Non Small Cell Lung Cancer
Conditions
Keywords
solid tumors, Mesothelioma, Carcinoma
Brief summary
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.
Interventions
DRUGPemetrexed
Administered intravenously as a continuous 10-minute infusion
DRUGCisplatin
Administered intravenously as a continuous 1-hour infusion
DRUGLY2603618
Administered intravenously as a continuous 1-hour infusion
Sponsors
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1: Recommended Phase 2 Dose of LY2603618 | Time of first dose to last dose | 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 \[ng/mL\]). |
| Phase 2: Progression-Free Survival Time | Randomization up to first date of PD or death from any cause (up to 6 months after the last participant entered treatment) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase 2: Overall Tumor Response Rate: Percentage of Participants Who Achieved a Confirmed Best Response of Completed Response (CR) or Partial Response (PR) | Randomization until date of disease progression (up to 6 months after the last participant was randomized) | 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. |
| Phase 2: Change in Tumor Size | Baseline, end of Cycle 2 | 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. |
| Phase 1: Pharmacokinetic: Maximum Plasma Concentration (Cmax) (LY2603618) | 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 | 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. |
| Phase 1: Pharmacokinetic: Cmax (Pemetrexed and Cisplatin) | 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. | 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. |
| Phase 1: Pharmacokinetic: Area Under the Plasma Concentration Versus Time Curve (AUC) (LY2603618) | 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 | 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. |
| Phase 1: Pharmacokinetic: AUC (Pemetrexed and Cisplatin) | 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. | 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. |
| Phase 2: Pharmacokinetic: AUC (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 | 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. |
| Phase 2: Change From Baseline to Long-term Follow up in Lung Cancer Symptom Scale (LCSS) | Randomization to the end of study (approximately 12 months after the last participant entered treatment) | 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. |
| Phase 1: Document Any Antitumor Activity Per Radiological Scans and/or Tumor Markers | Baseline through end of Phase 1 | 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. |
| 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) | Randomization until date of disease progression or death (up to 6 months after the last participant was randomized) | 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. |
| 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: Overall Survival | Randomization to the date of death from any cause through the time of study discontinuation (approximately 12 months after last participant was randomized) | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Deaths | Randomization through 12 months after the last participant was randomized | Deaths that occurred during the study are presented. A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Events module. |
Countries
Germany, Spain
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Phase 1: Pemetrexed + Cisplatin + LY2603618 Cycles 1-2 (21-day cycle):
Day 1: pemetrexed 500 mg/m\^2 + cisplatin 75 mg/m\^2
Day 2: LY2603618 130 to 275 mg
After 2 cycles, participants may have continued on study drug until disease progression, unacceptable toxicity, or other withdrawal criterion was met.
Pemetrexed, cisplatin, and LY2603618 were administered IV over 10 minutes, 1 hour, and 1 hour, respectively. | 14 |
| Phase 2: Pemetrexed + Cisplatin + LY2603618 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 determined from phase 1 (275 mg)
After 25 Oct 2012:
Day 1: pemetrexed 500 mg/m\^2 + cisplatin 75 mg/m\^2
After 4 cycles, participants may have continued on maintenance therapy until disease progression, unacceptable toxicity, or other withdrawal criterion was met.
Maintenance therapy (every 21 days):
Before 25 Oct 2012:
Day 1: pemetrexed 500 mg/m\^2
Day 2: LY2603618 dose determined from phase 1 (275 mg)
After 25 Oct 2012:
Day 1: pemetrexed 500 mg/m\^2
If, as of 25 Oct 2012, the participant was in maintenance therapy and randomized to the experimental arm, the participant was eligible to continue with pemetrexed/LY2603618 therapy if the investigator deemed it was in the participant's best interest and the participant consented.
Pemetrexed, cisplatin, and LY2603618 were administered IV over 10 minutes, 1 hour, and 1 hour, respectively. | 39 |
| Phase 2: Pemetrexed + Cisplatin Cycles 1-4 (21-day cycle):
Day 1: pemetrexed 500 mg/m\^2 + cisplatin 75 mg/m\^2
After 4 cycles, participants may have continued on maintenance therapy until disease progression, unacceptable toxicity, or other withdrawal criterion was met.
Maintenance therapy (every 21 days):
Day 1: pemetrexed 500 mg/m\^2
Pemetrexed was administered IV over 10 minutes, and cisplatin was administered IV over 1 hour. | 23 |
| Total | 76 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 6 | 2 |
| Overall Study | Physician Decision | 0 | 2 | 2 |
| Overall Study | Protocol Violation | 0 | 5 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 2 |
Baseline characteristics
| Characteristic | Phase 1: Pemetrexed + Cisplatin + LY2603618 | Phase 2: Pemetrexed + Cisplatin + LY2603618 | Phase 2: Pemetrexed + Cisplatin | Total |
|---|---|---|---|---|
| Age, Continuous | 57.9 years STANDARD_DEVIATION 11.4 | 57.9 years STANDARD_DEVIATION 10.1 | 56.4 years STANDARD_DEVIATION 9.8 | 57.4 years STANDARD_DEVIATION 10.1 |
| Eastern Cooperative Oncology Group (ECOG) Performance Status ECOG Status 0 | 11 Participants | 9 Participants | 7 Participants | 27 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status ECOG Status 1 | 3 Participants | 30 Participants | 15 Participants | 48 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status Missing | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Initial Pathological Diagnosis Adenocarcinoma, Bronchiolalveolar | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Initial Pathological Diagnosis Adenocarcinoma, Colon | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Initial Pathological Diagnosis Adenocarcinoma, Lung | 8 Participants | 38 Participants | 19 Participants | 65 Participants |
| Initial Pathological Diagnosis Adenocarcinoma, Moderately Diff., Lung | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Initial Pathological Diagnosis Carcinoma, Ampulla of Vater | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Initial Pathological Diagnosis Carcinoma, Breast | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Initial Pathological Diagnosis Carcinoma, Large Cell, Lung | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Initial Pathological Diagnosis Carcinoma, Lung | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Initial Pathological Diagnosis Carcinoma, Non-small Cell, Poorly Diff, Lung | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Initial Pathological Diagnosis Carcinoma, Pancreas | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Initial Pathological Diagnosis Mesothelioma, Malignum | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Initial Pathological Diagnosis Pleuritis Carcinomatosa | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 14 Participants | 39 Participants | 23 Participants | 76 Participants |
| Region of Enrollment Germany | 7 Participants | 15 Participants | 11 Participants | 33 Participants |
| Region of Enrollment Spain | 7 Participants | 24 Participants | 12 Participants | 43 Participants |
| Sex: Female, Male Female | 7 Participants | 15 Participants | 8 Participants | 30 Participants |
| Sex: Female, Male Male | 7 Participants | 24 Participants | 15 Participants | 46 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 14 / 14 | 37 / 39 | 22 / 22 |
| serious Total, serious adverse events | 1 / 14 | 16 / 39 | 6 / 22 |
Outcome results
Primary
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 frame: Time of first dose to last dose
Population: Phase 1 participants who received at least 1 dose of any of the study drugs.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 2: Pemetrexed + Cisplatin + LY2603618 | Phase 1: Recommended Phase 2 Dose of LY2603618 | 275 mg |
Primary
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.
Time frame: Randomization up to first date of PD or death from any cause (up to 6 months after the last participant entered treatment)
Population: All randomized Phase 2 participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 2: Pemetrexed + Cisplatin + LY2603618 | Phase 2: Progression-Free Survival Time | 4.7 months |
| Phase 2: Pemetrexed + Cisplatin | Phase 2: Progression-Free Survival Time | 1.5 months |
Comparison: The analysis for comparing progression-free survival time between the treatment arms used a Bayesian Augmented Control model with a hierarchical random-effects distribution on treatment effects. The final model incorporated historical data from a completed Phase 3 study (NCT00789373) to augment the prospective control arm data.
Secondary
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.
Time frame: Baseline through end of Phase 1
Population: All randomized Phase 1 participants.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase 2: Pemetrexed + Cisplatin + LY2603618 | Phase 1: Document Any Antitumor Activity Per Radiological Scans and/or Tumor Markers | 130 mg | 0 percentage of participants |
| Phase 2: Pemetrexed + Cisplatin + LY2603618 | Phase 1: Document Any Antitumor Activity Per Radiological Scans and/or Tumor Markers | 185 mg | 66.7 percentage of participants |
| Phase 2: Pemetrexed + Cisplatin + LY2603618 | Phase 1: Document Any Antitumor Activity Per Radiological Scans and/or Tumor Markers | 240 mg | 25.0 percentage of participants |
| Phase 2: Pemetrexed + Cisplatin + LY2603618 | Phase 1: Document Any Antitumor Activity Per Radiological Scans and/or Tumor Markers | 275 mg | 0 percentage of participants |
Secondary
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.
Time frame: 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
Population: Phase 1 participants who received at least 1 dose of LY2603618 and had samples collected for pharmacokinetic analysis.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 2: Pemetrexed + Cisplatin + LY2603618 | Phase 1: Pharmacokinetic: Area Under the Plasma Concentration Versus Time Curve (AUC) (LY2603618) | 130 mg, Cycle 2/Day 2, AUC(0-∞) | 11300 ng*h/mL | Geometric Coefficient of Variation 45 |
| Phase 2: Pemetrexed + Cisplatin + LY2603618 | Phase 1: Pharmacokinetic: Area Under the Plasma Concentration Versus Time Curve (AUC) (LY2603618) | 185 mg, Cycle 1/Day 2, AUC(0-24) | 13800 ng*h/mL | Geometric Coefficient of Variation 119 |
| Phase 2: Pemetrexed + Cisplatin + LY2603618 | Phase 1: Pharmacokinetic: Area Under the Plasma Concentration Versus Time Curve (AUC) (LY2603618) | 185 mg, Cycle 2/Day 2, AUC(0-24) | 12500 ng*h/mL | Geometric Coefficient of Variation 170 |
| Phase 2: Pemetrexed + Cisplatin + LY2603618 | Phase 1: Pharmacokinetic: Area Under the Plasma Concentration Versus Time Curve (AUC) (LY2603618) | 185 mg, Cycle 1/Day 2, AUC(0-tlast) | 18300 ng*h/mL | Geometric Coefficient of Variation 192 |
| Phase 2: Pemetrexed + Cisplatin + LY2603618 | Phase 1: Pharmacokinetic: Area Under the Plasma Concentration Versus Time Curve (AUC) (LY2603618) | 185 mg, Cycle 2/Day 2, AUC(0-tlast) | 14800 ng*h/mL | Geometric Coefficient of Variation 217 |
| Phase 2: Pemetrexed + Cisplatin + LY2603618 | Phase 1: Pharmacokinetic: Area Under the Plasma Concentration Versus Time Curve (AUC) (LY2603618) | 240 mg, Cycle 1/Day 2, AUC(0-tlast) | 32200 ng*h/mL | Geometric Coefficient of Variation 21 |
| Phase 2: Pemetrexed + Cisplatin + LY2603618 | Phase 1: Pharmacokinetic: Area Under the Plasma Concentration Versus Time Curve (AUC) (LY2603618) | 240 mg, Cycle 2/Day 2, AUC(0-tlast) | 27300 ng*h/mL | Geometric Coefficient of Variation 31 |
| Phase 2: Pemetrexed + Cisplatin + LY2603618 | Phase 1: Pharmacokinetic: Area Under the Plasma Concentration Versus Time Curve (AUC) (LY2603618) | 275 mg, Cycle 2/Day 2, AUC(0-tlast) | 30800 ng*h/mL | Geometric Coefficient of Variation 44 |
| Phase 2: Pemetrexed + Cisplatin + LY2603618 | Phase 1: Pharmacokinetic: Area Under the Plasma Concentration Versus Time Curve (AUC) (LY2603618) | 130 mg, Cycle 1/Day 2, AUC(0-24) | 8700 ng*h/mL | Geometric Coefficient of Variation 30 |
| Phase 2: Pemetrexed + Cisplatin + LY2603618 | Phase 1: Pharmacokinetic: Area Under the Plasma Concentration Versus Time Curve (AUC) (LY2603618) | 130 mg, Cycle 2/Day 2, AUC(0-24) | 9780 ng*h/mL | Geometric Coefficient of Variation 43 |
| Phase 2: Pemetrexed + Cisplatin + LY2603618 | Phase 1: Pharmacokinetic: Area Under the Plasma Concentration Versus Time Curve (AUC) (LY2603618) | 130 mg, Cycle 1/Day 2, AUC(0-tlast) | 10200 ng*h/mL | Geometric Coefficient of Variation 26 |
| Phase 2: Pemetrexed + Cisplatin + LY2603618 | Phase 1: Pharmacokinetic: Area Under the Plasma Concentration Versus Time Curve (AUC) (LY2603618) | 130 mg, Cycle 2/Day 2, AUC(0-tlast) | 11300 ng*h/mL | Geometric Coefficient of Variation 44 |
| Phase 2: Pemetrexed + Cisplatin + LY2603618 | Phase 1: Pharmacokinetic: Area Under the Plasma Concentration Versus Time Curve (AUC) (LY2603618) | 130 mg, Cycle 1/Day 2, AUC(0-∞) | 10200 ng*h/mL | Geometric Coefficient of Variation 26 |
| Phase 2: Pemetrexed + Cisplatin + LY2603618 | Phase 1: Pharmacokinetic: Area Under the Plasma Concentration Versus Time Curve (AUC) (LY2603618) | 185 mg, Cycle 1/Day 2, AUC(0-∞) | 18400 ng*h/mL | Geometric Coefficient of Variation 193 |
| Phase 2: Pemetrexed + Cisplatin + LY2603618 | Phase 1: Pharmacokinetic: Area Under the Plasma Concentration Versus Time Curve (AUC) (LY2603618) | 185 mg, Cycle 2/Day 2, AUC(0-∞) | 15700 ng*h/mL | Geometric Coefficient of Variation 253 |
| Phase 2: Pemetrexed + Cisplatin + LY2603618 | Phase 1: Pharmacokinetic: Area Under the Plasma Concentration Versus Time Curve (AUC) (LY2603618) | 240 mg, Cycle 1/Day 2, AUC(0-24) | 26200 ng*h/mL | Geometric Coefficient of Variation 19 |
| Phase 2: Pemetrexed + Cisplatin + LY2603618 | Phase 1: Pharmacokinetic: Area Under the Plasma Concentration Versus Time Curve (AUC) (LY2603618) | 240 mg, Cycle 2/Day 2, AUC(0-24) | 22100 ng*h/mL | Geometric Coefficient of Variation 31 |
| Phase 2: Pemetrexed + Cisplatin + LY2603618 | Phase 1: Pharmacokinetic: Area Under the Plasma Concentration Versus Time Curve (AUC) (LY2603618) | 240 mg, Cycle 1/Day 2, AUC(0-∞) | 32300 ng*h/mL | Geometric Coefficient of Variation 21 |
| Phase 2: Pemetrexed + Cisplatin + LY2603618 | Phase 1: Pharmacokinetic: Area Under the Plasma Concentration Versus Time Curve (AUC) (LY2603618) | 240 mg, Cycle 2/Day 2, AUC(0-∞) | 27500 ng*h/mL | Geometric Coefficient of Variation 31 |
| Phase 2: Pemetrexed + Cisplatin + LY2603618 | Phase 1: Pharmacokinetic: Area Under the Plasma Concentration Versus Time Curve (AUC) (LY2603618) | 275 mg, Cycle 1/Day 2, AUC(0-24) | 28900 ng*h/mL | Geometric Coefficient of Variation 24 |
| Phase 2: Pemetrexed + Cisplatin + LY2603618 | Phase 1: Pharmacokinetic: Area Under the Plasma Concentration Versus Time Curve (AUC) (LY2603618) | 275 mg, Cycle 2/Day 2, AUC(0-24) | 23500 ng*h/mL | Geometric Coefficient of Variation 31 |
| Phase 2: Pemetrexed + Cisplatin + LY2603618 | Phase 1: Pharmacokinetic: Area Under the Plasma Concentration Versus Time Curve (AUC) (LY2603618) | 275 mg, Cycle 1/Day 2, AUC(0-tlast) | 38100 ng*h/mL | Geometric Coefficient of Variation 36 |
| Phase 2: Pemetrexed + Cisplatin + LY2603618 | Phase 1: Pharmacokinetic: Area Under the Plasma Concentration Versus Time Curve (AUC) (LY2603618) | 275 mg, Cycle 1/Day 2, AUC(0-∞) | 38300 ng*h/mL | Geometric Coefficient of Variation 37 |
| Phase 2: Pemetrexed + Cisplatin + LY2603618 | Phase 1: Pharmacokinetic: Area Under the Plasma Concentration Versus Time Curve (AUC) (LY2603618) | 275 mg, Cycle 2/Day 2, AUC(0-∞) | 30900 ng*h/mL | Geometric Coefficient of Variation 44 |
Secondary
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.
Time frame: 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.
Population: Phase 1 participants who received at least 1 dose of pemetrexed or cisplatin and had samples collected for pharmacokinetic analysis.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 2: Pemetrexed + Cisplatin + LY2603618 | Phase 1: Pharmacokinetic: AUC (Pemetrexed and Cisplatin) | Pemetrexed, AUC (0-∞) | 160000 ng*h/mL | Geometric Coefficient of Variation 35 |
| Phase 2: Pemetrexed + Cisplatin + LY2603618 | Phase 1: Pharmacokinetic: AUC (Pemetrexed and Cisplatin) | T-platinum from cisplatin, AUC (0-tlast) | 163000 ng*h/mL | Geometric Coefficient of Variation 26 |
| Phase 2: Pemetrexed + Cisplatin + LY2603618 | Phase 1: Pharmacokinetic: AUC (Pemetrexed and Cisplatin) | Pemetrexed, AUC(0-tlast) | 159000 ng*h/mL | Geometric Coefficient of Variation 35 |
| Phase 2: Pemetrexed + Cisplatin + LY2603618 | Phase 1: Pharmacokinetic: AUC (Pemetrexed and Cisplatin) | T-platinum from cisplatin, AUC (0-∞) | 269000 ng*h/mL | Geometric Coefficient of Variation 26 |
Secondary
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.
Time frame: 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.
Population: Phase 1 participants who received at least 1 dose of pemetrexed or cisplatin and had samples collected for pharmacokinetic analysis.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 2: Pemetrexed + Cisplatin + LY2603618 | Phase 1: Pharmacokinetic: Cmax (Pemetrexed and Cisplatin) | Pemetrexed | 88300 ng/mL | Geometric Coefficient of Variation 28 |
| Phase 2: Pemetrexed + Cisplatin + LY2603618 | Phase 1: Pharmacokinetic: Cmax (Pemetrexed and Cisplatin) | T-platinum from cisplatin | 3710 ng/mL | Geometric Coefficient of Variation 43 |
Secondary
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.
Time frame: 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
Population: Phase 1 participants who received at least 1 dose of LY2603618 and had samples collected for pharmacokinetic analysis.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 2: Pemetrexed + Cisplatin + LY2603618 | Phase 1: Pharmacokinetic: Maximum Plasma Concentration (Cmax) (LY2603618) | 275 mg, Cycle 2/Day 2 | 3620 ng/mL | Geometric Coefficient of Variation 23 |
| Phase 2: Pemetrexed + Cisplatin + LY2603618 | Phase 1: Pharmacokinetic: Maximum Plasma Concentration (Cmax) (LY2603618) | 185 mg, Cycle 2/Day 2 | 2190 ng/mL | Geometric Coefficient of Variation 58 |
| Phase 2: Pemetrexed + Cisplatin + LY2603618 | Phase 1: Pharmacokinetic: Maximum Plasma Concentration (Cmax) (LY2603618) | 130 mg, Cycle 1/Day 2 | 1810 ng/mL | Geometric Coefficient of Variation 14 |
| Phase 2: Pemetrexed + Cisplatin + LY2603618 | Phase 1: Pharmacokinetic: Maximum Plasma Concentration (Cmax) (LY2603618) | 130 mg, Cycle 2/Day 2 | 1730 ng/mL | Geometric Coefficient of Variation 43 |
| Phase 2: Pemetrexed + Cisplatin + LY2603618 | Phase 1: Pharmacokinetic: Maximum Plasma Concentration (Cmax) (LY2603618) | 185 mg, Cycle 1/Day 2 | 2200 ng/mL | Geometric Coefficient of Variation 33 |
| Phase 2: Pemetrexed + Cisplatin + LY2603618 | Phase 1: Pharmacokinetic: Maximum Plasma Concentration (Cmax) (LY2603618) | 240 mg, Cycle 1/Day 2 | 3470 ng/mL | Geometric Coefficient of Variation 27 |
| Phase 2: Pemetrexed + Cisplatin + LY2603618 | Phase 1: Pharmacokinetic: Maximum Plasma Concentration (Cmax) (LY2603618) | 240 mg, Cycle 2/Day 2 | 2750 ng/mL | Geometric Coefficient of Variation 63 |
| Phase 2: Pemetrexed + Cisplatin + LY2603618 | Phase 1: Pharmacokinetic: Maximum Plasma Concentration (Cmax) (LY2603618) | 275 mg, Cycle 1/Day 2 | 4130 ng/mL | Geometric Coefficient of Variation 29 |
Secondary
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.
Time frame: Randomization to the end of study (approximately 12 months after the last participant entered treatment)
Population: All enrolled Phase 2 participants who had the baseline LCSS assessment and at least 1 post-baseline assessment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 2: Pemetrexed + Cisplatin + LY2603618 | Phase 2: Change From Baseline to Long-term Follow up in Lung Cancer Symptom Scale (LCSS) | Total LCSS | -10.7 units on a scale | Standard Deviation 14.1 |
| Phase 2: Pemetrexed + Cisplatin + LY2603618 | Phase 2: Change From Baseline to Long-term Follow up in Lung Cancer Symptom Scale (LCSS) | ASBI | -11.6 units on a scale | Standard Deviation 13.9 |
| Phase 2: Pemetrexed + Cisplatin | Phase 2: Change From Baseline to Long-term Follow up in Lung Cancer Symptom Scale (LCSS) | Total LCSS | -11.7 units on a scale | Standard Deviation 15.1 |
| Phase 2: Pemetrexed + Cisplatin | Phase 2: Change From Baseline to Long-term Follow up in Lung Cancer Symptom Scale (LCSS) | ASBI | -12.6 units on a scale | Standard Deviation 15.4 |
Secondary
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.
Time frame: Baseline, end of Cycle 2
Population: Participants with measureable disease (target lesions) at baseline who received at least 1 dose of study drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 2: Pemetrexed + Cisplatin + LY2603618 | Phase 2: Change in Tumor Size | -0.30 centimeters | Standard Deviation 0.541 |
| Phase 2: Pemetrexed + Cisplatin | Phase 2: Change in Tumor Size | -0.14 centimeters | Standard Deviation 0.277 |
p-value: 0.4924Wilcoxon (Mann-Whitney)
Secondary
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.
Time frame: Randomization until date of disease progression or death (up to 6 months after the last participant was randomized)
Population: All randomized Phase 2 participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 2: Pemetrexed + Cisplatin + LY2603618 | Phase 2: Clinical Benefit Rate: Percentage of Participant Who Achieved a Response of Stable Disease (SD), Partial Response (PR), or Complete Response (CR) | 69.2 percentage of participants |
| Phase 2: Pemetrexed + Cisplatin | Phase 2: Clinical Benefit Rate: Percentage of Participant Who Achieved a Response of Stable Disease (SD), Partial Response (PR), or Complete Response (CR) | 47.8 percentage of participants |
p-value: 0.0946Chi-squared
Secondary
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.
Time frame: Randomization to the date of death from any cause through the time of study discontinuation (approximately 12 months after last participant was randomized)
Population: All randomized Phase 2 participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 2: Pemetrexed + Cisplatin + LY2603618 | Phase 2: Overall Survival | 12.9 months |
| Phase 2: Pemetrexed + Cisplatin | Phase 2: Overall Survival | 6.6 months |
p-value: 0.2294Log Rank
Secondary
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.
Time frame: Randomization until date of disease progression (up to 6 months after the last participant was randomized)
Population: All randomized Phase 2 participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 2: Pemetrexed + Cisplatin + LY2603618 | Phase 2: Overall Tumor Response Rate: Percentage of Participants Who Achieved a Confirmed Best Response of Completed Response (CR) or Partial Response (PR) | 43.6 percentage of participants |
| Phase 2: Pemetrexed + Cisplatin | Phase 2: Overall Tumor Response Rate: Percentage of Participants Who Achieved a Confirmed Best Response of Completed Response (CR) or Partial Response (PR) | 21.7 percentage of participants |
p-value: 0.0824Chi-squared
Secondary
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.
Time frame: Cycle 1/Day 2 - predose, immediately prior to the end of the LY2603618 infusion, and 2-6, 24-48, and 72-96 hours postdose
Population: Phase 2 participants who received at least 1 dose of LY2603618 and had samples collected for pharmacokinetic analysis.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 2: Pemetrexed + Cisplatin + LY2603618 | Phase 2: Pharmacokinetic: AUC (LY2603618) | AUC (0-24) | 31400 ng*h/mL | Geometric Coefficient of Variation 49 |
| Phase 2: Pemetrexed + Cisplatin + LY2603618 | Phase 2: Pharmacokinetic: AUC (LY2603618) | AUC (0-tlast) | 39300 ng*h/mL | Geometric Coefficient of Variation 58 |
| Phase 2: Pemetrexed + Cisplatin + LY2603618 | Phase 2: Pharmacokinetic: AUC (LY2603618) | AUC (0-∞) | 41100 ng*h/mL | Geometric Coefficient of Variation 59 |
Secondary
Phase 2: Pharmacokinetic: Cmax (LY2603618)
Time frame: Cycle 1/Day 2 - predose, immediately prior to the end of the LY2603618 infusion, and 2-6, 24-48, and 72-96 hours postdose
Population: Phase 2 participants who received at least 1 dose of LY2603618 and had samples collected for pharmacokinetic analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 2: Pemetrexed + Cisplatin + LY2603618 | Phase 2: Pharmacokinetic: Cmax (LY2603618) | 4130 ng/mL | Geometric Coefficient of Variation 66 |
Secondary
Phase 2: Proportion of Participants Receiving Maintenance Therapy
Time frame: Cycle 5
Population: Zero participants analyzed. Treatment with LY2603618 was discontinued after 25 October 2012, data was not collected for analysis of the Phase 2: Proportion of Participants Receiving Maintenance Therapy.
Other Pre-specified
Deaths
Deaths that occurred during the study are presented. A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Events module.
Time frame: Randomization through 12 months after the last participant was randomized
Population: All enrolled participants.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase 2: Pemetrexed + Cisplatin + LY2603618 | Deaths | Total deaths | 0 Participants |
| Phase 2: Pemetrexed + Cisplatin + LY2603618 | Deaths | Deaths while on treatment | 0 Participants |
| Phase 2: Pemetrexed + Cisplatin + LY2603618 | Deaths | Death within 30 days of last dose of study drug | 0 Participants |
| Phase 2: Pemetrexed + Cisplatin + LY2603618 | Deaths | Deaths during follow-up period | 0 Participants |
| Phase 2: Pemetrexed + Cisplatin | Deaths | Deaths during follow-up period | 17 Participants |
| Phase 2: Pemetrexed + Cisplatin | Deaths | Total deaths | 21 Participants |
| Phase 2: Pemetrexed + Cisplatin | Deaths | Deaths while on treatment | 3 Participants |
| Phase 2: Pemetrexed + Cisplatin | Deaths | Death within 30 days of last dose of study drug | 1 Participants |
| Phase 2: Pemetrexed + Cisplatin | Deaths | Total deaths | 15 Participants |
| Phase 2: Pemetrexed + Cisplatin | Deaths | Death within 30 days of last dose of study drug | 0 Participants |
| Phase 2: Pemetrexed + Cisplatin | Deaths | Deaths during follow-up period | 14 Participants |
| Phase 2: Pemetrexed + Cisplatin | Deaths | Deaths while on treatment | 1 Participants |