E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
|
E.1.1.1 | Medical condition in easily understood language |
|
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 | 18.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10041068 |
E.1.2 | Term | Small cell lung cancer extensive stage |
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 | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of this study is to compare the efficacy of palifosfamide-tris in combination with carboplatin and etoposide (PaCE) chemotherapy to carboplatin and etoposide (CE) alone, as measured by overall survival (OS), in chemotherapy naïve subjects with extensive-stage SCLC. |
|
E.2.2 | Secondary objectives of the trial |
The secondary objectives are to:
- Assess secondary efficacy endpoints including time to progression, objective response rate (ORR), response duration, and effects on quality of life (QOL) and disease-related symptoms.
- Assess potential prognostic factors for OS (i.e., performance status, age, and gender).
- Assess the safety of PaCE chemotherapy in the study population.
- Collect tumor tissue samples for future analyses of potential biomarkers that may correlate with objective tumor response and/or clinical outcome. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male or female subjects, age ≥ 18 years.
2. Histological or cytological diagnosis of extensive-stage small cell lung cancer. (Note: Extensive-stage disease is defined as disease beyond the ipsilateral hemithorax, mediastinum and ipsilateral supraclavicular area and including malignant pleural or pericardial effusion or hematogenous metastases.)
3. No prior chemotherapy, adjuvant therapy, or radiotherapy for lung cancer. Exception: Prior radiotherapy for brain metastases is allowed provided that the subject has recovered from any acute treatment related toxicity.
4. Measurable or non-measureable disease as per RECIST v1.1 (Appendix 1).
5. ECOG Performance Status of 0, 1, or 2 (Appendix 2).
6. Adequate bone marrow, liver, and renal function, as assessed by the following laboratory requirements: a. Hemoglobin ≥10.0 g/dL
b. Absolute neutrophil count (ANC) ≥1,500/mm3
c. Platelet count ≥100,000/mm3
d. Total bilirubin ≤1.5 x upper limit of normal (ULN). For subjects with Gilbert’s Disease, Total bilirubin ≤3 x ULN
e. ALT and AST ≤2.5 x ULN. For subjects with documented liver metastases, ALT and AST ≤5×ULN
f. International Normalized Ratio (INR) ≤1.5, if not therapeutically anticoagulated. Subjects who are being therapeutically anticoagulated may be included provided
that the anticoagulation regimen is stable and closely monitored.
g. Estimated glomerular filtration rate (eGFR) ≥ 60 mL/minute/1.73 m2 as determined using the Modification of Diet in Renal Disease (MDRD) equation (Appendix 3);
in cases where the MDRD equation may not be suitable, a 24 hour urine creatinine clearance test may be substituted with prior approval of the Medical Monitor.
7. Male and female subjects of child bearing potential must agree to use a double-barrier method of birth control from the screening visit through 6 months after the last dose of study drug.
8. Written informed consent in compliance with the Human Investigation Review Committee (IEC/IRB) having jurisdiction over the site. |
|
E.4 | Principal exclusion criteria |
1. Exposure to any investigational agent within 30 days prior to randomization.
2. Previously untreated (non-irradiated), symptomatic brain metastases. No prior treatment is required for non-symptomatic brain metastases. Previously treated symptomatic brain
metastases are permitted.
3. Known allergy to any of the study drugs or their excipients.
4. Currently pregnant (confirmed with a positive serum pregnancy test) or nursing.
5. Unstable or clinically significant concurrent medical condition, psychiatric illness or social situation that would, in the opinion of the investigator, jeopardize the safety of a subject and/or their compliance with the protocol.
6. Clinically significant acute infection requiring systemic antibacterial, antifungal, or antiviral therapy within 7 days prior to randomization. (Suppressive therapy for chronic infections
allowed, for example: Subjects with HIV/AIDS with adequate antiviral therapy to control viral load would be allowed. Subjects with viral hepatitis with controlled viral load would be allowed
while on suppressive antiviral therapy.)
7. Major surgery or significant traumatic injury within 28 days of the time of randomization.
8. Presence of, or history of any illness or injury to the urinary tract (renal or post-renal) which may, in the opinion of the investigator, make the subject more susceptible to acute renal insufficiency.
9. Any malignancy other than small cell lung cancer within the last 5 years prior to randomization, with the exception of cervical carcinoma in situ, nonmelanoma skin cancer, or superficial bladder tumors (Ta, Tis, or T1) that have been successfully and curatively treated with no evidence of recurrent or residual disease. (Exception: Subjects with a history of malignancy other than SCLC may be enrolled after consultation with the medical monitor provided the patient’s prognosis is best defined by the ES-SCLC.) |
|
E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy variable, overall survival, is defined as the time from randomization to the date of death. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
The study design uses an adaptive group sequential approach with sample size reestimation at the interim analysis. This interim analysis will be performed after 125 deaths have been observed. |
|
E.5.2 | Secondary end point(s) |
For study purposes, data for tumor-related endpoints (e.g., ORR) will be determined by the investigators according to the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.1
Tumor-related secondary efficacy variables are defined as the following:
- PFS (progression free survival): Time from randomization to the date of PD or
death (if prior to progression). Subjects without PD or death occurring as of the
time of analysis will be censored as of the last date of disease evaluation.
- Objective response rate (ORR): Proportion of subjects achieving a confirmed PR (partial response) or CR (complete response) according to RECIST v1.1 during study treatment or within 21 days following termination of study treatment. All objective responses (CR or PR) require confirmation by a repeat tumor assessment at least 4 weeks (28 days) after the response is first observed in order for the response to be considered confirmed.
- Objective response duration: Time from the date of first objective response (PR or CR), with subsequent confirmation, until the date of PD or the occurrence of death (if death occurs earlier). Duration of response in subjects who have not progressed or died at the time of analysis will be censored as of the date of their last tumor assessment. |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary efficacy endpoints include ORR, PFS, duration of
response and changes in QOL and disease-related symptoms.
Tumor-related endpoints will be assessed according to Response
Evaluation Criteria in Solid Tumors (RECIST) v1.1 guidelines. |
|
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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | Yes |
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 | 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) | 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) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Carboplatin and Etoposide (background treatment) |
|
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 | 41 |
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 |
Canada |
France |
Germany |
Hungary |
Israel |
Italy |
Korea, Republic of |
Poland |
Russian Federation |
Taiwan |
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
|
The date that all randomized subjects have completed protocol defined survival follow-up. |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
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 |