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Clinical Trial Results:
A multicenter phase II trial to evaluate the efficacy and safety of pembrolizumab and gemcitabine in patients with HER2-negative Advanced Breast Cancer (ABC). “PANGEA-Breast”

Summary
EudraCT number	2016-001779-54
Trial protocol	ES
Global end of trial date

Results information
Results version number	v3(current)
This version publication date	21 Dec 2022
First version publication date	18 Mar 2022
Other versions	v1 , v2
Version creation reason	New data added to full data set New publication

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

GEICAM/2015-04

ISRCTN number

US NCT number

NCT03025880

WHO universal trial number (UTN)

Sponsor organisation name

GEICAM (FUNDACIÓN GRUPO ESPAÑOL DE INVESTIGACIÓN EN CÁNCER DE MAMA)

Sponsor organisation address

Avenida de los Pirineos 7, San Sebastián de los Reyes / Madrid, Spain, 28703

Public contact

Clinical Operations Department, GEICAM (Fundación Grupo Español de Investigación en Cáncer de Mama), +34 916592870, inicio_ensayos@geicam.org

Scientific contact

Clinical Operations Department, GEICAM (Fundación Grupo Español de Investigación en Cáncer de Mama), +34 916592870, inicio_ensayos@geicam.org

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Interim

Date of interim/final analysis

03 Jun 2019

Is this the analysis of the primary completion data?

Global end of trial reached?

Main objective of the trial

Run-in-phase: To determine the Recommended Phase II Dose (RP2D) of gemcitabine in combination with fixed doses of pembrolizumab. Phase II: To assess the efficacy of pembrolizumab in combination with gemcitabine in terms of Objective Response Rate (ORR) in patients with HER2-negative ABC.

Protection of trial subjects

Not applicable. It was not necessary to applied extra measures for protection of the subjects out of the good clinical practice environment.

Background therapy

Available data support the hypothesis of an immune mediated antitumor activity in breast carcinoma, and several lines of research are ongoing. It is critical to understand what happens in the tumoral microenvironment in order to design biological agents and approaches that might modulate the immune response towards cancer cell destruction. At this point and due to new knowledge emerged with immune checkpoints function at immune synapses, combinatorial schedules seem to be a promising strategy. In this sense, combining chemotherapy and immunotherapy is an interesting approach in chemo-sensitive diseases that will eventually synergize and reach meaningful clinical results. Gemcitabine is a cytotoxic drug with well-known immunostimulatory properties that include increasing antigen (neoantigens) threshold and cross-presentation (via APCs), with enhancement of T-cell response and generation of memory T cells. In addition, gemcitabine has demonstrated the ability to restore immune surveillance by reducing myeloid derived suppressor cells (MDSC) levels in murine models. Furthermore, gemcitabine-based schedules have demonstrated clinical activity in breast cancer. Pembrolizumab is a human programmed death receptor-1 (PD-1)-blocking antibody that has gained Food and Drug Administration (FDA) approval for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab treatment. In our opinion, there is sufficient evidence to consider that advanced breast carcinoma may be sensitive to immunotherapeutic approaches. Our proposal is based on a combination strategy with two immunostimulatory agents: gemcitabine (immunogenic apoptosis and elimination of MDSC) and pembrolizumab (blocking PD1/PD-L1 interaction) in advanced breast carcinoma (ABC) that may synergize and induce responses with long term clinical benefit.

Evidence for comparator

Actual start date of recruitment

28 Jun 2017

Long term follow-up planned

Yes

Long term follow-up rationale

Safety, Efficacy

Long term follow-up duration

100 Years

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Spain: 36

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

From June 2017 to May 2018, 36 patients were recruited in nine Spanish sites for the first stage of the Simon minimax two-stage design, but only 5 patients presented a response, so recruitment was stopped permanently

Screening details

Period 1 title

Overall trial (overall period)

Is this the baseline period?

Yes

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Run-in Phase Dose Level 0

Arm description

Eligible patients were enrolled and treated with Pembrolizumab at a dose of 200mg as an intravenous (IV) infusion on day 1 of each 21-day cycle in combination with Gemcitabine at a dose of 1,250mg/m2 (Dose Level 0) or 1,000mg/m2 (Dose Level -1) as a IV infusion on day 1 and 8 of each 21-day cycle. Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first. An initial exploratory run-in-phase will be performed to test the safety of the combination and determine the Recommended Phase II Dose (RP2D) of Gemcitabine in combination with fixed doses of Pembrolizumab .

Arm type

Experimental

Investigational medicinal product name

Pembrolizumab

Investigational medicinal product code

Other name

Keytruda

Pharmaceutical forms

Concentrate and solvent for solution for infusion

Routes of administration

Intravenous bolus use

Dosage and administration details

Pembrolizumab at a dose of 200mg as an intravenous (IV) 30 minutes infusion on day 1 of each 21-day cycle. Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first. Patients completing 24 months of uninterrupted treatment with pembrolizumab or 35 administrations of study medication will stop pembrolizumab treatment (though may continue with gemcitabine). Subjects who stop pembrolizumab after 24 months may be eligible for up to one year of additional pembrolizumab treatment if they progress after stopping it.

Investigational medicinal product name

Gemcitabine

Investigational medicinal product code

Other name

Gemzar

Pharmaceutical forms

Powder and suspension for suspension for injection

Routes of administration

Intravenous use

Dosage and administration details

Gemcitabine at a dose of 1,250mg/m2 as an intravenous (IV) 60 minutes infusion on day 1 and 8 of each 21-day cycle. Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first.

Phase II

Arm description

Eligible patients were enrolled and treated with Pembrolizumab (P) at a dose of 200mg as an intravenous (IV) infusion on day 1 of each 21-day cycle in combination with Gemcitabine (G) at a dose of 1,250mg/m2 (Recommended Phase II Dose (RP2D) from the run-in phase) as a IV infusion on day 1 and 8 of each 21-day cycle. Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first.

Arm type

Experimental

Investigational medicinal product name

Pembrolizumab

Investigational medicinal product code

Other name

Keytruda

Pharmaceutical forms

Concentrate and solvent for solution for infusion

Routes of administration

Intravenous bolus use

Dosage and administration details

Investigational medicinal product name

Gemcitabine

Investigational medicinal product code

Other name

Gemzar

Pharmaceutical forms

Powder and suspension for suspension for injection

Routes of administration

Intravenous use

Dosage and administration details

Number of subjects in period 1	Run-in Phase Dose Level 0	Phase II
Started	14	22
Completed	12	19
Not completed	2	3
Adverse event, serious fatal	1	1
Consent withdrawn by subject	-	1
Physician decision	-	1
Adverse event, non-fatal	1	-

Baseline characteristics

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Reporting group title

Run-in Phase Dose Level 0

Reporting group description

Reporting group title

Phase II

Reporting group description

Reporting group values	Run-in Phase Dose Level 0	Phase II	Total
Number of subjects	14	22	36
Age categorical
Units: Subjects
Adults (18-64 years)	14	19	33
From 65-84 years	0	3	3
Age continuous
Units: years
median (full range (min-max))	48.5 (32 to 61)	56 (31 to 77)	-
Gender categorical
Units: Subjects
Female	14	22	36
Male	0	0	0
Race
Units: Subjects
White	14	22	36
Menopause Status
Units: Subjects
Postmenopausal	10	16	26
Premenopausal	4	6	10
Eastern Cooperative Oncology Group (ECOG) status
ECOG score runs from 0 to 5, with 0 denoting perfect health and 5 death. 0 - Asymptomatic 1 - Symptomatic but completely ambulatory 2 - Symptomatic, <50% in bed during the day 3 - Symptomatic, >50% in bed, but not bedbound 4 - Bedbound 5 - Death
Units: Subjects
ECOG 0	7	16	23
ECOG 1	6	6	12
ECOG 2	1	0	1
Type of Disease for Cohort Purposes
Luminal A: estrogen-receptor (ER) and/or progesterone-receptor (PR) positive, Human Epidermal Growth Factor Receptor 2 (HER2) negative, low levels of Ki67. Luminal A are low-grade, tend to grow slowly and have the best prognosis. Luminal B: ER and/or PR positive, and HER2 positive or HER2 negative with high levels of Ki67. Luminal B grow faster than luminal A and their prognosis is worse. Triple-negative (TN): negative for ER, PR, and HER2. Is more aggressive and have poorer prognosis than Luminal due to there are fewer targeted medicines that treat TN.
Units: Subjects
Triple negative	9	12	21
Luminal A+B	5	10	15
Ki67 cut off 20%
Ki67 is a protein found in the nucleus of cells when they divide. Ki67 determines the proliferation rate. Tumors with high proliferation rates (> 20%) have a worse prognosis.
Units: Subjects
Ki67 < 20%	1	4	5
Ki67 >= 20	8	13	21
Ki67 not available or not done	5	5	10
Histopathologic Type
Units: Subjects
Ductal	13	20	33
Lobular	1	1	2
Other: Squamous Invasive Cancer	0	1	1
Histologic Grade
Cancer cells are given a Grade (G) when they are removed from the breast and checked under a microscope. The G is based on how much the cancer cells look like normal cells. G1 or well differentiated (score 3, 4, or 5): cells are slower-growing, and look more like normal breast tissue. G2 or moderately differentiated (score 6, 7): cells are growing at a speed of and look like cells somewhere between G1 and 3. G3 or poorly differentiated (score 8, 9): cells look very different from normal and will probably grow and spread faster.
Units: Subjects
Grade 1	0	1	1
Grade 2	4	10	14
Grade 3	6	10	16
Unknown	1	0	1
Not done	3	1	4

End points

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Reporting group title

Run-in Phase Dose Level 0

Reporting group description

Reporting group title

Phase II

Reporting group description

Primary: Incidence rate of Dose Limiting Toxicity (DLT)

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End point title

Incidence rate of Dose Limiting Toxicity (DLT) ^[1]

End point description

DLT was defined as the occurrence of any of the following adverse events (AE) or abnormal laboratory value (graded according to the NCI Common Terminology Criteria for AE (CTCAE) version 4.0), assessed as possibly, probably or definitively related to study drug/medication, occurring within the first cycle of study treatment: any Grade 4 thrombocytopenia or neutropenia lasting > 7 days; episcleritis, uveitis, or iritis of Grade 2 or higher, any Grade 4 toxicity, any Grade 3 toxicity EXCLUDING: nausea, vomiting, or diarrhea controlled by medical intervention within 72 hours, grade 3 rash in the absence of desquamation, no mucosal involvement, does not require steroids, and resolves to Grade 1 by the next scheduled dose of pembrolizumab, transient Grade 3 Aspartate Transaminase (AST) or Alanine Transaminase (ALT) elevation, defined as no more than 3 days with or without steroid use, discontinuation or delay of more than 2 weeks of any study drug/medication due to treatment-related AE.

End point type

Primary

End point timeframe

Up to cycle 1

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Not applicable

End point values	Run-in Phase Dose Level 0	Phase II
Number of subjects analysed	14	22
Units: Events	1	0

No statistical analyses for this end point

Primary: The Recommended Phase II Dose (RP2D) of gemcitabine

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End point title

The Recommended Phase II Dose (RP2D) of gemcitabine ^[2] ^[3]

End point description

Up to cycle 1

End point type

Primary

End point timeframe

The RP2D was decided by the internal committee taken into consideration the information obtained in the study and based on the number of DLT.

Notes
[2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Not applicable
[3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Not applicable

End point values	Run-in Phase Dose Level 0
Number of subjects analysed	14
Units: mg/m2	1250

No statistical analyses for this end point

Primary: Objective Response Rate (ORR)

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End point title

Objective Response Rate (ORR)

End point description

Tumor response was assessed using Response Evaluation Criteria In Solid Tumors Criteria (RECIST 1.1). ORR is defined as the percentage of patients with a Complete Response (CR) or Partial Response (PR) out of the patients from the efficacy population. Per RECIST, CR is defined as the disappearance of all target lesions; PR is defined as an >=30% decrease in the sum of the longest diameter of target lesions.

End point type

Primary

End point timeframe

Through study treatment, and average of 3 months

End point values	Run-in Phase Dose Level 0	Phase II
Number of subjects analysed	13	20
Units: Participants	0	5

ORR analysis

Comparison groups

Run-in Phase Dose Level 0 v Phase II

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[4]

Method

Parameter type

percentage

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

8.7

upper limit

49.1

Notes
[4] - The rate of OR and confidence interval

Secondary: Progression-Free Survival (PFS)

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End point title

Progression-Free Survival (PFS)

End point description

Tumor response was assessed using Response Evaluation Criteria In Solid Tumors Criteria (RECIST 1.1). PFS is defined as the time from enrollment to the first documented progression disease (PD), or death from any cause, whichever occurs first. PD is defined using RECIST, as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions

End point type

Secondary

End point timeframe

Through study treatment, and average of 3 months

End point values	Run-in Phase Dose Level 0	Phase II
Number of subjects analysed	13	20
Units: Months
median (confidence interval 95%)	3.1 (0.9 to 5.4)	2.6 (1.9 to 6.1)

No statistical analyses for this end point

Secondary: Clinical Benefit Rate (CBR)

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End point title

Clinical Benefit Rate (CBR)

End point description

Tumor response was assessed using Response Evaluation Criteria In Solid Tumors Criteria (RECIST 1.1) criteria. CBR was defined as the percentage of patients with a Complete Response (CR) or Partial Response (PR) plus stable disease (SD) out of the efficacy population. Per RECIST, CR is defined as the disappearance of all target lesions; PR is defined as an >=30% decrease in the sum of the longest diameter of target lesions; SD is defined as a failure to meet criteria for CR or PR in the absence of progressive disease. Overall Response (OR) = CR + PR.

End point type

Secondary

End point timeframe

Through study treatment, and average of 3 months

End point values	Run-in Phase Dose Level 0	Phase II
Number of subjects analysed	13	20
Units: Events	7	10

No statistical analyses for this end point

Secondary: Clinical Benefit Rate (CBR) at Least 24 Weeks

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End point title

Clinical Benefit Rate (CBR) at Least 24 Weeks

End point description

Tumor response was assessed using Response Evaluation Criteria In Solid Tumors Criteria (RECIST 1.1) criteria. CBR was defined as the percentage of patients with a Complete Response (CR) or Partial Response (PR) plus stable disease (SD) lasting at least 24 months out of the efficacy population. Per RECIST, CR is defined as the disappearance of all target lesions; PR is defined as an >=30% decrease in the sum of the longest diameter of target lesions; SD is defined as a failure to meet criteria for CR or PR in the absence of progressive disease lasting at least 24 months. Overall Response (OR) = CR + PR.

End point type

Secondary

End point timeframe

24 Weeks

End point values	Run-in Phase Dose Level 0	Phase II
Number of subjects analysed	13	20
Units: Events	1	5

No statistical analyses for this end point

Secondary: Response Duration (RD)

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End point title

Response Duration (RD)

End point description

Tumor response was assessed using Response Evaluation Criteria In Solid Tumors Criteria (RECIST 1.1) criteria. RD was defined as the time from the first documentation of objective tumor response (complete response (CR) or partial response (PR)) to the first documented progressive disease (PD), or to death due to any cause, whichever occurs first. Per RECIST, CR is defined as the disappearance of all target lesions; PR is defined as an >=30% decrease in the sum of the longest diameter of target lesions; PD is defined as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions

End point type

Secondary

End point timeframe

Through study treatment, and average of 3 months

End point values	Run-in Phase Dose Level 0	Phase II
Number of subjects analysed	14 ^[5]	22 ^[6]
Units: Months
median (confidence interval 95%)	0 (0 to 0)	4.3 (2.3 to 7.4)

Notes
[5] - No patients from Run-in phase have complete partial or complete response.
[6] - 5 patients from phase II have complete partial or complete response.

RD analysis

Comparison groups

Phase II v Run-in Phase Dose Level 0

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

survival median

Point estimate

4.3

Confidence interval

level

95%

sides

2-sided

lower limit

2.3

upper limit

10.3

Secondary: Overall Survival (OS)

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End point title

Overall Survival (OS)

End point description

OS is defined as the time from the date of enrollment to the date of death from any cause.

End point type

Secondary

End point timeframe

Through study

End point values	Run-in Phase Dose Level 0	Phase II
Number of subjects analysed	13	20
Units: Months
median (confidence interval 95%)	6.1 (1.3 to 11.7)	10.1 (7.3 to 17.7)

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

AE were reported after Informed Consent Document (ICD) and before study drugs until approximately 30 days following the discontinuation of study treatment

Assessment type

Systematic

Dictionary name

NCI-CTCAE

Dictionary version

4.03

Reporting group title

Run-in Phase Dose Level 0

Reporting group description

Reporting group title

Phase II

Reporting group description

Serious adverse events	Run-in Phase Dose Level 0	Phase II
Total subjects affected by serious adverse events
subjects affected / exposed	8 / 14 (57.14%)	4 / 22 (18.18%)
number of deaths (all causes)	11	11
number of deaths resulting from adverse events	0	0
Investigations
Platelet count decreased
subjects affected / exposed	2 / 14 (14.29%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Alanine aminotransferase increased
subjects affected / exposed	1 / 14 (7.14%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Aspartate aminotransferase increased
subjects affected / exposed	1 / 14 (7.14%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lymphocyte count decreased
subjects affected / exposed	1 / 14 (7.14%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Neutrophil count decreased
subjects affected / exposed	1 / 14 (7.14%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
White blood cell count decreased
subjects affected / exposed	1 / 14 (7.14%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour pain
subjects affected / exposed	1 / 14 (7.14%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Neurological decompensation
subjects affected / exposed	0 / 14 (0.00%)	1 / 22 (4.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	2 / 14 (14.29%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Oedema peripheral
subjects affected / exposed	0 / 14 (0.00%)	1 / 22 (4.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	0 / 14 (0.00%)	1 / 22 (4.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain upper
subjects affected / exposed	1 / 14 (7.14%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	1 / 14 (7.14%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
Hyperbilirubinaemia
subjects affected / exposed	1 / 14 (7.14%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Respiratory failure
subjects affected / exposed	1 / 14 (7.14%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Abdominal sepsis
subjects affected / exposed	1 / 14 (7.14%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Bacterial pyelonephritis
subjects affected / exposed	1 / 14 (7.14%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	0 / 14 (0.00%)	1 / 22 (4.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory tract infection
subjects affected / exposed	0 / 14 (0.00%)	1 / 22 (4.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Run-in Phase Dose Level 0	Phase II
Total subjects affected by non serious adverse events
subjects affected / exposed	14 / 14 (100.00%)	21 / 22 (95.45%)
Vascular disorders
Hot flush
subjects affected / exposed	0 / 14 (0.00%)	2 / 22 (9.09%)
occurrences all number	0	2
Hypertension
subjects affected / exposed	4 / 14 (28.57%)	0 / 22 (0.00%)
occurrences all number	7	0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	7 / 14 (50.00%)	14 / 22 (63.64%)
occurrences all number	9	21
Pyrexia
subjects affected / exposed	4 / 14 (28.57%)	6 / 22 (27.27%)
occurrences all number	8	7
Fatigue
subjects affected / exposed	0 / 14 (0.00%)	2 / 22 (9.09%)
occurrences all number	0	2
Pain
subjects affected / exposed	2 / 14 (14.29%)	0 / 22 (0.00%)
occurrences all number	2	0
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	1 / 14 (7.14%)	2 / 22 (9.09%)
occurrences all number	2	3
Psychiatric disorders
Anxiety
subjects affected / exposed	1 / 14 (7.14%)	1 / 22 (4.55%)
occurrences all number	1	1
Investigations
Neutrophil count decreased
subjects affected / exposed	7 / 14 (50.00%)	15 / 22 (68.18%)
occurrences all number	53	28
Platelet count decreased
subjects affected / exposed	8 / 14 (57.14%)	11 / 22 (50.00%)
occurrences all number	19	18
Alanine aminotransferase increased
subjects affected / exposed	9 / 14 (64.29%)	11 / 22 (50.00%)
occurrences all number	24	33
Aspartate aminotransferase increased
subjects affected / exposed	9 / 14 (64.29%)	13 / 22 (59.09%)
occurrences all number	30	34
Lymphocyte count decreased
subjects affected / exposed	13 / 14 (92.86%)	12 / 22 (54.55%)
occurrences all number	101	89
White blood cell count decreased
subjects affected / exposed	11 / 14 (78.57%)	18 / 22 (81.82%)
occurrences all number	82	68
Alkaline phosphatase increased
subjects affected / exposed	14 / 14 (100.00%)	10 / 22 (45.45%)
occurrences all number	51	46
INR increased
subjects affected / exposed	8 / 14 (57.14%)	2 / 22 (9.09%)
occurrences all number	33	5
Blood bilirubin increased
subjects affected / exposed	2 / 14 (14.29%)	2 / 22 (9.09%)
occurrences all number	3	4
Lymphocyte count increased
subjects affected / exposed	1 / 14 (7.14%)	1 / 22 (4.55%)
occurrences all number	1	2
Weight decreased
subjects affected / exposed	1 / 14 (7.14%)	1 / 22 (4.55%)
occurrences all number	1	1
Cardiac disorders
Tachycardia
subjects affected / exposed	1 / 14 (7.14%)	2 / 22 (9.09%)
occurrences all number	1	2
Nervous system disorders
Dizziness
subjects affected / exposed	0 / 14 (0.00%)	2 / 22 (9.09%)
occurrences all number	0	2
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	13 / 14 (92.86%)	21 / 22 (95.45%)
occurrences all number	136	218
Gastrointestinal disorders
Nausea
subjects affected / exposed	2 / 14 (14.29%)	6 / 22 (27.27%)
occurrences all number	4	7
Diarrhoea
subjects affected / exposed	2 / 14 (14.29%)	2 / 22 (9.09%)
occurrences all number	11	3
Vomiting
subjects affected / exposed	0 / 14 (0.00%)	2 / 22 (9.09%)
occurrences all number	0	2
Constipation
subjects affected / exposed	3 / 14 (21.43%)	1 / 22 (4.55%)
occurrences all number	3	2
Abdominal pain upper
subjects affected / exposed	2 / 14 (14.29%)	0 / 22 (0.00%)
occurrences all number	3	0
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed	1 / 14 (7.14%)	2 / 22 (9.09%)
occurrences all number	2	3
Pain of skin
subjects affected / exposed	2 / 14 (14.29%)	1 / 22 (4.55%)
occurrences all number	2	1
Pruritus
subjects affected / exposed	3 / 14 (21.43%)	0 / 22 (0.00%)
occurrences all number	3	0
Alopecia
subjects affected / exposed	0 / 14 (0.00%)	2 / 22 (9.09%)
occurrences all number	0	2
Renal and urinary disorders
Albuminuria
subjects affected / exposed	2 / 14 (14.29%)	0 / 22 (0.00%)
occurrences all number	2	0
Endocrine disorders
Hypothyroidism
subjects affected / exposed	2 / 14 (14.29%)	0 / 22 (0.00%)
occurrences all number	2	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 14 (0.00%)	2 / 22 (9.09%)
occurrences all number	0	3
Back pain
subjects affected / exposed	1 / 14 (7.14%)	2 / 22 (9.09%)
occurrences all number	1	2
Musculoskeletal chest pain
subjects affected / exposed	2 / 14 (14.29%)	1 / 22 (4.55%)
occurrences all number	2	1
Infections and infestations
Upper respiratory tract infection
subjects affected / exposed	2 / 14 (14.29%)	1 / 22 (4.55%)
occurrences all number	2	1
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	2 / 14 (14.29%)	3 / 22 (13.64%)
occurrences all number	2	3
Hypoalbuminemia
subjects affected / exposed	9 / 14 (64.29%)	10 / 22 (45.45%)
occurrences all number	21	30
Hyperglycemia
subjects affected / exposed	4 / 14 (28.57%)	7 / 22 (31.82%)
occurrences all number	23	15
Hypoglycemia
subjects affected / exposed	2 / 14 (14.29%)	3 / 22 (13.64%)
occurrences all number	4	6

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Were there any global substantial amendments to the protocol? Yes

27 Jun 2017

• Add inclusion criterion number 6 to be able to perform a biopsy in the inclusion and in the progression (if possible), for which the tumor lesions are to be biopsible. • Modify in the inclusion criteria number 8, the alkaline phosphatase limit for patients with hepatic, bone or disease metastases. • Update the information described in the biomarker analyses. • Update the information on the preparation of pembrolizumab, since before it contained the preparation of pembrolizumab in lyophilized powder, but the pembrolizumab used in this study was in solution. • Change the population by protocol for population effectiveness and clarify its definition. • Add the definition of what is considered an overdose of Gemcitabine. • Update the schedule of visits to be able to clarify if you have to recalculate the dose of gemcitabine and do not have to repeat the baseline analyses if you have done them in the 7 days before the 1 day 1 cycle. • Minor typographic changes

27 Nov 2017

• Add the possibility of analysing FT3 instead of only T3 • Minor typographic errors

19 Mar 2018

• Update the security changes collected in the new version of the Investigator Brochure v. 15 both in the protocol, updating the dose adjustment table of the pembrolizumab, as in the Informed Consent, updating the section of side effects. This new version of Consent Informed had to be signed only by new patients. • Modify inclusion criteria number 7 to restrict the inclusion of patients to those that present a functional status according to the ECOG scale of 0 or 1. • Add to the inclusion criteria number 9 a maximum number of previous lines of Chemotherapy for treatment of ABC. These two criteria are modified by their negative influence on the clinical evolution of patients impacting on the likelihood of them obtaining a benefit from the administration of treatment of the study, and therefore, in that it can carry out an adequate evaluation of the anti-tumor activity of this combination of drugs in the population in study. • Update the information on the administration of gemcitabine, as before the administration was shown in 60 minutes, but in the summary product characteristics (SmPC) is 30 minutes. • The dose adjustment section of gemcitabine has been updated to collect the assumption that there has been hematological toxicity in the previous cycle that has caused the omission of the dose of day 8. • Update the visits schedule to clarify that the peripheral blood sample which is to be taken in the end-of-treatment visit is in the case of discontinuation of pembrolizumab. • Minor typographic changes

Were there any global interruptions to the trial? Yes

Date	Interruption	Restart date
17 Apr 2018	Per protocol, a Simon minimax two-stage design was employed with the possibility of stopping early due to lack of response. Per this Simon design, the first stage included 31 evaluable patients, if at least 7 presented a response, recruitment will continue to include the 53 evaluable patients. The study was interrupted on 17-Apr-2018 as per Simon minimax two-stage design, when 33 evaluable patients were included and then the recruitment was stopped. Only 5 presented a response, so recruitment was permanently stopped.	-

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

Patients included were heavily pretreated in most of the cases with a median of 4 previous lines. There were no patient preselection with respect to their PD-L1 positivity or TILs density, wich is an adverse scenario for immunotherapy .

http://www.ncbi.nlm.nih.gov/pubmed/34771596
http://www.ncbi.nlm.nih.gov/pubmed/36463104

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Clinical Trial Results:
A multicenter phase II trial to evaluate the efficacy and safety of pembrolizumab and gemcitabine in patients with HER2-negative Advanced Breast Cancer (ABC). “PANGEA-Breast”

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Trial information

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Subject disposition

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Baseline characteristics

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End points

Primary: Incidence rate of Dose Limiting Toxicity (DLT)

Primary: Incidence rate of Dose Limiting Toxicity (DLT)

Primary: The Recommended Phase II Dose (RP2D) of gemcitabine

Primary: The Recommended Phase II Dose (RP2D) of gemcitabine

Primary: Objective Response Rate (ORR)

Primary: Objective Response Rate (ORR)

Secondary: Progression-Free Survival (PFS)

Secondary: Progression-Free Survival (PFS)

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Secondary: Clinical Benefit Rate (CBR)

Secondary: Clinical Benefit Rate (CBR) at Least 24 Weeks

Secondary: Clinical Benefit Rate (CBR) at Least 24 Weeks

Secondary: Response Duration (RD)

Secondary: Response Duration (RD)

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Secondary: Overall Survival (OS)

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Substantial protocol amendments (globally)

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Clinical trials

Clinical Trial Results: A multicenter phase II trial to evaluate the efficacy and safety of pembrolizumab and gemcitabine in patients with HER2-negative Advanced Breast Cancer (ABC). “PANGEA-Breast”

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Incidence rate of Dose Limiting Toxicity (DLT)

Primary: Incidence rate of Dose Limiting Toxicity (DLT)

Primary: The Recommended Phase II Dose (RP2D) of gemcitabine

Primary: The Recommended Phase II Dose (RP2D) of gemcitabine

Primary: Objective Response Rate (ORR)

Primary: Objective Response Rate (ORR)

Secondary: Progression-Free Survival (PFS)

Secondary: Progression-Free Survival (PFS)

Secondary: Clinical Benefit Rate (CBR)

Secondary: Clinical Benefit Rate (CBR)

Secondary: Clinical Benefit Rate (CBR) at Least 24 Weeks

Secondary: Clinical Benefit Rate (CBR) at Least 24 Weeks

Secondary: Response Duration (RD)

Secondary: Response Duration (RD)

Secondary: Overall Survival (OS)

Secondary: Overall Survival (OS)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

More information

Clinical Trial Results:
A multicenter phase II trial to evaluate the efficacy and safety of pembrolizumab and gemcitabine in patients with HER2-negative Advanced Breast Cancer (ABC). “PANGEA-Breast”