A Trial of Ipatasertib in Combination With Atezolizumab

NCT03673787 | Active Not Recruiting Phase 1

• 1 other identifier: CCR4720
• Study Type: interventional
• Target: 87
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Solid Tumor; Glioblastoma Multiforme; Prostate Cancer Metastatic

Outcome Measures

Primary Outcomes (2)

• To identify a maximum tolerated dose in Phase I

  Number of Participants With Treatment-Related Adverse Events as Assessed by CTCAE v4.0

  12 months

• To determine the number and type of treatment-related adverse events of the two drug combination as assessed by CTCAE v4.0

  Frequency and severity of treatment-emergent adverse events graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0.

  24 months

Secondary Outcomes (2)

• Determination of changes in immune-cell population in blood and plasma, using Fluorescence-Activated Cell Sorting (FACS)

  24 months

• To assess the tumour microenvironment by immunophenotyping

  24 months

Other Outcomes (2)

• Characterisation of the pharmacodynamic profile of exploratory biomarkers using RNA sequencing.

  24 months

• Evaluation of disease response by immune-modified RECIST criteria version 1.1

  24 months

Study Arms (2)

Phase I

EXPERIMENTAL

Increasing doses of ipatasertib in combination with a fixed dose of atezolizumab to establish the recommended phase II dose.

Drug: ipatasertib; Drug: Atezolizumab

Phase II

EXPERIMENTAL

The Phase II part of the study will evaluate the recommended phase II dose of ipatasertib identified in Phase I, in combination with atezolizumab, in six patient cohorts: patients with solid tumours who have hyperactivation of the PI3K pathway; patients with castrate-resistant prostate cancer with PTEN loss; patients with glioblastoma; patients with melanoma; patients solid tumour types refractory to immune-checkpoint inhibitors; patients with gynaecological cancers.

Drug: ipatasertib; Drug: Atezolizumab

Interventions

ipatasertib DRUG

Ipatasertib will be supplied as film-coated tablets in two strengths (100 and 200 mg) differentiated by size, shape, and weight of tablets. Ipatasertib tablets are packaged in high-density polyethylene bottles with desiccant.

Phase I; Phase II

Atezolizumab DRUG

Atezolizumab will be supplied as a single-use 20 mL USP/Ph. Eur Type 1 glass vial as a colourless-to-slightly-yellow, sterile, preservative-free clear liquid solution intended for intravenous (IV) administration.

Phase I; Phase II

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 ≥ 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

You may not qualify if:

• 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. 8.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).

Sponsors & Collaborators

• Institute of Cancer Research, United Kingdom: lead
• Hoffmann-La Roche: collaborator

Study Sites (1)

Royal Marsden Hospital NHS Foundation Trust

Sutton, Surrey, SM2 5PT, United Kingdom

Location

MeSH Terms

Conditions

Glioblastoma

Interventions

ipatasertib; atezolizumab

Condition Hierarchy (Ancestors)

Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Study Officials

• Juanita Lopez, MRCP

  National Health Service, United Kingdom

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: HEALTH SERVICES RESEARCH
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 10, 2018
• First Posted: September 17, 2018
• Study Start: August 13, 2018
• Primary Completion: March 1, 2026
• Study Completion: March 1, 2026
• Last Updated: May 14, 2025

Record last verified: 2025-05

Locations

GB (1)