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.
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.
