancer that is unresponsive or no longer responding to previous treatment |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10041067 |
| E.1.2 | Term | Small cell lung cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| to compare overall survival (OS) in subjects treated with dinutuximab and irinotecan versus subjects treated with irinotecan alone as a second-line treatment for relapsed or refractory small cell lung cancer (SCLC). |
|
| E.2.2 | Secondary objectives of the trial |
• To compare progression-free survival (PFS), objective response rate (ORR) (complete response [CR] + partial response [PR]) and clinical benefit rate (CR + PR + stable disease [SD]) in subjects treated with dinutuximab and irinotecan versus subjects treated with irinotecan alone.
• To compare the safety of subjects treated with dinutuximab and irinotecan versus subjects treated with irinotecan alone.
• To evaluate the pharmacokinetics of subjects treated with dinutuximab.
• To compare OS, PFS, ORR, and clinical benefit rate (CBR) in subjects treated with dinutuximab and irinotecan versus subjects treated with topotecan alone.
The exploratory objective of the study is to assess the relationship between selected biomarkers and survival of subjects treated with dinutuximab. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
3.1.1. Provide a signed informed consent form before any screening procedures.
3.1.2. Aged ≥18 years on the date of signing the informed consent form.
3.1.3. Have histologically or cytologically confirmed SCLC (undifferentiated small cell carcinoma arising in or consistent with lung cancer origin).
3.1.4. Documented (radiographic evidence of) relapse or disease progression during or after first-line platinum-based therapy (subjects refractory to initial platinum-based therapy are eligible).
3.1.5. Have no curative therapy available.
3.1.6. Have a life expectancy of at least 12 weeks.
3.1.7. Have Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
3.1.8. Have adequate bone marrow function as assessed by the following laboratory test results:
− Hemoglobin ≥9.0 g/dL or ≥5.6 mmol/L with erythropoietin or transfusion − Absolute neutrophil count (ANC) ≥1,500/mm3 or ≥1.5 x 109/L. − Platelet count ≥100,000/mm3 or ≥100 x 109/L
3.1.9. Have calculated creatinine clearance (CrCL) ≥30 mL/minute (using Cockcroft and Gault’s formula) or serum creatinine ≤1.5 times below the ULN.
3.1.10. Have adequate hepatic function, as assessed by the following laboratory test results:
− Total bilirubin ≤1.5 times the ULN. (Subjects with Gilbert’s Syndrome or other benign congenital hyperbilirubinemia may be eligible at the investigator’s discretion in consultation with the Medical Monitor.) − Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3.0 times ULN in subjects without liver metastases or ≤5.0 times ULN in subjects with liver metastases.
3.1.11. Women of reproductive potential must have a negative urine or serum beta human chorionic gonadotropin (β-HCG) pregnancy test obtained within 7 days prior to the first dose of study treatment (dinutuximab and/or chemotherapy)
− Women not of reproductive potential are female subjects who are postmenopausal or permanently sterilized (e.g. tubal occlusion, hysterectomy, bilateral salpingectomy).
3.1.12. Women of reproductive potential must agree to consistently use highly effective contraception / birth control between signing of the informed consent and 60 days after the last administration of the last study drug. Men with female partners of childbearing potential must agree to consistently use highly effective contraception / birth control between signing of the informed consent and 60 days after the last administration of the last study drug. The investigator or a designated associate should advise the subject how to achieve effective contraception. Highly effective methods of contraception / birth control are defined as those that result in a low failure rate (i.e. less than 1% per year) when used consistently and correctly, such as:
− Established use of oral, injected, or implanted hormonal methods of contraception by the female partner (of reproductive potential) of a male subject − Placement of an intrauterine device or intrauterine system − Surgical sterilization of the subject or his / her partner − True abstinence, when this is the established lifestyle of the subject. Due to the lack of adequate reproductive toxicity data on dinutuximab, subjects must use 2 forms of highly effective contraception (e.g. from the above list) concomitantly. Additionally, the use of condoms is required. It should also be noted that where 2 forms of effective contraception are required, a subject may choose to use a double-barrier method consisting of condom and cervical occlusive cap / diaphragm with spermicide. |
|
| E.4 | Principal exclusion criteria |
3.2.1. Candidate for re-treatment with original platinum-based regimen as second-line therapy.
3.2.2. Prior treatment with irinotecan, topotecan or dinutuximab.
3.2.3. Have active brain metastases. Subjects with brain metastases are allowed if they completed definitive brain therapy, are asymptomatic and radiologically stable, and if they are not currently receiving corticosteroids or radiation. Subjects in whom steroids are being tapered may be eligible with prior approval of the Medical Monitor.
3.2.4. Have mixed small-cell and non-small-cell histologic features.
3.2.5. Have a previous or concurrent cancer that is distinct in primary site or histology from the cancer being evaluated in this study, except cervical carcinoma in situ, treated basal cell carcinoma, superficial bladder tumors (Ta and Tis [carcinoma in situ]) or any previous cancer curatively treated <3 years ago.
3.2.6. Have a history or current evidence of uncontrolled cardiovascular disease including but not limited to the following conditions:
− Congestive heart failure of New York Heart Association (NYHA) grade 3 or greater. − Unstable angina (symptoms of angina at rest) or new-onset angina within 6 months. − Arterial thrombosis, deep vein thrombosis, or pulmonary embolism within 6 months. − Myocardial infarction or stroke within 6 months. − Pericarditis (any CTCAE v.4.03 grade), pericardial effusion (CTCAE v4.03 Grade ≥2).
3.2.7. Have a history of atypical thrombotic thrombocytopenic purpura (TTP) or hemolytic uremic syndrome (HUS).
3.2.8. Women who are pregnant or breast-feeding.
3.2.9. Have had a major surgery or significant trauma within 4 weeks of enrollment (Part 1) or randomization (Part 2).
3.2.10. Have had organ allograft or hematopoietic transplantation.
3.2.11. Have a history of hypersensitivity to any study drugs or their excipients, or intolerance to hydration due to preexisting pulmonary or cardiac impairment, or intolerance to opioid pain medications, or a history of severe hypersensitivity to any other antigen.
3.2.12. Have a history or current evidence of human immunodeficiency virus (HIV) infection.
3.2.13. Have active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection requiring treatment. Subjects with chronic HBV or HCV infection may be eligible at the investigator’s discretion if the subject is considered non-infectious based on serological markers.
3.2.14. Have an active infection that is clinically serious in the investigator’s opinion.
3.2.15. Exposure to any investigational agent within 21 days of enrollment (Part 1) or randomization (Part 2).
3.2.16. Exposure to any systemic chemotherapy or therapeutic radiation within 21 days of enrollment (Part 1) or randomization (Part 2).
3.2.17. Exposure to strong CYP3A4 and/or UGT1A1 inhibitors and strong CYP3A4 inducers within 14 days of enrollment (Part 1) or randomization (Part 2).
3.2.18. Have any clinical condition that is considered unstable or might jeopardize the safety of the subject and / or influence the subject’s compliance in the study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy endpoint is overall survival (OS)
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Secondary endpoints will be tested in the following sequence:
• PFS
• ORR
• CBR |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 98 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Bulgaria |
| Canada |
| France |
| Georgia |
| Germany |
| Hong Kong |
| Hungary |
| Italy |
| Korea, Republic of |
| Lithuania |
| Malaysia |
| New Zealand |
| Philippines |
| Poland |
| Romania |
| Russian Federation |
| Spain |
| Thailand |
| Ukraine |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| Last visit of the last subject |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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