A Study in Non Small Cell Lung Cancer

Study Overview
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Brief Summary
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LY2603618 is a selective inhibitor of the deoxyribonucleic acid (DNA) damage checkpoint kinase 1 (CHK1). It was being developed as a chemotherapeutic-enhancing agent in the treatment of cancer. Phase 1 studies have shown the feasibility of combining LY2603618 with either gemcitabine or pemetrexed. The objective of this study was to find the dose of LY2603618 that can be safely combined with standard doses of pemetrexed and cisplatin and to test if this triplet offered a significant improvement in progression-free survival (PFS) in participants with Stage IV nonsquamous non-small cell lung cancer (NSCLC) in the first-line of palliative treatment.

Official Title
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A Phase 1/Randomized Phase 2 Study to Evaluate LY2603618 in Combination With Pemetrexed and Cisplatin in Patients With Stage IV Non-small Cell Lung Cancer

Conditions
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Non Small Cell Lung Cancer

Intervention / Treatment
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* Drug: Pemetrexed
* Drug: Cisplatin
* Drug: LY2603618


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Phase 1 portion: Participants with a cytologic or histologic diagnosis of nonsquamous NSCLC that is classified as Stage IV according to the 7th edition of the American Joint Committee on Cancer (AJCC) classification and for whom the combination of pemetrexed and cisplatin is deemed to be appropriate Participants with histologic or cytologic diagnosis of malignant mesothelioma that is unresectable Participants 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 portion: Have a histological diagnosis of NSCLC other than predominantly squamous cell histology that is classified as Stage IV according to the 7th edition of the AJCC classification Eligible for a first line of palliative treatment with a platinum doublet Have archived or fresh tumor tissue (not cytology) Phase 1 participants can have measurable or nonmeasurable disease. Phase 2 participants must have at least 1 measurable lesion according to Investigational New Drug (Response Evaluation Criteria in Solid Tumors [RECIST], v1.1) 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 ≤1 on the Eastern Cooperative Oncology Group (ECOG) scale Have adequate hematologic, hepatic, and renal organ function Prior radiation therapy for treatment of cancer is allowed to <25% of the bone marrow, and participants 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 Exclusion Criteria: Have serious preexisting medical conditions or serious concomitant systemic disorders that would compromise the safety of the participant 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 participant 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 scan or magnetic resonance imaging 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 participant's ability to tolerate therapy Have known allergy to pemetrexed, cisplatin, LY2603618, or any ingredient of pemetrexed, cisplatin, or LY2603618 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 Participants taking non-steroidal anti-inflammatory drugs who cannot interrupt the treatment appropriately according to the guidelines 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 Have received more than 6 cycles of therapy containing an alkylating agent

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1: LY2603618 130 to 275 mg<br>Cycle 1-2 (21-day cycle): Day 1: pemetrexed 500 milligrams per meter square (mg/m^2) + cisplatin 75 mg/m^2 Day 2: LY2603618 at 130-275 milligrams (mg) After 2 cycles, participants may continue on study drug until disease progression, unacceptable toxicity, or other withdrawal criterion is met. | Drug: Pemetrexed<br>* Administered intravenously as a continuous 10-minute infusion<br>Drug: Cisplatin<br>* Administered intravenously as a continuous 1-hour infusion<br>Drug: LY2603618<br>* Administered intravenously as a continuous 1-hour infusion<br>|
| Experimental: Phase 2: Pemetrexed + Cisplatin + LY2603618<br>Cycles 1-4 (21-day cycle): Before 25 Oct 2012: Day 1: pemetrexed 500 mg/m^2 + cisplatin 75 mg/m^2 Day 2: LY2603618 dose from phase 1 portion of trial After 25 Oct 2012: Day 1: pemetrexed 500 mg/m^2 + cisplatin 75 mg/m^2 After 4 cycles, participants may continue on maintenance therapy until disease progression, unacceptable toxicity, or other withdrawal criterion is met. Maintenance Therapy Experimental Arm (every 21 days): Before 25 Oct 2012: Day 1: pemetrexed 500 mg/m^2 Day 2: LY2603618 dose determined from phase 1 After 25 Oct 2012: Day 1: pemetrexed 500 mg/m^2 If, as of 25 Oct 2012, participant was in maintenance therapy and randomized to the experimental arm, the participant is eligible to continue with pemetrexed (Day 1)/LY2603618 (Day 2) therapy if the investigator deems it is in the best interest of the participant and the participant consents. | Drug: Pemetrexed<br>* Administered intravenously as a continuous 10-minute infusion<br>Drug: Cisplatin<br>* Administered intravenously as a continuous 1-hour infusion<br>Drug: LY2603618<br>* Administered intravenously as a continuous 1-hour infusion<br>|
| Active Comparator: Phase 2: Pemetrexed + Cisplatin<br>Cycle 1-4 (21-day cycle): Day 1: pemetrexed 500 mg/m^2 + cisplatin 75 mg/m^2 After 4 cycles, participants may continue on maintenance therapy until disease progression, unacceptable toxicity, or other withdrawal criterion is met. Maintenance Therapy Comparator Arm: Phase 2 (every 21 days): Day 1: pemetrexed 500 mg/m^2 | Drug: Pemetrexed<br>* Administered intravenously as a continuous 10-minute infusion<br>Drug: Cisplatin<br>* Administered intravenously as a continuous 1-hour infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 2: Progression-Free Survival Time | Progression-free survival (PFS) time is defined as the time from the date of randomization to the first date of documented objective progressive disease (PD) or death from any cause. For participants who were not known to have had objective PD as of the data inclusion cut-off date for a particular analysis, PFS was censored at the date of the last objective progression-free disease assessments. For participants who took any subsequent systemic anticancer therapy prior to progression, PFS was censored at the date of the last objective progression-free disease assessment prior to the start date of any subsequent systemic anticancer therapy. PFS time was summarized using Kaplan-Meier estimates. | Randomization up to first date of PD or death from any cause (up to 6 months after the last participant entered treatment) | 
| Phase 1: Recommended Phase 2 Dose of LY2603618 | The recommended Phase 2 dose for LY2603618 when administered approximately 24 hours after pemetrexed and cisplatin was based on the maximum tolerated dose (MTD) and achievement of predefined LY2603618 plasma systemic exposures targets (area under the LY2603618 plasma concentration versus time curve from time zero to infinity [AUC(0-∞)] >21,000 nanogram*hour/milliliter [ng*h/mL] and maximum LY2603618 plasma concentration [Cmax] >2000 nanograms/milliliter [ng/mL]). | Time of first dose to last dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 2: Overall Survival | Overall survival (OS) time is defined as the time from the date of randomization to the date of death from any cause. For participants not known to have died as of the data cut-off date, OS time was censored at the last contact date the participant was known to be alive prior to the data cut-off date. OS was summarized using Kaplan-Meier estimates. | Randomization to the date of death from any cause through the time of study discontinuation (approximately 12 months after last participant was randomized) | 
| Phase 2: Overall Tumor Response Rate: Percentage of Participants Who Achieved a Confirmed Best Response of Completed Response (CR) or Partial Response (PR) | Overall response rate is the best response of CR or PR as classified by the investigators according to the Response Evaluation Criteria in Solid Tumors (RECIST, v1.1) guidelines. CR is defined as the disappearance of all target and non-target lesions, normalization of tumor marker level of non-target lesions, and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 millimeter (mm). PR is an at least 30% decrease in the sum of the diameters of target lesions (taking as reference the baseline sum diameter) without progression of non-target lesions or appearance of new lesions. Overall response rate is calculated as a total number of participants with CR or PR divided by the total number of participants with at least 1 measurable lesion, multiplied by 100. | Randomization until date of disease progression (up to 6 months after the last participant was randomized) | 
| Phase 2: Change in Tumor Size | Change in tumor size was based on tumor measurements collected according to RECIST, v1.1 guidelines. Tumor size is the sum of the tumor measurements (longest diameters) of target lesions at each tumor evaluation. Change in tumor size was defined as the change in log tumor size from baseline evaluation to the evaluation at the end of Cycle 2. | Baseline, end of Cycle 2 | 
| Phase 1: Pharmacokinetic: Maximum Plasma Concentration (Cmax) (LY2603618) | Cmax is reported for each LY2603618 dose level on Cycle 1 /Day 2 and Cycle 2 /Day 2. The number of pharmacokinetic observations (n) used in the analysis is presented for each dose level and time point. | Cycle 1/Day 2 - immediately prior to end of LY2603618 infusion, and 1, 3, 6, 24, 48, 72, and 144 hours postdose; Cycle 2/Day 2 - predose, immediately prior to end of LY2603618 infusion, and 1, 3, 6, 24, 48, 72, and 144 hours postdose | 
| Phase 1: Pharmacokinetic: Cmax (Pemetrexed and Cisplatin) | Cmax for pemetrexed and total platinum (t-platinum) from cisplatin is reported. The number of pharmacokinetic observations (n) used in the analysis is presented for each drug. | Pemetrexed: Cycle 1/Day 1 - immediately prior to end of pemetrexed infusion and 1, 2, 6 and 24 hours postdose. Cisplatin: Cycle 1/Day 1 - immediately prior to end of cisplatin infusion and 0.5, 1, 2, 6, 24, 72, 96, and 168 hours postdose. | 
| Phase 1: Pharmacokinetic: Area Under the Plasma Concentration Versus Time Curve (AUC) (LY2603618) | AUC from time zero to 24 hours (AUC[0-24]), AUC from time zero to the last time point with a measurable concentration (AUC[0-tlast]), and AUC from time zero to infinity (AUC[0-∞]) values are reported for each LY2603618 dose level on Cycle 1 /Day 2 and Cycle 2 /Day 2. The number of pharmacokinetic observations (n) used in the analysis is presented for each dose level and time point. | Cycle 1/Day 2 - immediately prior to end of LY2603618 infusion and 1, 3, 6, 24, 48, 72, and 144 hours postdose; Cycle 2/Day 2 - predose, immediately prior to end of LY2603618 infusion, and 1, 3, 6, 24, 48, 72, and 144 hours postdose | 
| Phase 1: Pharmacokinetic: AUC (Pemetrexed and Cisplatin) | AUC(0-tlast) and AUC(0-∞) values are reported for pemetrexed and t-platinum from cisplatin. The number of pharmacokinetic observations (n) used in the analysis is presented for each drug. | Pemetrexed: Cycle 1/Day 1 - immediately prior to end of pemetrexed infusion and 1, 2, 6 and 24 hours postdose. Cisplatin: Cycle 1/Day 1 - immediately prior to end of cisplatin infusion and 0.5, 1, 2, 6, 24, 72, 96, and 168 hours postdose. | 
| Phase 2: Pharmacokinetic: Cmax (LY2603618) |  | Cycle 1/Day 2 - predose, immediately prior to the end of the LY2603618 infusion, and 2-6, 24-48, and 72-96 hours postdose | 
| Phase 2: Pharmacokinetic: AUC (LY2603618) | AUC (0-24), AUC(0-tlast), and AUC(0-∞) values are reported for LY2603618. The number of pharmacokinetic observations (n) used in the analysis is presented. | Cycle 1/Day 2 - predose, immediately prior to the end of the LY2603618 infusion, and 2-6, 24-48, and 72-96 hours postdose | 
| Phase 2: Change From Baseline to Long-term Follow up in Lung Cancer Symptom Scale (LCSS) | Health-related quality of life and participant symptoms were assessed using the LCSS (patient scale). However, improper implementation of questionnaires at the site level reduced the sponsor's ability to accurately evaluate the impacted data. Therefore, the LCSS data should be interpreted with caution. The LCSS is a 9-item questionnaire. Six questions are symptom-specific measures for lung cancer (appetite, fatigue, cough, dyspnea, hemoptysis, and pain), and 3 summation items describe total symptomatic distress, activity status, and overall quality of life. Participant responses were measured using visual analogue scales (VAS) with 100-milliliter (mm) lines. Scores range from 0 (for best outcome) to 100 (for worst outcome). The Average Symptom Burden Index (ASBI) was calculated as the mean of 6 symptom-specific questions from the LCSS. The total LCSS score was calculated as the mean of 9 questions from the LCSS. | Randomization to the end of study (approximately 12 months after the last participant entered treatment) | 
| Phase 1: Document Any Antitumor Activity Per Radiological Scans and/or Tumor Markers | Overall response rate is presented. Overall response rate is defined as the percentage of participants with a best response of CR or PR as classified by the investigators according to RECIST, v1.1 criteria. CR is defined as the disappearance of all target and non-target lesions, normalization of tumor marker level of non-target lesions, and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR is an at least 30% decrease in the sum of the diameters of target lesions (taking as reference the baseline sum diameter) without progression of non-target lesions or appearance of new lesions. Overall response rate is calculated as a total number of participants with CR or PR divided by the total number of participants with at least 1 measurable lesion, multiplied by 100. | Baseline through end of Phase 1 | 
| Phase 2: Proportion of Participants Receiving Maintenance Therapy |  | Cycle 5 | 
| Phase 2: Clinical Benefit Rate: Percentage of Participant Who Achieved a Response of Stable Disease (SD), Partial Response (PR), or Complete Response (CR) | Clinical benefit rate is the best response CR, PR, or SD as classified by the investigators according to the RECIST, v1.1 guidelines. CR is defined as the disappearance of all target and non-target lesions, normalization of tumor marker level of non-target lesions, and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR is an at least 30% decrease in the sum of the diameters of target lesions (taking as reference the baseline sum diameter) without progression of non-target lesions or appearance of new lesions. SD is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum diameter since treatment started. Clinical benefit rate is calculated as a total number of participants with CR, PR, or SD divided by the total number of participants with at least 1 measurable lesion, multiplied by 100. | Randomization until date of disease progression or death (up to 6 months after the last participant was randomized) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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solid tumors, Mesothelioma, Carcinoma