Pertuzumab and Trastuzumab as Neoadjuvant Treatment in Patients With HER2-Positive Breast Cancer

• ClinicalTrials.gov Identifier: NCT01937117
• Recruitment Status: Active, not recruiting
• First Posted: September 9, 2013
• Results First Posted: April 12, 2019
• Last Update Posted: October 20, 2020
• Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Collaborators: Translational Breast Cancer Research Consortium; Genentech, Inc.
• Information provided by (Responsible Party): Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Tracking Information

• First Submitted Date: September 3, 2013
• First Posted Date: September 9, 2013
• Results First Submitted Date: March 18, 2019
• Results First Posted Date: April 12, 2019
• Last Update Posted Date: October 20, 2020
• Actual Study Start Date: January 30, 2014
• Actual Primary Completion Date: March 20, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 14, 2020)

Percent Change in Standardized Uptake Value (SUV) as Measured by SULmax on [18F]Fluorodeoxyglucose (FDG) Positron Emission Tomography (PET) [ Time Frame: Baseline and Day 15 ]

SULmax is the maximum SUV corrected for lean body mass. Change in SULmax from baseline to Day 15 on FDG PET in correlation with pathological complete response (pCR) in patients treated with preoperative pertuzumab/trastuzumab. pCR was defined as no viable invasive cancer in breast and axilla by local pathology review. SULmax was measured via spherical volume over the target primary breast cancer tissue.

Original Primary Outcome Measures (submitted: September 3, 2013)

Change in SUV on FDG PET [ Time Frame: 3 months ]

To correlate baseline and change (day 15) in SUV on FDG PET with pathological complete response (pCR) in patients treated with preoperative pertuzumab/trastuzumab

Current Secondary Outcome Measures (submitted: January 14, 2020)

• Change in ptDNA With Response [ Time Frame: 3 months ]
  To correlate PIK3CA mutation status and other genomic alterations (mutations/somatic rearrangements) qualitatively and quantitatively in plasma tumor DNA (ptDNA) with pCR
• Change in PI3K Pathway Activation With Response [ Time Frame: 3 months ]
  To correlate PI3K pathway activation (e.g. PTEN low and/or PIK3CA mutation, human epidermal growth factor receptor (HER) 1-4 expression and/or phosphorylation) in tumor samples and pCR
• Changes in Ki67 With Response [ Time Frame: 3 months ]
  To correlate baseline and change (day 15) in Ki67 with pCR

Original Secondary Outcome Measures (submitted: September 3, 2013)

• Change in ptDNA With Response [ Time Frame: 3 months ]
  To correlate PIK3CA mutation status and other genomic alterations (mutations/somatic rearrangements) qualitatively and quantitatively in plasma tumor DNA (ptDNA) with pCR
• Change in PI3K Pathway Activation With Response [ Time Frame: 3 months ]
  To correlate PI3K pathway activation (e.g. PTEN low and/or PIK3CA mutation, HER 1-4 expression and/or phosphorylation) in tumor samples and pCR
• Changes in Ki67 With Response [ Time Frame: 3 months ]
  To correlate baseline and change (day 15) in Ki67 with pCR

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Pertuzumab and Trastuzumab as Neoadjuvant Treatment in Patients With HER2-Positive Breast Cancer
• Official Title: A Phase 2 Clinical Trial Assessing the Correlation of Early Changes in Standardized Uptake Value (SUV) on Positron Emission Tomography (PET) With Pathological Complete Response (pCR) to Pertuzumab and Trastuzumab in Patients With Primary Operable HER2-Positive Breast Cancer
• Brief Summary: This research is being done to determine if early changes on a type of imaging procedure called PET (Positron Emission Tomography) can predict which patients are most likely to respond to the combination of trastuzumab and pertuzumab when given prior to surgery.
• Detailed Description: This study will evaluate for the first time the correlation between early changes in SUV and pCR in men and women with ER-negative, human epidermal growth factor receptor 2 (HER2)-positive breast cancer receiving trastuzumab and pertuzumab (PT) pre-operatively. This has not previously been evaluated in patients receiving anti HER2 therapy alone and as such is novel and potentially practice changing. The results from this phase 2 biomarker study will be used to plan a randomized study using a predefined cut point for SUV decline such that the investigators can further attempt to identify a group of individuals with HER2-positive early breast cancer who do not require cytotoxic chemotherapy in addition to anti-HER2 agents. This non-invasive biomarker approach will be of great interest to breast cancer oncologists and patients by facilitating a personalized approach to managing patients with HER2-positive disease that will undoubtedly spare toxicity and reduce the costs associated with anti-cancer strategies, without compromising efficacy.
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Breast Cancer

Intervention

• Procedure: Positron emission tomography (PET)
  PET will be performed at baseline and on day 15
  Other Name: FDG PET, PET/CT
• Drug: Trastuzumab
  8 mg/kg loading dose, then 6 mg/kg every 3 weeks, IV
  Other Name: Herceptin
• Drug: Pertuzumab
  840 mg as a loading dose, then 420 mg every 3 weeks, IV
  Other Name: Perjeta

Study Arms

Experimental: Trastuzumab and Pertuzumab

Preoperative treatment with trastuzumab (8 mg/kg loading dose, then 6 mg/kg every 3 weeks, IV) and pertuzumab (840 mg as a loading dose, then 420 mg every 3 weeks, IV) every 3 weeks for 4 doses (total 12 weeks or 3 months of treatment) as assessed by Positron Emission Tomography (PET)

Interventions:

• Procedure: Positron emission tomography (PET)
• Drug: Trastuzumab
• Drug: Pertuzumab

Publications *

Connolly RM, Leal JP, Solnes L, Huang CY, Carpenter A, Gaffney K, Abramson V, Carey LA, Liu MC, Rimawi M, Specht J, Storniolo AM, Valero V, Vaklavas C, Krop IE, Winer EP, Camp M, Miller RS, Wolff AC, Cimino-Mathews A, Park BH, Wahl RL, Stearns V. TBCRC026: Phase II Trial Correlating Standardized Uptake Value With Pathologic Complete Response to Pertuzumab and Trastuzumab in Breast Cancer. J Clin Oncol. 2019 Mar 20;37(9):714-722. doi: 10.1200/JCO.2018.78.7986. Epub 2019 Feb 5. Retraction in: J Clin Oncol. 2021 Jul 10;39(20):2319.

Retraction in:J Clin Oncol. 2021 Jul 10;39(20):2319

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: September 3, 2013): 88
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: September 2021
• Actual Primary Completion Date: March 20, 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Female and male patients, 18 years old or older
• Histologically proven infiltrating carcinoma of the breast on core needle biopsy that is: estrogen receptor (ER)/progesterone receptor (PR) ≤10% staining by immunohistochemistry (IHC) and HER2 positive - IHC 3+, in situ hybridization (ISH) ≥2.0, or average HER2 copy number ≥6.0 signals per cell or per current American Society of Clinical Oncology - College of American Pathologists (ASCO-CAP) or National Comprehensive Cancer Network (NCCN) guidelines. Note: All histological diagnostic material should be reviewed at enrolling institution as required per local standards.
• Unresected, untreated breast cancer that meets one of the following clinical stages (see Appendix A): T2, T3, or T4a-c lesion, any N, M0. Note: Patients with inflammatory breast cancer (T4d) are not eligible. Bilateral cancers are permitted with approval of the Protocol Chair.
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1 (Appendix B)

• Adequate organ function as follows:

  1. Absolute neutrophil count (ANC) ≥ 1,500/mm3
  2. Platelet count ≥ 100,000/mm3
  3. Hemoglobin ≥ 10 g/dL
  4. Creatinine ≤ 1.5 times the upper limit of normal with creatinine clearance ≥ 50 mL/min using the Modified Cockcroft-Gault method
  5. Bilirubin (total) ≤ 1.5 times upper limit normal (with exception of Gilberts syndrome)
  6. AST(SGOT), ALT(SGPT), and alkaline phosphatase ≤ 2 times the upper limit of normal
• Adequate cardiac function as defined by left ventricular ejection fraction (LVEF) ≥ 50% on echocardiogram or multi-gated acquisition scan (MUGA)
• Able and amenable to baseline and follow-up PET/CT imaging and study-specific biopsy procedures. Note: If there are any imaging concerns that the patient may not be suitable for quantitative PET/CT (e.g., a metallic device directly overlies the breast), discussion with the local and central radiologists is required to confirm eligibility for the trial. Also, it is expected that subjects have all PET/CT imaging done on pre-qualified machines for the study; if baseline imaging done on another machine, please contact the Protocol Chair/designee for guidance prior to confirming eligibility.
• The patient, if of childbearing potential, is willing to use effective, non-hormonal contraception while on treatment and for at least 6 months following the last dose of therapy.
• Patient understands the study regimen, its requirements, risks, and discomforts, and is able and willing to sign an informed consent form.

Exclusion Criteria:

• Received prior or ongoing local (e.g radiation) or systemic treatment (chemotherapy or endocrine therapy) for the current breast cancer. Patients who received tamoxifen or raloxifene or another agent for prevention of breast cancer may be included as long as the patient has discontinued the treatment at least one month prior to baseline study biopsy.
• Systemic treatment for prior cancer within the last 5 years, with the exception of adequately treated cone-biopsied in situ carcinoma of the cervix uteri and basal or squamous cell carcinoma of the skin.
• Women who are pregnant or nursing
• Current use of any investigational agents
• Known hypersensitivity to trastuzumab or pertuzumab
• Any medical condition that in the opinion of the investigator puts the patient at risk of potentially serious complications while on this therapy. Specifically, uncontrolled hypertension (systolic >150 and/or diastolic >100), unstable angina, congestive heart failure of any New York Heart Association (NYHA) classification, serious cardiac arrhythmia requiring treatment (exception: atrial fibrillation, paroxysmal supraventricular tachycardia), history of myocardial infarction within 6 months of enrollment.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01937117
• Other Study ID Numbers: TBCRC 026; TBCRC026 ( Other Identifier: Translational Breast Cancer Research Consortium (TBCRC) ); NA_00080994 ( Other Identifier: JHMIRB )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No
• Plan Description: There is no plan to share individual patient data.

• Responsible Party: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Study Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Collaborators

• Translational Breast Cancer Research Consortium
• Genentech, Inc.

Investigators

• Study Chair: Roisin Connolly, MBBCh; Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

• PRS Account: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Verification Date: September 2020