Urologic Neoplasms
Conditions
Brief summary
To assess the anti-tumor activity, as measured by response rate to bi-weekly pemetrexed plus cisplatin, in chemo-naive patients with diagnosed metastatic or locally advanced (non-resectable) urothelial cancer.
Interventions
DRUGpemetrexed
Phase 1: 300 mg/m\^2, intravenous (IV), days 1 and 15 every 28 days x 2 cycles (dose escalation: 300 mg/m\^2, 400 mg/m\^2, and 500 mg/m\^2) Phase 2: phase 1 determined dose, intravenous (IV), days 1 and 15 every 28 days until disease progression, unacceptable toxicity or patient decision to discontinue or 6 cycles of therapy
DRUGcisplatin
Phase 1: 50 mg/m\^2, intravenous (IV), days 1 and 15 every 28 days x 2 cycles Phase 2: 50 mg/m\^2, intravenous (IV), days 1 and 15 every 28 days until disease progression, unacceptable toxicity or patient decision to discontinue or 6 cycles of therapy
Sponsors
Eli Lilly and Company
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically proven locally advanced disease or metastatic transitional cell carcinoma of the urothelium including bladder, urethra, ureter, and renal pelvis. Patients should not be suitable for surgery or radiation with curative intent. However patients whose pre-chemotherapy sites of disease are restricted to the primary or regional lymph node sites and who have a major response to chemotherapy will be evaluated for post-chemotherapy surgical resection of residual cancer if the tumor has become resectable at the end of chemotherapy. * Measurable disease status, as defined in the Response Evaluation Criteria in Solid Tumors (RECIST) criteria (Therasse et al., 2000) * One course of prior radiation therapy is allowed. Prior radiation must have been completed at least 4 weeks before enrolment into the study and the patients must have recovered from all toxic effects.
Exclusion criteria
* Have central nervous system (CNS) or leptomeningeal metastases (unless the patient has completed successful local therapy for CNS metastases and has been off corticosteroids for at least 4 weeks before starting study therapy). A screening computed tomography (CT) or magnetic resonance imaging (MRI) before enrollment in the absence of a clinical suspicion of brain metastases is not required. * Inability to interrupt aspirin or other nonsteroidal anti-inflammatory agents 2 days before, the day of, and 2 days after the dose of pemetrexed plus cisplatin or cisplatin alone. If a patient is taking a nonsteroidal anti-inflammatory drug (NSAID) or salicylate with a long half-life (for example, naproxen, piroxicam, diflunisal) it should not be taken 5 days before the dose of pemetrexed (8-day period for long-acting agents such as piroxicam), the day of, and 2 days after the dose of pemetrexed plus cisplatin.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Best Overall Tumor Response | baseline to measured progressive disease (up to 620 days) | Best response recorded from the start of treatment until disease progression/recurrence using Response Evaluation Criteria In Solid Tumors (RECIST) criteria that defines when participants improve (respond), stay the same (stable), or worsen (progression) during treatment. Complete response (CR) = disappearance of all target lesions. Partial response (PR) = 30% decrease in the sum of the longest diameter of target lesions. Progressive disease (PD) = 20% increase in the sum of the longest diameter of target lesions. Stable disease (SD) = small changes that do not meet above criteria. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response | time of response to progressive disease (up to 620 days) | The duration of a complete response (CR) or partial response (PR) was defined as the time from first objective status assessment of CR or PR to the first time of progression or death as a result of any cause. Complete response (CR) = disappearance of all target lesions. Partial response (PR) = 30% decrease in the sum of the longest diameter of target lesions. |
| Duration of Stable Disease | time of no response or progression (up to 620 days) | Defined as time from study enrollment to the first progression of disease, complete response, partial response, or death from any cause. Complete response (CR) = disappearance of all target lesions. Partial response (PR) = 30% decrease in the sum of the longest diameter of target lesions. Progressive disease (PD) = 20% increase in the sum of the longest diameter of target lesions. Stable disease (SD) = small changes that do not meet above criteria. |
| Time to Progressive Disease | baseline to measured progressive disease (up to 620 days) | Defined as the time from study enrollment to the first date of disease progression. Time to disease progression was censored at the date of death if death was due to other cause. Progressive disease (PD) = 20% increase in the sum of the longest diameter of target lesions. |
| Time to Response | baseline to response (up to 620 days) | Defined as time from study enrollment to the first Complete Response or Partial Response (using RECIST criteria). Complete response (CR) = disappearance of all target lesions. Partial response (PR) = 30% decrease in the sum of the longest diameter of target lesions. |
| Progression-Free Survival | baseline to measured progressive disease (up to 620 days) | Defined as the time from study enrollment until disease progression or death from any cause. |
| Overall Survival | baseline to date of death from any cause (up to 620 days) | Overall survival is the duration from enrollment to death. For patients who are alive, overall survival is censored at the last contact. |
| Time to Treatment Failure (TTF) | baseline to stopping treatment (up to 620 days) | Time from study enrollment to first observation of disease progression, death from any cause, or early discontinuation of treatment (including toxicity or if patient had stable disease after 4 cycles). TTF was censored at date of last follow-up visit for patients who did not discontinue early, who were still alive, and who had not progressed. |
Countries
Spain
Participant flow
Pre-assignment details
A total of 59 participants entered the trial (21 in Phase 1 and 38 in Phase 2). Phase 1 determined the dose for Phase 2 to be 400 mg/m\^2. Phase 2 results are reported.
Participants by arm
| Arm | Count |
|---|---|
| Pemetrexed + Cisplatin Pemetrexed: phase 1 determined dose=400 mg/m2, intravenous (IV), days 1 and 15 every 28 days until disease progression, unacceptable toxicity or patient decision to discontinue or 6 cycles of therapy Cisplatin: 50 mg/m2, intravenous (IV), days 1 and 15 every 28 days until disease progression, unacceptable toxicity or patient decision to discontinue or 6 cycles of therapy | 38 |
| Total | 38 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 12 |
| Overall Study | Death | 2 |
| Overall Study | Lost to Follow-up | 1 |
| Overall Study | Other - Not Specified | 1 |
| Overall Study | Physician Decision | 13 |
| Overall Study | Progressive Disease | 7 |
Baseline characteristics
| Characteristic | Pemetrexed + Cisplatin |
|---|---|
| Age Continuous | 67.1 years STANDARD_DEVIATION 8.7 |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 0 - Fully Active | 21 participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 1 - Ambulatory, Restricted Strenuous Activity | 15 participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 2 - Ambulatory, No Work Activities | 2 participants |
| Height | 166 centimeters STANDARD_DEVIATION 7.5 |
| Location of Primary Tumor Bladder | 32 participants |
| Location of Primary Tumor Renal Pelvis | 4 participants |
| Location of Primary Tumor Ureter | 1 participants |
| Location of Primary Tumor Urethra | 1 participants |
| Region of Enrollment Spain | 38 participants |
| Sex: Female, Male Female | 7 Participants |
| Sex: Female, Male Male | 31 Participants |
| Weight | 77.4 kilograms STANDARD_DEVIATION 13.2 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 38 / — |
| serious Total, serious adverse events | 16 / — |
Outcome results
Primary
Best Overall Tumor Response
Best response recorded from the start of treatment until disease progression/recurrence using Response Evaluation Criteria In Solid Tumors (RECIST) criteria that defines when participants improve (respond), stay the same (stable), or worsen (progression) during treatment. Complete response (CR) = disappearance of all target lesions. Partial response (PR) = 30% decrease in the sum of the longest diameter of target lesions. Progressive disease (PD) = 20% increase in the sum of the longest diameter of target lesions. Stable disease (SD) = small changes that do not meet above criteria.
Time frame: baseline to measured progressive disease (up to 620 days)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pemetrexed + Cisplatin | Best Overall Tumor Response | Not Evaluated | 3 participants |
| Pemetrexed + Cisplatin | Best Overall Tumor Response | Not Performed | 3 participants |
| Pemetrexed + Cisplatin | Best Overall Tumor Response | Missing | 3 participants |
| Pemetrexed + Cisplatin | Best Overall Tumor Response | Stable Disease | 13 participants |
| Pemetrexed + Cisplatin | Best Overall Tumor Response | Progressive Disease | 1 participants |
| Pemetrexed + Cisplatin | Best Overall Tumor Response | Complete Response | 2 participants |
| Pemetrexed + Cisplatin | Best Overall Tumor Response | Partial Response | 13 participants |
Secondary
Duration of Response
The duration of a complete response (CR) or partial response (PR) was defined as the time from first objective status assessment of CR or PR to the first time of progression or death as a result of any cause. Complete response (CR) = disappearance of all target lesions. Partial response (PR) = 30% decrease in the sum of the longest diameter of target lesions.
Time frame: time of response to progressive disease (up to 620 days)
Population: 10 patients were censored.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pemetrexed + Cisplatin | Duration of Response | 184.100 days | Standard Error 19.595 |
Secondary
Duration of Stable Disease
Defined as time from study enrollment to the first progression of disease, complete response, partial response, or death from any cause. Complete response (CR) = disappearance of all target lesions. Partial response (PR) = 30% decrease in the sum of the longest diameter of target lesions. Progressive disease (PD) = 20% increase in the sum of the longest diameter of target lesions. Stable disease (SD) = small changes that do not meet above criteria.
Time frame: time of no response or progression (up to 620 days)
Population: 1 patient was censored.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pemetrexed + Cisplatin | Duration of Stable Disease | 80 days |
Secondary
Overall Survival
Overall survival is the duration from enrollment to death. For patients who are alive, overall survival is censored at the last contact.
Time frame: baseline to date of death from any cause (up to 620 days)
Population: 20 patients were censored.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pemetrexed + Cisplatin | Overall Survival | 264.190 days | Standard Error 15.13 |
Secondary
Progression-Free Survival
Defined as the time from study enrollment until disease progression or death from any cause.
Time frame: baseline to measured progressive disease (up to 620 days)
Population: 11 patients were censored
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pemetrexed + Cisplatin | Progression-Free Survival | 203 days |
Secondary
Time to Progressive Disease
Defined as the time from study enrollment to the first date of disease progression. Time to disease progression was censored at the date of death if death was due to other cause. Progressive disease (PD) = 20% increase in the sum of the longest diameter of target lesions.
Time frame: baseline to measured progressive disease (up to 620 days)
Population: 19 patients were censored
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pemetrexed + Cisplatin | Time to Progressive Disease | 260.182 days | Standard Error 22.954 |
Secondary
Time to Response
Defined as time from study enrollment to the first Complete Response or Partial Response (using RECIST criteria). Complete response (CR) = disappearance of all target lesions. Partial response (PR) = 30% decrease in the sum of the longest diameter of target lesions.
Time frame: baseline to response (up to 620 days)
Population: 16 patients were censored.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pemetrexed + Cisplatin | Time to Response | 111.816 days | Standard Error 6.48 |
Secondary
Time to Treatment Failure (TTF)
Time from study enrollment to first observation of disease progression, death from any cause, or early discontinuation of treatment (including toxicity or if patient had stable disease after 4 cycles). TTF was censored at date of last follow-up visit for patients who did not discontinue early, who were still alive, and who had not progressed.
Time frame: baseline to stopping treatment (up to 620 days)
Population: 1 patient was censored
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pemetrexed + Cisplatin | Time to Treatment Failure (TTF) | 133.5 days |