APROC : A phase1b/2 Study Evaluating the Efficacy of APR-246, a First-in-class Agent Targeting Mutant p53 in the Treatment of Platinum Resistant Advanced and Metastatic Oesophageal or Gastro-oesophageal Junction Cancers

Male or<br/>FemaleGender Male or
Female

RecruitingStatus Recruiting

Systemic<br/>Therapy TrialTypeSystemic
Therapy Trial

One/TwoPhase One/Two

18+Age Over 18

Oesophagus<br/>CancersCancer LocationOesophagus
Cancers

Systemic therapy | Stomach and upper gastrointestinal tractGastro-oesophageal junction ,Oesophagus

Trial Overview Read MoreRead more

This phase Ib/II trial is trying to determine whether the drug APR-246 and two chemotherapy drugs (5-FU and cisplatin) are safe and effective in the treatment of platinum resistant oesophageal cancer.
 

This trial is treating patients with Oesophageal and Gastro-Oesophageal Junction.

This is a systemic therapy trial.

You may be able to join this trial if:

  • You have had treatment but your cancer has gotten worse or has not responded to the treatment you have been given.
  • Your cancer has spread to other parts of the body.

You may be excluded from this trial if:

  • You have a certain disease or psychological condition.
  • You have been diagnosed with a prior or secondary type of cancer.
  • You have had certain treatments, surgical procedures or drugs.
  • You have previously been treated (or are currently being treated) on a clinical trial.

Clinical trials have complex eligibility criteria - talk to your doctor about your interest in this trial.

Clinical Summary Read MoreRead more

Trial Identifiers

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Scientific Title

A phase1b/2 Study Evaluating the Efficacy of APR-246, a First-in-class Agent Targeting Mutant p53 in the Treatment of Platinum Resistant Advanced and Metastatic Oesophageal or Gastro-oesophageal Junction Cancers

Other Non-Commercial Sponsor

Peter MacCallum Cancer Centre

Summary

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. Despite a high prevalence in developing countries, and an increasing incidence in Western populations, there are very few good quality or randomised trials available to guide practice for metastatic OC. 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.

Recruiting Hospitals Read MoreRead more

Monash Health, Medical Oncology
Clayton
Early Phase Research Study Coordinator
earlyphase.oncresearch@monashhealth.org
0474 769 510

PCCTU (Parkville Cancer Clinical Trials Unit) *
Parkville
Ms Marian Lieschke
marian.lieschke@petermac.org
03 8559 7140

Western Health - Sunshine Hospital
St Albans
Ms Heike Raunow
Heike.Raunow@wh.org.au
03 8395 9167

Trial Overview: General information about a clinical trial. This section provides an overview of who might be able to join this trial and what type of treatment is involved.

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