This is a single centre, proof-of-concept phase I trial of atezolizumab in combination with
ipatasertib. There are two parts to this study, the dose escalation phase (Part A) and the
dose expansion phase (Part B). Part A, will determine the maximum tolerated dose (MTD) and
recommended Phase II dose (RP2D). This will be followed by the Part B dose expansion phase to
further characterise the safety and tolerability and to assess the pharmacodynamic activity
of the combination.
This is a Phase 1 trial of atezolizumab in combination with ipatasertib. There are two parts
to this study. Part A: dose escalation, and Part B: dose expansion.
The investigators will investigate the combination of a fixed dose of atezolizumab (1200mg)
in combination with escalating doses of ipatasertib in patients with advanced solid tumours
(Cohort A1) and patients with resectable glioblastoma multiforme (GBM) (Cohort A2).
Cohort A1 (advanced solid tumours):
There will be an ipatasertib run-in phase of 14 days of continuous oral dosing with paired
pre and post-treatment blood and tissue samples. Combinations dosing will commence on Cycle 1
Day 1 with the atezolizumab infusion. Cycle 1 will therefore be 35 days. Only patients with
advanced solid tumours recruited into Cohort A1 will be included in dose escalation decisions
and determination of the MTD and recommended Phase 2 dose (RP2D) for part B.
Cohort A2 (potentially resectable GBMs):
There will be an ipatasertib run-in phase of at least 14 days and up to 21 days followed by
surgical resection of the patient's tumour (5 day window for surgery). Ipatasertib dosing
will be stopped 48 hours prior to surgery and combination dosing on Cycle1Day1 (C1D1) will
commence after recovery. Accrual to Cohort A2 will run in parallel Cohort A1 without formal
dose escalations and patients in Cohort A2 will not be included in dose escalation decisions
for Cohort A1.
Patients will be enrolled into the expansion phase (Part B) to further characterize the
tolerability of the RP2D (established in Cohort A1) of the combination in specific subgroups
of patients. Part B of the study will have a pre-screening component for patients with solid
tumours (Cohorts B1 and B2) to allow for enrichment for these specific subgroups of patients.
Part B of the study will have three cohorts:
Cohort B1: patients with solid tumours with hyperactivation of PI3K pathway as
determined by pathogenic mutations identified by next generation sequencing (NGS) (eg
known activating mutations in PIK3CA, AKT1, AKT2) or PTEN loss (assessed by
immunohistochemistry (IHC) (n=12).
Cohort B2: patients with castrate-resistant prostate cancer with PTEN loss as assessed
by IHC (n=12)
Cohort B3: patients with glioblastoma (n=12) of which at least three (n=3) patients will
have potentially resectable recurrent glioblastomas.
Cohort B4: patients with melanoma post progression on immune-checkpoint inhibitors
Cohort B5: patients with other tumour types refractory to immune checkpoint inhibitors
(where immune checkpoint inhibitors are licensed, e.g. bladder cancer, head and neck
SCC, NSCLC) (n=12)
Approximately 12 patients with solid tumours and 3 patients with glioblastoma will be entered
into Part A of this trial and a further 72 patients will be enrolled into part B of the trial
for an expected maximum of 87 patients on the study. If the MTD is reached in Part A with
less than 15 patients enrolled, the investigators may enrol further patients at the R2PD in
Part A to a maximum of 15 patients to include sufficient numbers of patients for the
proof-of-concept translational studies. Additional subjects may be enrolled in a given cohort
to ensure that the required number of evaluable subjects in each cohort is achieved.
If you are confirmed eligible after full screening, you will be required to understand and sign the informed consent if you decide to enroll in the study. Once enrolled you may be asked to make scheduled visits over a period of time.
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