A Trial of Ipatasertib in Combination With Atezolizumab

Inclusion Criteria: 1. 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. 2. 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 3. 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. 4. Life expectancy of at least 12 weeks. 5. World Health Organisation (WHO) performance status of 0-1 6. 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 ≥ 100 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 ≥ 50 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 7.18 years or over 8.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: * 1.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. 2.Ongoing Grade 2 or greater toxicities from pre-existing conditions or from previous treatments. Exceptions to this are alopecia. 3.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. 4.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. 5.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. 6.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. 7.Major surgery within four weeks of the first dose of study treatment. 8.History of malabsorption syndrome or other condition that would interfere with enteral absorption. 9.At high medical risk because of non-malignant systemic disease including active uncontrolled infection. 10.Known to be serologically positive for hepatitis B, hepatitis C or human immunodeficiency virus (HIV). 11.Has a known history of clinically significant liver disease, including viral or other hepatitis or cirrhosis. 12.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. 13.Has a known history of severe allergic anaphylactic reactions to chimeric, human or humanized antibodies, or fusion proteins. 14.Has a known hypersensitivity to CHO cell products or any component of the atezolizumab formulation. 15.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 1 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. 16.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. 17.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 \[NYHA Grade 2\] 18.Prior bone marrow transplant or have had extensive radiotherapy to greater than 25% of bone marrow within eight weeks. 19.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. 20.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. 21.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. 22.Is taking or requiring the continued use of any of the prohibited concomitant medications listed in 5.8 Concomitant medication and treatment. 23.Any other condition which in the Investigator's opinion would not make the patient a good candidate for the clinical trial.