Non Small Cell Lung Cancer
Conditions
Brief summary
This trial investigates pemetrexed and cisplatin followed by pemetrexed and cisplatin in combination with radiotherapy in participants with locally advanced, non-small cell lung cancer (NSCLC). The purpose of the study is to assess the antitumor activity as measured by progression free survival 1 year after start of treatment with study drug.
Detailed description
The participants will receive 2 cycles of pemetrexed and cisplatin. If the participants achieve complete response, partial response or stable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) guidelines, have ≤35% of the total calculated lung volume receive more than 20 Gy (V20) according to the 3-dimensional (3-D) radiotherapy planning Dose Volume Histograms, have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, have no residual neurological toxicity \> Grade 2 according to Common Terminology Criteria for Adverse Events (CTCAE), they will receive 2 additional cycles of pemetrexed and cisplatin, combined with radiotherapy. The combination of radiotherapy will begin 22 to 36 days after completion of the second infusion of induction therapy with pemetrexed-cisplatin.
Interventions
DRUGPemetrexed
500 milligrams per square meter (mg/m²) intravenous infusion on Day 1 of a 21 day cycle for 2 cycles: with possibility of 2 additional cycles.
DRUGCisplatin
75 mg/m² intravenous infusion on Day 1 of a 21 day cycle for 2 cycles; with the possibility of 2 additional cycles.
RADIATIONThoracic Radiotherapy
Administered at 2 gray (Gy)/fraction after completion of the pemetrexed and cisplatin infusions on Day 1 of Cycle 3 and will continue daily (5 days per week) until the total delivered dose reaches a therapeutic goal of 66 Gy, over approximately 7 weeks.
Sponsors
Eli Lilly and Company
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologic or cytologic diagnosis of unresectable nonsquamous Stage IIIA or Stage IIIB (without malignant pleural/pericardial effusions) NSCLC. * Have an ECOG performance status of 0 or 1. * Previous radiation therapy should have been limited and must not have included thoracic radiation, whole pelvis radiation, or radiation to \>25% of the participant's bone marrow, participants must have recovered from the toxic effects of radiation treatment prior to study enrollment (except for alopecia). Prior radiotherapy must be completed 30 days before study entry. * Have at least 1 unidimensionally measurable lesion meeting RECIST guidelines, version 1.0. * Estimated life expectancy of at least 12 weeks. * Participant compliance and geographic proximity that allow adequate follow-up. * Adequate bone marrow reserve, hepatic-, renal- and pulmonary function. * Participants must sign an Informed Consent Document. * Participants must have a total lung V20 less than or equal to 35%. * For women: Must be surgically sterile, postmenopausal, or compliant with a medically approved contraceptive regimen, 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 a contraceptive regimen during and for 6 months after the treatment period. * Have not received prior systemic anticancer therapy for NSCLC.
Exclusion criteria
* Have received treatment within the last 30 days of enrollment with a drug that has not received regulatory approval for any indication at the time of study entry. * Have previously completed or withdrawn from this study or any other study investigating pemetrexed. * Have a serious concomitant systemic disorder that, in the opinion of the investigator, would compromise the participant's ability to adhere to the protocol. * 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. * Have had a prior malignancy other than NSCLC, carcinoma in situ of the cervix, or non-melanoma skin cancer, unless that prior malignancy was diagnosed and definitively treated at least 5 years previously with no subsequent evidence of recurrence. Participants with a history of low-grade (Gleason score less than or equal to 6) localized prostate cancer will be eligible even if diagnosed less than 5 years previously. * Are receiving concurrent administration of any other antitumor therapy. * Have had weight loss of more than 10% over the previous 3 months before study entry. * Are unable to interrupt aspirin or other non-steroidal anti-inflammatory drugs (NSAIDs), other than an aspirin dose less than or equal to 1.3 grams per day, for at least 2 days before (5 days for long-acting agents), the day of, and for at least 2 days after administration of pemetrexed. * Are unable or unwilling to take folic acid or vitamin B12 supplementation. * Are unable or unwilling to take corticosteroids. * Have received a recent yellow fever vaccination (within 30 days of enrollment) or are receiving concurrent yellow fever vaccination. * Have known hypersensitivity to pemetrexed, cisplatin, or any of the excipients in these medicinal products. * Have evidence of clinical hearing loss. * Have clinically significant third-space fluid collections, that cannot be controlled by drainage or other procedures prior to study entry.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 1 Year Progression Free Survival | Date of first dose to date of objectively determined PD or death [every cycle up to 4 cycles and then every 3 months up to 1 year (1 cycle=21 days)] | Progression free survival (PFS) was defined as the time from study enrollment to the first observation of progressive disease (PD) or death from any cause. For participants not known to have died as of the data cut-off date and who did not have objective PD, PFS was censored at the date of the last objective progression-free disease assessment. For participants who received subsequent systemic anticancer therapy (after discontinuation from the study drug) prior to objectively determined PD or death, PFS was censored at the date of the last objective progression-free disease assessment prior to start of postdiscontinuation chemotherapy. If a participant did not have a complete baseline disease assessment, then PFS was censored at the enrollment date, regardless whether or not objectively determined PD or death had been observed for the participant. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | Date of first dose to date of death (up to 35.4 months) | Overall survival (OS) was the duration from enrollment to death due to any cause. Participants who were alive were censored at the last contact. |
| Number of Participants With an Objective Tumor Response | Date of first dose through end of follow-up [up to 30 weeks (1 cycle=21 days)] | Participants with confirmed complete response (CR), confirmed partial response (PR), stable disease (SD), or progressive disease (PD) according to Response Evaluation Criteria In Solid Tumors (RECIST, version 1.0) criteria, as well as participants with a not evaluable/tumor response unknown. CR: disappearance of all tumor lesions. PR: either a) at least a 30% decrease in sum of longest diameter (LD) of target lesions taking as a reference baseline sum LDs, or b) complete disappearance of target lesions, with persistence (not worsening) of 1 or more nontarget lesions. In either case, no new lesions appeared. SD: small changes that did not meet above criteria. PD: at least a 20% increase in sum of LD of target lesions taking as reference smallest sum LD recorded since treatment started or appearance of 1 or more new lesions. Participants who discontinued study treatment (for reasons other than progression) before entering concurrent phase were considered to have non-evaluable response. |
Countries
France, Germany, Italy, Spain
Participant flow
Pre-assignment details
Study treatment had 2 phases and follow-up. Induction phase: 2 cycles of pemetrexed-cisplatin. Then, if eligible, the concurrent phase: 2 more cycles of pemetrexed-cisplatin and thoracic radiotherapy. Follow-up period: Started when treatment discontinued or completed, and lasted up to 2 years after first dose of pemetrexed.
Participants by arm
| Arm | Count |
|---|---|
| Pemetrexed, Cisplatin, and Thoracic Radiotherapy Induction phase (2 cycles). Pemetrexed: 500 milligrams per square meter (mg/m²) intravenous infusion on Day 1 of 21-day cycle. Cisplatin: 75 mg/m² intravenous infusion on Day 1 of 21-day cycle.
Participants eligible for concurrent phase (2 more cycles of pemetrexed-cisplatin treatment and radiotherapy) if they had complete response, partial response, or stable disease (Response Evaluation Criteria in Solid Tumors guidelines), total lung volume receiving more than 20 gray (Gy) ≤35% (dose volume histogram), 0 or 1 Eastern Cooperative Oncology Group performance status, no residual neurological toxicity \>Grade 2 (Common Terminology Criteria for Adverse Events).
Thoracic Radiotherapy: 2 Gy/fraction after completion of pemetrexed and cisplatin infusions on Day 1 of Cycle 3 and continued daily (5 days per week) until total delivered dose was 66 Gy, over approximately 7 weeks.
Folic acid, Vitamin B12 supplements, and prophylactic dexamethasone administered per approved pemetrexed label. | 90 |
| Total | 90 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Concurrent Therapy Phase | Adverse Event | 4 |
| Concurrent Therapy Phase | Physician Decision | 1 |
| Concurrent Therapy Phase | Protocol Violation | 2 |
| Concurrent Therapy Phase | Withdrawal by Subject | 3 |
| Induction Phase | Adverse Event | 2 |
| Induction Phase | Entry Criteria Not Met | 3 |
| Induction Phase | Lost to Follow-up | 1 |
| Induction Phase | Physician Decision | 1 |
Baseline characteristics
| Characteristic | Pemetrexed, Cisplatin, and Thoracic Radiotherapy |
|---|---|
| Age, Continuous | 61.7 years STANDARD_DEVIATION 8.15 |
| Current Tobacco Use Current use of tobacco | 28 participants |
| Current Tobacco Use Former user of tobacco | 55 participants |
| Current Tobacco Use Never used tobacco | 7 participants |
| Eastern Cooperative Oncology Group (ECOG) performance status (PS) ECOG PS=0 | 59 participants |
| Eastern Cooperative Oncology Group (ECOG) performance status (PS) ECOG PS=1 | 31 participants |
| Eastern Cooperative Oncology Group (ECOG) performance status (PS) ECOG PS=2 | 0 participants |
| Initial pathological diagnosis Adenocarcinoma (lung) | 81 participants |
| Initial pathological diagnosis Carcinoma (large cell, lung) | 7 participants |
| Initial pathological diagnosis Carcinoma (non-small cell, lung, NOS) | 1 participants |
| Initial pathological diagnosis Carcinoma (non-small cell, poorly differentiated) | 1 participants |
| Race/Ethnicity, Customized White | 90 participants |
| Region of Enrollment France | 9 participants |
| Region of Enrollment Germany | 42 participants |
| Region of Enrollment Italy | 22 participants |
| Region of Enrollment Spain | 17 participants |
| Sex: Female, Male Female | 39 Participants |
| Sex: Female, Male Male | 51 Participants |
| Stage of Disease Stage IIIA | 32 participants |
| Stage of Disease Stage IIIB | 56 participants |
| Stage of Disease Stage IV | 2 participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 85 / 90 |
| serious Total, serious adverse events | 23 / 90 |
Outcome results
Primary
1 Year Progression Free Survival
Progression free survival (PFS) was defined as the time from study enrollment to the first observation of progressive disease (PD) or death from any cause. For participants not known to have died as of the data cut-off date and who did not have objective PD, PFS was censored at the date of the last objective progression-free disease assessment. For participants who received subsequent systemic anticancer therapy (after discontinuation from the study drug) prior to objectively determined PD or death, PFS was censored at the date of the last objective progression-free disease assessment prior to start of postdiscontinuation chemotherapy. If a participant did not have a complete baseline disease assessment, then PFS was censored at the enrollment date, regardless whether or not objectively determined PD or death had been observed for the participant.
Time frame: Date of first dose to date of objectively determined PD or death [every cycle up to 4 cycles and then every 3 months up to 1 year (1 cycle=21 days)]
Population: Intent-to-treat population: participants who received at least 1 dose of either study drug (pemetrexed or cisplatin). The number of participants censored was 35.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pemetrexed, Cisplatin, and Thoracic Radiotherapy | 1 Year Progression Free Survival | 53.7 percentage of participants |
Comparison: Null hypothesis (H0): 1-year PFS ≤45% and the alternative hypothesis (H1): 1-year PFS ≥60%, at a 2-sided alpha level of 5%, assuming that PFS time followed an exponential distribution.p-value: 0.0645maximum likelihood estimate
Secondary
Number of Participants With an Objective Tumor Response
Participants with confirmed complete response (CR), confirmed partial response (PR), stable disease (SD), or progressive disease (PD) according to Response Evaluation Criteria In Solid Tumors (RECIST, version 1.0) criteria, as well as participants with a not evaluable/tumor response unknown. CR: disappearance of all tumor lesions. PR: either a) at least a 30% decrease in sum of longest diameter (LD) of target lesions taking as a reference baseline sum LDs, or b) complete disappearance of target lesions, with persistence (not worsening) of 1 or more nontarget lesions. In either case, no new lesions appeared. SD: small changes that did not meet above criteria. PD: at least a 20% increase in sum of LD of target lesions taking as reference smallest sum LD recorded since treatment started or appearance of 1 or more new lesions. Participants who discontinued study treatment (for reasons other than progression) before entering concurrent phase were considered to have non-evaluable response.
Time frame: Date of first dose through end of follow-up [up to 30 weeks (1 cycle=21 days)]
Population: Intent-to-treat population: Participants who received at least 1 dose of study drug (pemetrexed or cisplatin).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pemetrexed, Cisplatin, and Thoracic Radiotherapy | Number of Participants With an Objective Tumor Response | Complete Response | 9 participants |
| Pemetrexed, Cisplatin, and Thoracic Radiotherapy | Number of Participants With an Objective Tumor Response | Partial Response | 45 participants |
| Pemetrexed, Cisplatin, and Thoracic Radiotherapy | Number of Participants With an Objective Tumor Response | Stable Disease | 16 participants |
| Pemetrexed, Cisplatin, and Thoracic Radiotherapy | Number of Participants With an Objective Tumor Response | Disease Progression | 12 participants |
| Pemetrexed, Cisplatin, and Thoracic Radiotherapy | Number of Participants With an Objective Tumor Response | Not evaluable/Response unknown | 8 participants |
Secondary
Overall Survival
Overall survival (OS) was the duration from enrollment to death due to any cause. Participants who were alive were censored at the last contact.
Time frame: Date of first dose to date of death (up to 35.4 months)
Population: Intent-to-treat population: participants who received at least 1 dose of study drug (pemetrexed or cisplatin). The number of participants censored was 45.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pemetrexed, Cisplatin, and Thoracic Radiotherapy | Overall Survival | 26.2 months |