Fibroblast growth factor receptors (FGFR) Inhibition for Epithelial Solid Tumours

Phase 1

Completed

Conditions: Epithelial Solid Tumours
Cancer
Epithelial tumour

Registration Number: ISRCTN44149443

Lead Sponsor: niversity of Leeds (UK)

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Completed

Sex: All

Target Recruitment: 28

Inclusion Criteria

1. Provision of written informed consent
2. Age 25 years or greater
3. Histologically confirmed locally advanced / metastatic non-haematological malignancy
3.1. Dose-escalation cohort
3.2. Any locally-advanced and/or metastatic malignancy for which no recognised standard treatment is available (including tumours refractory to previous standard therapies), and for whom gemcitabine and cisplatin would be appropriate treatment. Any number of previous lines of therapy are permitted OR
3.3. Locally advanced and/or metastatic transitional cell carcinoma, of the urinary tract, as in the randomised expansion cohort
3.4. Dose 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
4. Radiologically measurable disease (randomised expansion cohort only)
4.1. 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
5. Fit to receive cisplatin-containing combination chemotherapy
6. Minimum life expectancy of 18 weeks
7. WHO Performance Status 0-1
8. Adequate renal function [glomerular filtration rate (GFR) greater than or equal to 60ml/min, uncorrected for surface area and measured by isotopic means]
9. Adequate bone marrow function (absolute neutrophil count greater than or equal to 1.5 x 109/L and platelets greater than or equal to 100 x 109/L at screening)
10. Adequate liver function i.e. plasma bilirubin less than or equal to 1.5 x ULN (upper limit of normal), and ALT and ALP less than or equal to 2.5 x ULN (ALP less than or equal to 5 x ULN in case of liver metastases), at screening
11. Prothrombin time (PT) or International Normalized Ratio (INR) less than or equal to 1.5
12. Serum total calcium and/or phosphate less than or equal to ULN

Exclusion Criteria

1. Being considered for subsequent radical treatment with the possibility of cure
2. Prior treatments with any of the following, prior to first dose of study treatment:
2.1. AZD4547
2.2. Any investigational agents or study drugs from a previous clinical study within 30 days
2.3. Any other chemotherapy, immunotherapy or anticancer agents within 3 weeks
2.4. Major surgery within 4 weeks
2.5. Radiotherapy
2.5.1. With a wide field of radiation or involving >30% of total bone marrow volume, within 4 weeks
2.5.2. With a limited field of radiation, for palliation, within 2 weeks
3. Any unresolved toxicities from prior therapy greater than Common Terminology Criteria for Adverse Events (CTCAE) grade 1 (with the exception of alopecia) at the time of registration
4. Any of the following pre-existing conditions
4.1. Other malignant disease
4.1.1. Previous malignancy other than non-melanoma skin cancer, cervical carcinoma in situ or incidental localised prostate cancer
4.1.2. 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 study treatment
4.2. Infections: Clinically significant bacterial or fungal infection
4.2.1 Known active viral infection with: human immunodeficiency virus (HIV), hepatitis B or C virus
4.3. Gastro-intestinal: Previous bowel resection or other condition which might preclude adequate absorption of AZD4547
4.4. Other: any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension, active bleeding diatheses
5. Any of the following ophthalmological criteria:
5.1. Current evidence or previous history of retinal pigmented epithelium detachment (RPED)
5.2. Previous laser treatment or intra-ocular injection for treatment of macular degeneration
5.3. Current evidence or previous history of dry or wet age-related macular degeneration
5.4. Current evidence or previous history of retinal vein occlusion (RVO)
5.5. Patients with uncontrolled glaucoma or intra-ocular pressure greater than or equal to 21mm Hg at screening.
6. 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 study treatment
7. Men or women who are not prepared to practise methods of contraception of proven efficacy
8. Any patient who, in the judgment of the investigator, is unlikely to comply with study procedures, restrictions or requirements

Study & Design

Study Type: Interventional

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
<br> 1. Dose-escalation cohort:<br> 1.1. Dose-Limiting Toxicities (DLTs), Maximum Tolerated Dose (MTD) of AZD4547 in combination with GC<br> 1.2. Recommended Dose for Sustained Tolerability (RDST) for use in the randomized expansion cohort of this trial and in subsequent studies.<br> 2. Randomised expansion cohort:<br> 2.1. Relative proportions of participants experiencing any grade 3/4 CTCAE v4.02 toxicity within first cycle of treatment of AGC and GC regimens.<br>

Secondary Outcome Measures

Name	Time	Method
o secondary outcome measures

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