Ovarian cancer or recurrent, advanced, solid tumours. Cancer Ovarian cancer
Conditions
Interventions
Dose Escalation Phase:
Paclitaxel 80mg/m2 IV, days 1, 8 and 15 every 28 days for up to 6 cycles
LY2940680 PO Daily Days 1-28 of a 28 day cycle. Dose cohorts as below:
Dose Level LY2940680 Dose PO
-1
Sponsors
NHS Greater Glasgow and Clyde
Eligibility
Sex/Gender
All
Age
18 Years to 120 Years
Inclusion criteria
Inclusion criteria: Inclusion criteria of the dose escalation phase: Histologically or cytologically confirmed advanced solid tumours refractory to standard therapy or for whom weekly paclitaxel is considered, by the investigator, to be an appropriate therapy. Inclusion criteria of the dose expansion phase: 1. Histologically confirmed high grade serous or G3 endometrioid epithelial ovarian, fallopian tube or primary peritoneal cancer with progressive or recurrent disease (patients with carcinosarcoma are eligible but mucinous, clear cell carcinoma and grade 1 or 2 tumours are not eligible). Progression may be defined radiologically by RECIST 1.1 or by CA125 criteria in combination with clinical symptoms or signs indicative of progression. Asymptomatic rise of CA125 alone will not be defined as progressive disease. Progression of disease must have occurred within 6 months of the last dose of platinum chemotherapy. 2. = 1 previous platinum based chemotherapy. This may have been given in the adjuvant setting. 3. No previous treatment with single agent weekly paclitaxel for relapsed disease. Weekly paclitaxel may have been given in the first line setting if given in combination with platinum chemotherapy. 4. No contra-indication to an image guided biopsy and tumour amenable to image guided biopsy. 5. Measurable or non-measurable disease. 6. Patients must have archival formalin-fixed paraffin-embedded tissue from their original diagnosis available for the purposes of translational research. 7. Patients with synchronous tumours e.g. ovarian and endometrial or history of prior malignancy are eligible provided that there is biopsy evidence that the disease measurable on CT and/or MRI is ovarian in origin The following inclusion criteria will be required for all patients: 1. Written informed consent 2. Performance status =2 (ECOG) 3. Estimated life expectancy = 3 months 4. Age = 18 years 5. Adequate haematological, renal and hepatic function as defined by: 5.1 Haemoglobin (Hb)> 10g/dl 5.2 Neutrophil Count> 1.5 x 109/l 5.3 Platelets> 100 x 109/l 5.4 INR 50 mL/ min (calculated using the Wright formula or measured by EDTA clearance) 5.6 Total bilirubin =1.5 x ULN and ALT and AST = 2.5 x ULN 6. No history of grade 2 peripheral neuropathy at any time during prior treatment and no greater than grade 1 residual peripheral neuropathy. 7. No use within the last 7 days of or requirement to continue medications that are strong inhibitors of CYP3A4. 8. No prior treatment with LY2940680 or other Hedgehog pathway inhibitor. 9. Female patients with reproductive potential must have a negative serum pregnancy test within 7 days of trial enrolment and agree to use an effective double barrier method of contraception during and for 6 months after last dose of treatment. Male patients of childbearing potential and their female partner must also agree to use an effective double barrier method of contraception during and for 6 months after treatment. 10. No symptoms or signs of gastrointestinal obstruction requiring parenteral nutrition or hydration or any other gastro-intestinal disorders or abnormalities, including difficulty swallowing, that would interfere with drug absorption, including ileostomies. 11. Ability to swallow capsules. 12. No significant cardiovascular diseases, including uncontrolled hypertension, clinic
Exclusion criteria
Exclusion criteria: The exclusion criteria are covered by the negative inclusion criteria
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| The primary outcome measure of the dose escalation phase is the maximum tolerated dose of LY2940680 when administered orally in combination with intravenous paclitaxel 80mg/m2 administered on day 1, 8 and 15 of a 28 day cycles based on clinical and laboratory toxicity which will be classified and graded according to CTCAE v 4. The primary outcome of the dose expansion phase is the toxicity of the combination of LY2940680 at the recommended dose level and weekly paclitaxel (80mg/m2, IV days 1, 8 and 15 every 28 days) in recurrent platinum resistant ovarian cancer. The causality of each adverse event to LY2940680 and paclitaxel will be classified and graded according to CTCAE v 4. | — |
Secondary
| Measure | Time frame |
|---|---|
| The secondary outcome measures of the dose escalation phase are: 1. Pharmacokinetics: Cmax, T max and AUC of LY2940680, its metabolite LSN3185556 and paclitaxel 2. Response rate will be defined by RECIST 1.1 3. Progression free survival (PFS) defined as the time from first treatment dose to first appearance of progressive disease as defined by RECIST 1.1 or death from any cause. Patients still alive and without progression at the time of analysis will be censored at the last date known to be alive. 4. Overall survival will be measured from the date of first treatment dose to the date of death from any cause. Patients still alive at the time of analysis will be censored at the last date known to be alive. The secondary outcome measures of the dose expansion phase are: 1. Dose intensity of paclitaxel is defined as the actual dose intensity as a percentage of the intended dose. Actual dose intensity is defined as the total dose (expressed as mg/m2) / length of treatment in weeks. The length of treatment will be defined as the time from day 1 of the first treatment to 4 weeks after the day 1 of the last treatment. The intended dose intensity is defined as what the patient should have received over the same period if there were no dose reductions, omissions or delays. 2. Response rate will be defined by RECIST 1.1 and defined by Combined GCIG criteria. To be evaluable for response a patient must receive at least two cycles of trial treatment and have an evaluable tumour response. All eligible patients will be included in the response rate calculation. The subset that will be assigned a response category are all patients who have received at least two cycles of treatment. 3. Progression free survival (PFS) defined as the time from first treatment dose to first appearance of progressive disease as defined by RECIST 1.1 or death from any cause. Patients still alive and without progression at the time of analysis will be censored at the last date known to be alive. Progress | — |
Countries
England, Scotland, United Kingdom
Contacts
Public ContactKaren Allan
Outcome results
None listed