| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Epithelial Solid Tumours. Locally advanced and/or metastatic transitional cell carcinoma (pure or mixed histology) of (upper or lower) urinary tract, including bladder cancer. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Epithelial tumours of the urinary tract including bladder cancer. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| 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 |
Dose Escalation Cohort
To investigate the safety, tolerability and feasibility of the novel AGC (AZD4547 with gemcitabine and cisplatin) combination in advanced non-haematological malignancies.
Randomised Expansion Cohort
To obtain a preliminary indication of the relative toxicities of AGC compared to GC in locally-advanced/metastatic TCC of the urinary bladder (and other urothelial) cancers.
|
|
| E.2.2 | Secondary objectives of the trial |
Randomised Expansion Cohort
To obtain a preliminary assessment of the relative activity of AGC, relative to GC, in locally-advanced/metastatic TCC of the urinary bladder (and other urothelial) cancers.
To guide the development of a potential subsequent, randomised controlled trial of AGC as neoadjuvant chemotherapy, as a component of radical treatment for life-threatening, but potentially-curable muscle-invasive bladder TCC.
Exploratory
Dose escalation cohort
To investigate the pharmacokinetics of the 3 drugs in combination.
Randomised expansion cohort
To collect blood & tumour samples and to perform functional imaging studies for potential future exploratory research studies, including:
- correlation of anatomical response data with functional imaging studies to assess the value of functional imaging as a biomarker for anti-tumour activity
- correlation of anatomical response data and functional imaging studies with molecular profiles of tumour samples to assess the value |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Provision of written, informed consent, signed and dated, prior to any trial-specific procedures, sampling or analyses
Age ≥25 years.
Histologically-confirmed locally advanced/metastatic non-haematological malignancy (a diagnosis based upon cytology is not acceptable).
Dose escalation cohort:
- 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 AZD4547 is a reasonable option in the context of a clinical trial. Any number of previous lines of therapy are permitted
- Locally advanced and/or metastatic transitional cell carcinoma of the bladder (or other urinary tract sites), as in the randomised expansion cohort, may be included in the dose escalation cohort
Randomised Expansion cohort:
- Locally advanced and/or metastatic transitional cell carcinoma (pure or mixed histology) of (upper or lower) urinary tract, including bladder cancer. 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.
Radiologically measurable disease (randomised expansion cohort only)
T4b Nany Many, Tany N2-3 Many or Tany Nany M1 TCC of the urinary tract (as above), not amenable to curative treatment with surgery or radiotherapy.
Minimum life expectancy of 3 months
WHO Performance Status 0-1
Adequate renal function (GFR ≥60ml/min, measured by isotopic means, uncorrected for surface area)
Adequate bone marrow function (absolute neutrophil count ≥1.5 x 10^9/L and platelets ≥100 x 10^9/L)
Adequate liver function i.e. plasma bilirubin ≤1.5 x ULN, and ALT and ALP ≤2.5 x ULN (ALP ≤5 x ULN in case of liver metastases)
Prothrombin time (PT) ≤1. 5 x ULN or International Normalized Ratio (INR) ≤1. 5
Serum total calcium and/or phosphate ≤ ULN
|
|
| E.4 | Principal exclusion criteria |
Being considered for subsequent radical treatment with the possibility of cure
Prior treatments with any of the following, prior to first dose of trial treatment:
a. AZD4547 or any other agent known to inhibit FGFRs
b. Any Investigational Medicinal Products within 30 days
c. Any other chemotherapy, immunotherapy or anticancer agents within 3 weeks
d. Concomitant medications as documented in the protocol and unable to meet any washout periods as required.
e. Major surgery within 4 weeks
f. Radiotherapy
i. with a wide field of radiation or involving >30% of total bone marrow volume, within 4 weeks
ii. with a limited field of radiation, for palliation, within 2 week
Any unresolved toxicities from prior therapy greater than CTCAE grade 1 (with the exception of alopecia) at the time of registration
Any of the following pre-existing conditions:
a. Other malignant disease
i. (Randomised expansion cohort only) Recent or concurrent active malignancy arising from a primary site other than the urinary tract; participants with a history of a separate, treated malignancy, diagnosed 5 or more years previously, can be regarded as cured of their previous tumour, for the purposes of this trial, and may be entered. Current active non-melanoma skin cancer, cervical carcinoma in situ or incidental, localised prostate cancer are also permissible.
b. Previously-identified central nervous system (CNS) metastases unless asymptomatic, treated and stable and not requiring steroids for at least 4 weeks prior to start of trial treatment.
c. Infections
d. Gastro-intestinal: any condition which might preclude adequate absorption of AZD4547 (e.g. previous small bowel resection)
e. Cardiac: unstable cardiac conditions and risk factors for QTc prolongation.
f. Ophthalmic conditions
History of allergic reactions to any of the drugs used in this trial
Unsuitable to receive cisplatin or gemcitabine
Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension, active bleeding diatheses
Women who are pregnant or breast feeding - women of child-bearing potential must have a negative pregnancy test performed within 7 days prior to the start of trial treatment
Men or women who are not prepared to practise methods of contraception of proven efficacy
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Dose Escalation Cohort:
• Dose-Limiting Toxicities (DLTs), within the first cycle (until cycle 2, day 1), in order to establish the Maximum Tolerated Dose (MTD) of AZD4547 in combination with GC (AGC).
• CTCAE grade 3 or 4 toxicity within the first 3 cycles of treatment to determine the Recommended Dose for Sustained Tolerability
Randomised Expansion cohort:
• Proportion of participants treated who experience any grade 3/4 CTCAE toxicity throughout all treatment cycles
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
DLTs to calculate Maximum Tolerated Dose and grade 3/4 CTCAE toxicities will be summarised at the end of the first cycle. DLTs to calcualte Recommended Dose for Sustained Tolerability will be summarised after the third cycle.
Any grade 3/4 CTCAE toxicity in the randomised dose expansion cohort will be summarised throught out all treatment cycles. |
|
| E.5.2 | Secondary end point(s) |
Dose escalation cohort:
• Safety and toxicity profiles beyond the first three cycles of treatment
Randomised dose expansion cohort:
• Further toxicity safety and toxicity profiles
• Objective response rate within 18 weeks of randomisation
• Disease Control Rate within 18 weeks of randomisation
• Change in tumour size within 18 weeks from randomisation
• Progression-free survival to 18 weeks post randomisation
• Overall survival
• Number of participants withdrawing from treatment
• Number of participants experiencing dose delays, and compliance profile of AZD4547 administration
• Proportion of bladder tumours with FGFR3 mutation and/or FGFR1 or FGFR3 over-expression.
Exploratory Endpoints
Dose Escalation Cohort:
• Pharmacokinetic parameters of AZD4547, gemcitabine and cisplatin, in combination (including Cmax, Tmax, Css, t1/2, AUC, clearance)
Randomised Expansion Cohort:
• Response as per functional imaging.
• Molecular profiles of tumour samples
• Molecular profiles of blood samples
• Proportion of patients for whom FGFR mutation status can be obtained within 14 days.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Toxicity and safety profiles will be summarised at the end of each cycle and overall (18 weeks). Disease Control Rate and change in tumour size will be summarised at 18 weeks. Progression-free survival and survival estimates will be presented at 18 weeks and as appropriate. The proportion of patients for whom FGFR mutation status can be obtained will be evaluated at the time of final analysis. |
|
| 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 | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| 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) | 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 | |
| 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 8 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.5.1 | Number of sites anticipated in the EEA | 0 |
| 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 end of trial is defined as the date of the last participant’s last data item |
|
| 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 |
Print
