| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Locally Advanced, non-Resectable or Metastatic Urothelial Cancer |
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| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Of the Phase I: To determine the Maximum Tolerated Dose (MTD) of the biweekly combination of ALIMTA plus cisplatin in patients with locally advanced or metastatic cancer with no other standard curative or palliative therapeutic options.
Of the Phase II: To assess the antitumor activity, as measured by response rate (proportion of patients with complete response or partial response) to biweekly ALIMTA plus cisplatin, in chemonaive patients with diagnosed metastatic or locally advanced (non-resectable) urothelial cancer.
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| E.2.2 | Secondary objectives of the trial |
Of the Phase 1:
· To determine the quantitative and qualitative toxicities of the combination in this patient population.
· To determine the recommended dose of biweekly ALIMTA plus cisplatin for the subsequent Phase 2 study.
· To document antitumor activity of biweekly ALIMTA plus cisplatin in patients with measurable disease.
Of the Phase 2:
· To evaluate the toxicity profile of the combination in urothelial cancer patients.
· To assess the following time-to-event efficacy variable in bladder cancer patients treated within the protocol:
§ Time to response
§ Duration of response
§ Duration of stable disease
§ Time to documented progressive disease
§ Time to treatment failure
§ Progression-free survival
§ Overall survival
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| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
[1] Histologic or cytologic diagnosis of locally advanced or metastatic cancer with no standard potentially curative therapy.
[2] Performance status 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) scale.
[3] Measurable or non measurable disease.
[4] Estimated life expectancy of at least 12 weeks.
[5] Prior radiation to the whole pelvis is not allowed. Prior palliative radiation therapy allowed if completed at least 2 weeks prior to study enrollment.
[6] Patient compliance and geographic proximity that allow adequate follow-up.
[7] Adequate organ function including the following: Adequate bone marrow reserve: platelets ³100 x 109/L, hemoglobin ³90 g/L, absolute neutrophil count (ANC) ³1.5 x 109/L. Hepatic: bilirubin £1.5 times the upper limit of normal (x ULN); alkaline phosphatase (AP), aspartate transaminase (AST), and alanine transaminase (ALT) <3 x ULN, or <5 x ULN with liver metastases. · Adequate renal function (Creatinine Clearance (CrCl) (>45 mL/min). CrCl will be assessed by calculation from serum/plasma creatinine formula (Cockcroft and Gault) or directly measured. If done measured value will take precedent over calculated. Urological procedures (such as ureteral stent (i.e. double j catheter) or percutaneous nephrostomy) are allowed prior to inclusion in the trial in order to relieve urinary tract obstruction and to improve renal function.
[8] Signed informed consent from patient.
[9] At least 18 years of age.
[10] Patients must take medically approved contraceptive precautions (if necessary) during the trial and for 3 months afterwards. Females with childbearing potential must have a negative serum pregnancy test within 7 days prior to study enrollment.
Inclusion criteria for Phase II:
[1] Histologically proven stage IV locally advanced disease (T4 b any N, or any T N2-3 ) or metastatic (M1) transitional cell carcinoma of the urothelium (pure or mixed) 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.
[2] Measurable disease status, as defined in the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Patients must have measurable disease that is outside a previously irradiated area or a new lesion that has grown in a previous irradiated area.
[3] 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.
[4] Patients may have previously received one neoadjuvant and/or adjuvant chemotherapy regimen. No previous chemotherapy for metastatic disease.
[5] ECOG performance status of 0, 1, or 2
[6] Estimated life expectancy ³ 12 weeks.
[7] Patient compliance and geographic proximity that allow adequate follow-up
[8] Adequate organ function including the following: Adequate bone marrow reserve: platelets ³100 x 109/L, hemoglobin ³90 g/L, absolute neutrophil count (ANC) ³1.5 x 109/L. Hepatic: bilirubin £1.5 times the upper limit of normal (x ULN); alkaline phosphatase (AP), aspartate transaminase (AST), and alanine transaminase (ALT) <3 x ULN, or <5 x ULN with liver metastases. · Adequate renal function (Creatinine Clearance (CrCl) (>45 mL/min). CrCl will be assessed by calculation from serum/plasma creatinine formula (Cockcroft and Gault) or directly measured. If done measured value will take precedent over calculated. Urological procedures (such as ureteral stent (i.e. double j catheter) or percutaneous nephrostomy) are allowed prior to inclusion in the trial in order to relieve urinary tract obstruction and to improve renal function.
[9] Patients must sign an informed consent document
[10] Patients must be at least 18 years of age
[11] Male and female patients with reproductive potential must use a reliable contraceptive method if appropriate (for example, intrauterine device [IUD], birth control pills, or barrier device) during the study. Female patients with reproductive potential must have a negative serum pregnancy test within 7 days of study enrollment
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| E.4 | Principal exclusion criteria |
[1] Have received treatment within the last 30 days with a drug that has not received regulatory approval for any indication at the time of study entry
[2] Have received other forms of chemotherapy within the four weeks prior to enrollment
[3] 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 CT or MRI before enrollment in the absence of a clinical suspicion of brain metastases is not required.
[4] Pregnancy or breast-feeding.
[5] Serious concomitant systemic disorders (e.g, active infection) that, in the opinion of the investigator, would compromise the safety of the patient and his or her ability to complete the study. Patients previously treated with a nephrotoxic antibiotic are at risk of further toxicity due to cisplatin and should be very carefully monitored..
[6] Inability to interrupt aspirin or other nonsteroidal anti-inflammatory agents 2 days before, the day of, and 2 days after the dose of ALIMTA plus cisplatin or cisplatin alone. If a patient is taking a NSAID or salicylate with a long half-life (for example, naproxen, piroxicam, diflunisal) it should not be taken 5 days before the dose of ALIMTA (8-day period for long-acting agents such as piroxicam), the day of, and 2 days after the dose of ALIMTA plus cisplatin or cisplatin alone.
[7] Presence of clinically significant third-space fluid collections (for example, ascites or pleural effusions).
[8] Inability or unwillingness to take folic acid or vitamin B12 supplementation.
[9] Grade 2 or greater peripheral neuropathy according to the CTC, version 3.0.
[10] Presence of any clinically significant cardiac arrhythmia, congestive heart failure, or complete bundle branch block functional Class III or worse, according to the New York Heart Association (NYHA.)
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Phase 1:Primary: maximum tolerated dose (MTD)Secondary: quantitative and qualitative toxic profile of the ALIMTA plus cisplatin combination; recommended dose for Phase 2, response rate in evaluable patients.Phase 2:Primary: response rate.Secondary:Toxicity profile of the combination in bladder cancer patients.To assess the following time-to-event efficacy variable:§ Time to response§ Duration of response§ Duration of stable disease § Time to documented progressive disease§ Time to treatment failure§ Progression-free survival§ Overall survival |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | Information not present in EudraCT |
| E.7.4 | Therapeutic use (Phase IV) | Information not present in EudraCT |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | |
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