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

• Study Type: Interventional
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Breast Cancer
• Interventions: Procedure: Positron emission tomography (PET); Drug: Trastuzumab; Drug: Pertuzumab
• Enrollment: 88

Participant Flow

Recruitment Details
Pre-assignment Details

Arm/Group Title	Trastuzumab and Pertuzumab
Arm/Group Description	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) Positron emission tomography (PET): PET will be performed at baseline and on day 15 Trastuzumab: 8 mg/kg loading dose, then 6 mg/kg every 3 weeks, IV Pertuzumab: 840 mg as a loading dose, then 420 mg every 3 weeks, IV
Period Title: Overall Study
Started	88
Completed	75
Not Completed	13
Reason Not Completed
Disease Progression	7
Physician Decision	4
Adverse Event	2

Baseline Characteristics

Arm/Group Title		Trastuzumab and Pertuzumab
Arm/Group Description		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) Positron emission tomography (PET): PET will be performed at baseline and on day 15 Trastuzumab: 8 mg/kg loading dose, then 6 mg/kg every 3 weeks, IV Pertuzumab: 840 mg as a loading dose, then 420 mg every 3 weeks, IV
Overall Number of Baseline Participants		88
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Median (Standard Deviation); Unit of measure: Years
	Number Analyzed	88 participants
		58 (12.6)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	88 participants
	Female	88 100.0%
	Male	0 0.0%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	88 participants
	Hispanic or Latino	5 5.7%
	Not Hispanic or Latino	79 89.8%
	Unknown or Not Reported	4 4.5%
Race/Ethnicity, Customized; Measure Type: Count of Participants; Unit of measure: Participants	Number Analyzed	88 participants
White		75 85.2%
Black or African American		7 8.0%
Other		6 6.8%
Region of Enrollment; Measure Type: Count of Participants; Unit of measure: Participants
United States	Number Analyzed	88 participants
		88 100.0%
Eastern Cooperative Oncology Group (ECOG) Performance Status [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	88 participants
	0	76 86.4%
	1	12 13.6%
		[1] Measure Description: The ECOG scale measures performance status, with scores ranging from 0-5; 0= fully active, performs without restriction, 1= can ambulate, but restricted in physically strenuous activity, 2= ambulatory and capable of self-care, but unable to work, active for >50% of waking hours, 3= limited self-care, confined to bed or chair for >50% of waking hours, 4= completely disabled, totally confined to bed/chair, 5= deceased
Baseline clinical tumor size [1]; Median (Standard Deviation); Unit of measure: Cm
	Number Analyzed	88 participants
		3.7 (2)
		[1] Measure Description: Primary breast tumor size in centimeters (cm)
Clinical tumor T staging [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	88 participants
	T1	0 0.0%
	T2	66 75.0%
	T3	19 21.6%
	T4	3 3.4%
		[1] Measure Description: T refers to the extent (size) of the tumor and is based off the staging system used for breast cancer is the American Joint Committee on Cancer (AJCC). Staging is as follows: T1= tumor <= 2cm in greatest dimension, T2= tumor >2cm in greatest dimension, T3= tumor >5cm in greatest dimension, and T4= tumor of any size with direct extension to chest wall (T4a) or skin (T4b). A higher number reflects a more progressive stage.
Baseline clinical nodal status [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	88 participants
	Negative	45 51.1%
	Positive	43 48.9%
		[1] Measure Description: Based from the American Joint Committee on Cancer (AJCC) TNM system, this measures whether participants' cancer has spread to lymph nodes near the breast.
Clinical tumor N staging [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	88 participants
	N0	45 51.1%
	N1	38 43.2%
	N2	3 3.4%
	N3	2 2.3%
		[1] Measure Description: AJCC staging: N0= no regional lymph node (LN) metastasis ("mets"), N1= mets in movable ipsilateral axillary LN; N2= mets in ipsilateral axillary LNs fixed or matted, or in clinically apparent ipsilateral internal mammary LN without of clinically evident axillary LN mets; N3= mets in ipsilateral infraclavicular LN, or in clinically apparent ipsilateral internal mammary LNs and in the presence of clinically evident axillary LN mets; or mets in ipsilateral supraclavicular LN with or without axillary or internal mammary lymph node involvement. A higher number reflects a greater region of mets.
Baseline clinical stage [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	88 participants
	Stage I	0 0.0%
	Stage II	74 84.1%
	Stage III	14 15.9%
	Stage IV	0 0.0%
		[1] Measure Description: Based on AJCC TNM staging (as described above): earliest stage breast cancers are stage 0 (carcinoma in situ). It then ranges from stage I (1) through IV (4), with a higher stage reflecting worse outcome. Stage I= T1N0M0, Stage II= T0N1M0, T1N1M0, T2N0M0, T2N1M0, T3N0M0, Stage III= T0N2M0, T1N2M0, T2N2M0, T3N1M0, T3N2M0, T4N0M0, T4N1M0, T4N2M0, any TN3M0.
Tumor Grade [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	88 participants
	Grade 1	0 0.0%
	Grade 2	22 25.0%
	Grade 3	66 75.0%
		[1] Measure Description: Tumor grade measures how much the cancer cells look like normal cells. Grading is as follows: Grade 1 (well differentiated)= the cells are slower-growing, and look more like normal breast tissue; Grade 2 (moderately differentiated)= the cells are growing at a speed of and look like cells somewhere between grades 1 and 3, Grade 3 (poorly differentiated) = the cells look very different from normal cells and will probably grow and spread faster. A higher grade reflects a worse prognosis.
Additional neoadjuvant therapy [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	88 participants
	Yes	25 28.4%
	No	59 67.0%
	N/A	4 4.5%
		[1] Measure Description: Study treatment was pertuzumab and trastuzumab. If required by care team, participants could receive additional treatment, outside of the protocol, prior to surgery.
Type of Surgery [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	88 participants
	Mastectomy	51 58.0%
	Breast-conserving therapy	33 37.5%
	N/A	4 4.5%
		[1] Measure Description: Type of surgical intervention received.

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

Data was evaluable in only 83/88 participants.

Arm/Group Title		Trastuzumab and Pertuzumab
Arm/Group Description:		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) Positron emission tomography (PET): PET will be performed at baseline and on day 15 Trastuzumab: 8 mg/kg loading dose, then 6 mg/kg every 3 weeks, IV Pertuzumab: 840 mg as a loading dose, then 420 mg every 3 weeks, IV
Overall Number of Participants Analyzed		83
Mean (Standard Deviation); Unit of Measure: percent reduction in SULmax
pCR	Number Analyzed	28 participants
		61.9 (22.3)
no pCR	Number Analyzed	55 participants
		34.3 (31.9)

2. Secondary Outcome

Title	Change in ptDNA With Response
Description	To correlate PIK3CA mutation status and other genomic alterations (mutations/somatic rearrangements) qualitatively and quantitatively in plasma tumor DNA (ptDNA) with pCR
Time Frame	3 months

Outcome Measure Data Not Reported

3. Secondary Outcome

Title	Change in PI3K Pathway Activation With Response
Description	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
Time Frame	3 months

Outcome Measure Data Not Reported

4. Secondary Outcome

Title	Changes in Ki67 With Response
Description	To correlate baseline and change (day 15) in Ki67 with pCR
Time Frame	3 months

Outcome Measure Data Not Reported

Adverse Events

Time Frame	Up to 16 weeks
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Trastuzumab and Pertuzumab
Arm/Group Description	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) Positron emission tomography (PET): PET will be performed at baseline and on day 15 Trastuzumab: 8 mg/kg loading dose, then 6 mg/kg every 3 weeks, IV Pertuzumab: 840 mg as a loading dose, then 420 mg every 3 weeks, IV
All-Cause Mortality
	Trastuzumab and Pertuzumab
	Affected / at Risk (%)
Total	0/88 (0.00%)
Serious Adverse Events
	Trastuzumab and Pertuzumab
	Affected / at Risk (%)	# Events
Total	2/88 (2.27%)
Gastrointestinal disorders
Enterocolitis † 1 [1]	1/88 (1.14%)	1
Injury, poisoning and procedural complications
Sepsis † 1 [1]	1/88 (1.14%)	2
1 Term from vocabulary, CTCAE (4.0); † Indicates events were collected by systematic assessment; [1] Not related to study product.
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	4.4%
	Trastuzumab and Pertuzumab
	Affected / at Risk (%)	# Events
Total	88/88 (100.00%)
Gastrointestinal disorders
Diarrhea † 1	80/88 (90.91%)	80
Dyspepsia † 1	5/88 (5.68%)	5
Mucositis † 1	12/88 (13.64%)	12
Nausea † 1	24/88 (27.27%)	24
General disorders
Fatigue † 1	30/88 (34.09%)	30
Chills † 1	10/88 (11.36%)	10
Nervous system disorders
Headache † 1	13/88 (14.77%)	13
Dysgeusia † 1	6/88 (6.82%)	6
Skin and subcutaneous tissue disorders
Rash (NOS) † 1	17/88 (19.32%)	17
Dry skin † 1	5/88 (5.68%)	5
1 Term from vocabulary, CTCAE (4.0); † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

• Name/Title: Roisin Connolly
• Organization: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Phone: (410) 614-9217
• EMail: rconnol2@jhmi.edu

Publications of Results:

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

• Responsible Party: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• ClinicalTrials.gov Identifier: NCT01937117
• Other Study ID Numbers: TBCRC 026; TBCRC026 ( Other Identifier: Translational Breast Cancer Research Consortium (TBCRC) ); NA_00080994 ( Other Identifier: JHMIRB )
• First Submitted: September 3, 2013
• First Posted: September 9, 2013
• Results First Submitted: March 18, 2019
• Results First Posted: April 12, 2019
• Last Update Posted: October 20, 2020