Anti-PD-1 Monoclonal Antibody in Advanced, Trastuzumab-resistant, HER2-positive Breast Cancer (PANACEA)

• ClinicalTrials.gov Identifier: NCT02129556
• Recruitment Status: Completed
• First Posted: May 2, 2014
• Results First Posted: February 15, 2019
• Last Update Posted: February 15, 2019
• Sponsor: ETOP IBCSG Partners Foundation
• Collaborator: Breast International Group
• Information provided by (Responsible Party): ETOP IBCSG Partners Foundation

• Study Type: Interventional
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Metastatic Breast Cancer
• Intervention: Drug: MK-3475
• Enrollment: 58

Participant Flow

Recruitment Details
Pre-assignment Details

Arm/Group Title	Phase Ib 2 mg/kg	Phase Ib 10 mg/kg	Phase II PD-L1+	Phase II PD-L1-
Arm/Group Description	HER2-positive, PD-L1 expressing, unresectable loco-regional or metastatic breast carcinoma that progressed on prior trastuzumab-based therapy. In the Phase Ib portion of the trial, two weight-based doses of MK-3475 were specified in the dose escalation (2 mg/kg and 10 mg/kg).	HER2-positive, PD-L1 expressing, unresectable loco-regional or metastatic breast carcinoma that progressed on prior trastuzumab-based therapy. In the Phase Ib portion of the trial, two weight-based doses of MK-3475 were specified in the dose escalation (2 mg/kg and 10 mg/kg).	HER2-positive, PD-L1 expressing, unresectable loco-regional or metastatic breast carcinoma that progressed on prior trastuzumab-based therapy. The Phase II portion of the trial used a flat dose of 200 mg of MK-3475 based on emerging data from the sponsor.	HER2-positive, PD-L1 negative, unresectable loco-regional or metastatic breast carcinoma that progressed on prior trastuzumab-based therapy. The Phase II portion of the trial used a flat dose of 200 mg of MK-3475 based on emerging data from the sponsor.
Period Title: Overall Study
Started	3	3	40	12
Completed	3	3	37	12
Not Completed	0	0	3	0

Baseline Characteristics

Arm/Group Title		Phase Ib	Phase II PD-L1+	Phase II PD-L1-	Total
Arm/Group Description		HER2-positive, PD-L1 expressing, unresectable loco-regional or metastatic breast carcinoma that progressed on prior trastuzumab-based therapy	HER2-positive, PD-L1 expressing, unresectable loco-regional or metastatic breast carcinoma that progressed on prior trastuzumab-based therapy	HER2-positive, PD-L1 negative, unresectable loco-regional or metastatic breast carcinoma that progressed on prior trastuzumab-based therapy	Total of all reporting groups
Overall Number of Baseline Participants		6	40	12	58
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	6 participants	40 participants	12 participants	58 participants
		48 (9.5)	51.2 (10.4)	54.5 (5.2)	51.5 (9.4)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	6 participants	40 participants	12 participants	58 participants
	Female	6 100.0%	40 100.0%	12 100.0%	58 100.0%
	Male	0 0.0%	0 0.0%	0 0.0%	0 0.0%
Race/Ethnicity, Customized; Measure Type: Count of Participants; Unit of measure: Participants	Number Analyzed	6 participants	40 participants	12 participants	58 participants
Caucasian		4 66.7%	30 75.0%	8 66.7%	42 72.4%
Asian		0 0.0%	2 5.0%	1 8.3%	3 5.2%
Other		0 0.0%	1 2.5%	0 0.0%	1 1.7%
Missing		2 33.3%	7 17.5%	3 25.0%	12 20.7%
Region of Enrollment; Measure Type: Count of Participants; Unit of measure: Participants	Number Analyzed	6 participants	40 participants	12 participants	58 participants
Austria		0 0.0%	0 0.0%	1 8.3%	1 1.7%
Belgium		0 0.0%	6 15.0%	3 25.0%	9 15.5%
Italy		0 0.0%	6 15.0%	1 8.3%	7 12.1%
Australia		4 66.7%	13 32.5%	4 33.3%	21 36.2%
France		2 33.3%	15 37.5%	3 25.0%	20 34.5%

Outcome Measures

1. Primary Outcome

Title	Dose-Limiting Toxicity (DLT) of MK-3475 in Combination With Trastuzumab
Description	Determination of dose-limiting toxicity (DLT) which is defined as an adverse event or abnormal laboratory value assessed as suspected to be trial treatment related (possible, probable or definite) and unrelated to disease or disease progression. Toxicities and lab values will be graded according to the NCI CTCAE (v4.0).; Any grade-3 or greater non-hematological adverse event lasting at least one week;; Any grade-4 hematological toxicity; or,; Any adverse event resulting in a delay starting cycle 2 of more than 14 days.
Time Frame	Within the first 21 days

Outcome Measure Data

Analysis Population Description

Patients enrolled during phase Ib portion, a patient receiving one or more doses of MK-3475 and trastuzumab is considered evaluable.

Arm/Group Title	Phase Ib 2 mg/kg	Phase Ib 10 mg/kg
Arm/Group Description:	HER2-positive, PD-L1 expressing, unresectable loco-regional or metastatic breast carcinoma that progressed on prior trastuzumab-based therapy	HER2-positive, PD-L1 expressing, unresectable loco-regional or metastatic breast carcinoma that progressed on prior trastuzumab-based therapy
Overall Number of Participants Analyzed	3	3
Measure Type: Count of Participants; Unit of Measure: Participants
	0 0.0%	0 0.0%

2. Primary Outcome

Title	Objective Response Rate (ORR)
Description	Confirmed CR or PR as best overall response. At the time of each restaging, patients will be classified as achieving complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), or non-evaluable for response according to RECIST (Version 1.1) criteria.
Time Frame	Clinical and radiological tumor assessment will be performed by CT scan or MRI at baseline, at weeks 12, 18 and 24, then every 12 weeks until progression, or 24 weeks after stop of treatment if before progression.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase Ib	Phase II PD-L1+	Phase II PD-L1-
Arm/Group Description:	HER2-positive, PD-L1 expressing, unresectable loco-regional or metastatic breast carcinoma that progressed on prior trastuzumab-based therapy. All 6 patients in Phase Ib were combined when reporting clinical measures for secondary outcomes and adverse events, for stronger response rates.	HER2-positive, PD-L1 expressing, unresectable loco-regional or metastatic breast carcinoma that progressed on prior trastuzumab-based therapy	HER2-positive, PD-L1 negative, unresectable loco-regional or metastatic breast carcinoma that progressed on prior trastuzumab-based therapy
Overall Number of Participants Analyzed	6	40	12
Measure Type: Number; Number (90% Confidence Interval); Unit of Measure: proportion of participants
	0.17; (0.01 to 0.58)	0.15; (0.07 to 0.29)	0.00; (0.00 to 0.18)

3. Secondary Outcome

Title	Duration of Response (DoR)
Description	Duration of response (DoR) is defined among patients with objective response (confirmed CR or PR as best overall response) as the interval between dates of first documentation of objective response and first documentation of progressive disease. In the absence of documented progressive disease, follow-up will be censored at date of last disease assessment.
Time Frame	From date of first documentation of objective response until first documentation of progressive disease, up to 24 weeks after stop of treatment (=30 months)

Outcome Measure Data

Analysis Population Description

Patients who achieved objective response

Arm/Group Title	Phase Ib	Phase II PD-L1+	Phase II PD-L1-
Arm/Group Description:	HER2-positive, PD-L1 expressing, unresectable loco-regional or metastatic breast carcinoma that progressed on prior trastuzumab-based therapy. All 6 patients in Phase Ib were combined when reporting clinical measures for secondary outcomes and adverse events, for stronger response rates.	HER2-positive, PD-L1 expressing, unresectable loco-regional or metastatic breast carcinoma that progressed on prior trastuzumab-based therapy	HER2-positive, PD-L1 negative, unresectable loco-regional or metastatic breast carcinoma that progressed on prior trastuzumab-based therapy
Overall Number of Participants Analyzed	1	6	0
Median (90% Confidence Interval); Unit of Measure: months
	23.1	3.5; (2.7 to 999999)

4. Secondary Outcome

Title	Time to Progression (TTP)
Description	Time to progression (TTP) defined as the interval between the dates of the start of trial treatment and first documentation of progressive disease. In the absence of documented progressive disease, follow-up will be censored at date of last disease assessment
Time Frame	From the first trial treatment until first documentation of progressive disease up to 24 weeks after stop of treatment (=30 months)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase Ib	Phase II PD-L1+	Phase II PD-L1-
Arm/Group Description:	HER2-positive, PD-L1 expressing, unresectable loco-regional or metastatic breast carcinoma that progressed on prior trastuzumab-based therapy. All 6 patients in Phase Ib were combined when reporting clinical measures for secondary outcomes and adverse events, for stronger response rates.	HER2-positive, PD-L1 expressing, unresectable loco-regional or metastatic breast carcinoma that progressed on prior trastuzumab-based therapy	HER2-positive, PD-L1 negative, unresectable loco-regional or metastatic breast carcinoma that progressed on prior trastuzumab-based therapy
Overall Number of Participants Analyzed	6	40	12
Median (90% Confidence Interval); Unit of Measure: months
	2.5; (1.1 to 2.7)	2.7; (2.6 to 4.9)	2.5; (1.4 to 999999)

5. Secondary Outcome

Title	Disease Control Rate (DCR)
Description	The proportion of patients with best confirmed RECIST response of CR, PR, or duration of SD of at least 24 weeks (measured from first dose of trial treatment).
Time Frame	From the start of trial treatment until confirmed CR, PR, or SD lasting for 24 weeks or longer

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase Ib	Phase II PD-L1+	Phase II PD-L1-
Arm/Group Description:	HER2-positive, PD-L1 expressing, unresectable loco-regional or metastatic breast carcinoma that progressed on prior trastuzumab-based therapy. All 6 patients in Phase Ib were combined when reporting clinical measures for secondary outcomes and adverse events, for stronger response rates.	HER2-positive, PD-L1 expressing, unresectable loco-regional or metastatic breast carcinoma that progressed on prior trastuzumab-based therapy	HER2-positive, PD-L1 negative, unresectable loco-regional or metastatic breast carcinoma that progressed on prior trastuzumab-based therapy
Overall Number of Participants Analyzed	6	40	12
Measure Type: Number; Number (90% Confidence Interval); Unit of Measure: proportion of participants
	0.17; (0.01 to 0.58)	0.25; (0.14 to 0.39)	0.00; (0.00 to 0.18)

6. Secondary Outcome

Title	Progression-Free Survival (PFS)
Description	The interval between the dates of the first dose of trial treatment until first documentation of disease progression or death, whichever occurs first. Patients with new non-breast cancer malignancy must continue to be followed for progression of the original breast cancer. For patients without progression, follow-up is censored at the date of last disease assessment without progression, unless death occurs within 12 weeks following the date last known progression-free, in which case the death will be counted as a PFS event.
Time Frame	From the date of first treatment dose until documented disease progression or death from any cause. whichever occur first, assessed up to 30 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase Ib	Phase II PD-L1+	Phase II PD-L1-
Arm/Group Description:	HER2-positive, PD-L1 expressing, unresectable loco-regional or metastatic breast carcinoma that progressed on prior trastuzumab-based therapy. All 6 patients in Phase Ib were combined when reporting clinical measures for secondary outcomes and adverse events, for stronger response rates.	HER2-positive, PD-L1 expressing, unresectable loco-regional or metastatic breast carcinoma that progressed on prior trastuzumab-based therapy	HER2-positive, PD-L1 negative, unresectable loco-regional or metastatic breast carcinoma that progressed on prior trastuzumab-based therapy
Overall Number of Participants Analyzed	6	40	12
Median (90% Confidence Interval); Unit of Measure: months
	2.5; (1.1 to 2.7)	2.7; (2.6 to 4.0)	2.5; (1.4 to 2.7)

7. Secondary Outcome

Title	Overall Survival (OS) at 12 Months
Description	OS is defined as the time from the first dose of trial treatment to death from any cause. For patients who are lost to follow-up or who have no documentation of death at the time of final analysis, follow-up is censored at the date of last assessment of vital status. OS at 12 months by Kaplan-Meier estimates.
Time Frame	Time from start of trial treatment to death from any cause, assessed up to 30 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase Ib	Phase II PD-L1+	Phase II PD-L1-
Arm/Group Description:	HER2-positive, PD-L1 expressing, unresectable loco-regional or metastatic breast carcinoma that progressed on prior trastuzumab-based therapy. All 6 patients in Phase Ib were combined when reporting clinical measures for secondary outcomes and adverse events, for stronger response rates.	HER2-positive, PD-L1 expressing, unresectable loco-regional or metastatic breast carcinoma that progressed on prior trastuzumab-based therapy	HER2-positive, PD-L1 negative, unresectable loco-regional or metastatic breast carcinoma that progressed on prior trastuzumab-based therapy
Overall Number of Participants Analyzed	6	40	12
Measure Type: Number; Number (90% Confidence Interval); Unit of Measure: proportion of participants
	0.67; (0.27 to .88)	.65; (.50 to .76)	.12; (.01 to .36)

Adverse Events

Time Frame	From the date of signature of informed consent until 30 days after all treatment discontinuation, regardless of whether it was considered related to a medication. AEs were to be reported at the end of every treatment cycle, at the End-of-Treatment visit, and up to 30 days after cessation of trial treatment. Serious adverse event and pregnancy data were to be collected for 90 days following the end of treatment.
Adverse Event Reporting Description	Any grade of any observed AE was to be reported on the AE form. There were no specifications of targeted AEs. Symptoms of the targeted cancer were not to be reported as AEs. AEs were categorized and graded according to CTCAE V4.
Arm/Group Title	Phase Ib		Phase II (PD-L1+ and PD-L1-)
Arm/Group Description	HER2-positive, PD-L1 expressing, unresectable loco-regional or metastatic breast carcinoma that progressed on prior trastuzumab-based therapy. All 6 patients in Phase I were combined when reporting clinical measures for secondary outcomes adverse events for stronger response rates.		HER2-positive, PD-L1 expressing or PD-L1 negative, unresectable loco-regional or metastatic breast carcinoma that progressed on prior trastuzumab-based therapy. For adverse events, Phase II cohorts were combined since PD-L1 status does not affect toxicity.
All-Cause Mortality
	Phase Ib		Phase II (PD-L1+ and PD-L1-)
	Affected / at Risk (%)		Affected / at Risk (%)
Total	4/6 (66.67%)		25/52 (48.08%)
Serious Adverse Events
	Phase Ib		Phase II (PD-L1+ and PD-L1-)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/6 (66.67%)		25/52 (48.08%)
Blood and lymphatic system disorders
Anemia †	0/6 (0.00%)		1/52 (1.92%)	1
Cardiac disorders
Takotsubo cardiomyopathy †	1/6 (16.67%)	2	0/52 (0.00%)	0
Pericardial effusion †	0/6 (0.00%)		2/52 (3.85%)	2
Ear and labyrinth disorders
Vertigo †	1/6 (16.67%)	1	0/52 (0.00%)	0
Eye disorders
Retinal vein occlusion †	0/6 (0.00%)		1/52 (1.92%)	1
Gastrointestinal disorders
Gastroenteritis †	1/6 (16.67%)	1	0/52 (0.00%)	0
Vomiting †	1/6 (16.67%)	1	0/52 (0.00%)	0
Diarrhea †	0/6 (0.00%)		1/52 (1.92%)	1
General disorders
Death †	2/6 (33.33%)	2	9/52 (17.31%)	9
Hepatobiliary disorders
Bile duct dilatation †	0/6 (0.00%)		1/52 (1.92%)	1
Hepatic hemorrhage †	0/6 (0.00%)		1/52 (1.92%)	1
Drug-induced liver injury †	0/6 (0.00%)		1/52 (1.92%)	1
Immune system disorders
Lambert-Eaton syndrome †	0/6 (0.00%)		1/52 (1.92%)	1
Autoimmune hepatitis †	0/6 (0.00%)		1/52 (1.92%)	1
Infections and infestations
Catheter-related infection †	0/6 (0.00%)		1/52 (1.92%)	1
Sepsis †	0/6 (0.00%)		1/52 (1.92%)	1
Investigations
GGT increased †	0/6 (0.00%)		1/52 (1.92%)	1
Musculoskeletal and connective tissue disorders
Shoulder pain †	1/6 (16.67%)	1	0/52 (0.00%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Glioblastoma multiforme †	0/6 (0.00%)		1/52 (1.92%)	1
Nervous system disorders
CNS metastases †	1/6 (16.67%)	1	0/52 (0.00%)	0
Paresthesia †	0/6 (0.00%)		1/52 (1.92%)	1
Neurological paresis †	0/6 (0.00%)		1/52 (1.92%)	1
Aphasia †	0/6 (0.00%)		1/52 (1.92%)	1
Psychiatric disorders
Cognitive disturbance †	0/6 (0.00%)		1/52 (1.92%)	1
Renal and urinary disorders
Acute renal impairment †	0/6 (0.00%)		1/52 (1.92%)	1
Reproductive system and breast disorders
Disease progression †	2/6 (33.33%)	2	6/52 (11.54%)	6
Breast infection †	0/6 (0.00%)		1/52 (1.92%)	1
Respiratory, thoracic and mediastinal disorders
Upper respiratory infection †	0/6 (0.00%)		2/52 (3.85%)	2
Plural effusion †	0/6 (0.00%)		1/52 (1.92%)	1
Pneumonitis †	0/6 (0.00%)		3/52 (5.77%)	3
Dyspnea †	0/6 (0.00%)		3/52 (5.77%)	3
Pulmonary embolism †	0/6 (0.00%)		1/52 (1.92%)	1
Skin and subcutaneous tissue disorders
Rash †	0/6 (0.00%)		1/52 (1.92%)	1
Vascular disorders
Intracranial hypertension †	0/6 (0.00%)		1/52 (1.92%)	1
† Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	0%
	Phase Ib		Phase II (PD-L1+ and PD-L1-)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/6 (100.00%)		50/52 (96.15%)
Blood and lymphatic system disorders
Anemia †	4/6 (66.67%)	6	8/52 (15.38%)	8
Fever †	0/6 (0.00%)	0	1/52 (1.92%)	1
Lymph node pain †	0/6 (0.00%)	0	1/52 (1.92%)	1
Reactive thrombocytosis †	0/6 (0.00%)	0	1/52 (1.92%)	1
Cardiac disorders
Pericardial effusion †	0/6 (0.00%)	0	1/52 (1.92%)	1
Sinus tachycardia †	0/6 (0.00%)	0	1/52 (1.92%)	1
Takotsubo cardiomyopathy †	1/6 (16.67%)	2	0/52 (0.00%)	0
Ear and labyrinth disorders
Ear pain †	0/6 (0.00%)	0	1/52 (1.92%)	1
Hearing impaired †	1/6 (16.67%)	1	0/52 (0.00%)	0
Vertigo †	1/6 (16.67%)	3	2/52 (3.85%)	3
Endocrine disorders
Hyperthyroidism †	1/6 (16.67%)	1	1/52 (1.92%)	1
Hypothyroidism †	1/6 (16.67%)	1	2/52 (3.85%)	2
Eye disorders
Dry eye †	0/6 (0.00%)	0	2/52 (3.85%)	2
Retinal vascular disorder †	0/6 (0.00%)	0	1/52 (1.92%)	1
Visual field defect left lower quadrants †	0/6 (0.00%)	0	1/52 (1.92%)	1
Gastrointestinal disorders
Abdominal pain †	0/6 (0.00%)	0	2/52 (3.85%)	3
Abdominal pain, intermittent †	0/6 (0.00%)	0	1/52 (1.92%)	1
Colitis †	0/6 (0.00%)	0	1/52 (1.92%)	1
Constipation †	0/6 (0.00%)	0	5/52 (9.62%)	6
Diarrhea †	2/6 (33.33%)	5	9/52 (17.31%)	11
Dry mouth †	1/6 (16.67%)	1	2/52 (3.85%)	2
Gastritis †	1/6 (16.67%)	1	1/52 (1.92%)	1
Gastroenteritis †	1/6 (16.67%)	1	0/52 (0.00%)	0
Gastroesophageal reflux disease †	0/6 (0.00%)	0	2/52 (3.85%)	2
Gastrointestinal pain †	0/6 (0.00%)	0	1/52 (1.92%)	1
Mucositis oral †	0/6 (0.00%)	0	3/52 (5.77%)	3
Nausea †	1/6 (16.67%)	2	11/52 (21.15%)	14
Nausea with weight loss †	1/6 (16.67%)	1	0/52 (0.00%)	0
Tongue mycosis †	0/6 (0.00%)	0	1/52 (1.92%)	1
Vomiting †	2/6 (33.33%)	2	3/52 (5.77%)	4
General disorders
Anemia †	0/6 (0.00%)	0	1/52 (1.92%)	1
Asthenia †	0/6 (0.00%)	0	1/52 (1.92%)	1
Diaphoresis †	0/6 (0.00%)	0	1/52 (1.92%)	1
Edema limbs †	0/6 (0.00%)	0	4/52 (7.69%)	4
Edema trunk †	0/6 (0.00%)	0	1/52 (1.92%)	1
Fatigue †	3/6 (50.00%)	4	16/52 (30.77%)	23
Fever †	1/6 (16.67%)	1	3/52 (5.77%)	5
Flu-like symptoms †	0/6 (0.00%)	0	5/52 (9.62%)	5
Hoarseness †	0/6 (0.00%)	0	1/52 (1.92%)	1
Infusion related reaction †	0/6 (0.00%)	0	1/52 (1.92%)	1
Left breast tumour bleeding †	0/6 (0.00%)	0	1/52 (1.92%)	1
Localized edema †	1/6 (16.67%)	1	0/52 (0.00%)	0
Malaise †	0/6 (0.00%)	0	1/52 (1.92%)	1
Non-cardiac chest pain †	0/6 (0.00%)	0	2/52 (3.85%)	4
Pain †	0/6 (0.00%)	0	6/52 (11.54%)	10
Hepatobiliary disorders
Bile duct dilatation †	0/6 (0.00%)	0	1/52 (1.92%)	2
Immune system disorders
Autoimmune disorder †	0/6 (0.00%)	0	1/52 (1.92%)	1
Infections and infestations
Bronchial infection †	0/6 (0.00%)	0	3/52 (5.77%)	3
Catheter-related infection †	1/6 (16.67%)	1	1/52 (1.92%)	1
Dental †	0/6 (0.00%)	0	1/52 (1.92%)	1
Esophageal infection †	0/6 (0.00%)	0	1/52 (1.92%)	1
Laryngitis †	0/6 (0.00%)	0	1/52 (1.92%)	1
Pharyngitis †	0/6 (0.00%)	0	2/52 (3.85%)	4
Rhinitis infective †	0/6 (0.00%)	0	3/52 (5.77%)	4
Sepsis †	0/6 (0.00%)	0	1/52 (1.92%)	1
Sinusitis †	1/6 (16.67%)	1	1/52 (1.92%)	1
Skin infection †	1/6 (16.67%)	1	1/52 (1.92%)	1
Upper respiratory infection †	2/6 (33.33%)	4	2/52 (3.85%)	3
Urinary tract infection †	1/6 (16.67%)	1	1/52 (1.92%)	3
Yeasts in the stool †	0/6 (0.00%)	0	1/52 (1.92%)	1
Investigations
Alanine aminotransferase increased †	1/6 (16.67%)	1	4/52 (7.69%)	4
Alkaline phosphatase increased †	0/6 (0.00%)	0	3/52 (5.77%)	4
Aspartate aminotransferase increased †	0/6 (0.00%)	0	3/52 (5.77%)	4
Blood bilirubin increased †	0/6 (0.00%)	0	1/52 (1.92%)	3
Drug induced liver injury †	0/6 (0.00%)	0	1/52 (1.92%)	1
Ggt increased †	0/6 (0.00%)	0	5/52 (9.62%)	11
Hypercalcemia †	0/6 (0.00%)	0	1/52 (1.92%)	1
Leucocyte count decreased †	0/6 (0.00%)	0	1/52 (1.92%)	1
Lipase increased †	0/6 (0.00%)	0	3/52 (5.77%)	6
Lymphocyte count decreased †	1/6 (16.67%)	1	1/52 (1.92%)	1
Neutrophil count decreased †	0/6 (0.00%)	0	2/52 (3.85%)	2
Serum amylase increased †	0/6 (0.00%)	0	3/52 (5.77%)	3
Weight loss †	0/6 (0.00%)	0	4/52 (7.69%)	4
White blood cell decreased †	0/6 (0.00%)	0	1/52 (1.92%)	1
Metabolism and nutrition disorders
Anorexia †	0/6 (0.00%)	0	4/52 (7.69%)	4
Hypercalcemia †	0/6 (0.00%)	0	3/52 (5.77%)	3
Hyperglycemia †	0/6 (0.00%)	0	1/52 (1.92%)	1
Hyperkalemia †	0/6 (0.00%)	0	3/52 (5.77%)	3
Hyperuricemia †	0/6 (0.00%)	0	1/52 (1.92%)	1
Hypoalbuminemia †	1/6 (16.67%)	1	2/52 (3.85%)	3
Hypocalcemia †	1/6 (16.67%)	1	1/52 (1.92%)	1
Hypokalemia †	0/6 (0.00%)	0	1/52 (1.92%)	1
Musculoskeletal and connective tissue disorders
Arthralgia †	2/6 (33.33%)	3	6/52 (11.54%)	6
Back pain †	0/6 (0.00%)	0	3/52 (5.77%)	5
Bone pain †	0/6 (0.00%)	0	2/52 (3.85%)	2
Buttock pain †	0/6 (0.00%)	0	1/52 (1.92%)	1
Shoulder pain †	2/6 (33.33%)	2	0/52 (0.00%)	0
Myalgia †	2/6 (33.33%)	2	4/52 (7.69%)	4
Neck pain †	0/6 (0.00%)	0	1/52 (1.92%)	1
Pain †	0/6 (0.00%)	0	1/52 (1.92%)	1
Pain in extremity †	0/6 (0.00%)	0	1/52 (1.92%)	1
Stiffness †	0/6 (0.00%)	0	1/52 (1.92%)	1
Nervous system disorders
Aphasia †	0/6 (0.00%)	0	1/52 (1.92%)	1
Aphonia †	0/6 (0.00%)	0	1/52 (1.92%)	2
Ataxia †	0/6 (0.00%)	0	1/52 (1.92%)	1
Balance disorder †	0/6 (0.00%)	0	1/52 (1.92%)	1
Cognitive disturbance †	0/6 (0.00%)	0	1/52 (1.92%)	1
Dizziness †	0/6 (0.00%)	0	2/52 (3.85%)	2
Dysesthesia †	0/6 (0.00%)	0	1/52 (1.92%)	1
Dysgeusia †	0/6 (0.00%)	0	1/52 (1.92%)	1
Dysphasia †	0/6 (0.00%)	0	1/52 (1.92%)	1
Headache †	2/6 (33.33%)	3	8/52 (15.38%)	15
Loss of hand motor traction †	1/6 (16.67%)	1	0/52 (0.00%)	0
Memory impairment †	1/6 (16.67%)	1	1/52 (1.92%)	1
Paresthesia †	0/6 (0.00%)	0	1/52 (1.92%)	1
Static cerebellar syndrom †	0/6 (0.00%)	0	1/52 (1.92%)	1
Tremor †	0/6 (0.00%)	0	1/52 (1.92%)	1
Vasovagal reaction †	0/6 (0.00%)	0	1/52 (1.92%)	1
Psychiatric disorders
Anxiety †	1/6 (16.67%)	1	2/52 (3.85%)	2
Insomnia †	2/6 (33.33%)	2	1/52 (1.92%)	1
Renal and urinary disorders
Acute renal impairment †	0/6 (0.00%)	0	1/52 (1.92%)	1
Chronic kidney disease †	0/6 (0.00%)	0	1/52 (1.92%)	1
UTI †	0/6 (0.00%)	0	1/52 (1.92%)	1
Reproductive system and breast disorders
Breast pain †	0/6 (0.00%)	0	2/52 (3.85%)	2
Respiratory, thoracic and mediastinal disorders
Bronchopulmonary hemorrhage †	1/6 (16.67%)	1	0/52 (0.00%)	0
Cough †	1/6 (16.67%)	1	9/52 (17.31%)	12
Dyspnea †	3/6 (50.00%)	4	11/52 (21.15%)	18
Epistaxis †	0/6 (0.00%)	0	1/52 (1.92%)	1
Epistaxis: seasonal †	0/6 (0.00%)	0	1/52 (1.92%)	1
Laryngeal inflammation †	0/6 (0.00%)	0	1/52 (1.92%)	1
Nasal congestion †	1/6 (16.67%)	1	0/52 (0.00%)	0
Pleural effusion †	0/6 (0.00%)	0	2/52 (3.85%)	3
Pneumonia †	1/6 (16.67%)	2	0/52 (0.00%)	0
Pneumonitis †	0/6 (0.00%)	0	4/52 (7.69%)	4
Pneumothorax †	0/6 (0.00%)	0	1/52 (1.92%)	1
Productive cough †	0/6 (0.00%)	0	2/52 (3.85%)	2
Respiratory distress †	0/6 (0.00%)	0	1/52 (1.92%)	1
Shortness of breath †	0/6 (0.00%)	0	1/52 (1.92%)	1
Sinus disorder †	0/6 (0.00%)	0	1/52 (1.92%)	1
Sore throat †	0/6 (0.00%)	0	1/52 (1.92%)	1
Upper respiratory tract infection †	0/6 (0.00%)	0	1/52 (1.92%)	1
Viral upper respiratory tract infection †	1/6 (16.67%)	1	3/52 (5.77%)	4
Skin and subcutaneous tissue disorders
Cutaneous rash †	0/6 (0.00%)	0	1/52 (1.92%)	7
Cutaneous toxicity on legs and arms †	0/6 (0.00%)	0	1/52 (1.92%)	1
Dry skin †	0/6 (0.00%)	0	1/52 (1.92%)	1
Erysipelas †	0/6 (0.00%)	0	1/52 (1.92%)	2
Hyperhidrosis †	0/6 (0.00%)	0	1/52 (1.92%)	1
Palmar-plantar erythrodysesthesia syndrome †	0/6 (0.00%)	0	1/52 (1.92%)	1
Photosensitivity †	0/6 (0.00%)	0	1/52 (1.92%)	1
Pruritus †	0/6 (0.00%)	0	5/52 (9.62%)	6
Rash - face †	1/6 (16.67%)	1	0/52 (0.00%)	0
Rash acneiform †	1/6 (16.67%)	2	2/52 (3.85%)	3
Rash maculo-papular †	0/6 (0.00%)	0	3/52 (5.77%)	4
Redness ankle and feet †	0/6 (0.00%)	0	1/52 (1.92%)	1
Shingles †	0/6 (0.00%)	0	1/52 (1.92%)	1
Vascular disorders
Hot flashes †	0/6 (0.00%)	0	1/52 (1.92%)	1
Hypertension †	0/6 (0.00%)	0	6/52 (11.54%)	12
Hypotension †	0/6 (0.00%)	0	1/52 (1.92%)	1
Intracranial hypertension †	0/6 (0.00%)	0	1/52 (1.92%)	1
Lymphedema †	0/6 (0.00%)	0	1/52 (1.92%)	1
Lymphedema right leg †	0/6 (0.00%)	0	1/52 (1.92%)	1
Thromboembolic event †	0/6 (0.00%)	0	1/52 (1.92%)	1
† 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: Heidi Roschitzki-Voser
• Organization: International Breast Cancer Study Group (IBCSG)
• Phone: +41 31 511 94 18
• EMail: heidi.roschitzki@ibcsg.org

Publications:

Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J, Norton L. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001 Mar 15;344(11):783-92. doi: 10.1056/NEJM200103153441101.

Hurvitz SA, Betting DJ, Stern HM, Quinaux E, Stinson J, Seshagiri S, Zhao Y, Buyse M, Mackey J, Driga A, Damaraju S, Sliwkowski MX, Robert NJ, Valero V, Crown J, Falkson C, Brufsky A, Pienkowski T, Eiermann W, Martin M, Bee V, Marathe O, Slamon DJ, Timmerman JM. Analysis of Fcgamma receptor IIIa and IIa polymorphisms: lack of correlation with outcome in trastuzumab-treated breast cancer patients. Clin Cancer Res. 2012 Jun 15;18(12):3478-86. doi: 10.1158/1078-0432.CCR-11-2294. Epub 2012 Apr 13.

Denkert C, Loibl S, Noske A, Roller M, Muller BM, Komor M, Budczies J, Darb-Esfahani S, Kronenwett R, Hanusch C, von Torne C, Weichert W, Engels K, Solbach C, Schrader I, Dietel M, von Minckwitz G. Tumor-associated lymphocytes as an independent predictor of response to neoadjuvant chemotherapy in breast cancer. J Clin Oncol. 2010 Jan 1;28(1):105-13. doi: 10.1200/JCO.2009.23.7370. Epub 2009 Nov 16. Erratum In: J Clin Oncol. 2010 Feb 1;28(4):708.

Loi S, Sirtaine N, Piette F, Salgado R, Viale G, Van Eenoo F, Rouas G, Francis P, Crown JP, Hitre E, de Azambuja E, Quinaux E, Di Leo A, Michiels S, Piccart MJ, Sotiriou C. Prognostic and predictive value of tumor-infiltrating lymphocytes in a phase III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG 02-98. J Clin Oncol. 2013 Mar 1;31(7):860-7. doi: 10.1200/JCO.2011.41.0902. Epub 2013 Jan 22.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Loi S, Giobbie-Hurder A, Gombos A, Bachelot T, Hui R, Curigliano G, Campone M, Biganzoli L, Bonnefoi H, Jerusalem G, Bartsch R, Rabaglio-Poretti M, Kammler R, Maibach R, Smyth MJ, Di Leo A, Colleoni M, Viale G, Regan MM, Andre F; International Breast Cancer Study Group and the Breast International Group. Pembrolizumab plus trastuzumab in trastuzumab-resistant, advanced, HER2-positive breast cancer (PANACEA): a single-arm, multicentre, phase 1b-2 trial. Lancet Oncol. 2019 Mar;20(3):371-382. doi: 10.1016/S1470-2045(18)30812-X. Epub 2019 Feb 11.

• Responsible Party: ETOP IBCSG Partners Foundation
• ClinicalTrials.gov Identifier: NCT02129556
• Other Study ID Numbers: IBCSG 45-13 / BIG 4-13; 2013-004770-10 ( EudraCT Number )
• First Submitted: April 24, 2014
• First Posted: May 2, 2014
• Results First Submitted: October 3, 2018
• Results First Posted: February 15, 2019
• Last Update Posted: February 15, 2019