| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| 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 | 21.1 |
| 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 |
Primary Objective Part I
-Describe the safety and tolerability of irinotecan liposome injection
monotherapy administered every 2 weeks
- To determine the irinotecan liposome injection monotherapy dose (85 mg/m2
or 70 mg/m2 administered every 2 weeks) for Part 2 of this study
Primary Objective Part II
To compare overall survival ( OS )following treatment with irinotecan liposome injection with ( OS ) following treatment with IV topotecan. |
|
| E.2.2 | Secondary objectives of the trial |
secondary Objective Part I:
To assess the preliminary efficacy of irinotecan liposome injection (at either the
85 mg/m2 dose level or the 70 mg/m2 dose level as determined by:
Objective response rate (ORR)
Progression free survival (PFS)
Overall survival (OS)
Secondary Objective Part II
To compare the following between the treatment arms:
Progression free survival (PFS)
Objective response Rate (ORR)
Patient Reported Outcomes (PRO)
Safety profile |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
General Inclusion Criteria
1. At least 18 years of age
2. Able to understand and provide the study informed consent
3. ECOG performance status of 0 or 1
4. Life expectancy ≥12 weeks
Disease Specific Inclusion Criteria
5. Histopathologically or cytologically confirmed small cell lung cancer according to the International Association for the Study of Lung Cancer (IASLC) histopathological classification. Mixed or combined subtypes according to the IASLC are not allowed.
6. Evaluable disease as defined by RECIST Version 1.1 guidelines (patients with non-target lesions are eligible)
7. Radiologically confirmed progression on or after first-line platinum based chemotherapy
carboplatin or cisplatin) or chemo-radiation including platinumbased chemotherapy for treatment of limited or extensive SCLC. In addition to platinum-based regimen, one line of immunotherapy as monotherapy or in combination in first or in second line setting is allowed.
8. Recovered from the effects of any prior chemotherapy, surgery, radiotherapy or other anti-neoplastic therapy (recovered to grade 1 or better, with the exception of alopecia, peripheral neuropathy, or ototoxicity).
Hematologic, Biochemical and Organ Function Inclusion Criteria
9. During the Screening period, adequate bone marrow reserves as evidenced by:
a. Absolute neutrophil count > 1,500 cells/μL (1.5 x 109/L) without the use of hematopoietic growth factors within the immediately preceding 14 days;
b. Platelet count > 100,000 cells/μL (100 x 109/L);
c. Hemoglobin > 9 g/dL; transfusions are allowed
10. Adequate hepatic function as evidenced by:
a. Serum total bilirubin within normal range for the institution
b. Aspartate aminotransferase and alanine aminotransferase ≤ 2.5 x upper limit of normal (ULN) (≤ 5 x ULN is acceptable if liver metastases is present)
c. Serum albumin ≥3.0 g/dL (≥30 g/L)
11. Adequate renal function as evidenced by a serum creatinine ≤ 1.5 x ULN and creatinine clearance ≥40 mL/min. Actual body weight should be used for calculating creatinine clearance using the Cockcroft-Gault Equation (except for patients with body mass index > 30 kg/m2 when lean body weight should be used instead):
Serum Creatinine (mg/min)= (140-Age (years)×(Weight(kg)) ×Sex
72× Serum Creatinine (mg/dL)
where Sex = 1 for males and 0.85 for females.
12. Electrocardiogram without any clinically significant findings at screening, as per investigator’s assessment.
Additional Disease Specific Inclusion Criteria
13. Patients with certain types of asymptomatic CNS metastases that meet ALL the following criteria are eligible.
a. Patients with asymptomatic CNS metastases prior to enrollment
b. Prior radiation for CNS metastatic disease is completed ≥4 weeks prior to enrollment
c. CNS metastases that are stable or have decreased according to the post radiation follow up scan that is conducted at least 4 weeks after completion of radiation treatment for CNS lesion.
d. Patients have discontinued corticosteroids or are on stable low-dose steroids (prednisone or equivalent 10 mg daily or less) for at least 1 week after completion of radiation for CNS lesion prior to enrollment. |
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| E.4 | Principal exclusion criteria |
General Exclusion Criteria
1. Any medical or social condition deemed by the Investigator to be likely to interfere with a patient’s ability to sign informed consent, cooperate and participate in the study, or interfere with the interpretation of the results
2. Pregnant or breast feeding; females of child-bearing potential must test negative for pregnancy at the time of enrollment based on a serum pregnancy test. Females of childbearing potential are defined as fertile, following menarche and until becoming postmenopausal unless permanently sterile. Postmenopausal
women are defined as those that have an absence of menstruation for at least 2 years. If necessary, follicle stimulating hormone results >50 IU/L at screening are confirmatory in the absence of a clear postmenopausal history. Permanent sterilization methods include hysterectomy, bilateral salpingectomy and
bilateral oophorectomy.
Male patients must agree to use condoms during the study and for 4 months following the last dose of study drug. Female patients of reproductive potential must agree to use a highly effective method of birth control, during the study and for 1 month following the last dose of study drug.
Disease Specific Exclusion Criteria
3. Patients with large cell neuroendocrine lung carcinoma
4. Patients who have received any of the following treatments:
a. Prior treatment regimens with irinotecan, topotecan or any other topoisomerase I inhibitor including investigational topoisomerase I inhibitors.
b. Retreatment with platinum-based regimen after relapse of first-line platinum-containing therapy;
c. Any antibody-drug conjugates or molecular targeted agents (e.g. poly ADP-ribose polymerase inhibitors), either alone or in combination with other treatments.
d. More than one line of prior immunotherapy
e. Any other additional regimen of prior cytotoxic chemotherapy, not described above.
5. Patients with a history (any grade) of immunotherapy induced colitis or pneumonitis, based on clinical assessment and/or confirmed by biopsy
6. Patients with any of the following CNS metastases:
a. Patients who have developed new or progressive brain metastases within three months following prophylactic and/or therapeutic cranial radiation (whole brain or stereotactic radiation) as defined by imaging
b. Patients with symptomatic CNS metastases.
c. Patients with carcinomatous meningitis
7. Unable to discontinue the use of strong CYP3A4 or UGT1A1 inhibitors at least 1 week or strong CYP3A4 inducers at least 2 weeks prior to receiving the first dose of irinotecan liposome injection
8. Have a previous or concurrent cancer that is distinct in primary site or histology from the cancer being evaluated in this study, except carcinoma in situ, treated basal cell carcinoma, superficial bladder tumors (Ta and Tis [carcinoma in situ]) or any previous cancer curatively treated with last specific treatment >3 years ago without evidence of recurrence.
9. Investigational therapy administered within 4 weeks, or within a time interval less than at least 5 half-lives (whichever is less) of the investigational agent, prior to the first scheduled day of dosing in this study
Hematologic, Biochemical and Organ Function Exclusion Criteria
10. Severe cardiovascular and pulmonary disease (e.g. myocardial infarction, unstable angina pectoris, coronary angioplasty or stenting, deep vein thrombosis, stroke, pulmonary fibrosis, active uncontrolled bleeding, or a known bleeding diathesis) less than 6 months before inclusion
11. New York Heart Association Class III or IV congestive heart failure, ventricular arrhythmias or uncontrolled blood pressure
12. Active infection (e.g. acute bacterial infection, tuberculosis, active hepatitis B/C or active human immunodeficiency virus) which in the Investigator’s opinion might compromise the patient’s participation in the trial or affect the study outcome
13. Known hypersensitivity to any of the components of irinotecan liposome injection, other liposomal products, or topotecan
14. Clinically significant gastrointestinal disorder including hepatic disorders, bleeding, inflammation, occlusion, or diarrhea > grade 1
Additional Disease Specific Exclusion Criterion (only applicable in France, per request of French Regulatory Authorities)
15. Patients who, per investigator assessment, are suitable for a second line platinum-based regimen following relapse after first-line platinum-based therapy. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Primary Efficacy end point is Overall Survival |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Overall survival is defined as the number of months from randomization in Part 2 to the date of death. Assuming enrollment over 24 months with a ramp-up to a maximum of 21 patients per month ans lost-to-follow-up rate of 5% across both treatment arms, the timing of the primary analysis is expected to be at 37 months. An interim OS analysis for futility will be conducted when approximately 29% of the planed final number of OS events (i.e., 100 of 350 OS events) has been observed in the intent-to-treat (ITT) population. |
|
| E.5.2 | Secondary end point(s) |
| Secondary efficacy end points are Progression free survival, objective response rate and change from baseline inpatient reported symptoms (dyspnea and cough). |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Key secondary endpoints will be tested no more than once. To control the overall Type I error rate for the comparison between ininotecan liposome injection and topotecan for the primary and secondary endpoints, a hierarchical approach will be applied to the statistical testing of the secondary endpoints. The statistical inference for the first secondary endpoint of PFS will only be performed if the primary endpoint, OI, is statistically significant. The second secondary endpoint of ORR will only be tested if PFS is statistically significant. Similarly, the PRO endpoints will only be ested if ORR is statistically significant. Any parameter which is not statistically significant will be regarded as descriptive and exploratory. |
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| 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 | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
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| 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) | No |
| 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 | 2 |
| 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.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 60 |
| 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 |
| Brazil |
| China |
| Korea, Republic of |
| Taiwan |
| United States |
| Russian Federation |
| Turkey |
| Ukraine |
| Serbia |
| Belgium |
| France |
| Germany |
| Hungary |
| Italy |
| Poland |
| Romania |
| Spain |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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