• 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 MedDRA version: 16.0 Level: PT Classification code 10029522 Term: Non-small c
Conditions
Interventions
Product Code: LY2603618
Pharmaceutical Form: Powder for solution for infusion
CAS Number: 911222-45-2
Current Sponsor code: LY2603618
Other descriptive name: checkpoint kinase I inhibitor
Concentratio
Sponsors
Eli Lilly and Company
Eligibility
Sex/Gender
All
Inclusion criteria
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
Exclusion criteria
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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: 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.;Secondary Objective: 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;Primary end point(s): Progression Free Survival based on RECIST;Timepoint(s) of evaluation of this end point: 6 months after last patient is randomized | — |
Secondary
| Measure | Time frame |
|---|---|
| Timepoint(s) of evaluation of this end point: Death or discontinuation of study;Secondary end point(s): Overall Survival, Change in Tumor Size, Overall Tumor response rate, duration of response and symptom assessment | — |
Countries
Germany
Contacts
Public ContactClinical Trial Information
Eli Lilly
Outcome results
None listed