Description:
This is a two stage study, with an initial dose escalation phase I study and subsequent
double blind randomised phase II controlled trial. Eligible patients are post-menopausal
women with metastatic ER+ breast cancer not suitable for surgical resection. Patients should
be suitable for endocrine treatment, but have received no more than 3 previous lines of
endocrine treatment and up to 1 line of chemotherapy for metastatic disease. They will also
have had progressive disease during treatment with an aromatase inhibitor. Following the
dose-escalation in stage 1, patients will be randomised to receive fulvestrant plus either
placebo or 480mg (or maximum tolerated dose) of AZD5363 oral capsules or tablets taken once
daily.
Patients will receive fulvestrant in combination with either placebo or AZD5363 until disease
progression. Patients may continue to receive fulvestrant and AZD5363/placebo treatment even
after the last trial visit.
Title
- Brief Title: Fulvestrant +/- Akt Inhibition in Advanced Aromatase Inhibitor Resistant Breast Cancer
- Official Title: A Phase 1b/2 Randomised Placebo Controlled Trial of Fulvestrant +/- AZD5363 in Postmenopausal Women With Advanced Breast Cancer Previously Treated With a Third Generation Aromatase Inhibitor
Clinical Trial IDs
- ORG STUDY ID:
FAKTION
- NCT ID:
NCT01992952
Conditions
- Estrogen Receptor Positive Breast Cancer
Interventions
Drug | Synonyms | Arms |
---|
AZD5363 | | AZD5363 plus fulvestrant |
Placebo | | Placebo plus fulvestrant |
Fulvestrant | | AZD5363 plus fulvestrant |
Purpose
This is a two stage study, with an initial dose escalation phase I study and subsequent
double blind randomised phase II controlled trial. Eligible patients are post-menopausal
women with metastatic ER+ breast cancer not suitable for surgical resection. Patients should
be suitable for endocrine treatment, but have received no more than 3 previous lines of
endocrine treatment and up to 1 line of chemotherapy for metastatic disease. They will also
have had progressive disease during treatment with an aromatase inhibitor. Following the
dose-escalation in stage 1, patients will be randomised to receive fulvestrant plus either
placebo or 480mg (or maximum tolerated dose) of AZD5363 oral capsules or tablets taken once
daily.
Patients will receive fulvestrant in combination with either placebo or AZD5363 until disease
progression. Patients may continue to receive fulvestrant and AZD5363/placebo treatment even
after the last trial visit.
Detailed Description
Phase 1 (n=9-12)
As fulvestrant and AZD5363 have not previously been administered to this population, we have
incorporated an initial phase I dose escalation:
- 3 patients will receive fulvestrant 500mg on day 1 and 400mg AZD5363 oral capsules or
tablets bd 4 days on and 3 days off. They will be assessed for dose limiting toxicity
(DLT) on day 1, 15 and 28 of cycle 1. The safety review committee (SRC) will meet to
review DLT reports when the third patient finishes cycle 1.
- If 400mg is tolerable (0/3-6 or 1-6 has a DLT) then the dose of AZD5363 will be
escalated to 480mg.
- If 480mg is tolerable in a cohort of 6 patients then 480mg will be the Maximum tolerated
dose (MTD).
- If 480mg is not tolerable (2/6 patients have a DLT), then the 400mg dose will be the
MTD.
- If 400mg is not tolerable (2 or more patients have a DLT) then the dose will be reduced
to 320mg for the next cohort of 6 patients.
- if 320mg is tolerable in a cohort of 6 patients, then 320mg will be the MTD.
- if 320mg is not tolerable, then the trial will not proceed. If patients are withdrawn
for reasons other than toxicity during Stage 1 before DLT assessments then they will be
replaced.
Phase 2 (n=136)
Recruitment in to Phase 2 will commence after all 6 patients in Stage 1 have completed at
least 1 cycle of therapy and the SRC have given the go-ahead. Patients will be randomised to
one of two arms:
Arm A (control arm): Fulvestrant + placebo The control arm will consist continuous 28 day
cycles of fulvestrant 500mg on day 1, plus placebo capsule or tablet bd 4 days on and 3 days
off.
Arm B (experimental arm): Fulvestrant + AZD5363 The experimental arm will consist continuous
28 day cycles of fulvestrant 500mg on day 1, plus AZD5363 capsule or tablet bd 4 days on and
3 days off.
A further safety assessment will be made after 20 patients have been randomised to receive
AZD5363 or placebo and have at least 1 cycle of protocol treatment in stage 2.
Phase 2 will have 3 stages, this is because we want to investigate whether tumours with
certain characteristics are more likely to respond to the AZD5363. As mentioned above, we
will test the tumour tissue for the presence of a PIK3CA mutation (a gene encoding catalytic
subunit of class 1 PI3K) and for low levels of phosphatase and tensin homolog (PTEN).
Laboratory research has shown that tumours with these characteristics may respond better to
the AZD5363. Tumours which do not have these characteristics are called wild-type, and we
want to make sure we don't recruit too many of these patients if they might not benefit from
the treatment.
We will start off by recruiting all eligible patients. However, when we know that we have 40
patients with wild-type tumours, and they have been on trial treatment for eight weeks, we
will stop recruiting patients with wild-type tumours. This means that we will do a blood test
to confirm the tumour has the PIK3CA mutation before a patient can be entered onto the study.
We will perform a review of the tumour measurements in this wild-type group to determine
whether the tumours of the patients receiving AZD5363 have shrunk more than patients
receiving placebo. If there is no evidence that the tumour has shrunk in the AZD5363 group
compared to placebo, we will not recruit any more patients with wild-type tumours. If there
is evidence that that the tumours have shrunk in the AZD5363 group, we will start recruiting
patients with wild-type tumours again.
Trial Arms
Name | Type | Description | Interventions |
---|
AZD5363 plus fulvestrant | Experimental | Fulvestrant 500mg and AZD5363 4 days on 3 days off at dose determined in safety run in (maximum 480mg and minimum 320mg bd) | |
Placebo plus fulvestrant | Active Comparator | Fulvestrant 500mg D1, D15 (cycle 1) and D1 of a 28 cycle thereafter. AZD5363 placebo 4 days on 3 days off | |
Eligibility Criteria
Inclusion Criteria:
- Post-menopausal Women
- Life expectancy 3 months
- Histological confirmation of ER+ breast cancer
- Clinical or histological confirmation of metastatic or locally advanced disease not
amenable to surgical resection
- Measurable or non-measurable disease
- Adequate bone marrow, renal and hepatic function
- Eastern Cooperative Oncology Group (ECOG) performance status < or equal to 2
- Progressive disease whilst receiving an aromatase inhibitor (AI) for metastatic breast
cancer (MBC)
- Relapsed with metastatic disease whilst receiving an AI in adjuvant setting
- Up to 3 prior lines of endocrine therapy for Advanced Breast Cancer
- Up to 1 line of chemotherapy for Advanced Breast Cancer
- Patient willing to donate archival tumour sample
- Patient willing to donate baseline blood sample
- Suitable for further endocrine therapy
Exclusion Criteria:
- Previous treatment with fulvestrant or PI3K/mTOR(mammalian target of rapamycin )/Akt
inhibitor therapy
- Treatment with chemotherapy, immunotherapy or targeted, biologic or tumour
embolisation within 21 days of study drug administration
- Palliative radiotherapy within 7 days of study drug
- Clinically significant abnormalities in glucose metabolism
- Rapidly progressive visceral disease not suitable for further endocrine therapy
- Known brain or leptomeningeal metastases
- Any co-existing medical condition precluding trial entry including significant cardiac
disease (to be defined in the protocol)
- Concomitant medication unsuitable for combination with trial medication
Maximum Eligible Age: | N/A |
Minimum Eligible Age: | 18 Years |
Eligible Gender: | Female |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | Phase 1b primary outcome measure: Maximum Tolerated Dose of AZD5363 in combination with fulvestrant |
Time Frame: | 6 months |
Safety Issue: | |
Description: | To establish the MTD of AZD5363 in combination with fulvestrant and to establish a recommended phase 2 dose |
Secondary Outcome Measures
Measure: | Number of patients with adverse events |
Time Frame: | Up to 12 months after the last patient is randomised |
Safety Issue: | |
Description: | To determine the number of patients reporting adverse events and to summarise the different types of adverse events experienced in each trial arm. |
Measure: | Objective response rate |
Time Frame: | Up to 12 months after the last patient is randomised |
Safety Issue: | |
Description: | The objective response rate will be used to determine the proportion of patients who responded to treatment. |
Measure: | Overall survival |
Time Frame: | Up to 12 months after the last patient is randomised |
Safety Issue: | |
Description: | The time from randomisation to death, with those still alive censored at date last seen |
Measure: | The influence of mutational status of PIK3CA and the presence of complete loss of PTEN on outcome in the two treatment groups |
Time Frame: | Up to 12 months after the last patient is randomised |
Safety Issue: | |
Description: | The mutational status of PIK3CA and the presence of complete loss of PTEN will be assessed at baseline. |
Measure: | Fulvestrant pharmacokinetics |
Time Frame: | Cycle 1 Day 15, Cycle 2 Day 1 and Cycle 3 Day 1 |
Safety Issue: | |
Description: | The minimum concentration (Cmin) of fulvestrant will be measured to determine whether AZD5363 affects the metabolism of fulvestrant. |
Measure: | Number of patients requiring dose modifications |
Time Frame: | Up to 12 months after the last patient is randomised |
Safety Issue: | |
Description: | The number of participants requiring dose modifications of AZD5363 and fulvestrant will be summarised for each trial arm. This will be broken down into the number of patients who withdraw from treatment and the number who were dose reduced while on treatment. |
Details
Phase: | Phase 1/Phase 2 |
Primary Purpose: | Interventional |
Overall Status: | Active, not recruiting |
Lead Sponsor: | Velindre NHS Trust |
Last Updated
April 8, 2021