A Trial of Ipatasertib in Combination With Atezolizumab

  • STATUS
    Recruiting
  • End date
    Nov 26, 2022
  • participants needed
    87
  • sponsor
    Institute of Cancer Research, United Kingdom
Updated on 26 June 2021
platelet count
cancer
measurable disease
AKT
serum bilirubin
neutrophil count
aptt
PTEN

Summary

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.

Description

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.

Part A:

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.

Part B:

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 (n=12)
  • 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)
  • Cohort B6: patients with gynaecological cancers (including ovarian cancer, cervical cancer, endometrial cancer) (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.

Details
Condition Glioblastoma Multiforme, Solid Tumors, Solid Tumor, Solid Neoplasm, Metastatic Prostate Cancer, Prostate Cancer Metastatic, Solid Tumour, glioblastoma
Treatment Atezolizumab, Ipatasertib
Clinical Study IdentifierNCT03673787
SponsorInstitute of Cancer Research, United Kingdom
Last Modified on26 June 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

PART A1: Patients with histologically or cytologically confirmed malignant advanced solid tumours refractory to conventional treatment, or for which no conventional therapy exists or is declined by the patient
PART A2: Patients with advanced glioblastoma with potentially surgically
resectable disease
PART B1: Patients with histologically or cytologically confirmed malignant
advanced solid tumours, refractory to conventional treatment, or for which no
conventional therapy exists or is declined by the patient, with somatic
mutations or other aberrations predicted to result in a hyperactivated
PI3K-AKT pathway (eg activating mutations in PIK3CA, AKT1, AKT2) or PTEN loss
(assessed by immunohistochemistry (IHC) (n=12)
PART B2: Patients with histologically or cytologically confirmed malignant
castrate refractory prostate cancer, refractory to conventional treatment, or
for which no conventional therapy exists or is declined by the patient, with
PTEN loss confirmed by immunohistochemistry H-score <30 as established in our
local laboratory PART B3: Patients with relapsed histologically confirmed
glioblastoma. At least 3 patients will need to have potentially surgically
resectable disease
\. Part A1: Evaluable disease as assessed by immune-modified RECIST 1.1
(solid tumours)
Part A2: Evaluable disease as assessed by Response-assessment in Neuro-
Oncology (RANO) criteria for glioblastoma patients. Part B1: Measurable
disease as assessed by immune-modified RECIST Part B2: Measurable disease as
assessed by immune-modified RECIST 1.1 OR evaluable disease as per Prostate
Cancer Working Group 3 (PCWG 3) criteria Part B3: Measurable disease as
assessed by RANO
\. All patients with advanced solid tumours must be willing and able to have
fresh paired tissue biopsies for biomarker analysis. All patients with
potentially resectable glioblastomas being considered for Part A2 and Part B3
must be willing and able to have surgical resection with fresh tissue samples
provided for translational studies
\. Life expectancy of at least 12 weeks
\. World Health Organisation (WHO) performance status of 0-1
\. Haematological and biochemical indices within the ranges shown below
These measurements must be performed within one week prior to the first dose
of either Investigational Medicinal Product (IMP)
Haemoglobin (Hb) 9.0 g/dL Absolute neutrophil count 1.5 x 109/L Platelet count
x 109/L Serum bilirubin 1.5 x upper limit of normal (ULN) Alanine
aminotransferase (ALT) and aspartate aminotransferase (AST) 2.5 x (ULN) unless
raised due to tumour in which case up to 5 x ULN is permissible
Either
Creatinine OR IF Creatinine > 1.5 times ULN then Calculated creatinine
clearance <1.5 times ULN
mL/min (uncorrected value)
Coagulation INR < 1.5 APTT <1.5x ULN (except for potentially resectable
glioblastoma patients enrolled onto the surgical resection arms where the APTT
should be <1.2x ULN Triglycerides 300 mg/dL Cholesterol 300 mg/dL
18 years or over
Written (signed and dated) informed consent and be capable of co-operating
with treatment and follow-up 9.Female patients with reproductive potential
must have a negative serum pregnancy test within 14 days prior to start of
trial

Exclusion Criteria

Radiotherapy, endocrine therapy, immunotherapy or chemotherapy during the previous four weeks (six weeks for nitrosoureas, Mitomycin-C) and four weeks for investigational medicinal products) before treatment, except for hormonal therapy with luteinizing hormone-releasing hormone (LHRH) analogues for medical castration in patients with castrate resistant prostate cancer, which are permitted, and bisphosphonates or RANK ligand antagonists that are permitted for the management of bone metastases
Ongoing Grade 2 or greater toxicities from pre-existing conditions or from
previous treatments. Exceptions to this are alopecia
Clinically significant abnormalities of glucose metabolism as defined by any
of the
following
Diagnosis of diabetes mellitus types I or II (irrespective of management)
Glycosylated haemoglobin (HbA1C) 7.50% at screening
Fasting Plasma Glucose 8.3mmol/L (150 mg/dL) at screening. Fasting is defined as no caloric intake for at least 8 hours
Ability to become pregnant (or already pregnant or lactating). However
those female patients who have a negative serum pregnancy test before
enrolment and agree to use two highly effective forms of contraception (oral
injected or implanted hormonal contraception and condom, have an intra-uterine
device and condom, diaphragm with spermicidal gel and condom) from time of
consent, during the trial and for six months afterwards are considered
eligible
Male patients with partners of child-bearing potential (unless they agree to
take measures not to father children by using one form of highly effective
contraception [condom plus spermicide] during the trial and for six months
afterwards). Men with pregnant or lactating partners should be advised to use
barrier method contraception (for example, condom plus spermicidal gel) to
prevent exposure to the foetus or neonate
For patients with solid tumours, known untreated or active central nervous
system (CNS) metastases (progressing or requiring corticosteroids for
symptomatic control). Patients with a history of treated CNS metastases are
eligible, provided they meet all of the following criteria
Evaluable or measurable disease outside the CNS is present
Radiographic demonstration of improvement upon the completion of CNS-directed therapy and no evidence of interim progression between the completion of CNS-directed therapy and the baseline disease assessment
Not requiring corticosteroids
Major surgery within four weeks of the first dose of study treatment
History of malabsorption syndrome or other condition that would interfere
with enteral absorption
At high medical risk because of non-malignant systemic disease including
active uncontrolled infection
Known to be serologically positive for hepatitis B, hepatitis C or human
immunodeficiency virus (HIV)
Has a known history of clinically significant liver disease, including
viral or other hepatitis or cirrhosis
Has an active autoimmune disease that has required systemic treatment in
past 3 months (i.e. with use of disease modifying agents, corticosteroids or
immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or
physiologic corticosteroid replacement therapy for adrenal or pituitary
insufficiency, etc.) is not considered a form of systemic treatment. Patients
with a history of inflammatory bowel diseases such as Crohn's disease or
ulcerative colitis will be excluded from the study. Patients with Sjogren's
syndrome will not be excluded from the study. In addition patients that
experienced a Grade 2 or higher immune-related AE's on treatment with
immunotherapy will be excluded from the study. Patients with inactive
autoimmune disease which has previously required systemic therapy, may be
considered on a case-by-case basis after discussion with the sponsor
Has a known history of severe allergic anaphylactic reactions to chimeric
human or humanized antibodies, or fusion proteins
Has a known hypersensitivity to CHO cell products or any component of the
atezolizumab formulation
Has a diagnosis of immunodeficiency or is receiving systemic steroid
therapy or any other form of immunosuppressive therapy within 14 days prior to
the first dose of trial treatment. The use of physiologic doses of
corticosteroids may be approved after consultation with the chief
Investigator. Stable use (i.e., no change in dose within 1 month prior to Day
of Cycle 1 of inhaled corticosteroids is allowed
In the Part B dose expansion only, patients with castrate-resistant prostate
cancer who have been on long-term steroids, will be allowed, provided the
average total daily dose of steroids for the two weeks prior to commencement
of trial is 10mg prednisolone/day. Again, in the Part B3 dose expansion only
patients with glioblastoma will be allowed to be enrolled if they had been on
a stable dose of steroids 3mg Dexamethasone for at least 5 days prior to Day 1
of Cycle 1
Has received a live vaccine within 30 days of planned start of study
therapy. Note: The killed virus vaccines used for seasonal influenza vaccines
for injection are allowed; however intranasal influenza vaccines (e.g
FluMist) are live attenuated vaccines and are not allowed
Any of the following cardiac criteria
Mean resting corrected QT interval (QTc) > 470 msec obtained from 3 consecutive electrocardiograms (ECGs) within 5 minutes of each other
Any clinically significant abnormalities in rhythm, conduction or morphology of resting ECG, e.g. complete left bundle branch block, third degree heart block. Controlled atrial fibrillation is allowed
Experience of any of the following procedures or conditions in the preceding 6 months: coronary artery bypass graft, angioplasty, vascular stent, myocardial infarction, angina pectoris, congestive heart failure New York Heart Association [NYHA Grade 2]
Prior bone marrow transplant or have had extensive radiotherapy to greater
than 25% of bone marrow within eight weeks
Current malignancies of other types, with the exception of adequately
treated cone-biopsied in situ carcinoma of the cervix uteri and basal or
squamous cell carcinoma of the skin. Cancer survivors, who have undergone
potentially curative therapy for a prior malignancy, have no evidence of that
disease for three years or more and are deemed at negligible risk for
recurrence, are eligible for the trial
Is a participant or plans to participate in another interventional clinical
trial, whilst taking part in this Phase I study of ipatasertib and
atezolizumab. Participation in an observational trial would be acceptable
Patients with prior exposure to a PI3K or AKT inhibitors will be excluded
from this study. Patients with prior exposure to mTOR inhibitors will be
permitted to be enrolled on study. Patients with prior exposure to
immunotherapy (either CTLA-4, PD-1/PD-L1 inhibitor/cellular therapy) will be
excluded from the dose escalation Part A of the study, but will be permitted
to enrol onto the Part B dose expansion as long as they did not experience any
Grade 2 immune-adverse event toxicity while on their prior immunotherapy
Is taking or requiring the continued use of any of the prohibited
concomitant medications listed in 5.8 Concomitant medication and treatment
Any other condition which in the Investigator's opinion would not make the
patient a good candidate for the clinical trial
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