| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
• Histological diagnosis of Stage IV NSCLC other than predominantly squamous cell histology.
• Mesothelioma in advanced or metastatic stage for whom the combination with pemetrexed and cisplatin is deemed to be appropriate.
• Solid tumors with no other standard therapeutic option with ≤2
previous systemic chemotherapies for their disease and a maximum of 6 cycles
of alkylating agents in all previous therapy settings |
|
| 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 | 10029522 |
| E.1.2 | Term | Non-small cell lung cancer stage IV |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 16.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10025055 |
| E.1.2 | Term | Lung cancer non-small cell stage IV |
| 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 |
Primary objective of the Phase 1 part determination of the recommended Phase 2 dose of LY2603618.
Primary objective of the Phase 2 part are Determination if the progression-free survival (PFS) time, from the date of randomization to induction therapy, is improved for patients with Stage IV nonsquamous NSCLC when LY2603618 is added to the first-line therapy of 4 cycles of pemetrexed and cisplatin followed by maintenance therapy of pemetrexed
with or without LY2603618
Due to the dosing regimen changes, subgroup analysis on patients who were treated per JMMG Amendemnt (c) will be performed for PFS. |
|
| E.2.2 | Secondary objectives of the trial |
Phase 1 part:
• Characterization of the preliminary safety and toxicity profile of
LY2603618 in combination with pemetrexed and cisplatin
• Evaluation of the PK of LY2603618, pemetrexed, and cisplatin when used in combination
• Documentation of any antitumor activity observed after administration
of LY2603618 in combination with pemetrexed and cisplatin
Phase 2:
• Further evaluation the PK of LY2603618 in combination with
pemetrexed and cisplatin
• Determination of change in tumor size (CTS), overall tumor response
rate (ORR), or clinical benefit rate (stable disease [SD], partial response
[PR], and complete response [CR] are improved after treatment with
LY2603618 in combination with 4 cycles of pemetrexed and cisplatin
compared to 4 cycles of pemetrexed and cisplatin alone
• Exploration of the relationship between protein 53 (p53) pathway
function and response to study drugs using primary and secondary
efficacy endpoints.
See section 6.2 of the protocol |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
•Patients with a cytologic or histologic diagnosis of nonsquamous NSCLC which is classified as Stage IV according to the seventh edition of the American Joint Committee on Cancer (AJCC) classification and for whom the combination of pemetrexed and cisplatin is deemed to be appropriate.
• Patients with histologic or cytologic diagnosis of malignant mesothelioma which is unresectable
• Patients with histologic or cytologic diagnoses of advanced or metastatic solid tumors who are not candidates for any standard therapy and for whom the combination with pemetrexed and cisplatin is deemed to be appropriate.
Phase 2:
• Have a Histological diagnosis of Stage IV NSCLC other than predominantly squamous cell histology (will subsequently be referred to as "nonsquamous" NSCLC for ease of reference) which is classified as Stage IV according to the seventh edition of the AJCC classification
• Nonsquamous histology includes the histology of adenocarcinoma, large cell, and others (NSCLC and not otherwise specified [NOS] (Scagliotti et al. 2008; Ciuleano et al. 2009). Patients with large cell-tumours with neuroendocrine differentiation are not eligible)
• Be eligible for a first line of palliatative treatment with a platinum doublet and
have not received any prior systemic chemotherapy, immunotherapy, targeted therapy or biological therapy for NSCLC. Previous adjuvant therapy is not allowed.
• Have archived tumor tissue or tissue from a fresh tumor biopsy. Cytology specimens are not allowed. The biopsy material should correspond to untreated tumor. If a patient has received prior radiotherapy, the patient is eligible only if a new biopsy has been obtained before entering this trial as part of the standard diagnostic plan for the patient
• Phase 1 patients can have measurable or nonmeasurable disease. Phase 2 patients must have at least 1 measurable lesion according to Investigational New Drug (IND) (Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1) definitions. Tumor lesions located in a previously irradiated area can be considered measurable if they are new or if have shown unequivocal progression.
• Have a performance status of ≤1 on the Eastern Cooperative Oncology Group (ECOG) scale
• Males or females at least 18 years of age
• Have given written informed consent prior to any study-specific procedures
• Have adequate organ function including:
• Hematologic: Absolute neutrophil count (ANC) ≥1.5 x 109/L, platelets ≥100 x 109/L, and hemoglobin ≥9 g/dL. Transfusions are allowed to meet this requirement.
• Hepatic: bilirubin ≤1.5 times the upper limit of normal (ULN); alkaline phosphatase (AP), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) ≤3 times ULN (AP, AST, and ALT ≤5 times ULN is acceptable if liver has tumor involvement).
• Renal: Calculated creatinine clearance (CrCl) (Cockcroft-Gault formula; see Protocol Attachment JMMG.4), ≥45 mL/min. Patient can also be enrolled based on measured CrCl according to local laboratory values. In case of discrepancy between measured and calculated CrCl, the measured value will be considered for enrollment.
[9]Prior radiation therapy for treatment of cancer is allowed to <25% of the bone marrow (Christy and Eckerman 1987), and patients must have recovered from the acute toxic effects of their treatment prior to study enrollment. Prior radiation to the whole pelvis is not allowed. Prior radiotherapy must be completed at least 4 weeks before study entry.
• For women: Must be surgically sterile, postmenopausal, or compliant with a highly reliable contraceptive method (failure rate <1%) during and for 6 months after the treatment period; must have a negative serum or urine pregnancy test within 7 days before study enrollment and must not be breast-feeding.
For men: Must be surgically sterile or compliant with a contraceptive regimen during and for 6 months after the treatment period
• Agree to take the prescribed premedications per the pemetrexed label
|
|
| E.4 | Principal exclusion criteria |
• Are currently enrolled in, or discontinued within the last 28 days from, a clinical trial involving an off-label use of an investigational drug or device (other than the study drug used in this study), or concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study.
• Have serious preexisting medical conditions or serious concomitant systemic disorders that would compromise the safety of the patient or his/her ability to complete the study, at the discretion of the investigator (for example, unstable angina pectoris or uncontrolled diabetes mellitus). Special attention should be paid to kidney and heart conditions that may be worsened with cisplatin treatment or hydration.
• Have central nervous system (CNS) metastases (unless the patient has completed successful local therapy for CNS metastases and has been off corticosteroids for at least 4 weeks before starting study therapy). A screening computed tomography (CT) scan or magnetic resonance imaging (MRI) before enrollment in the absence of a clinical suspicion of brain metastases is not required.
•Have current active infection that would, in the opinion of the investigator, compromise the patient’s ability to tolerate therapy
• Females who are pregnant or lactating
• Have known positive test results in human immunodeficiency virus (HIV), hepatitis B surface antigen (HBSAg), or hepatitis C antibodies (HCAb). Testing is not required unless circumstances warrant confirmation.
• Have previously completed or withdrawn from this study or any other study investigating LY2603618 or any other Chk1 inhibitor.
• Have known allergy to pemetrexed, cisplatin, LY2603618, or any ingredient of pemetrexed, cisplatin, or LY2603618 (like Captisol®; CYDEX Pharmaceuticals, Inc.)
• Have clinically significant (by physical exam) third-space fluid collections; for example, ascites or pleural effusions that cannot be controlled by drainage or other procedures prior to study entry
• Patients taking non-steroidal anti-inflammatory drugs (NSAIDs) who cannot interrupt the treatment appropriately according to the guidelines (see Section 9.8).
• Have received a recent yellow-fever vaccination (within 28 days of enrollment) or are receiving concurrent yellow-fever vaccination.
Phase 1 portion:
• Have received more than 2 previous lines of chemotherapy for the advanced/metastatic disease). One extra line of adjuvant/neoadjuvant chemotherapy will be allowed if it was completed 1 year prior to enrollment. There is no limitation in the number of previous targeted agents (approved or investigational) if they do not have significant bone marrow toxicity.
• Have received more than 6 cycles of therapy containing an alkylating agent.
•Have had a prior malignancy other than NSCLC, 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 low grade (Gleason score ≤6) localized prostate cancer will be eligible even if diagnosed less than 5 years previously. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression Free Survival based on RECIST |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 6 months after last patient is randomized |
|
| E.5.2 | Secondary end point(s) |
| Overall Survival, Change in Tumor Size, Overall Tumor response rate, duration of response and symptom assessment |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Death or discontinuation of study |
|
| 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 | 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 |
| Changes in Laboratory Endpoints |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| 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 | No |
| E.8.1.5 | Parallel group | No |
| 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.8.4.1 | Number of sites anticipated in Member State concerned | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 32 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| 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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