Oesophageal CarcinomaPhase 1/2APROCNCT02999893
A Study of APR-246 in Oesophageal Cancer
A Phase 1/2 study testing APR-246 in people with Oesophageal Carcinoma, run by Peter MacCallum Cancer Centre, Australia at 5 sites in Australia.
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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Oesophageal Carcinoma
- What is being tested?
- APR-246
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 5 participants
- Where
- 5 sitesAustralia
- Study dates
- 11 Apr 2017to 7 Feb 2021
- Phase
- Phase 1/2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Male or female aged 18 years or older at screening
- Histologically-confirmed metastatic or advanced oesophageal or oesophago-gastric junction adenocarcinoma or squamous cell carcinoma
- Radiologic disease progression at or within 6 months of platinum containing chemotherapy in the advanced/metastatic or adjuvant setting
- Measurable disease as per RECIST1.1 criteria
- Measurable lesions must not have previously had radiotherapy or must have progressed following radiotherapy
- Patients may have had up to 2 lines of previous chemotherapy in the metastatic/advanced setting or 3 lines including adjuvant therapy. If patients have a maintenance strategy following platinum containing chemotherapy (e.g. fluoropyrimidine alone) this will not be considered a separate line of treatment.
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- Patient has provided written informed consent for the trial
- Tumour tissue available from the initial surgical resection or any previous biopsies taken at any time before screening. Either a FFPE block or 15 unstained sections from the tumour tissue block must be available for the purpose of translation research studies. Obtaining archived tumour material or unstained sections from an archived tumour block will suffice to meet this requirement. The availability of the tumour material must be confirmed at Screening for a patient to be eligible. If no archival tissue block is available and/or fewer than 15 unstained sections are available, eligibility must be confirmed with the Coordinating Principal Investigator or delegate.
- Patients must have adequate haematological, renal, hepatic and pulmonary functions as defined by:
- Absolute neutrophil count ≥1.5 x 109/L
- Haemoglobin ≥ 10 g/L
- Platelet count ≥100 x 109/L
- Total serum bilirubin ≤ 1.5 x upper normal limit
- Alanine aminotransferase (ALT) ≤ 2.5 x upper normal limit or ≤ 5 x upper limit of normal if liver metastases are present
- Renal: A creatinine clearance rate of greater than 60 mL/minute
- Have a performance status of 0 or 1 on the ECOG Performance Scale
- Life expectancy greater than 3 months
- Female patients of childbearing potential must be willing to use two methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 60 days after the last dose of study medication. Patients of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year.
- Male patients should agree to use an adequate method of contraception starting with the first dose of study therapy through 60 days after the last dose of study therapy.
- Willing to comply with trial therapy and trial-related investigations and evaluations
- Willing to consent to the use of their collected tumour specimen and blood samples as detailed in the protocol for future scientific research including but not limited to DNA, RNA and protein based biomarker detection
- Patient is available for follow up throughout time on trial
- Recovered from previous toxicities (except alopecia)
Who cannot join
- Women who are pregnant or lactating
- More than 2 lines of previous chemotherapy in the advanced or metastatic setting
- Previous radiotherapy to all sites of measurable disease without post-radiotherapy progression
- Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the date of registration
- Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the patient's participation for the full duration of the trial, or is not in the best interest of the patient to participate, in the opinion of the treating investigator
- Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
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- Patients with a history of non-compliance to medical regimens or who are considered potentially unreliable or will be unable to complete the entire study
- Surgery or over 40Gy radiation to the primary tumour within 6 weeks of date of registration
- Presence of symptomatic or uncontrolled brain or central nervous system metastases which require radiotherapy, surgery or ongoing use of corticosteroids
- Known HIV positive status, active hepatitis B or C
- Patients requiring or undergoing concurrent treatment with live vaccines
- Patients requiring or undergoing concurrent treatment with phenytoin
- Concurrent malignancy requiring therapy (excluding non-invasive carcinoma or carcinoma in-situ)
- Common Terminology Criteria for Adverse Events of at least grade 2 neuropathy
- Patient has hearing loss requiring a hearing aid or intervention indicated.
Trial locations and contacts
5 sites in 1 country.
5 sites in 1 country
Australia5 sites
Monash Medical Centre
Clayton, Victoria, 3000
Austin Health
Heidelberg, Victoria, 3000
Peter MacCallum Cancer Centre
Melbourne, Victoria, 3002
Alfred Hospital
Prahran, Victoria, 3000
Sunshine Hospital Western Health
Sunshine, Victoria, 3000
About this study
Official 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
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.
Read the detailed 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.
- Conditions
- Oesophageal Carcinoma
- Being tested
- APR-246
- Medical subject headings
- Esophageal Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
APR-246Drug
APR-246 (also known as PRIMA-1MET), a first-in-class agent targeting mutant p53 resulting in re-expression of wild-type p53 activity.
| Study group | Role | What they receive |
|---|---|---|
| APR-246 | Experimental | The trial regimen consists of the investigational agent APR-246, along with standard chemotherapy, Cisplatin and 5-FU. A maximum of 8 cycles of treatment will be given.
APR-246 and 5-FU must both commence on Day 1 and given on days 1 to 4 via intravenous infusion over 6 hours, whilst 5-FU must be given as a continuous infusion over 96 hours.
On Days 2-4, APR-246 must be given first via intravenous infusion over 6 hours, then commence cisplatin via intravenous infusion over one hour.
This is a dose-escalation study to determine the maximum tolerated dose (MTD) of the combination therapy. The 3 dose levels are described as follows:
Dose Level 1:
APR-246 Dose: 75mg/kg LBM Cisplatin Dose: 25mg/m2 5-FU Dose: 750mg/m2/ day CI
Dose Level 2:
APR-246 Dose: 100mg/kg LBM Cisplatin Dose: 25mg/m2 5-FU Dose: 750mg/m2/ day CI
Dose Level -1:
APR-246 Dose: 50mg/kg LBM Cisplatin Dose: 25mg/m2 5-FU Dose: 750mg/m2/ day CI Receives: Drug: APR-246 |
What is being measured
The primary outcome is the main question the study is designed to answer.
Establish the safety profile of combined APR-246 plus cisplatin and 5FU as measured by the satisfactorily low rate of adverse events described according to NCI CTCAE v 4.03.
Measured: 3 weeks post commencement of treatment.
Secondary outcomes (1)
Evidence of clinical efficacy of a combined APR-246 and cisplatin/5FU chemotherapy regimen as confirmed by CT/PET/MRI scan.
Measured: 6 and 12 weeks post commencement of treatment.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted21 Dec 2016 (estimated)
- Study start11 Apr 2017
- Primary completion16 Oct 2020
- Study completion7 Feb 2021
Why it stopped: Funding ceased
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Oesophageal CarcinomaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 5 participants (actual)
Sponsor and investigators
- Lead sponsor
- Peter MacCallum Cancer Centre, Australia
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Lara Lipton, MB.BS FRACP, Study chair, Peter MacCallum Cancer Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02999893
- Sponsor's protocol ID
- 16/012
- Acronym
- APROC
- Status last verified
- Dec 2021
- First submitted
- 5 Dec 2016
- Last updated
- 13 Dec 2021
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 13 Dec 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official 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
- ClinicalTrials.gov ID
- NCT02999893
- Acronym / sponsor ID
- APROC / 16/012
- Conditions
- Oesophageal Carcinoma
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Funding ceased
- Enrolment
- 5 participants (actual)
- Lead sponsor
- Peter MacCallum Cancer Centre, AustraliaUniversity, hospital or other
- Study start
- 11 Apr 2017 (actual)
- Primary completion
- 16 Oct 2020 (actual)
- Study completion
- 7 Feb 2021 (actual)
- First posted
- 21 Dec 2016 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed 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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| APR-246 | Experimental | Drug: APR-246The trial regimen consists of the investigational agent APR-246, along with standard chemotherapy, Cisplatin and 5-FU. A maximum of 8 cycles of treatment will be given. APR-246 and 5-FU must both commence on Day 1 and given on days 1 to 4 via intravenous infusion over 6 hours, whilst 5-FU must be given as a continuous infusion over 96 hours. On Days 2-4, APR-246 must be given first via intravenous infusion over 6 hours, then commence cisplatin via intravenous infusion over one hour. This is a dose-escalation study to determine the maximum tolerated dose (MTD) of the combination therapy. The 3 dose levels are described as follows: Dose Level 1: APR-246 Dose: 75mg/kg LBM Cisplatin Dose: 25mg/m2 5-FU Dose: 750mg/m2/ day CI Dose Level 2: APR-246 Dose: 100mg/kg LBM Cisplatin Dose: 25mg/m2 5-FU Dose: 750mg/m2/ day CI Dose Level -1: APR-246 Dose: 50mg/kg LBM Cisplatin Dose: 25mg/m2 5-FU Dose: 750mg/m2/ day CI |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (23 listed)
- Male or female aged 18 years or older at screening
- Histologically-confirmed metastatic or advanced oesophageal or oesophago-gastric junction adenocarcinoma or squamous cell carcinoma
- Radiologic disease progression at or within 6 months of platinum containing chemotherapy in the advanced/metastatic or adjuvant setting
- Measurable disease as per RECIST1.1 criteria
- Measurable lesions must not have previously had radiotherapy or must have progressed following radiotherapy
Key exclusion criteria (15 listed)
- Women who are pregnant or lactating
- More than 2 lines of previous chemotherapy in the advanced or metastatic setting
- Previous radiotherapy to all sites of measurable disease without post-radiotherapy progression
- Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the date of registration
- Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the patient's participation for the full duration of the trial, or is not in the best interest of the patient to participate, in the opinion of the treating investigator
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| APR-246APR-246 (also known as PRIMA-1MET), a first-in-class agent targeting mutant p53 resulting in re-expression of wild-type p53 activity. | Drug | APR-246 |
Primary outcome
Establish the safety profile of combined APR-246 plus cisplatin and 5FU as measured by the satisfactorily low rate of adverse events described according to NCI CTCAE v 4.03.
Time frame: 3 weeks post commencement of treatment.
1 secondary outcome
Evidence of clinical efficacy of a combined APR-246 and cisplatin/5FU chemotherapy regimen as confirmed by CT/PET/MRI scan.
Time frame: 6 and 12 weeks post commencement of treatment.
Results and safety
The study was stopped early (reason given: Funding ceased). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 13 Dec 2021.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Lara Lipton, MB.BS FRACP study chair
Peter MacCallum Cancer Center
5 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing APR-246 in people with Oesophageal Carcinoma, run by Peter MacCallum Cancer Centre, Australia at 5 sites in Australia.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 23 inclusion and 15 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 13 Dec 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 5 sites in Australia. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was stopped early (reason given: Funding ceased). Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Establish the safety profile of combined APR-246 plus cisplatin and 5FU as measured by the satisfactorily low rate of adverse events described according to NCI CTCAE v 4.03. (time frame: 3 weeks post commencement of treatment.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 Dec 2021.