GDF-15 and Its Relationship With Treatment-related ADverse Events in Breast Cancer (GRADE)

March 9, 2026 updated by: Breast Cancer Trials, Australia and New Zealand

A Multi-centre, Prospective Cohort Study to Explore the Relationship Between Changes in GDF-15 Levels and Treatment-related Adverse Events During T-DXd Treatment in Breast Cancer Patients.

GRADE is trying to find out if there is a link between a hormone called GDF-15 and the side effects that people can experience when taking T-DXd.

GDF-15 can be measured in the blood. GDF-15 levels in the blood will go up when the body is stressed under certain conditions, including breast cancer. There is a link between high GDF-15 levels and the nausea and vomiting experienced with "morning sickness" in pregnancy. It has also been shown that GDF-15 levels will go up with the use of other types of chemotherapy that are known to cause nausea and vomiting.

Side effects such as feeling sick (nausea), vomiting and weight loss are common with T-DXd. Sometimes, these can be so severe that treatment needs to be stopped early. The investigators can't predict who will get bad side effects and who will not.

If the investigators can find out if there is a link between GDF-15 and the side effects of T-DXd, they can use this information in future clinical trials.

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

Detailed Description

Growth differentiation factor 15 (GDF-15), a stress-related hormone also known as macrophage inhibitory cytokine-1 (MIC-1), is a member of the transforming growth factor-beta (TGF-β) superfamily. It is not expressed under basal conditions but can be released in response to pro-inflammatory conditions such as obesity, insulin resistance, renal and heart failure, and malignancy.

Pre-clinical studies have established the role of elevated GDF-15 levels in tumour and platinum-based chemotherapy induced emesis and cachexia. It has also been proposed as a biomarker for all-cause mortality, as well as for poor prognoses in patients with cancer.

The hypothesis is that there is a positive correlation between increased levels of GDF-15 and the severity of treatment-related adverse events (particularly nausea, vomiting and cachexia) experienced by patients with breast cancer receiving T-DXd.

The aim of the study is to explore the relationship between relative change in levels of GDF-15 from baseline (pre-treatment) to after receiving T-DXd (post-C2 and at end of treatment) and the severity of treatment-related adverse events experienced by patients with breast cancer receiving T-DXd.

If a positive relationship is found with any or all of these objectives, then monoclonal antibodies inhibiting GDF-15 (such as ponsegromab or visugromab) may present a promising therapeutic and supportive option for patients receiving T-DXd.

Study Type

Interventional

Enrollment (Estimated)

150

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Australia
    • New South Wales
      • Newcastle, New South Wales, Australia, 2290
        • Lake Macquarie Private Hospital
        • Contact:
        • Principal Investigator:
          • Nick Zdenkowski, Dr
    • Victoria
      • Melbourne, Victoria, Australia, 3000
        • Peter MacCallum Cancer Centre
        • Contact:
        • Principal Investigator:
          • Sherene Loi, Prof
  • Japan
      • Okayama, Japan, 700-8558
        • Okayama University Hospital
        • Contact:
        • Principal Investigator:
          • Tadahiko Shien, Prof
  • United States
    • Massachusetts
      • Boston, Massachusetts, United States, 02215
        • Dana-Farber Cancer Institute
        • Contact:
        • Principal Investigator:
          • Michelle Li, Dr

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  1. Participants aged ≥18 years.
  2. Histologically confirmed diagnosis of metastatic/advanced unresectable HER2-positive or HER2-low breast cancer.
  3. Planned to start treatment with T-DXd.
  4. Life expectancy of at least 4 months.

Exclusion Criteria:

  1. Current active reversible causes of decreased food intake, as determined by the Investigator.
  2. Receiving tube feedings or any kind of parenteral nutrition at the time of enrolment into the study.
  3. Ongoing cachexia attributable to other reasons unrelated to cancer or cancer treatment as determined by the Investigator that may confound interpretation of weight loss due to T-DXd.
  4. Current adherence to a calorie-restricted diet with the intention of weight loss.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Supportive Care
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Other: Blood Collection for GDF-15
Blood collection for GDF-15 during T-DXd treatment.
Other: Blood collection for GDF-15

Blood samples of 20-30mL (approximately 1-2 tablespoons in total) will be taken 4 times:

  • Before first treatment with T-DXd
  • Two times during treatment (after the first and second doses of T-DXd); and
  • At the end of T-DXd treatment.

At each blood collection, participants will be asked about:

  • T-DXd side effects
  • Medications prescribe for T-DXd side effects
  • Weighed to see if their weight changes during treatment.

Personal and health information will also be collected from participants:

  • Date of birth and age, sex, ethnicity, height, weight, and activity levels.
  • Details about their cancer: diagnosis, type of cancer, other treatments, and pathology results.
  • Details about any previous pregnancies: how many, and the severity of any nausea or vomiting experienced during these pregnancies.
  • Details about their best response to treatment with T-DXd.
  • Details about the reason they stop T-DXd treatment.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Nausea prior to Cycle 3 of T-DXd, graded according to Common Terminology Criteria for Adverse Advents (CTCAE) v5.0.
Time Frame: From baseline to after receiving 2 cycles of T-DXd treatment (each cycle is 28 days).
To investigate if the percentage change in levels of GDF-15 from baseline to after receiving 2 cycles of T-DXd is associated with moderate/high grade nausea (CTCAE Grade 2-4) experienced at this timepoint by patients with metastatic/advanced unresectable HER2-positive or HER2-low breast cancer.
From baseline to after receiving 2 cycles of T-DXd treatment (each cycle is 28 days).

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Vomiting prior to Cycle 3 of T-DXd, graded as per CTCAE v5.0.
Time Frame: From baseline to after receiving 2 cycles of T-DXd treatment (each cycle is 28 days).
To investigate if the percentage change in levels of GDF-15 from baseline to after receiving 2 cycles of T-DXd is associated with moderate/high grade vomiting (CTCAE Grade 2-4) experienced by patients at this timepoint.
From baseline to after receiving 2 cycles of T-DXd treatment (each cycle is 28 days).
Weight loss (cachexia) prior to Cycle 3 of T-DXd, graded as per CTCAE v5.0.
Time Frame: From baseline to after receiving 2 cycles of T-DXd treatment (each cycle is 28 days).
To investigate if the percentage change in levels of GDF-15 from baseline to after receiving 2 cycles of T-DXd is associated with moderate/high grade cachexia (CTCAE Grade 2-4) experienced by patients at this timepoint.
From baseline to after receiving 2 cycles of T-DXd treatment (each cycle is 28 days).
Percentage change in GDF-15 and its correlation with treatment-related adverse events (TRAEs)
Time Frame: From baseline to after receiving 2 cycles of T-DXd treatment (each cycle is 28 days).
To explore the correlation of the percentage change in levels of GDF-15 with the treatment-related adverse events (CTCAE Grade 2-4). Treatment-related adverse events (TRAEs) are adverse events classified as possibly, probably or definitely related to T-DXd treatment. TRAEs will be graded as per CTCAE v5.0.
From baseline to after receiving 2 cycles of T-DXd treatment (each cycle is 28 days).
Progression-free survival (PFS)
Time Frame: Time from treatment start with T-DXd to the first occurrence of disease progression or death due to any cause, whichever came first, assessed up to 6 months.
To explore the relationship between baseline levels of GDF-15 and progression-free survival (PFS) on T-DXd
Time from treatment start with T-DXd to the first occurrence of disease progression or death due to any cause, whichever came first, assessed up to 6 months.
Time to treatment failure (TTF)
Time Frame: Time from treatment start with T-DXd to discontinuation of treatment for any reason, including disease progression, treatment toxicity, and death, whichever came first, assessed up to 6 months.
To explore the relationship between baseline levels of GDF-15 and time to treatment failure (TTF) on T-DXd.
Time from treatment start with T-DXd to discontinuation of treatment for any reason, including disease progression, treatment toxicity, and death, whichever came first, assessed up to 6 months.
HER2 copy number
Time Frame: Prior to treatment commencement.
To explore the relationship between HER2 copy number and change in levels of GDF-15. HER2 copy number determined by in-situ hybridization (ISH) on most recent available histopathology specimen or tumour/plasma genomic data (DNA/RNA), preferably in the metastatic setting
Prior to treatment commencement.

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Exploratory: Association of baseline levels of GDF-15 with Treatment Related Adverse Events (TRAEs).
Time Frame: TRAEs occurring after Cycle 2, after Cycle 3 and within 30 days of end of treatment with T-DXd (each cycle is 28 days).
To explore if baseline levels of GDF-15 are associated with the incidence and severity of TRAEs experienced by patients on T-DXd, graded as per CTCAE v5.0.
TRAEs occurring after Cycle 2, after Cycle 3 and within 30 days of end of treatment with T-DXd (each cycle is 28 days).
Exploratory: Longitudinal change in weight after 2 cycles of T-DXd
Time Frame: After receiving 2 cycles of T-DXd (each cycle is 28 days).
To explore if the longitudinal change in levels of GDF-15 from baseline to after receiving 2 cycles of T-DXd is associated with trends in weight change. Weight change is measured as a percentage of baseline weight. End-of-treatment is defined as cessation of treatment due to disease progression or treatment toxicity.
After receiving 2 cycles of T-DXd (each cycle is 28 days).
Exploratory: Longitudinal change in weight at end-of-treatment
Time Frame: At end-of-treatment with T-DXd; end-of-treatment is defined as cessation of treatment due to disease progression or treatment toxicity, whichever came first, assessed up to 6 months.
To explore if the longitudinal change in levels of GDF-15 from baseline at end-of-treatment with T-DXd is associated with trends in weight change. Weight change is measured as a percentage of baseline weight.
At end-of-treatment with T-DXd; end-of-treatment is defined as cessation of treatment due to disease progression or treatment toxicity, whichever came first, assessed up to 6 months.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Breast Cancer Trials, Australia and New Zealand

Investigators

  • Study Director: Heath Badger, Breast Cancer Trials, Australia and New Zealand
  • Study Chair: Sherene Loi, Prof, Peter MacCallum Cancer Centre, Australia
  • Study Chair: Michelle Li, Dr, Peter MacCallum Cancer Centre, Australia

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

March 1, 2026

Primary Completion (Estimated)

March 1, 2028

Study Completion (Estimated)

September 1, 2028

Study Registration Dates

First Submitted

February 26, 2026

First Submitted That Met QC Criteria

March 9, 2026

First Posted (Actual)

March 11, 2026

Study Record Updates

Last Update Posted (Actual)

March 11, 2026

Last Update Submitted That Met QC Criteria

March 9, 2026

Last Verified

March 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • BCT 2502

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

Anonymised Individual Patient Data (IPD) collected during the trial.

IPD Sharing Time Frame

Data will be made available for request after publication of the main/final study results; no end date.

IPD Sharing Access Criteria

Researchers who submit a research proposal and BCT Data Request Application, which is assessed by BCT to have appropriate scientific value. Applications will be subject to approval by Breast Cancer Trials concept@bctrials.org.au (refer to BCT Data Sharing Guidelines).

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • ANALYTIC_CODE

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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