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

Official title

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.

Overview

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.

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.

Interventions

• 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:

Primary outcome measures

• 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).]

Secondary outcome measures (6)

• 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).]
• 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).]
• 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).]
• 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.]
• 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.]
• HER2 copy number [Time frame: Prior to treatment commencement.]

Eligibility criteria

Inclusion criteria

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

Exclusion criteria

• Current active reversible causes of decreased food intake, as determined by the Investigator.
• Receiving tube feedings or any kind of parenteral nutrition at the time of enrolment into the study.
• 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.
• Current adherence to a calorie-restricted diet with the intention of weight loss.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Supportive care

Study locations

Australia · 2 centers

• Lake Macquarie Private Hospital — Newcastle
• Peter MacCallum Cancer Centre — Melbourne

United States · 1 center

• Dana-Farber Cancer Institute — Boston

Japan · 1 center

• Okayama University Hospital — Okayama

Identifiers

NCT: NCT07465172 · BCT 2502

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗