Description:
Study Design and Treatment:
This is a multicenter phase II trial, with an initial exploratory run-in-phase, to evaluate
the efficacy and safety of pembrolizumab in combination with gemcitabine in patients with
HER2-negative ABC that have previously received anthracyclines and taxanes (unless clinically
contraindicated). In hormone receptor positive patients, previous treatment with 2 or more
lines of hormone therapy will also be required. Patients must have at least one measurable
lesion that can be accurately assessed at baseline and is suitable for repeated assessment by
CT, MRI or plan X-ray. Approximately 53 patients (up to a maximum of 65 patients depending on
the results of the run-in-phase) will be included in this trial.
Title
- Brief Title: Trial to Evaluate Efficacy and Safety of Pembrolizumab and Gemcitabine in HER2-negative ABC
- Official Title: 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"
Clinical Trial IDs
- ORG STUDY ID:
GEICAM/2015-04
- SECONDARY ID:
2016-001779-54
- NCT ID:
NCT03025880
Conditions
Interventions
| Drug | Synonyms | Arms |
|---|
| Pembrolizumab | Keytruda | Single arm |
| Gemcitabine | Gemzar | Single arm |
Purpose
Study Design and Treatment:
This is a multicenter phase II trial, with an initial exploratory run-in-phase, to evaluate
the efficacy and safety of pembrolizumab in combination with gemcitabine in patients with
HER2-negative ABC that have previously received anthracyclines and taxanes (unless clinically
contraindicated). In hormone receptor positive patients, previous treatment with 2 or more
lines of hormone therapy will also be required. Patients must have at least one measurable
lesion that can be accurately assessed at baseline and is suitable for repeated assessment by
CT, MRI or plan X-ray. Approximately 53 patients (up to a maximum of 65 patients depending on
the results of the run-in-phase) will be included in this trial.
Detailed Description
Study Design and Treatment (continuation):
The study will include two cohorts of patients: i) Triple Negative and ii) Luminal A+B, with
an approximate 1:1 distribution between both groups.
A safety dose testing or "run-in-phase", with a 6+6 design, in which toxicity will be
evaluated within the first cycle, will be performed since pembrolizumab in combination with
gemcitabine has not been previously tested. Initially 6 patients will be included in the
study at dose level 0 (gemcitabine at a dose of 1,250mg/m2 as an IV infusion on day 1 and 8
of each 21-day cycle and pembrolizumab at a dose of 200mg as an IV infusion on day 1 of each
21-day cycle):
- If ≤ 2 patients experience Dose Limiting Toxicity (DLT), 6 additional patients will be
included at the current dose level. If there is a confirmation of this dose to be safe
(≤ 3 patients experiencing DLT), this will be considered the RP2D and it will be used
for the following recruited patients.
- If ≥ 3 patients experience DLT within the first 6 patients, or ≥ 4 within the first 12
patients included at dose level 0, a de-escalation to dose level -1 (gemcitabine at a
dose of 1,000mg/m2 as an IV infusion on day 1 and 8 of each 21-day cycle and
pembrolizumab at a dose of 200mg as an IV infusion on day 1 of each 21-day cycle) will
be performed. In this case, a group of 12 additional patients will be included at dose
level -1, if ≥ 4 experience DLT, this combination will be considered too toxic and the
study will be stopped. If ≤ 3 experience DLT with this combination, this will be
considered the RP2D and it will be used for the following recruited patients.
Initially 3 patients will be allowed for inclusion simultaneously. These 3 patients will be
followed closely during the first cycle to observe the occurrence of any DLT. At the times
these 3 patients are completing the first cycle, the next 3 patients will be included one by
one, until the first cohort is completed.
If none of these 6 patients have a DLT, up to 4 patients will be allowed for inclusion from
the second cohort of 6 patients; they will follow the same procedure as in the first cohort.
If one of these patients from the second cohort has a DLT, the inclusion will be in smaller
groups (with a maximum number of 4 patients with DLT) and following the same procedure as in
the first cohort of 6 patients.
An internal committee will periodically review the safety data in order to take the decision
to maintain or decrease the dose level. This internal committee will consist of the chief
investigator, the Grupo Español de Cáncer de Mama (GEICAM) Scientific Director and the study
statistician. The meetings will be performed by teleconference to take these decisions as
quickly as possible once the last patient finishes the first cycle of treatment. Other
meetings will be considered ad-hoc whenever necessary (i.e when new DLTs appear).
Patients included in the run-in-phase at the same dose than that in the phase II will be
considered for the phase II analysis.
Study Drug/Medication:
Eligible patients will be 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 or 1,000mg/m2 (this dose will be
explored in combination with pembrolizumab in the initial exploratory run-in-phase if
necessary) as an intravenous (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. 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.
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.
Primary Objective:
- 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.
Primary End-point:
- Run-in-phase: To determine the incidence rate of Dose Limiting Toxicity (DLT) within the
first cycle of the combination.
- Phase II: Objective Response Rate (ORR) is defined as Complete Response (CR) plus
Partial Response (PR) according to Response Evaluation Criteria in Solid Tumours
(RECIST) version 1.1.
Secondary Objectives:
The following secondary objectives will be studied:
- To assess other efficacy measures of the combination in patients included in the phase
II (including those in the run-in-phase at the same dose that in the phase II).
- To determine safety and tolerability of the combination in all patients included in the
study.
Secondary End-points:
The following secondary end-points will be studied:
- Efficacy:
- Progression-Free Survival (PFS) assessed according to RECIST version 1.1 by the
investigator.
- Clinical Benefit Rate (CBR) defined as Complete Response (CR) plus Partial Response
(PR) plus Stable Disease (SD) lasting ≥ 24 weeks according to RECIST version 1.1.
- Response Duration (RD) assessed according to RECIST version 1.1.
- Overall Survival (OS). With special interest on long term responders (i.e. alive
and without disease progression after 24 months of study treatment).
- Safety will be assessed by standard clinical and laboratory tests (haematology, serum
chemistry). Adverse Events (AE) grade will be defined by the NCI CTCAE (National Cancer
Institute Common Terminology Criteria for Adverse Events) version 4.0.
Exploratory Objectives:
The following exploratory objectives will be studied in all patients included in the study
unless otherwise specified:
- To assess other efficacy measures of the combination based on immune-related (ir)
response criteria in patients included in the phase II (including those in the
run-in-phase at the same dose that in the phase II).
- To search for tumour tissue and peripheral blood biomarkers of clinical activity.
- To compare biomarkers data from cohorts of healthy volunteers (if available) with data
from patients included in the study.
Exploratory End-points:
The following exploratory end-points will be studied:
- Efficacy:
- ORR is defined as immune-related Complete Response (irCR) plus immune-related
Partial Response (irPR) according to immune-related RECIST (irRECIST).
- Progression-Free Survival (PFS) assessed according to irRECIST by the investigator.
- Clinical Benefit Rate (CBR) defined as irCR plus irPR plus immune-related Stable
Disease (irSD) lasting ≥ 24 weeks according to irRECIST.
- Response Duration (RD) assessed according to irRECIST.
- A set of immune biomarkers will be analysed and correlated with evolution of the disease
and efficacy of pembrolizumab in combination with gemcitabine (ORR and other efficacy
end-points: PFS, CBR and RD), paying special attention to long term responders.
- This set of immune biomarkers will be compared with those from healthy volunteers (if
available).
Study population:
Patients with HER2-negative advanced breast cancer.
Justification of Sample size determination:
A Simon's minimax two-stage design will be employed with the possibility of stopping early
due to lack of response. Results from previous studies showed that gemcitabine produced a
response rate of around 20%, this will be our expected H0. With the combination of
pembrolizumab and gemcitabine, we expect to increase this rate to 35% what will be our H1 (an
absolute increase of 15%), with an alpha error of 0.05 and a statistical power of 80%, we
will need to include 53 evaluable patients in this trial. The first stage will include 31
evaluable patients, if at least 7 present a response, recruitment will continue to include
the 53 evaluable patients. The null hypothesis of H0=20% will be rejected if 16 or more
responses are observed in 53 patients.
Statistical Analyses:
Demographics and Baseline Characteristics: Standard descriptive statistics, such as the mean,
median, range and proportion, will be used to summarize the patient sample and to estimate
parameters of interest.
Safety Analyses: AEs and Serious Adverse Events (SAE) will be reported in frequency tables
(overall and by intensity). The safety analysis will be performed in the population that has
received at least one dose of any of the study drugs/medications.
Efficacy Analyses: All efficacy endpoints will be evaluated in the Per-protocol and Intent to
treat (ITT) populations.
Biomarker analysis:The biomarker analysis will be exploratory and descriptive. For continuous
variables, mean, standard deviation, median, minimum and maximum values will be provided.
Categorical variables will be summarized by numbers and proportions. Biomarker endpoints will
be evaluated in all patients enrolled in the study with available samples.
Study Duration:
The end date of study is date of last patient´s death or the date when there is sufficient
data to achieve the primary and secondary objectives and all patients have ended the study
treatment, whichever comes first.
Performing exploratory objectives will be independent of the date of the end of the study.
Trial Arms
| Name | Type | Description | Interventions |
|---|
| Single arm | Experimental | Eligible patients will be 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 or 1,000mg/m2 (this dose will be explored in combination with P in the initial exploratory run-in-phase if necessary) 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 G in combination with fixed doses of P. | |
Eligibility Criteria
Inclusion Criteria:
1. The patient has signed and dated the informed consent document and it has been
obtained before conducting any procedure specifically for the study.
2. Female ≥ 18 years of age on day of signing informed consent.
3. Histological/cytological confirmation of breast cancer with evidence of advanced
disease, not amenable to resection or radiation therapy with curative intent.
4. Documented luminal A, luminal B (HER2-negative) or triple negative disease by
immunohistochemistry (IHQ) and/or in situ hybridization (FISH/CISH/SISH) based on
local testing on the most recent tumour biopsy defined as follows:
Luminal A: tumour with positive oestrogen receptor (ER) status (≥1% of tumour cells
with ER expression) and HER2-negative status (IHQ score 0/1+ or negative by in situ
hybridization defined as a HER2/chromosome enumeration probe 17 (CEP17) ratio < 2 or
for single probe assessment a HER2 copy number < 4) and high progesterone receptor
(PgR) (≥ 20% of tumour cells with PgR expression) and low Ki67 (< 14%).
Luminal B (HER2-negative): tumour with positive ER status (≥1% of tumour cells with ER
expression) and HER2-negative status (IHQ score 0/1+ or negative by in situ
hybridization defined as a HER2/CEP17 ratio < 2 or for single probe assessment a HER2
copy number < 4) and either low or negative PgR (< 20% of tumour cells with PgR
expression) and/or high Ki67 (≥ 14%).
Triple negative: tumour with negative hormone receptor status (<1% of tumour cells
with ER and PgR expression) and HER2-negative status (IHQ score 0/1+ or negative by in
situ hybridization defined as a HER2/CEP17 ratio < 2 or for single probe assessment a
HER2 copy number < 4).
5. Have at least one unidimensionally measurable lesion by RECIST 1.1.
6. Patient agrees to the collection of a metastatic tumor sample (biopsy) at the time of
inclusion and at progression (whenever possible).
7. Have a performance status of 0, 1 or 2 on the Eastern Cooperative Oncology Group
(ECOG) Performance Scale.
8. Demonstrate adequate organ function as follows (all screening labs should be performed
within 7 days of study treatment initiation):
Bone marrow:
Absolute Neutrophil Count (ANC) ≥ 1,500/mm3 (1.5x109/l) Platelets ≥ 100,000/mm3
(100x109/l) Hemoglobin ≥ 9g/dl or ≥ 5.6 mmol/l without transfusion or erythropoietin
(EPO) dependency (within 7 days of assessment)
Hepatic:
Serum total bilirubin ≤ 1.5 x Upper Limit of Normal (ULN) Alkaline Phosphatase ≤ 2.5 x
ULN Aspartate aminotransferase (AST) (SGOT) and Alanine aminotransferase (ALT) (SGPT)
≤ 2.5 x ULN or ≤ 5 x ULN for patients with liver metastases Albumin ≥ 2.5 g/dl
Renal:
Serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 60 ml/min for patients with
creatinine levels > 1.5 x ULN
Coagulation:
International Normalized Ratio (INR) or Prothrombin Time (PT) ≤ 1.5 xULN unless
patient is receiving anticoagulant therapy as long as PT or PTT is within therapeutic
range of intended use of anticoagulants.
Activated Partial Thromboplastin Time (aPTT) ≤ 1.5 x ULN unless patient is receiving
anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use
of anticoagulants.
9. Prior treatment with anthracyclines and taxanes (unless clinically contraindicated)
and two or more prior lines of hormone therapy in hormone receptor positive disease.
10. At least 3 months life expectancy.
11. Patient of childbearing potential should have a negative urine or serum pregnancy
within 72 hours prior to receiving the first dose of study drug/medication. If the
urine test is positive or cannot be confirmed as negative, a serum pregnancy test will
be required.
12. Patients of childbearing potential (see section 4.4. for definition) must be willing
to use an adequate method of contraception as outlined in Section 4.4. -
Contraception, for the course of the study through 120 days after the last dose of
study medication.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred
contraception for the subject.
13. Willingness and ability to comply with scheduled visits, treatment plan, laboratory
tests and other study procedures.
Exclusion Criteria:
1. HER2-positive disease by immunohistochemistry or in situ hybridation (FISH-SISH-CISH).
2. Patient is currently participating or has participated in a study of an
investigational agent and received study therapy or used an investigational device
within 4 weeks of the first dose of study drug/medication.
3. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study
day 1 or who has not recovered (i.e., ≤ grade 1 or at baseline) from adverse events
due to agents administered more than 4 weeks earlier.
4. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy
within 2 weeks prior to study day 1 or who has not recovered (i.e., ≤ grade 1 or at
baseline) from adverse events due to a previously administered agent.
- Note: Patients with ≤ grade 2 neuropathy are an exception to this criterion and
may qualify for the study.
- Note: If patient received major surgery, they must have recovered adequately from
the toxicity and/or complications from the intervention prior to starting
therapy.
5. Has received prior therapy with an anti-Programmed death-1 (PD), anti-PD-L1, or
anti-PD-L2 agent.
6. Has received a live vaccine within 30 days of planned start of study therapy.
o Note: Seasonal influenza vaccines for injection are generally inactivated flu
vaccines and are allowed; however, intranasal influenza vaccines (e.g., Flu-Mist) are
live attenuated vaccines, and are not allowed.
7. Has hypersensitivity to pembrolizumab, gemcitabine or any of theirs excipients.
8. Has known active central nervous system (CNS) metastases and/or carcinomatous
meningitis. Patients with previously treated brain metastases may participate provided
they are stable (without evidence of progression by imaging for at least four weeks
prior to the first dose of trial treatment and all neurologic symptoms have returned
to baseline), have no evidence of new or enlarging brain metastases, and are not using
steroids for at least 7 days prior to trial treatment. This exception does not include
carcinomatous meningitis which is excluded regardless of clinical stability.
9. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
other form of immunosuppressive therapy within 7 days prior to the first dose of study
drug/medication.
10. Has an active autoimmune disease that has required systemic treatment in the past 2
years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive
drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
form of systemic treatment.
11. Has a current or prior malignancy within the previous 5 years (other than breast
cancer or adequately treated basal cell or squamous cell carcinoma of the skin or
in-situ carcinoma of the cervix).
12. Has a history of (non-infectious) pneumonitis that required steroids or current
pneumonitis.
13. Has an active infection requiring systemic therapy.
14. Has a known history of active Tuberculosis Bacillus (TB) or Human Immunodeficiency
Virus (HIV) (HIV 1/2 antibodies) or a known active Hepatitis B (e.g., HBsAg reactive)
or Hepatitis C (e.g., hepatitis C virus (HCV) RNA [qualitative] is detected).
15. Has a history or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the trial, interfere with the patient's
participation for the full duration of the trial, or is not in the best interest of
the patient to participate, in the opinion of the treating investigator.
16. Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.
17. Patient is pregnant or breastfeeding, or expecting to conceive within the projected
duration of the trial, starting with the baseline visit through 120 days after the
last dose of trial treatment.
| Maximum Eligible Age: | N/A |
| Minimum Eligible Age: | 18 Years |
| Eligible Gender: | Female |
| Healthy Volunteers: | No |
Primary Outcome Measures
| Measure: | Incidence rate of Dose Limiting Toxicity (DLT) within the first cycle |
| Time Frame: | Up to cycle 1 |
| Safety Issue: | |
| Description: | DLT is 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. |
Secondary Outcome Measures
| Measure: | Progression-Free Survival (PFS) |
| Time Frame: | Through study treatment |
| Safety Issue: | |
| Description: | PFS is defined as the time from enrollment to the first documented progressive disease, using RECIST version 1.1, or death from any cause, whichever occurs first. |
| Measure: | Clinical Benefit Rate (CBR) |
| Time Frame: | Through study treatment |
| Safety Issue: | |
| Description: | CBR is defined as complete response (CR), partial response (PR), or stable disease (SD) ≥ 24 weeks according to the RECIST version 1.1. |
| Measure: | Response Duration (RD) |
| Time Frame: | Through study treatment |
| Safety Issue: | |
| Description: | RD is defined as the time from the first documentation of objective tumor response (CR or PR) to the first documented progressive disease using RECIST version 1.1, or to death due to any cause, whichever occurs first. |
| Measure: | Overall Survival (OS). |
| Time Frame: | Through study treatment |
| Safety Issue: | |
| Description: | OS is defined as the time from the date of enrollment to the date of death from any cause. |
| Measure: | The Number of Participants Who Experienced Adverse Events (AE) |
| Time Frame: | Through study treatment up to 1 month after discontinuation |
| Safety Issue: | |
| Description: | Safety assessments to be performed at baseline and during the study: Vital signs assessments will include blood pressure, pulse and body temperature. A baseline standard 12-lead electrocardiogram (ECG) is mandatory. Safety laboratory assessments will be performed: hemoglobin, platelet count, White Blood Cell (WBC), Absolute Neutrophil Count (ANC) and Absolute Lymphocyte Count (ALC), albumin, alkaline phosphatase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, serum creatinine, creatinine clearance (for patients with creatinine levels > 1.5 x ULN), glucose and urea, International Normalized Ratio (INR)/ Prothrombin time (PT) and activated partial thromboplastin time (aPTT), total or free triiodothyronine (T3 or FT3), free thyroxine (FT4) and Thyroid-stimulating hormone (TSH), Urinalysis. AEs will be graded according to NCI-CTCAE (National Cancer Institute Common Terminology Criteria for Adverse Events) version 4.0. |
Details
| Phase: | Phase 2 |
| Primary Purpose: | Interventional |
| Overall Status: | Active, not recruiting |
| Lead Sponsor: | Spanish Breast Cancer Research Group |
Trial Keywords
- Advanced Breast Cancer
- Pembrolizumab
- HER2-negative
Last Updated
August 14, 2019
