| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced cancers including transitional cell carcinoma of the urothelium |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10038517 |
| E.1.2 | Term | Renal pelvis cancer NOS |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10005003 |
| E.1.2 | Term | Bladder cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10046375 |
| E.1.2 | Term | Ureter cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| 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 |
The overall objective of this trial is to assess whether the addition of temsirolimus to standard cipslatin/gemcitabine cancer chemotherapy is a safe and effective treatment for patients with advanced malignancy and an effective treatment for patients with advanced urothelial cancer.
Phase I of the trial aims to establish the appropriate dose and schedule of temsirolimus when used in combination with gemcitabine and and cisplatin for patients with advanced non-haematological malignancy.
Phase II of the trial aims to establish activity, safety and feasibility of this combination in participants with advanced transitional cell carcinoma of the urothelium. Activity will be measured by determining the number of patients who are alive at six months and have responded completely or partially to treatment or who have stable disease, according to strict radiological criteria i.e. progression-free survival (PFS) six months after enrolment. |
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| E.2.2 | Secondary objectives of the trial |
The secondary objective of the Phase I stage of the trial is to determine the pharmacokinetic profile of temsirolimus in combination with cisplatin and gemcitabine.
The secondary objectives of the Phase II stage of the trial are to determine:
• Tolerability (side effects) and feasibility of use (number of participants requiring dose delays or reduction and / or treatment withdrawal)
• Objective response rate as assessed by RECIST
• PFS (time-to-event). Time from enrolment to any progression (based on RECIST) and/or death. Those progression-free and alive will be censored at time last seen.
• Overall survival (OS). Time from enrolment to any death. Those still alive will be censored at time last seen.
• Toxicity, during and after treatment, will be assessed using National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03. SAEs will also be collected in real time.
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| Participants will be asked to participate in an optional sub-study of the main TOTEM trial (see full title provided in Section A.3 of this form) and detailed in Section 12.0 Ancillary Studies of the trial protocol supplied with this application. All TOTEM participants will be asked to consider the provision of additional blood samples before and after the TOTEM trial treatment, and for permission to analyse previous tumour tissue specimens (e.g. from prior TURBT and/or cystectomy/nephro-ureterectomy). The objective is to analyse these samples to gain a better understanding of the 3-drug gemcitabine/temsirolimus/cisplatin treatment in urothelial cancer. All Phase I patients will be asked to give additional blood samples for pharmokinetic analysis, with the objective of determining how the subject's body handles the drug. |
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| E.3 | Principal inclusion criteria |
1.Provision of written, informed consent, signed and dated, prior to any trial-specific procedures, sampling or analyses.
2.Age ≥16 years.
3.Histologically-confirmed locally advanced/metastatic non-haematological malignancy (a diagnosis based upon cytology is not acceptable).
a.Phase I
Locally advanced and/or metastatic disease which is not amenable to curative treatment with surgery or radiotherapy.
i.Any locally-advanced and/or metastatic solid cancer for which gemcitabine and cisplatin is either an accepted standard treatment or for which there is no remaining standard treatment, but gemcitabine and cisplatin with temsirolimus is a reasonable option in the context of a clinical trial. Any number of previous lines of therapy are permitted.
ii.Locally advanced and/or metastatic transitional cell carcinoma of the bladder (or other urinary tract sites), as in Phase II, may be included in the dose escalation cohort.
b.Phase II
i.Radiologically measurable (RECIST 1.1), locally advanced and/or metastatic (T4b Nany Many, Tany N2-3 Many or Tany Nany M1) transitional cell carcinoma (pure or mixed histology) of (upper or lower) urinary tract, including bladder cancer, which is not amenable to curative treatment with surgery or radiotherapy.
ii.No prior systemic therapy for locally advanced or metastatic disease; patients who have received prior neoadjuvant or adjuvant chemotherapy for potentially-curable urothelial cancer (up to 4 cycles), completed at least 6 months prior to first documented disease progression, will be eligible.
4.Estimated life expectancy ≥ 3 months.
5.WHO Performance Status 0-2.
6.Fit to receive cisplatin-containing combination chemotherapy.
7.No prior radiotherapy within 1 month prior to registration or involving more than 30% of total bone marrow volume.
8.No investigational drug within 1 month prior to registration.
9.Adequate renal function (GFR >60ml/min, uncorrected for surface area and measured by isotopic means).
10.Adequate bone marrow function (absolute neutrophil count ≥1.5 x 109/L and platelets ≥100 x 109/L at screening).
11.Adequate liver function (Bilirubin ≤1.5 x ULN, and ALT and ALP ≤2.5 x ULN, at screening or >5x ULN if judged by the investigator to be related to liver metastases.
12.Prothrombin time (PT) or International normalized ratio (INR) ≤1.5.
13.Written informed consent.
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| E.4 | Principal exclusion criteria |
1.Patients with transitional cell carcinoma in whom subsequent radical treatment is being considered with a view to possible cure.
2.Previous malignancy in the past 3 years other than non-melanoma skin cancer, cervical carcinoma in situ, incidental localised prostate cancer or previous non-invasive TCC.
3.Previously-identified central nervous system (CNS) metastases - routine screening by cross-sectional imaging of the head is not a requirement for trial entry and should only be performed if clinically indicated.
4.Women who are pregnant or breast feeding.
5.Men and women not prepared to practice a medically acceptable* form of birth control during the trial and for 6 months after the end of treatment.
i.Women of child bearing potential* must have a negative pregnancy test performed within 7 days prior to the start of treatment and be prepared to use a medically acceptable method of contraception** during and for 6 months after the end of treatment if they are at present or become sexually active during the trial.
ii.Women not of child bearing potential*** must insist that their partners use a condom during the trial and for 6 months after the end of treatment if they are at present or become sexually active during the trial.
*Women of child bearing potential are defined as any female who has experienced menarche and who does not meet the criteria for “women not of childbearing potential.
**Medically acceptable methods of contraception include:
•Oral contraception and male condom
•Intra-uterine device (IUD) and male condom
•Diaphragm with spermicide and male condom
•Injected or implanted hormonal methods of contraception and male condom
•Vasectomy and male condom
•Complete sexual abstinence
*** Women not of child bearing potential are defined as women who are postmenopausal or permanently sterilised (e.g. tubal occlusion, hysterectomy or bilateral salpingectomy).
6.Known infection with human immunodeficiency virus (HIV) or chronic hepatitis B or C infection or any other clinically significant bacterial or fungal infection. Note: testing not required unless clinically indicated.
7.Symptomatic coronary artery disease, myocardial infarction within the last 6 months, congestive cardiac failure (New York Health Association (NYHA) class III or IV), uncontrolled or symptomatic cardiac arrhythmia.
8.Concurrent anticoagulant therapy with warfarin or un-fractionated heparin - patients requiring anti-coagulation may be entered after successful conversion to low molecular weight heparin (LMWH).
9.Concomitant medications which have known adverse interactions with the trial treatment.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase I -Primary endpoints:
•Dose-Limiting Toxicities (DLTs), within the first cycle (until cycle 2, day 1), in order establish the Maximum Tolerated Dose (MTD) of temsirolimus in combination with gemcitabine and cisplatin (GTC)
•Adverse Events (AEs) within the first 3 cycles of treatment to determine the Recommended Dose for Sustained Tolerability (RDST)
Phase II - Primary endpoint:
•Progression-free survival (PFS) at six months from date of enrolment. This is the proportion of patients who are alive at six months and have responded completely or partially to treatment, or who have stable disease, according to strict radiological criteria
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| E.5.2 | Secondary end point(s) |
Phase I-Secondary endpoints:
•Tolerability (side-effects) and feasibility of use (number of participants requiring dose delays or reduction and / or treatment withdrawal) beyond the first three cycles of treatment
Phase I-Exploratory endpoints:
•To determine the pharmacokinetic profile of temsirolimus in combination with cisplatin and gemcitabine
•To determine the pharmacodynamics and pharmacogenetics of temsirolimus in combination with gemcitabine/cisplatin
Phase II- Secondary endpoints:
•Tolerability (side-effects) and feasibility of use (number of participants requiring dose delays or reduction and / or treatment withdrawal)
•Objective response rate as assessed by Response Evaluation Criteria in Solid Tumours (RECIST) v1.1
•PFS (time-to-event). Time from enrolment to any progression (based on RECIST) and/or death. Participants will be censored at time last seen, or date last known to be alive, unless a death or disease progression has been recorded.
•Overall survival (OS). Time from enrolment to any death. Those still alive will be censored at time last seen.
•Toxicity, during and after treatment, will be assessed using National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03. SAEs will also be collected in real time.
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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 | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
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| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description |
| First administration to humans in combination with cisplatin and gemcitabine |
|
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| 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.8.2.3.1 | Comparator description |
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| 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.8.4.1 | Number of sites anticipated in Member State concerned | 13 |
| 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 | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
The protocol treatment phase will be followed by a follow-up period which will continue for one year after enrolment.
For the purposes of MHRA and MREC, the study end date is deemed to be the date of last data capture. |
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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 | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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