| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Extensive Disease Small Cell Lung Cancer |
|
| 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 | 16.0 |
| 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 |
Phase 1b
Determine a safe and tolerable Phase 2 dose of LY2940680 in combination with carboplatin and etoposide followed by LY2940680 in patients with extensive-stage SCLC.
Phase 2
Progression-free survival. |
|
| E.2.2 | Secondary objectives of the trial |
Phase 1b
• The pharmacokinetic parameters of LY2940680, its active metabolite, LSN3185556, carboplatin, and etoposide
• Antitumor activity
• Explore the changes induced by LY2940680 in combination with carboplatin and etoposide in biomarkers in skin samples
Phase 2
To compare LY2940680 in combination with carboplatin and etoposide followed by LY2940680 with that of carboplatin and etoposide plus placebo followed by placebo with regard to the following:
• Overall Survival (OS)
• Change in tumor size (CTS)
• overall response rate (ORR) and clinical benefit rate
• Safety profile of LY2940680 when administered in combination with carboplatin and etoposide
• Characterize pharmacokinetics (PK) of LY2940680, its metabolite LSN3185556, carboplatin, and etoposide |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
[1] Histological or cytological diagnosis of SCLC, including malignant pleural effusion that is extensive stage per the International Staging System
[2] Performance status of 0 to 1 on the Eastern Cooperative Oncology Group (ECOG) performance status schedule (Oken et al. 1982).
[3] No prior systemic chemotherapy, immunotherapy, or biological therapy for SCLC.
[4] Prior radiation therapy allowed to <25% of the bone marrow. Patients who have received prior radiation to the whole pelvis or chest for the treatment of SCLC are not eligible. Prior radiotherapy must be completed at least 2 weeks before study enrollment. Patients must have recovered from the acute toxic effects of the treatment prior to study enrollment.
[5] At least 1 unidimensionally measurable lesion meeting RECIST version 1.1 (Eisenhauer et al. 2009). A measurable lesion is defined as a lesion that can be accurately measured in at least 1 dimension and is ≥20 mm with conventional techniques or is ≥10 mm with spiral computed tomography (CT) scan (longest diameter to be recorded). Positron emission tomography (PET) scans and ultrasounds may not be used for lesion measurements.
[6] Adequate organ function including the following:
a. Adequate bone marrow reserve: absolute neutrophil (segmented and bands) count (ANC) ≥1.5 x 109/L, platelets ≥100 x 109/L, and hemoglobin ≥9 g/dL.
b.. Hepatic: bilirubin ≤1.5 times the upper limit of normal (ULN), alkaline phosphatase (AP), ALT and aspartate transaminase (AST) ≤3.0 x ULN (AP, AST, and ALT ≤5 x ULN is acceptable if liver has tumor involvement).
c.Renal: calculated creatinine clearance (CrCl) ≥50 mL/min based on the standard Cockcroft and Gault formula (Cockcroft and Gault 1976).
[7] Estimated life expectancy of at least 12 weeks.
[8] For women: Must be surgically sterile, post-menopausal, or compliant with at least 2 forms of medically approved contraceptive precautions during and for 6 months after the treatment period; must have a negative serum pregnancy test within 7 days before study enrollment, and must not be breast-feeding. For men: Must be surgically sterile or compliant with at least 2 forms of medically approved contraceptive precautions during and for 6 months after the treatment period.
[9] Patient compliance and geographic proximity that allow adequate follow up.
[10] Patient must sign an informed consent document.
[11] Are ≥ 18 years of age.
[12] Availability of a tumor tissue sample.
[13] Are able to swallow capsules. |
|
| E.4 | Principal exclusion criteria |
[14] Are currently enrolled in, or discontinued within the last 30 days from, a clinical trial involving an investigational product or non-approved use of a drug or device, or concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study.
[15] Have previously participated in a study involving LY2940680.
[16] Have previously received treatment with carboplatin or etoposide.
[17] Have a mixed histological diagnosis of SCLC and NSCLC.
[18] Have a serious concomitant systemic disorder that, in the opinion of the investigator, would compromise the patient’s ability to adhere to the protocol.
[19] Have an active infection (≥38.5ºC and/or receiving IV antibiotic therapy).
[20] Have a serious cardiac condition, such as myocardial infarction within 6 months, angina, or heart disease as defined by the New York Heart Association Class III or IV.
[21] Have had recent (within 30 days of study treatment) or concurrent yellow fever vaccination.
[22] Have had a prior malignancy other than SCLC, carcinoma in situ of the cervix, or nonmelanoma skin cancer, unless that prior malignancy was diagnosed and definitively treated at least 5 years previously with no subsequent evidence of recurrence. Patients with a history of non-metastatic prostate cancer, including biochemical relapse only, will be eligible even if diagnosed less than 5 years previously.
[23] Symptomatic central nervous system (CNS) metastases and asymptomatic CNS metastases requiring concurrent corticosteroid therapy. Treated stable CNS metastases are allowed; the patient must be stable after radiotherapy for ≥2 weeks and off of corticosteroids for ≥1 week.
[24] Presence of clinically significant (eg, symptomatic) third-space fluid collections, for example, ascites or pleural effusions that cannot be controlled by drainage or other procedures prior to study entry.
[25] Significant weight loss (that is, ≥10%) over the 6-week period prior to study entry.
[26] Concurrent administration of any other antitumor therapy. An exception will be made for non-metastatic prostate cancer patients continuing androgen blockade therapy only or breast cancer patients continuing adjuvant antiestrogen therapy only (for example, an aromatase inhibitor).
[27] Females who are breastfeeding.
[28] Have corrected QT interval (QTc) of >470 msec on screening electrocardiogram (ECG).
[29] Have received medications that are strong inhibitors of CYP3A4 within 7 days prior to receiving study drug. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase 1: Determination of a safe and tolerable Phase 2 dose
Phase 2: Progression-free survival |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Phase 1: After all patients have completed at least 1 cycle of study treatment
Phase 2:
-PFS: Baseline to measured progressive disease or date of death due to any cause |
|
| E.5.2 | Secondary end point(s) |
1. Safety and toxicity
2. PK parameters including AUC and Cmax
3. Tumor measurements
4. Overall survival |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Safety: during the entire study drug treatment phase and 30 days after discontinuation
2. PK: before and after dose on days 1,2,3 in cycles 1 and 2 and days 1 and 2 of cycle 7.
3. Tumor measurements: baseline and every 2nd treatment cycle
4. Overall Survival: Baseline until death of any cause |
|
| 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 | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| 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) | No |
| 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 | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Ph1 portion is open, and Ph2 portion is randomized/double-blind |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| 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.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.5.1 | Number of sites anticipated in the EEA | 6 |
| 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 |
| Canada |
| Korea, Republic of |
| United States |
|
| 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
|
End of Trial is defined as when: A sufficient number of events (at least 100 events) have been observed for final analysis
of the OS secondary endpoint and the last patient has discontinued study treatment and completed the 30-day safety follow-up visit. |
|
| 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 | 1 |
| 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 | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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