DYNAMIC – Pancreas

Pancreatic cancer is an aggressive disease with few long term survivors.  The poor outlook for patients diagnosed with pancreatic cancer is associated with the difficulty to detect pancreatic cancer at an early stage and poor response to chemotherapy and radiotherapy.  A biomarker that can inform clinicians of a patient’s risk of disease recurrence and guide treatment decisions would have a major impact on the management of pancreatic cancer – ctDNA may act as one such biomarker.

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Trial Status

In activation

Cancer Type

Pancreatic

 

If you think this trial is relevant to your situation, please contact your Cancer Specialist to discuss further.

Aim

Pancreatic cancer is an aggressive disease with few long term survivors.  The poor outlook for patients diagnosed with pancreatic cancer is associated with the difficulty to detect pancreatic cancer at an early stage and poor response to chemotherapy and radiotherapy.  A biomarker that can inform clinicians of a patient’s risk of disease recurrence and guide treatment decisions would have a major impact on the management of pancreatic cancer – ctDNA may act as one such biomarker.

Summary

A biomarker that can inform clinicians of a patient’s risk of disease recurrence and guide treatment decisions would have a major impact on the management of pancreatic cancer – ctDNA may act as one such biomarker.  Studies have examined the implications of DNA alterations and ctDNA in pancreatic cancer patients.  It was found that patients who were ctDNA positive after surgery were at greater risk of the disease returning than those with undetectable alterations.  The presence of ctDNA at the time of diagnosis also provided a predictor of disease relapse.  By understanding and grouping pancreatic cancer patients based on risk of recurrence and utilising a biomarker such as ctDNA, it may be possible to determine which patients are at greater risk of disease recurrence and escalate their chemotherapy to more intensive therapy accordingly. Conversely, patients with negative ctDNA post-operatively at low risk of relapse may possibly be spared the toxicity associated with more aggressive combination regimens.

 

Trial Status

In Activation

Cancer Type

Pancreatic

If you think this clinical trial may be relevant to your patient or to discuss further, please contact the Clinical Trial team.

Protocol Title

Circulating Tumour DNA Analysis Informing Adjuvant Chemotherapy in Early Stage Pancreatic Cancer: A Multicentre Randomised Study (DYNAMIC-Pancreas)

AIM

Primary Objective:

  • To demonstrate that a ctDNA-informed adjuvant therapy approach following curative intent surgery for localised pancreatic cancer could reduce the proportion of patients, compared to standard of care treatment, that have detectable ctDNA after completing adjuvant therapy

Secondary Objectives:

  • To explore if a ctDNA-informed adjuvant therapy approach could improve recurrence free survival compared to standard of care
  • To explore if a ctDNA-informed adjuvant therapy approach could improve overall survival compared to standard of care
  • To correlate post-operative ctDNA results with recurrence-free and overall survival
  • To correlate end of treatment ctDNA results with recurrence-free and overall survival

Exploratory Objectives

  • To demonstrate the feasibility of an adjuvant chemotherapy strategy (treatment de-escalation or escalation) based on post-operative ctDNA results.
  • To explore if a ctDNA-informed adjuvant therapy approach could reduce the duration and/or intensity of chemotherapy use compared to standard of care for selected patients, without compromising survival outcomes
  • To explore the health economic impact of a ctDNA-informed adjuvant therapy approach compared to standard of care

Background

Pancreatic cancer is an aggressive disease. It carries a poor prognosis which is in part related to the inability to detect pancreatic cancer at an early stage, the potential for early spread and its poor sensitivity to chemotherapy or radiotherapy. Pancreatic cancer is predicted to be the second leading cause of cancer-related deaths by 2020. Currently, long-term survival can only be achieved with surgical resection of localised disease but relapse rates are as high as 80-85% despite “curative” resection. Adjuvant therapy can reduce the rate of relapse and is recommended for patients undergoing surgical resection for curative intent.   The high rate of relapse following potentially curative surgery highlights the need for better strategies to inform treatment. The use of a biomarker, circulating tumour DNA (ctDNA), could be one such strategy.

Patients with positive ctDNA results following surgery would be defined as having a high risk of relapse. For these patients, adjuvant chemotherapy would be escalated to a more intensive therapy. Conversely, patients with negative post-op ctDNA would be spared the toxicity associated with more aggressive combination regimens, with minimal to no risk of compromising survival outcome.

The major driver of this study is to demonstrate that a ctDNA-directed approach to adjuvant chemotherapy for patients with early stage pancreatic cancer could lead to significant gains in preventing recurrence through treatment escalation, ultimately improving survival. However, also of great importance is the potential of a ctDNA-directed approach to reduce unnecessary treatment (treatment de-escalation) in low risk patients, reducing treatment related toxicity, and direct and indirect treatment related costs.

CLINICAL TRIAL DESIGN

Patients will be randomised 1:1 into either a non-biomarker driven, standard of care (SOC) adjuvant treatment arm (Cohort A) or a ctDNA informed biomarker driven arm (cohort B), where treatment will be determined by the ctDNA results after surgery (i.e Cohort B1– ctDNA informed, biomarker negative; Cohort B2 – ctDNA informed, biomarker positive).

In Cohort A, patients will receive standard of care chemotherapy.  In the biomarker driven arms Cohort B1 & B2, treatment will be offered according to the ctDNA result. Patients who are “ctDNA-negative” will be treated with a de-escalated treatment strategy.  Patients in the biomarker driven arm who are “ctDNA-positive” will be treated with an escalation chemotherapy strategy involving either triplet therapy (fluoropyrimidine, irinotecan and oxaliplatin) FOLFIRINOX OR gemcitabine plus nab-paclitaxel (Abraxane).

Key Eligibility Criteria

INCLUSION CRITERIA

  1. Subjects who have undergone complete macroscopic resection for adenocarcinoma of the pancreas (R0 or R1 resection) with “curative” intent.
  2. A representative tumour sample is available for molecular testing within 28 days after surgery
  3. Fit for adjuvant chemotherapy
  4. ECOG performance status 0-2
  5. Subjects able to attend for administration of adjuvant therapy.
  6. Subjects are accessible for follow up
  7. No evidence of malignant ascites, liver metastasis, spread to other distant abdominal organs, peritoneal metastasis, spread to extra-abdominal organs – CT chest/ abdomen/ pelvis scan within 12 weeks prior to randomisation.
  8. Fully informed written consent given

EXCLUSION CRITERIA:

  1. History of another primary cancer within the last 3 years, with the exception of non-melanomatous skin cancer and carcinoma in situ of the cervix
  2. Inadequate organ function:
    1. Moderate/severe renal impairment (GFR<30 ml/min), as calculated by the Cockcroft and Gault equation
    2. Absolute neutrophil count <1.0×109/L
    3. Platelet count <75×109/L
    4. Haemoglobin <80 g/L
    5. Aspartate aminotransferase/Alanine aminotransferase >2.5 x upper limit of normal
  3. Medical or psychiatric condition or occupational responsibilities that may preclude compliance with the protocol.
  4. Patients with TNM stage IV disease
  5. Patients with R2 resection status
  6. Patients younger than 18 years
  7. Clinically significant cardiovascular disease – i.e. active or <12 months since e.g. cerebrovascular accident, myocardial infarction, unstable angina, New York Heart Association grade II or greater congestive heart failure, serious cardiac arrhythmia requiring medication, uncontrolled hypertension

Contact Email

DYNAMIC-P@mh.org.au

Principal Investigators

Professor Peter Gibbs

Associate Professor Jeanne Tie
Dr Belinda Lee

Funding

The Marcus Foundation