Non-Small-Cell Lung Cancer
Conditions
Brief summary
This is a two-arm, parallel, open-label, Phase 2 multicenter study of pemetrexed as first line combination therapy with either cisplatin or carboplatin in the palliative setting of stage IIIb and IV non-small cell lung cancer patients. Approximately 130 patients will be included in about 15 centers in Germany and randomized to one of the above treatment regimens in a 1:1 ratio. Chemotherapy will be administered over a maximum of six cycles with a standard length of 21 days. Primary objective will be the Progression Free Survival Time of patients as assessed in both treatment arms.
Interventions
DRUGPemetrexed
500 mg/m2, intravenous (IV), every 21 days x 6 cycles
DRUGCisplatin
75 mg/m2, intravenous (IV), every 21 days x 6 cycles
DRUGCarboplatin
Area under the concentration curve (AUC) 5, intravenous (IV), every 21 days x 6 cycles
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
* Cytologically and/or histologically confirmed NSCLC Stage IIIb or IV * No previous systemic chemotherapy for this cancer * At least one uni-dimensionally measurable lesion meeting Response Evaluation Criteria In Solid Tumors (RECIST) criteria * Eastern Cooperative Oncology Group (ECOG) Performance status of 0 or 1 and adequate organ function * Prior radiation therapy allowed but limited to \<25% of the patient's bone marrow
Exclusion criteria
* Serious concomitant systemic disorder or active infection * Mild to moderate renal insufficiency, but unable to interrupt salicylates or other nonsteroidal anti-inflammatory drugs * Symptomatic central nervous system (CNS) metastases requiring concurrent corticosteroid therapy * Presence of clinically significant third-space fluid collections
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Surviving Progression-Free at 6 Months (Progression Free Survival [PFS] Rate) | Randomization to Month 6 | For this study, we used the exponential distribution (assumption done for the calculation of the sample size) to estimate the PFS rate. The PFS rate (%) and the 95% confidence intervals were calculated based on the following formula: exp(-6 λ) ± 1.96 \* exp(-6 λ) \* (-6 λ)/√r. Where λ was calculated based on the Maximum-Likelihood estimator for ln(λ) as given by (Collett 2003): ln(λ) = ln\[ r / ∑ti \] with r = number of patients with events up to 6 months, ti = survival time of patient i (i=1,…,n), event or censored up to 6 months, and n= total number of patients per treatment group. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | Randomization to date of death from any cause (up to 1 year) | Defined as the time from randomization to the date of death from any cause. |
| Number of Participants With Tumor Response (as Basis for Response Rate) | Every 6 weeks for 6 months during the treatment period, and every 3 months during the follow-up period, until disease progression | Best overall response was evaluated using RECIST Criteria which define when cancer patients improve (respond), stay the same (stabilize), or worsen (progression) during treatment. CR: complete response, disappearance of all target lesions; PR: partial response, 30% decrease in sum of the longest diameter of target lesions; PD: progressive disease, 20% increase in sum of the longest diameter of target lesions; SD: stable disease, small changes not meeting above criteria. Response Rate: number of participants with response(CR+PR)per total population, multiplied by 100 to give a percentage. |
| Time to Treatment Failure (TTF) | Randomization to stopping of treatment, progression, death or initiation of further chemotherapy, whichever occurs first (up to 1 year) | Defined as time from randomization to the first date of disease progression, death due to any cause, or early discontinuation of treatment (any reason), whichever occurred first |
| Pharmacology Toxicities | Every 21-day cycle for up to 6 cycles | Number of patients experiencing Grade 3 or 4 hematologic and non-hematologic adverse events (AEs) possibly related to study drug or protocol procedures in this study (a subset of those listed in the AE Module). AEs were graded using the Common Terminology Criteria for Adverse Events version 3.0 (CTCAE v3.0) for defining and grading specific adverse events. A grading (severity) scale is provided for each adverse event term. Grades range from 0 (none) to 5 (death). Grade 3 AEs are severe and undesirable; Grade 4 AEs are life-threatening or disabling. |
Countries
Germany
Participant flow
Pre-assignment details
136 patients signed informed consent. Of these, 3 patients were discontinued prior to randomization (1x protocol entry criteria not met, 2x patient decision); 133 patients were randomized, 130 patients started study drug.
Participants by arm
| Arm | Count |
|---|---|
| Pemetrexed + Cisplatin Pemetrexed 500 mg/m2 intravenous (IV); Cisplatin 75 mg/m2 IV, every 21 days for 6 cycles | 65 |
| Pemetrexed + Carboplatin Pemetrexed 500 mg/m2 intravenous (IV); Carboplatin area under the concentration curve (AUC) 5 IV, every 21 days for 6 cycles | 65 |
| Total | 130 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 11 | 4 |
| Overall Study | Death Due to Adverse Event | 0 | 2 |
| Overall Study | Death Due to Study Disease | 2 | 1 |
| Overall Study | Death - Related to Study Drug | 1 | 2 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Physician Decision | 7 | 3 |
| Overall Study | Progressive Disease | 13 | 20 |
| Overall Study | Withdrawal by Subject | 3 | 3 |
Baseline characteristics
| Characteristic | Pemetrexed + Cisplatin | Pemetrexed + Carboplatin | Total |
|---|---|---|---|
| Age Continuous | 62.3 years STANDARD_DEVIATION 8.43 | 62.4 years STANDARD_DEVIATION 7.51 | 62.4 years STANDARD_DEVIATION 7.95 |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 0 - Fully Active | 40 participants | 45 participants | 85 participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 1 - Ambulatory, Restricted Strenuous Activity | 25 participants | 20 participants | 45 participants |
| Histopathology Adenocarcinoma | 38 participants | 44 participants | 82 participants |
| Histopathology Bronchioalveolar Carcinoma | 0 participants | 1 participants | 1 participants |
| Histopathology Large Cell Carcinoma | 6 participants | 3 participants | 9 participants |
| Histopathology Mixed Cell Carcinoma | 0 participants | 1 participants | 1 participants |
| Histopathology NSCLC, Not Otherwise Specified | 9 participants | 3 participants | 12 participants |
| Histopathology Squamous Cell Carcinoma | 12 participants | 13 participants | 25 participants |
| Presence of Bone and Brain Metastases Bone Metastases | 14 participants | 11 participants | 25 participants |
| Presence of Bone and Brain Metastases Brain Metastases | 2 participants | 1 participants | 3 participants |
| Race/Ethnicity, Customized Caucasian | 65 participants | 65 participants | 130 participants |
| Region of Enrollment Germany | 65 participants | 65 participants | 130 participants |
| Sex: Female, Male Female | 23 Participants | 19 Participants | 42 Participants |
| Sex: Female, Male Male | 42 Participants | 46 Participants | 88 Participants |
| Smoking Status Current Smoker | 15 participants | 16 participants | 31 participants |
| Smoking Status Never Smoked | 9 participants | 7 participants | 16 participants |
| Smoking Status Past Smoker | 41 participants | 42 participants | 83 participants |
| Stage of disease Stage IIIb (locally advanced disease) | 5 participants | 9 participants | 14 participants |
| Stage of disease Stage IV (metastatic disease) | 61 participants | 58 participants | 119 participants |
| Time Since Patient Stopped Smoking | 10.1 years STANDARD_DEVIATION 12.31 | 7.4 years STANDARD_DEVIATION 10.56 | 8.7 years STANDARD_DEVIATION 11.46 |
| Use of Tobacco Products | 31.7 years STANDARD_DEVIATION 12.74 | 34.6 years STANDARD_DEVIATION 11.47 | 33.2 years STANDARD_DEVIATION 12.15 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 61 / 65 | 59 / 65 |
| serious Total, serious adverse events | 22 / 65 | 28 / 65 |
Outcome results
Primary
Percentage of Participants Surviving Progression-Free at 6 Months (Progression Free Survival [PFS] Rate)
For this study, we used the exponential distribution (assumption done for the calculation of the sample size) to estimate the PFS rate. The PFS rate (%) and the 95% confidence intervals were calculated based on the following formula: exp(-6 λ) ± 1.96 \* exp(-6 λ) \* (-6 λ)/√r. Where λ was calculated based on the Maximum-Likelihood estimator for ln(λ) as given by (Collett 2003): ln(λ) = ln\[ r / ∑ti \] with r = number of patients with events up to 6 months, ti = survival time of patient i (i=1,…,n), event or censored up to 6 months, and n= total number of patients per treatment group.
Time frame: Randomization to Month 6
Population: Full Analysis Set: All patients randomized who received at least one dose of study drug
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pemetrexed + Cisplatin | Percentage of Participants Surviving Progression-Free at 6 Months (Progression Free Survival [PFS] Rate) | 52.8 percentage |
| Pemetrexed + Carboplatin | Percentage of Participants Surviving Progression-Free at 6 Months (Progression Free Survival [PFS] Rate) | 39.3 percentage |
Comparison: Hypothesis testing was done independently for each treatment arm (no direct treatment group comparison).95% CI: [40.3, 65.3]
Comparison: Hypothesis testing was done independently for each treatment arm (no direct treatment group comparison).95% CI: [27.8, 50.8]
Secondary
Number of Participants With Tumor Response (as Basis for Response Rate)
Best overall response was evaluated using RECIST Criteria which define when cancer patients improve (respond), stay the same (stabilize), or worsen (progression) during treatment. CR: complete response, disappearance of all target lesions; PR: partial response, 30% decrease in sum of the longest diameter of target lesions; PD: progressive disease, 20% increase in sum of the longest diameter of target lesions; SD: stable disease, small changes not meeting above criteria. Response Rate: number of participants with response(CR+PR)per total population, multiplied by 100 to give a percentage.
Time frame: Every 6 weeks for 6 months during the treatment period, and every 3 months during the follow-up period, until disease progression
Population: Full Analysis Set: All patients randomized who received at least one dose of study drug
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pemetrexed + Cisplatin | Number of Participants With Tumor Response (as Basis for Response Rate) | Partial Response | 21 participants |
| Pemetrexed + Cisplatin | Number of Participants With Tumor Response (as Basis for Response Rate) | Stable Disease | 31 participants |
| Pemetrexed + Cisplatin | Number of Participants With Tumor Response (as Basis for Response Rate) | Disease Progression | 7 participants |
| Pemetrexed + Cisplatin | Number of Participants With Tumor Response (as Basis for Response Rate) | Unknown/Not Done | 6 participants |
| Pemetrexed + Carboplatin | Number of Participants With Tumor Response (as Basis for Response Rate) | Unknown/Not Done | 5 participants |
| Pemetrexed + Carboplatin | Number of Participants With Tumor Response (as Basis for Response Rate) | Partial Response | 13 participants |
| Pemetrexed + Carboplatin | Number of Participants With Tumor Response (as Basis for Response Rate) | Disease Progression | 15 participants |
| Pemetrexed + Carboplatin | Number of Participants With Tumor Response (as Basis for Response Rate) | Stable Disease | 32 participants |
Comparison: Response rates were evaluated separately for each treatment arm95% CI: [21.2, 45.1]
Comparison: Response rates were evaluated separately for each treatment arm95% CI: [11.1, 31.8]
Secondary
Overall Survival
Defined as the time from randomization to the date of death from any cause.
Time frame: Randomization to date of death from any cause (up to 1 year)
Population: Full Analysis Set: All patients randomized who received at least one dose of study drug
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pemetrexed + Cisplatin | Overall Survival | 11.7 months |
| Pemetrexed + Carboplatin | Overall Survival | 8.9 months |
Secondary
Pharmacology Toxicities
Number of patients experiencing Grade 3 or 4 hematologic and non-hematologic adverse events (AEs) possibly related to study drug or protocol procedures in this study (a subset of those listed in the AE Module). AEs were graded using the Common Terminology Criteria for Adverse Events version 3.0 (CTCAE v3.0) for defining and grading specific adverse events. A grading (severity) scale is provided for each adverse event term. Grades range from 0 (none) to 5 (death). Grade 3 AEs are severe and undesirable; Grade 4 AEs are life-threatening or disabling.
Time frame: Every 21-day cycle for up to 6 cycles
Population: Full Analysis Set: All patients randomized who received at least one dose of study drug
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pemetrexed + Cisplatin | Pharmacology Toxicities | Any Grade 3/4 Toxicity | 29 participants |
| Pemetrexed + Cisplatin | Pharmacology Toxicities | Grade 3/4 Leucopenia | 8 participants |
| Pemetrexed + Cisplatin | Pharmacology Toxicities | Grade 3/4 Neutropenia | 11 participants |
| Pemetrexed + Cisplatin | Pharmacology Toxicities | Grade 3/4 Anemia | 5 participants |
| Pemetrexed + Cisplatin | Pharmacology Toxicities | Grade 3/4 Thrombocytopenia | 2 participants |
| Pemetrexed + Cisplatin | Pharmacology Toxicities | Grade 3/4 Nausea | 3 participants |
| Pemetrexed + Cisplatin | Pharmacology Toxicities | Grade 3/4 Vomiting | 2 participants |
| Pemetrexed + Cisplatin | Pharmacology Toxicities | Grade 3/4 Fatigue | 2 participants |
| Pemetrexed + Cisplatin | Pharmacology Toxicities | Grade 3/4 Anorexia | 1 participants |
| Pemetrexed + Cisplatin | Pharmacology Toxicities | Grade 3/4 Urinary Tract Infection | 0 participants |
| Pemetrexed + Carboplatin | Pharmacology Toxicities | Grade 3/4 Fatigue | 2 participants |
| Pemetrexed + Carboplatin | Pharmacology Toxicities | Any Grade 3/4 Toxicity | 36 participants |
| Pemetrexed + Carboplatin | Pharmacology Toxicities | Grade 3/4 Nausea | 5 participants |
| Pemetrexed + Carboplatin | Pharmacology Toxicities | Grade 3/4 Leucopenia | 12 participants |
| Pemetrexed + Carboplatin | Pharmacology Toxicities | Grade 3/4 Urinary Tract Infection | 2 participants |
| Pemetrexed + Carboplatin | Pharmacology Toxicities | Grade 3/4 Neutropenia | 17 participants |
| Pemetrexed + Carboplatin | Pharmacology Toxicities | Grade 3/4 Vomiting | 1 participants |
| Pemetrexed + Carboplatin | Pharmacology Toxicities | Grade 3/4 Anemia | 7 participants |
| Pemetrexed + Carboplatin | Pharmacology Toxicities | Grade 3/4 Anorexia | 2 participants |
| Pemetrexed + Carboplatin | Pharmacology Toxicities | Grade 3/4 Thrombocytopenia | 11 participants |
Secondary
Time to Treatment Failure (TTF)
Defined as time from randomization to the first date of disease progression, death due to any cause, or early discontinuation of treatment (any reason), whichever occurred first
Time frame: Randomization to stopping of treatment, progression, death or initiation of further chemotherapy, whichever occurs first (up to 1 year)
Population: Full Analysis Set: All patients randomized who received at least one dose of study drug
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pemetrexed + Cisplatin | Time to Treatment Failure (TTF) | 3.0 months |
| Pemetrexed + Carboplatin | Time to Treatment Failure (TTF) | 3.4 months |