First clinical evaluation of a phosphoinositide 3-kinase (PI3K) inhibitor for the treatment of advanced prostate cancer.

Lead Research Organisation: Institute of Cancer Research
Department Name: Medicine

Abstract

Future advances in the treatment of cancer depend on the translation of our knowledge of cancer biology to novel treatments in order to deliver individualised patient treatment. Laboratory research is rapidly characterising the key genes, or molecular switches, that regulate cellular behaviour, allowing the identification of the defects in these switches that result in the loss of cell control and cancer growth. A common feature of a large number of human cancers including prostate, ovarian, breast, colorectal, brain and childhood cancers is defective molecular switches of a key cellular pathway called the PI3K pathway. Loss of control of this pathway is very common in prostate cancer. Researchers at the Cancer Research UK Centre for Cancer Therapeutics, at the Institute of Cancer Research, have developed rationally designed drugs specifically targeting PI3K, in collaboration with colleagues at PIramed. These drugs stop tumour growth in the laboratory, and due to their high selectivity have an attractive side-effects profile, unlike cancer chemotherapy, sparing the patient unwanted adverse effects. Since there is overwhelming laboratory evidence supporting the development of anticancer drugs against this pathway, particularly in prostate cancer patients, we now propose the first clinical trials of PDP-101620, a drug developed against this key switch, in consenting patients with advanced cancer who have failed all known anticancer treatments. This clinical trial will first evaluate whether PDP101620 can safely prevent the function of PI3K, the critical molecular switch it was specifically designed to block. Once this is successfully completed, the optimal dose and administration frequency resulting in maximal anticancer effect will be determined utilising sophisticated molecular testing and cancer imaging. This will then lead to the evaluation of PI3K blockade by PDP-101620 in patients with advanced prostate cancer, whose cancer has spread outside the prostate and failed standard treatment. The effect that this target modulation has on advanced prostate cancer growth will be determined. It is envisioned that treatment with PDP-101620 will inhibit prostate cancer growth in many but not all patients with this disease, resulting in patient benefit by prolonging survival and improving quality of life with a favourable side-effect profile. These studies will support the prospective identification of patients likely to benefit from PDP101620.

Technical Summary

Background:
There is overwhelming evidence to support the development of phosphoinositide 3-Kinase (PI3K) inhibitors as anticancer agents. This pathway is commonly deregulated in many cancers including prostate cancers. PI3K is a key molecular target for the treatment of prostate cancer, which is the second commonest cause of cancer related deaths in men in the UK and remains a major unmet clinical need.

Preliminary data:
We have recently identified and fully characterised several PI3K inhibitors, which demonstrate selectivity for PI3K class 1 with low nanomolar potency for p110a, p110b and p110d isoforms. These agents have significant antitumour activity showing greater than 50%-78% growth inhibition in many different xenograft models with abnormal PI3K signaling pathways, reducing the phosphorylation of AKT and p70S6K in vitro and in vivo. This PI3K inhibition leads to decreased intra-tumour 1H phosphocholine levels on magnetic resonance spectroscopy and G1/S cell cycle arrest, decreasing 18F fluorothymidine uptake on positron emission tomography.

Research Plan:
We plan to perform the first clinical trial of a PI3K inhibitor with the clinical development candidate, PDP101620, in patients with advanced cancer.

Trial hypotheses:
1. The PI3K inhibitor PDP101620 can be safely administered to cancer patients at doses that inhibit PI3K signaling and tumour growth.
2. The study of the pharmacokinetic-pharmacodynamic profile of PDP101620 with molecular imaging utilising magnetic resonance spectroscopy (MRS) and 3-deoxy-3[18F]-fluorothymidine positron emission tomography (18F-FLT-PET) can optimise dosing and schedule.
3. PI3K inhibition by PDP101620 has clinically significant antitumour activity in patients with hormone refractory prostate cancer (HRPC) with activated PI3K signaling, resulting in the blockade of downstream signaling and the inhibition of proliferation in HRPC cells.

Aims:
1. To conduct a ?proof of principle? first in man clinical trial with PDP101620 evaluating feasibility, safety and PK-PD profile to demonstrate PI3K inhibition.
2. To establish the optimal dose and schedule of PDP101620 by PK-PD profiling, and molecular imaging evaluating total choline levels by 1H MRS; and decreased tracer uptake on 18F-FLT PET.
3. To perform a Phase II clinical trial in patients with HRPC to evaluate the biological effects and antitumour activity of PI3K inhibition by PDP101620, and to identify molecular predictors of antitumour activity to support patient selection.

Implications:
These studies are vital for the future optimal evaluation of PDP101620 in large randomised trials in advanced HRPC as part of a strategy for the rapid regulatory approval of PDP101620, which involves selecting patients most likely to benefit from PI3K inhibition.

Publications

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Attard G (2011) New strategies in metastatic prostate cancer: targeting the androgen receptor signaling pathway. in Clinical cancer research : an official journal of the American Association for Cancer Research

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Brunetto AT (2013) First-in-human, pharmacokinetic and pharmacodynamic phase I study of Resminostat, an oral histone deacetylase inhibitor, in patients with advanced solid tumors. in Clinical cancer research : an official journal of the American Association for Cancer Research

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Dolly SO (2016) Phase I Study of Apitolisib (GDC-0980), Dual Phosphatidylinositol-3-Kinase and Mammalian Target of Rapamycin Kinase Inhibitor, in Patients with Advanced Solid Tumors. in Clinical cancer research : an official journal of the American Association for Cancer Research

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Frenel JS (2015) Serial Next-Generation Sequencing of Circulating Cell-Free DNA Evaluating Tumor Clone Response To Molecularly Targeted Drug Administration. in Clinical cancer research : an official journal of the American Association for Cancer Research

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Rafii S (2015) Higher Risk of Infections with PI3K-AKT-mTOR Pathway Inhibitors in Patients with Advanced Solid Tumors on Phase I Clinical Trials. in Clinical cancer research : an official journal of the American Association for Cancer Research

 
Description London Movember Prostate Cancer Centre, Ref. CEO13-2-002
Amount £5,204,881 (GBP)
Funding ID CEO13-2-002 
Organisation Prostate Cancer UK 
Sector Charity/Non Profit
Country United Kingdom
Start 07/2014 
End 07/2019
 
Description Re-AKT Study
Amount £3,745,484 (GBP)
Funding ID D3610C00013 
Organisation AstraZeneca 
Sector Private
Country United Kingdom
Start 03/2014 
End 03/2017
 
Title Clinical assays for determining PI3KC pathway signalling 
Description Platelet rich plasma assay for pAKT. Hair follicle assays for p-PRAS. Immunohistochemical and 4-colour FISH assays for PTEN loss. 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact These assays are assisting us in dose selection for these drugs targeting this pathway as well as potential predictive biomarkers 
 
Description Genentech GDC0068 
Organisation Genentech, Inc
Country United States 
Sector Private 
PI Contribution We have worked with Genentech in running trials with GDC0068 in combination with XYZ and also in combination with Abiraterone. Prof de Bono has been involved in developing the study protocol and planning the study design. In addition, our Centre has been the lead recruiter for the study. Our Cancer Biomarker team has provided central lab service towards CTC analysis & PTEN testing via IHC for the entire trial.
Collaborator Contribution Genentech have funded the clinical trial, provided IMP and funded laboratory services.
Impact Established that PI3K/AKT targeted drugs may have immense therapeutic implications in CRPC patients. In addition, our work supports the use of CTCs as a non-invasive, real time biopsy to determine PTEN gene status, further supporting prognostic and predictive value of PTEN status in CTCs in trials of PI3K/AKT targeted therapies.
Start Year 2013
 
Description Phase I trial of GDC0941, a PI3K inhibitor 
Organisation Genentech, Inc
Department Drug Development
Country United States 
Sector Private 
PI Contribution Written the clinical trial protocol and a separate ICR sponsored biomarker protocol specific to this trial to pursue pharmacodynamic, predictive and intermediate endpoint biomarkers.
Collaborator Contribution Our collaborators helped us work to optimize the clinical development of GDC0941, a compound generated by chemists at our institution.
Impact Multiple oral and poster presentations at national and international meetings; these outputs have involved multidisciplinary researchers including basic scientists, molecular pathology staff, translational scientists and clinicians
Start Year 2007
 
Title GDC0941 
Description Small molecule inhibitor of PIK3CA; now entering Phase II trials and Phase I combination trials. Our Phase I trial is ongoing. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2007
Development Status Under active development/distribution
Impact This agent is one of the most promising new PIK3CA inhibitors. 
 
Description ESMO 2016 Congress talk 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Talk on PTEN loss as a predictive biomarker for the Akt inhibitor ipatasertib combined with abiraterone acetate in patients with metastatic castration-resistant prostate cancer.
Year(s) Of Engagement Activity 2016
URL http://oncologypro.esmo.org/Topics/Translational-Research/Biomarkers/PTEN-loss-as-a-predictive-bioma...
 
Description GU ASCO 2017 talk 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Dr Michael Kolinsky's poster presentation at GU ASCO titled: A phase I dose-escalation study of enzalutamide in combination with the AKT inhibitor AZD5363 in patients with metastatic castration resistant prostate cancer.
Year(s) Of Engagement Activity 2017
 
Description Presentation at multiple national and international meetings including ASCO and the NCI-AACR-EORTC meetings 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Health professionals
Results and Impact Several hundred cancer researchers attended these presentations

Due to our leadership in this field we are now running several Phase I trials of drugs targeting this pathway including an AKT inhibitor (MK2206), a PIK3CA and TOR kinase inhibitor GDC0980, as well as of TOR kinase inhibitors with AstraZeneca AZD8055 and AZD2014.
Year(s) Of Engagement Activity 2009,2010