Fallopian Tube Cancer, Ovarian Cancer, Primary Peritoneal Cancer
Conditions
Brief summary
The purpose of this study is to investigate whether the addition of the Src inhibitor saracatinib (AZD0530) to weekly paclitaxel improves efficacy, compared with paclitaxel plus placebo, in patients with relapsed platinum-resistant ovarian cancer. The trial will also determine toxicity and ascertain whether the combination of paclitaxel plus saracatinib should proceed to a phase III trial.
Detailed description
A multicentre, randomised, double-blind, placebo-controlled Phase II trial will be conducted. The overall aim of the trial is to investigate whether the addition of saracatinib to weekly paclitaxel improves efficacy, as measured by progression free survival, compared with paclitaxel plus placebo. The trial will also determine toxicity and ascertain whether the combination of paclitaxel plus saracatinib should proceed to a phase III trial. The toxicity data from Study NCT00610714 (D8180C00015) suggests that a small number of patients could experience febrile neutropaenia during their first chemotherapy cycle. To combat this, saracatinib (175 mg OD)/matched placebo will begin 1 week prior to commencement of chemotherapy, and be given continuously until progression. All patients will receive cycles of weekly paclitaxel chemotherapy. One cycle will consist of weekly paclitaxel (80 mg/m2) for 6 weeks followed by 2 weeks rest. If there is evidence of on-going response after 4 cycles, 3 further cycles of saracatinib/placebo plus weekly paclitaxel will be given, unless there is dose-limiting toxicity or the patient requests to discontinue treatment. If best response is stable disease after 4 cycles, treatment should be discontinued but may continue at the discretion of the Investigator.
Interventions
DRUGPaclitaxel
Paclitaxel 80 mg/m2 weekly for 6 weeks followed by a 2 week break (1 cycle), for 4 cycles initially (32 weeks). If there is evidence of on-going response after 4 cycles, 3 further cycles will be given, unless there is dose-limiting toxicity or the patient requests to discontinue treatment. If best response is stable disease after 4 cycles, treatment should be discontinued but may continue at the discretion of the Investigator.
DRUGSaracatinib
Saracatinib 175 mg PO once daily, to begin 1 week prior to commencement of chemotherapy, taken continuously until progression
DRUGMatched placebo
Matched placebo PO once daily, to begin 1 week prior to commencement of chemotherapy, taken continuously until progression
Sponsors
AstraZeneca
Cancer Research UK
University College, London
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Confirmed relapsed ovarian, fallopian tube or primary peritoneal cancer AND relapse within the platinum-resistant (progression must not be based on Cancer Antigen 125 (CA125) alone) time-frame, i.e. have progressed within 6 months of platinum therapy. * Patients need not have received prior taxane; if patients have received prior taxane, the interval since treatment must be known. Patients will be stratified as \<6 months or 6+ months taxane interval/no prior taxane. * Patients will generally have received at least 2 lines of prior chemotherapy, but may enter if they have relapsed within 6 months of first line therapy. Patients may have received prior liposomal doxorubicin, although this is NOT a requirement. The treatment immediately prior to study entry need not be platinum-based. * Measurable or evaluable disease (if not measurable by Response Evaluation Criteria In Solid Tumours (RECIST) v1.1 criteria, patients must be evaluable by Gynecologic Cancer InterGroup (GCIG) CA125 criteria). * Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0-2 * Adequate haematological and biochemical function.
Exclusion criteria
* Prior administration of weekly paclitaxel. * Tumours of malignant mixed mesodermal (MMMT) or mucinous subtypes, or non-epithelial ovarian cancers (e.g. Brenner tumours, Sex-cord tumours). * Unresolved bowel obstruction. * Chemotherapy within the preceding 3 weeks. * Radiotherapy within the preceding 3 weeks. * Treatment with any investigational agent within the preceding 4 weeks or within 5 half-lives of the investigational agent, whichever is longer. * Known leptomeningeal involvement or intracranial disease. * Evidence of interstitial lung disease (bilateral, diffuse, parenchymal lung disease). * Resting ECG with measurable QTc interval of \>480 msec at 2 or more time points within a 24 hour period. * Pregnant or lactating females. * Fertile women of childbearing potential not willing to use highly effective contraception for the duration of trial treatment and for at least 6 months after the last administration of saracatinib +/- paclitaxel. * Inability or unwillingness to give informed consent. * Ongoing active infection or a documented history of HIV infection, Hepatitis B or C. * Concurrent congestive heart failure or prior history of New York Heart Association (NYHA) class III/IV cardiac disease. * Concurrent autoimmune disorder, e.g. systemic lupus or any demyelinating disease. * Use of immunosuppressive therapy or corticosteroids taken within the 4 weeks prior to study entry and during the treatment period.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 6 Month Progression-free Survival Rate (PFS) (Based on Combined Response Evaluation Criteria In Solid Tumours (RECIST) v1.1 +/- Gynecologic Cancer Intergroup (GCIG) CA125 Criteria) | Using RECIST v1.1 at baseline; at Week 7 or 8 of each chemotherapy cycle; and 3 monthly during follow up. CA125 response will be assessed at baseline, weeks 1, 3 and 6 of each chemotherapy cycle, and at every follow up visit. | Where a patient's disease is not measurable by RECIST v1.1, response may be based on GCIG CA125 criteria plus symptoms. The 6 month progression-free survival rate will be calculated by the trial statistician during the final analysis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate Based on Investigator Assessment Based on RECIST v1.1 +/- GCIG CA125 Criteria | Using RECIST v1.1 at baseline; at Week 7 or 8 of each chemotherapy cycle; and 3 monthly during follow up. CA125 response will be assessed at baseline, weeks 1, 3 and 6 of each chemotherapy cycle, and at every follow up visit. | Where a patient's disease is not measurable by RECIST v1.1, response may be based on GCIG CA125 criteria plus symptoms. |
| Median Duration of Response | Using RECIST v1.1 at baseline; at Week 7 or 8 of each chemotherapy cycle; and 3 monthly during follow up. CA125 response will be assessed at baseline, weeks 1, 3 and 6 of each chemotherapy cycle, and at every follow up visit. | Where a patient's disease is not measurable by RECIST v1.1, response may be based on GCIG CA125 criteria plus symptoms. Duration of Response will be calculated by the trial statistician during the final analysis. |
| Overall Survival | First saracatinib/placebo dose until death, assessed up to 36 months | — |
| Median Time To Progression Based on RECIST v1.1 and GCIG CA125 Criteria | Using RECIST v1.1 at baseline; at Week 7 or 8 of each chemotherapy cycle; and 3 monthly during follow up. CA125 response will be assessed at baseline, weeks 1, 3 and 6 of each chemotherapy cycle, and at every follow up visit. | Where a patient's disease is not measurable by RECIST v1.1, response may be based on GCIG CA125 criteria plus symptoms. Time To Progression will be calculated by the trial statistician during the final analysis. |
| Median PFS | From first saracatinib/placebo dose to first documented progression and/or death, assessed up to 36 months | — |
| Quality of Life: Trial Outcome Index (TOI) Based on FACT-O | Patients will fill in FACT-O questionnaires at the following timepoints: baseline; Weeks 1, 3 and 6 of every chemotherapy cycle; at every follow up visit | The TOI value for each patient is derived at each timepoint by calculating the sum of 3 subscales: Physical Well-Being (PWB), Functional Well-Being (FWB), Additional Concerns. Each subscale score is derived from questions with 4 answers (0=not at all, 1=a little bit, 2=somewhat, 3=quite a bit, 4=very much). In each subscale reversals are performed and the individual question scores added together. This value is then multiplied by the number of questions within the subscale, and divided by the number of questions answered to derive a subscale score. The higher each subscale score, the better the QoL. PWB 7 questions, lower values=better QoL. FWB 7 questions, higher values=better QoL. Additional concerns 11 questions (higher values in 6 questions=better QoL; higher values in 5 questions=worse QoL) The TOI is reported for each arm based on the average TOI score of each patient calculated across the outcome measure time frame. The higher the TOI, the better the QoL. |
Countries
United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Saracatinib Plus Weekly Paclitaxel Paclitaxel: Paclitaxel 80 mg/m2 weekly for 6 weeks followed by a 2 week break (1 cycle), for 4 cycles initially (32 weeks). If there is evidence of on-going response after 4 cycles, 3 further cycles will be given, unless there is dose-limiting toxicity or the patient requests to discontinue treatment. If best response is stable disease after 4 cycles, treatment should be discontinued but may continue at the discretion of the Investigator.
Saracatinib: Saracatinib 175 mg PO once daily, to begin 1 week prior to commencement of chemotherapy, taken continuously until progression | 71 |
| Placebo Plus Weekly Paclitaxel Paclitaxel: Paclitaxel 80 mg/m2 weekly for 6 weeks followed by a 2 week break (1 cycle), for 4 cycles initially (32 weeks). If there is evidence of on-going response after 4 cycles, 3 further cycles will be given, unless there is dose-limiting toxicity or the patient requests to discontinue treatment. If best response is stable disease after 4 cycles, treatment should be discontinued but may continue at the discretion of the Investigator.
Matched placebo: Matched placebo PO once daily, to begin 1 week prior to commencement of chemotherapy, taken continuously until progression | 36 |
| Total | 107 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 10 | 6 |
| Overall Study | Disease progression | 34 | 14 |
| Overall Study | Dose limiting Adverse Event | 2 | 1 |
| Overall Study | Other | 3 | 2 |
| Overall Study | Other reason | 3 | 3 |
| Overall Study | Protocol Violation | 2 | 1 |
| Overall Study | Serious Adverse Event | 3 | 1 |
| Overall Study | Withdrawal by Subject | 3 | 0 |
Baseline characteristics
| Characteristic | Saracatinib Plus Weekly Paclitaxel | Placebo Plus Weekly Paclitaxel | Total |
|---|---|---|---|
| Age, Continuous | 62.8 years | 66.9 years | 63.4 years |
| Cancer Antigen 125 (CA125) | 628 U/mL | 667 U/mL | 648 U/mL |
| Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0 | 23 participants | 15 participants | 38 participants |
| Eastern Cooperative Oncology Group Performance Status (ECOG PS) 1 | 45 participants | 20 participants | 65 participants |
| Eastern Cooperative Oncology Group Performance Status (ECOG PS) 2 | 3 participants | 1 participants | 4 participants |
| Histological subtype Clear cell | 6 participants | 1 participants | 7 participants |
| Histological subtype Grade 1/2 endometrioid | 3 participants | 1 participants | 4 participants |
| Histological subtype Grade 3 endometrioid | 2 participants | 2 participants | 4 participants |
| Histological subtype High grade serous | 46 participants | 27 participants | 73 participants |
| Histological subtype Low grade serous | 4 participants | 2 participants | 6 participants |
| Histological subtype Undifferentiated | 7 participants | 2 participants | 9 participants |
| Histological subtype Unknown | 3 participants | 1 participants | 4 participants |
| International Federation of Gynecology and Obstetrics(FIGO) Ovarian Cancer Staging at diagnosis I | 6 participants | 2 participants | 8 participants |
| International Federation of Gynecology and Obstetrics(FIGO) Ovarian Cancer Staging at diagnosis II | 5 participants | 1 participants | 6 participants |
| International Federation of Gynecology and Obstetrics(FIGO) Ovarian Cancer Staging at diagnosis III | 45 participants | 31 participants | 76 participants |
| International Federation of Gynecology and Obstetrics(FIGO) Ovarian Cancer Staging at diagnosis IV | 11 participants | 1 participants | 12 participants |
| International Federation of Gynecology and Obstetrics(FIGO) Ovarian Cancer Staging at diagnosis Unknown | 4 participants | 1 participants | 5 participants |
| Number of lines of Prior Chemotherapy 1-2 | 43 participants | 19 participants | 62 participants |
| Number of lines of Prior Chemotherapy >2 | 26 participants | 17 participants | 43 participants |
| Number of lines of Prior Chemotherapy Unknown | 2 participants | 0 participants | 2 participants |
| Number of lines of Prior Chemotherapy | 2.0 lines of chemotherapy | 2.0 lines of chemotherapy | 2.0 lines of chemotherapy |
| Prior Surgery No | 2 participants | 5 participants | 7 participants |
| Prior Surgery Unknown | 2 participants | 0 participants | 2 participants |
| Prior Surgery Yes | 67 participants | 31 participants | 98 participants |
| Prior Taxane Interval <6 months | 15 participants | 8 participants | 23 participants |
| Prior Taxane Interval >=6 months/None | 56 participants | 28 participants | 84 participants |
| Region of Enrollment United Kingdom | 71 participants | 36 participants | 107 participants |
| Sex: Female, Male Female | 71 Participants | 36 Participants | 107 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 20 / 69 | 7 / 35 |
| serious Total, serious adverse events | 40 / 69 | 18 / 35 |
Outcome results
Primary
6 Month Progression-free Survival Rate (PFS) (Based on Combined Response Evaluation Criteria In Solid Tumours (RECIST) v1.1 +/- Gynecologic Cancer Intergroup (GCIG) CA125 Criteria)
Where a patient's disease is not measurable by RECIST v1.1, response may be based on GCIG CA125 criteria plus symptoms. The 6 month progression-free survival rate will be calculated by the trial statistician during the final analysis.
Time frame: Using RECIST v1.1 at baseline; at Week 7 or 8 of each chemotherapy cycle; and 3 monthly during follow up. CA125 response will be assessed at baseline, weeks 1, 3 and 6 of each chemotherapy cycle, and at every follow up visit.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Saracatinib Plus Weekly Paclitaxel | 6 Month Progression-free Survival Rate (PFS) (Based on Combined Response Evaluation Criteria In Solid Tumours (RECIST) v1.1 +/- Gynecologic Cancer Intergroup (GCIG) CA125 Criteria) | 29 percentage of participants |
| Placebo Plus Weekly Paclitaxel | 6 Month Progression-free Survival Rate (PFS) (Based on Combined Response Evaluation Criteria In Solid Tumours (RECIST) v1.1 +/- Gynecologic Cancer Intergroup (GCIG) CA125 Criteria) | 34 percentage of participants |
p-value: 0.5795% CI: [0.65, 1.23]Regression, Cox
Secondary
Median Duration of Response
Where a patient's disease is not measurable by RECIST v1.1, response may be based on GCIG CA125 criteria plus symptoms. Duration of Response will be calculated by the trial statistician during the final analysis.
Time frame: Using RECIST v1.1 at baseline; at Week 7 or 8 of each chemotherapy cycle; and 3 monthly during follow up. CA125 response will be assessed at baseline, weeks 1, 3 and 6 of each chemotherapy cycle, and at every follow up visit.
Secondary
Median PFS
Time frame: From first saracatinib/placebo dose to first documented progression and/or death, assessed up to 36 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Saracatinib Plus Weekly Paclitaxel | Median PFS | 4.7 months |
| Placebo Plus Weekly Paclitaxel | Median PFS | 5.3 months |
p-value: 0.99Regression, Cox
Secondary
Median Time To Progression Based on RECIST v1.1 and GCIG CA125 Criteria
Where a patient's disease is not measurable by RECIST v1.1, response may be based on GCIG CA125 criteria plus symptoms. Time To Progression will be calculated by the trial statistician during the final analysis.
Time frame: Using RECIST v1.1 at baseline; at Week 7 or 8 of each chemotherapy cycle; and 3 monthly during follow up. CA125 response will be assessed at baseline, weeks 1, 3 and 6 of each chemotherapy cycle, and at every follow up visit.
Secondary
Objective Response Rate Based on Investigator Assessment Based on RECIST v1.1 +/- GCIG CA125 Criteria
Where a patient's disease is not measurable by RECIST v1.1, response may be based on GCIG CA125 criteria plus symptoms.
Time frame: Using RECIST v1.1 at baseline; at Week 7 or 8 of each chemotherapy cycle; and 3 monthly during follow up. CA125 response will be assessed at baseline, weeks 1, 3 and 6 of each chemotherapy cycle, and at every follow up visit.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Saracatinib Plus Weekly Paclitaxel | Objective Response Rate Based on Investigator Assessment Based on RECIST v1.1 +/- GCIG CA125 Criteria | 29 percentage of participants |
| Placebo Plus Weekly Paclitaxel | Objective Response Rate Based on Investigator Assessment Based on RECIST v1.1 +/- GCIG CA125 Criteria | 43 percentage of participants |
Secondary
Overall Survival
Time frame: First saracatinib/placebo dose until death, assessed up to 36 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Saracatinib Plus Weekly Paclitaxel | Overall Survival | 10.1 months |
| Placebo Plus Weekly Paclitaxel | Overall Survival | 12.3 months |
p-value: 0.81Regression, Cox
Secondary
Quality of Life: Trial Outcome Index (TOI) Based on FACT-O
The TOI value for each patient is derived at each timepoint by calculating the sum of 3 subscales: Physical Well-Being (PWB), Functional Well-Being (FWB), Additional Concerns. Each subscale score is derived from questions with 4 answers (0=not at all, 1=a little bit, 2=somewhat, 3=quite a bit, 4=very much). In each subscale reversals are performed and the individual question scores added together. This value is then multiplied by the number of questions within the subscale, and divided by the number of questions answered to derive a subscale score. The higher each subscale score, the better the QoL. PWB 7 questions, lower values=better QoL. FWB 7 questions, higher values=better QoL. Additional concerns 11 questions (higher values in 6 questions=better QoL; higher values in 5 questions=worse QoL) The TOI is reported for each arm based on the average TOI score of each patient calculated across the outcome measure time frame. The higher the TOI, the better the QoL.
Time frame: Patients will fill in FACT-O questionnaires at the following timepoints: baseline; Weeks 1, 3 and 6 of every chemotherapy cycle; at every follow up visit
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Saracatinib Plus Weekly Paclitaxel | Quality of Life: Trial Outcome Index (TOI) Based on FACT-O | 66.89 units on a scale | Standard Error 1.89 |
| Placebo Plus Weekly Paclitaxel | Quality of Life: Trial Outcome Index (TOI) Based on FACT-O | 73.10 units on a scale | Standard Error 2.56 |
p-value: 0.0476Mixed Models Analysis