Clinical Trial Details
— Status: Terminated
Administrative data
NCT number |
NCT02999893 |
Other study ID # |
16/012 |
Secondary ID |
|
Status |
Terminated |
Phase |
Phase 1/Phase 2
|
First received |
|
Last updated |
|
Start date |
April 11, 2017 |
Est. completion date |
February 7, 2021 |
Study information
Verified date |
December 2021 |
Source |
Peter MacCallum Cancer Centre, Australia |
Contact |
n/a |
Is FDA regulated |
No |
Health authority |
|
Study type |
Interventional
|
Clinical Trial Summary
The purpose of this study is to determine whether APR-246, 5-FU and cisplatin are safe and
effective in the treatment of platinum resistant oesophageal cancer.
Description:
Cancer of the oesophagus (OC) is distinguished by having a poor outcome for most patients and
an incidence that is rising faster than any other solid cancer. It is already the eighth most
common cancer, and the sixth most common cause of death from cancer, worldwide. The majority
of patients are diagnosed with late stage disease, which is incurable with the current
standard multimodality therapy. Thus, there is a critical need to develop new treatments for
this disease.
Surprisingly, despite its high prevalence in developing countries, and its increasing
incidence in Western populations, metastatic OC remains an 'orphan disease' with very few
good quality or randomised trials available to guide practice. As a result, treatment for OC
has changed little over the past few decades, and as a consequence there has been only modest
improvement in overall survival for patients with this disease.
TP53, a key tumour suppressor gene, is mutated in 70-80% of OC (both adenocarcinoma and
squamous cell carcinoma) providing an attractive potential target for an OC therapy.
Although paired tissue studies in primary and metastatic OC are lacking, p53 mutations occur
very early in oesophageal carcinogenesis and are unlikely to be lost in advanced disease. OC
with mutant (mut)-p53 are more resistant to conventional chemotherapy and mut-p53 is
associated with poor patient prognosis. Over the last decade, several novel drugs have been
developed that target mut-p53 and restore wild-type (wt)-p53 function in cancer cells. Of
these, APR-246 (also known as PRIMA-1MET), a first-in-class agent targeting mutant p53
resulting in re-expression of wild-type p53 activity, has proven to be the most effective
against a wide range of mutants. APR-246 is a pro-drug that gives rise to the active compound
methylene quinuclidinone (MQ), which covalently binds to thiol groups on cysteine residues in
the p53 core domain resulting in refolding of mut-p53 protein and restoration of its tumour
suppressor activity.
While the reactivation of mut-p53 is thought to be the primary mode of action of APR-246,
preclinical studies have suggested potential alternative mechanisms (e.g. through the
depletion of cellular glutathione levels) may also be contributing to the efficacy of
APR-246, especially when used in combination with cisplatin/5-FU chemotherapy. Thus, the
anti-tumour activity of APR-246 may not be limited to mut-p53 bearing tumours.
Mutation of p53 is the most common genetic aberration in oesophageal cancer being detected in
up to 80% of both oesophageal squamous cell cancers and adenocarcinomas.
APR-246 is a first-in-class agent targeting mutant p53. In vitro and in vivo preclinical
models have demonstrated that APR-246 has excellent efficacy in OC (both adenocarcinoma and
squamous cell carcinoma) and potently synergises with chemotherapies used in the treatment of
OC, restoring sensitivity to chemotherapy-resistant tumours. An initial phase I clinical
trial has shown APR-246 to be safe in humans and early results from a currently running phase
Ib/II trial of APR-246 with carboplatin and liposomal doxorubicin in ovarian cancer have been
promising. Together, these data provide a strong rationale for investigating the efficacy of
APR-246 in OC.