Unraveling KAdcyla Resistance In Human Epidermal Growth Factor Receptor 2(HER2) Positive Advanced Breast Cancer (KATIA) (KATIA)

"Unraveling KAdcyla (Trastuzumab Emtansine; T-DM1) Resistance In HER2-positive Advanced Breast Cancer (ABC): a Prospective GEICAM Study"

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.

Study Overview

• Status: Completed
• Conditions: Advanced Breast Cancer

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.

• Study Type: Observational
• Enrollment (Actual): 32

Contacts and Locations

Study Locations

• Spain
  • Barcelona, Spain, 08025
    • Hospital Universitario Santa Creu i Sant Pau
  • Barcelona, Spain, 08908
    • ICO L´Hospitalet
  • Madrid, Spain, 28040
    • Hospital Universitario Fundacion Jimenez Diaz
  • Madrid, Spain, 28007
    • Hospital General Universitario Gregorio Marañón
  • Madrid, Spain
    • Hopsital Clínico San Carlos
  • Málaga, Spain
    • Hospital Universitario Virgen de La Victoria
  • Valencia, Spain
    • Hospital Clínico Universitario de Valencia
  • Andalucía
    • Sevilla, Andalucía, Spain, 41009
      • Hospital Universitario Virgen Macarena
  • Cataluña
    • Barcelona, Cataluña, Spain, 08003
      • Hospital del Mar
  • Murcia
    • El Palmar, Murcia, Spain, 30120
      • Hospital Clínico Universitario "Virgen de la Arrixaca"

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: N/A
• Genders Eligible for Study: All

• 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.

Description

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.

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Only
• Time Perspectives: Prospective

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Genomic alterations on tumor samples with Objective Response (OR) to Kadcyla	Genomic alterations at baseline Formalin-Fixed Paraffin-Embedded (FFPE) tumor samples (primary tumor or metastatic sample) will be analysed by F-One. This test provides information about genomic alterations (base substitutions, insertions/deletions, copy number variations and rearrangements) in 315 cancer-related genes plus introns from 28 genes often rearranged or altered in cancer (https://foundationone.com/docs/FoundationOne). OR (complete response plus partial response) will be measured in tumor assessments performed approximately every 3 cycles, based on the investigator assessment according to the standard institutional guidelines using RECIST version 1.1.	Estimated median of 12 months (until disease progression is confirmed)
Tumor-specific mutation in plasma samples with OR to Kadcyla	Tumor-specific mutation identification will be measured by the test Foundation ACT (F-ACT) on plasma samples collected at baseline and at progression.This test probes 62 cancer-related genes across the 4 classes of genomic alterations (https://www.foundationmedicine.com/genomic-testing/foundation-act). OR (complete response plus partial response) will be measured in tumor assessments performed approximately every 3 cycles, based on the investigator assessment according to the standard institutional guidelines using RECIST version 1.1.	Estimated median of 12 months (until disease progression is confirmed)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Genomic alterations on tumor samples with progression-free survival (PFS)	Genomic alterations at baseline FFPE tumor samples (primary tumor or metastatic sample) will be analysed by F-One. This test provides information about genomic alterations (base substitutions, insertions/deletions, copy number variations and rearrangements) in 315 cancer-related genes plus introns from 28 genes often rearranged or altered in cancer (http://foundationone.com/docs/FoundationOne). Progression-free survival (PFS) to Kadcyla and subsequent treatment lines based on the investigator's assessment at 6 and 12 months.	Estimated median of 12 months (until disease progression is confirmed)
Tumor-specific mutation in plasma samples with progression-free survival (PFS)	Tumor-specific mutation in plasma samples with OR Tumor-specific mutation identification will be measured by the test Foundation ACT (F-ACT) on plasma samples collected at baseline and at progression. Progression-free survival (PFS) to Kadcyla and subsequent treatment lines based on the investigator's assessment	Estimated median of 12 months (until disease progression is confirmed)
Genomic alterations on tumor samples with Progression-free survival	Genomic alterations at baseline FFPE tumor samples (primary tumor or metastatic sample) will be analysed by F-One. This test provides information about genomic alterations (base substitutions, insertions/deletions, copy number variations and rearrangements) in 315 cancer-related genes plus introns from 28 genes often rearranged or altered in cancer (http://foundationone.com/docs/FoundationOne). Progression-free survival (PFS) to Kadcyla and subsequent treatment lines based on the investigator's assessment	Estimated median of 12 months (until disease progression is confirmed)
Genomic alterations on tumor samples with Time to Progression (TTP)	Genomic alterations at baseline FFPE tumor samples (primary tumor or metastatic sample) will be analysed by F-One. This test provides information about genomic alterations (base substitutions, insertions/deletions, copy number variations and rearrangements) in 315 cancer-related genes plus introns from 28 genes often rearranged or altered in cancer (http://foundationone.com/docs/FoundationOne). Time to progression (TTP) to Kadcyla and subsequent treatment lines based on the investigator's assessment.	Estimated median of 12 months (until disease progression is confirmed)
Tumor-specific mutation in plasma samples with Progression-free survival	Tumor-specific mutation identification will be measured by the test Foundation ACT (F-ACT) on plasma samples collected at baseline and at progression. Progression-free survival (PFS) to Kadcyla and subsequent treatment lines based on the investigator's assessment	Estimated median of 12 months (until disease progression is confirmed)
Tumor-specific mutation in plasma samples Time to Progression (TTP)	Tumor-specific mutation identification will be measured by the test Foundation ACT (F-ACT) on plasma samples collected at baseline and at progression. Time to progression (TTP) to Kadcyla and subsequent treatment lines based on the investigator's assessment.	Estimated median of 12 months (until disease progression is confirmed)
Number of participants with treatment-related adverse events as assessed by CTCAE v5.0	Adverse events will be assessed by standard clinical and laboratory tests (hematology, serum chemistry). Adverse events grade will be defined by the NCI-CTCAE v5.0. Dose/schedule modifications will be also recorded.	Through study treatment, estimated median of 12 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Genomic alterations on tumor samples correlation with overall survival (OS)	Genomic alterations at baseline FFPE tumor samples (primary tumor or metastatic sample) will be analysed by F-One. This test provides information about genomic alterations (base substitutions, insertions/deletions, copy number variations and rearrangements) in 315 cancer-related genes plus introns from 28 genes often rearranged or altered in cancer (http://foundationone.com/docs/FoundationOne).	Estimated median of 12 months (until disease progression is confirmed)
Tumor-specific mutation in plasma samples with overall survival (OS)	Tumor-specific mutation identification will be measured by the test Foundation ACT (F-ACT) on plasma samples collected at baseline and at progression.	Estimated median of 12 months (until disease progression is confirmed)
Tumor-specific mutation in plasma samples during Kadcyla treatment with clinical benefit to the subsequent lines of therapy in terms of PFS and TTP.	Tumor-specific mutation identification and clonal evolution in correlative plasma samples: Detection of specific gene mutations found in corresponding tissue samples through targeted sequencing (by Illumina MySeq) will be performed on plasma samples at baseline, during Kadcyla treatment and at end of treatment (EOT)/progression. This will be performed using digital Polymerase Chain Reaction (PCR) on circulating tumor DNA (ctDNA) for clonal dynamics monitoring during Kadcyla treatment. Progression-free survival (PFS) to Kadcyla and subsequent treatment lines based on the investigator's assessment Time to progression (TTP) to Kadcyla and subsequent treatment lines based on the investigator's assessment.	Estimated median of 12 months (until disease progression is confirmed)
Serum levels of T-DM1 conjugate and total trastuzumab	Serum levels of T-DM1 conjugate and total trastuzumab (including both conjugated and unconjugated trastuzumab) will be quantified using a validated enzyme-linked immunosorbent assay. samples will obtained on cycles 1, 2 and 3: Pre-dose and 30 mins after end-of-Kadcyla infusion	Estimated median of 12 months (until disease progression is confirmed)
Plasma DM1 concentrations	Plasma DM1 concentrations will be determined by QPS Netherlands BV (Groningen, Netherlands) using a validated liquid chromatography-tandem mass spectrometry method Plasma DM1 concentrations will be determined by QPS Netherlands BV (Groningen, Netherlands) using a validated liquid chromatography-tandem mass spectrometry method. Plasma samples will obtained on cycles 1, 2 and 3: Pre-dose and 30 mins after end-of-Kadcyla infusion	Estimated median of 12 months (until disease progression is confirmed)
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.		Estimated median of 12 months (until disease progression is confirmed)
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.		Estimated median of 12 months (until disease progression is confirmed)

Collaborators and Investigators

• Sponsor: Spanish Breast Cancer Research Group
• Collaborators: Roche Farma, S.A
• Investigators: Study Director: Study director, Hospital del Mar, Barcelona, Spain; Study Director: Study director, Fundación Jiménez-Díaz, Madrid, Spain

Study record dates

Study Major Dates

• Study Start (Actual): June 12, 2018
• Primary Completion (Actual): June 21, 2022
• Study Completion (Actual): June 21, 2022

Study Registration Dates

• First Submitted: January 10, 2019
• First Submitted That Met QC Criteria: January 31, 2019
• First Posted (Actual): February 4, 2019

Study Record Updates

• Last Update Posted (Estimate): January 13, 2023
• Last Update Submitted That Met QC Criteria: January 12, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Keywords: HER2-positive
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms
• Other Study ID Numbers: GEICAM/2017-04

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No