Background
Methods/Design
Objectives
Study design
Phase Ib dose escalation component
Day | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 | 12 | 13 | 14 | 15 | 16 | 17 | 18 | 19 | 20 | 21 |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
SGI-110 | X | X | X | X | X | ||||||||||||||||
Cisplatin | X | ||||||||||||||||||||
Gemcitabine | X | X | |||||||||||||||||||
(Granulocyte-colony stimulating factor)a | (X) | (X) | (X) | (X) | (X) | (X) | (X) |
Dose level | SGI-110 dose, per treatment cycle |
---|---|
−1 | 10 mg/m2, daily, on days 1–5 |
1 | 20 mg/m2, daily, on days 1–5 |
2 | 30 mg/m2, daily, on days 1–5 |
3 | 45 mg/m2, daily, on days 1–5 |
4 | 60 mg/m2, daily, on days 1–5 |
Cohort size (evaluable patients) | Dose limiting toxicities in cycle 1 | Actions |
---|---|---|
3–6 | 0 | Cohorts 1–3: dose escalation to the next cohort Cohort 4: MTD is established at this dose level |
< 6 | 1 | Expand cohort to include up to 6 evaluable patients and re-evaluate |
6 | 1 | Cohorts 1–3: dose escalation to the next cohort Cohort 4: MTD is established at this dose |
≥ 2 | ≥ 2 | Dose level will be considered a non-tolerated dose; no further recruitment to this cohort and dose escalation will cease Cohort 1: The combination will be considered non-viable (consider incorporation of granulocyte-colony stimulating factor G-CSF) Cohorts 2–4: The previous dose level will be expanded to incorporate six evaluable patients (consider incorporation of G-CSF) |
Phase IIa randomised component
Ethical and regulatory aspects
Study participants
Inclusion criteria |
All patients |
1. Eastern Cooperative Oncology Group performance status of 0 or 1 |
2. Glomerular filtration rate estimation of ≥ 60 mL/min according to either the Cockcroft and Gault formula or by Cr-51 EDTA or Tc-99m DTPA clearance |
3. Adequate haematological parameters: |
• Haemoglobin ≥ 90 g/L |
• Neutrophil count ≥ 1.5 × 109/L |
• Platelets ≥ 100 × 109/L |
4. Adequate biochemical parameters: |
• Bilirubin ≤ 1.5 × upper limit of normal (ULN) |
• ALT and ALP ≤ 2.5 × ULN (ALP ≤ 5 × ULN if caused by liver or bone metastases) |
5. Aged 16 years or over |
6. Life expectancy > 3 months |
7. Provision of written informed consent |
Patients in the dose escalation phase: |
8. Incurable histologically or cytologically confirmed, locally advanced or metastatic, solid cancer, for which the use of gemcitabine and cisplatin is a clinically appropriate treatment in the view of the local principal investigator; any number of previous lines of systemic chemotherapy is permitted |
Patients in the dose expansion phase: |
9. Bladder cancer with a pure or predominant component of transitional cell carcinoma |
10. Clinical stage T2-4a N0 M0 |
11. Planned to commence GC for 3 or 4 cycles with neoadjuvant (i.e. curative) intent prior to a planned radical cystectomy |
Exclusion criteria |
All patients |
1. Unresolved toxicities from prior therapy greater than CTCAE v4.03 grade 1 (with the exception of alopecia) at the time of registration |
2. Prior radiotherapy to > 30% of bone marrow |
3. Major surgery within 30 days of registration/randomisation |
4. Any investigational medicinal product within 30 days registration/randomisation |
5. Allergy or other known intolerance to any of the proposed study drugs, including supportive agents and inclusive of G-CSF and locally utilised anti-emetics |
6. Previously identified central nervous system metastases unless treated and clinically stable and not requiring steroids for at least 4 weeks prior to the start of trial treatment |
7. Coronary artery bypass graft, angioplasty, vascular stent, myocardial infarction, unstable angina pectoris or congestive cardiac failure (New York Heart Association ≥ class II) within the last 6 months |
8. 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) |
9. Patients of child-bearing potential who are not using a highly effective method of contraception |
10. Any patient who, in the judgment of the local investigator, is unlikely to comply with trial procedures, restrictions or requirements |
11. Any patient who has received a live vaccine within 4 weeks of initiation of their treatment |
Patients in the dose expansion phase: |
12. Recent or current separate other malignancy; current non-melanoma skin cancer, cervical carcinoma in situ or incidental localised prostate cancer is permissible; participants with a history of a separate other malignancy having completed all active treatment 2 or more years previously may be entered |