Clinical trial NCT03829306: Unraveling KAdcyla Resistance In Human Epidermal Growth Factor Receptor 2(HER2) Positive Advanced Breast Cancer (KATIA)
Official title: "Unraveling KAdcyla (Trastuzumab Emtansine; T-DM1) Resistance In HER2-positive Advanced Breast Cancer (ABC): a Prospective GEICAM Study"
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Advanced Breast Cancer
Keywords: HER2-positive
Lead sponsor: Spanish Breast Cancer Research Group
Sponsor class: OTHER
Collaborators: name: Roche Farma, S.A
First posted: 2019-02-04
Enrollment: 32
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Observational model: CASE_ONLY
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: The target population for inclusion in this study is HER2-positive Advanced Breast Cancer patients who are planned to be treated with Kadcyla whithin the approved indication in Spain.

Brief summary: The study aim is to perform a comprehensive and integrated characterization of mechanisms of primary and acquired resistance to Kadcyla in a prospective cohort of progressive/recurrent HER2-positive breast cancer patients.

Detailed description: This exploratory project is a prospective and multicenter study designed to evaluate the mechanisms of primary and acquired resistance to Kadcyla in a cohort of 50 progressive/recurrent HER2+ BC patients planned to be treated with Kadcyla within the approved indication in Spain.

This study will collect high quality molecular data derived from the analysis of serial biological samples (primary tumor and/or metastatic tissue, plasma, serum and whole blood samples), together with annotated clinical follow up, to reach a better understanding of the biological events that drive breast cancer progression and response/resistance to Kadcyla in ABC patients.

Eligibility criteria: Inclusion Criteria:

- Patients are eligible to be included in the study only if they meet all of the following criteria and according to the corresponding Summary of Product Characteristics (SmPC):

1. The patient has signed and dated the informed consent form (ICF) and it has been obtained before conducting any study specific procedure.
2. Female or male patients ≥ 18 years of age on day of signing informed consent.
3. Documented HER2-positive breast cancer based on local laboratory determination (preferably assessed on the most recent tumor biopsy available).
4. Patients with evidence of advanced disease not amenable to resection or radiation therapy with curative intent who are planned to receive Kadcyla within the approved indication in Spain: as a single agent for the treatment of adult patients with HER2-positive, unresectable locally advanced or metastatic breast cancer who previously received trastuzumab and a taxane, separately or in combination. Patients should have either:

   * Received prior therapy for locally advanced or metastatic disease, or
   * Developed disease recurrence during or within six months of completing adjuvant therapy
5. Presence of measurable disease according to RECIST 1.1 for assessment of tumor response.
6. Availability of tumor tissue sample from the primary tumor and/or the recurrence/metastatic site. Effort will be made to obtain a biopsy from a metastatic site in easily accessible tissues.
7. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1.
8. Patient must have a life expectancy ≥16 weeks.
9. Resolution of all acute toxic effects of prior anti-cancer therapy or surgical procedures to NCI-CTCAE v5.0 Grade ≤ 1 (except alopecia or other toxicities not considered a safety risk for the patient at investigator´s discretion).
10. Negative serum pregnancy test result for women of childbearing potential and for women who have experienced menopause onset \< 12 months prior to study entry.
11. Willingness and ability to comply with the protocol for the duration of the study including tumor and blood sample collection and undergoing the standard medical practice visits.

Exclusion Criteria:

* Patients will be excluded from the study if they meet any of the following criteria and according to the corresponding Summary of Product Characteristics (SmPC):

  1. Patients receiving any systemic chemotherapy or radiotherapy (except for palliative reasons), within 3 weeks prior to study entry (or a longer period depending on the defined characteristics of the agents used).
  2. Patients with symptomatic uncontrolled brain metastases. A scan to confirm the absence of brain metastases is not required. Patients with brain metastases may be eligible for the study only if more than 4 weeks elapsed from treatment completion for these metastases (including radiation and/or surgery) and are clinically stable at the time of study entry.
  3. Major surgical procedure unrelated to breast cancer or significant traumatic injury within 28 days prior to study entry or anticipation of the need for major surgery during the period of Kadcyla administration.
  4. To present contraindications for the treatment with Kadcyla according to the corresponding Summary of Product Characteristics (SmPC).
  5. Known hypersensitivity to Kadcyla, excipients and/or murine proteins.
  6. Pregnancy or breast feeding women.
  7. Persistent toxicities ( NCI-CTCAE v 5.0 grade 2) caused by previous cancer therapy (except alopecia or other toxicities not considered a safety risk for the patient at investigator´s discretion).
  8. Immunocompromised patients, e.g., patients who are known to be serologically positive for human immunodeficiency virus (HIV).
  9. Known active liver disease, for example, due to hepatitis viruses B (HBV), hepatitis viruses C (HCV), autoimmune hepatic disorders, or sclerosing cholangitis.
  10. History of concurrent or previously treated non-breast malignancies except for appropriately treated 1) non-melanoma skin cancer and/or 2) in situ carcinomas, including cervix and colon. A patient with previous invasive non-breast cancer is eligible provided he/she has been disease free for more than 5 years.
  11. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or Kadcyla administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.

Primary outcomes:
measure: Genomic alterations on tumor samples with Objective Response (OR) to Kadcyla
timeFrame: Estimated median of 12 months (until disease progression is confirmed)
measure: Tumor-specific mutation in plasma samples with OR to Kadcyla
timeFrame: Estimated median of 12 months (until disease progression is confirmed)
Secondary outcomes:
measure: Genomic alterations on tumor samples with progression-free survival (PFS)
timeFrame: Estimated median of 12 months (until disease progression is confirmed)
measure: Tumor-specific mutation in plasma samples with progression-free survival (PFS)
timeFrame: Estimated median of 12 months (until disease progression is confirmed)
measure: Genomic alterations on tumor samples with Progression-free survival
timeFrame: Estimated median of 12 months (until disease progression is confirmed)
measure: Genomic alterations on tumor samples with Time to Progression (TTP)
timeFrame: Estimated median of 12 months (until disease progression is confirmed)
measure: Tumor-specific mutation in plasma samples with Progression-free survival
timeFrame: Estimated median of 12 months (until disease progression is confirmed)
measure: Tumor-specific mutation in plasma samples Time to Progression (TTP)
timeFrame: Estimated median of 12 months (until disease progression is confirmed)
measure: Number of participants with treatment-related adverse events as assessed by CTCAE v5.0
timeFrame: Through study treatment, estimated median of 12 months
Other outcomes:
measure: Genomic alterations on tumor samples correlation with overall survival (OS)
timeFrame: Estimated median of 12 months (until disease progression is confirmed)
measure: Tumor-specific mutation in plasma samples with overall survival (OS)
timeFrame: Estimated median of 12 months (until disease progression is confirmed)
measure: Tumor-specific mutation in plasma samples during Kadcyla treatment with clinical benefit to the subsequent lines of therapy in terms of PFS and TTP.
timeFrame: Estimated median of 12 months (until disease progression is confirmed)
measure: Serum levels of T-DM1 conjugate and total trastuzumab
timeFrame: Estimated median of 12 months (until disease progression is confirmed)
measure: Plasma DM1 concentrations
timeFrame: Estimated median of 12 months (until disease progression is confirmed)
measure: Correlation of genomic alterations detected by 22 gene Next Generation Sequencing (NGS) and FoundationOne® (F-One) on tumor samples and FoundationACT® (F-ACT) in plasma at baseline.
timeFrame: Estimated median of 12 months (until disease progression is confirmed)
measure: Correlation of HER2 amplification levels in tumor between Fluorescence In-Situ Hybridization (FISH) (local and central) and Copy Number Variation (CNV) provided by F-One.
timeFrame: Estimated median of 12 months (until disease progression is confirmed)
Locations:
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen Macarena
state: Andalucía
city: Barcelona
country: Spain
facility: Hospital del Mar
state: Cataluña
city: El Palmar
country: Spain
facility: Hospital Clínico Universitario "Virgen de la Arrixaca"
state: Murcia
city: Barcelona
country: Spain
facility: Hospital Universitario Santa Creu i Sant Pau
city: Barcelona
country: Spain
facility: ICO L´Hospitalet
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Marañón
city: Madrid
country: Spain
facility: Hospital Universitario Fundación Jiménez Díaz
city: Madrid
country: Spain
facility: Hopsital Clínico San Carlos
city: Málaga
country: Spain
facility: Hospital Universitario Virgen de la Victoria
city: Valencia
country: Spain
facility: Hospital Clínico Universitario de Valencia
Study officials:
affiliation: Hospital del Mar, Barcelona, Spain
name: Study director
role: STUDY_DIRECTOR
affiliation: Fundación Jiménez-Díaz, Madrid, Spain
name: Study director
role: STUDY_DIRECTOR
References: