Pembrolizumab + Paclitaxel in Hormone Receptor-positive (HR+)/Human Epidermal Growth Factor Receptor 2-negative (HER2-) Non-luminal (by PAM50) Advanced Breast Cancer After Cyclin-dependent Kinase 4/6 (CDK4/6) Inhibitors Progression

  • End date
    Nov 1, 2024
  • participants needed
  • sponsor
    SOLTI Breast Cancer Research Group
Updated on 1 August 2021
measurable disease
breast cancer
growth factor
endocrine therapy
hormone therapy
advanced breast cancer
epidermal growth factor receptor
bone metastases
human epidermal growth factor
aromatase inhibitor
her2-negative breast cancer
immunological adjuvant


This is an open-label, single arm, multicenter phase II study evaluating treatment with pembrolizumab in combination with paclitaxel in patients with locally advanced or metastatic non-luminal Hormone receptor-positive, HER2-negative (hereafter referred to as HR+/HER2-) breast cancer who had recurrence or progression while receiving previous therapy with a CDK inhibitor in the adjuvant setting or to treat advanced disease (or both).


The study will utilize a 2-stage, single arm, Simon's 2-stage design1 with one (efficacy) interim and a final analysis. The interim analysis will be conducted when 15 patients are evaluable for Overall Response Rate (ORR) as determined locally by the investigator through the use of RECIST v.1.1. If 5 or fewer responses are observed in up to 15 patients of evaluable population (EP), the trial will be terminated in favor of the null for futility. Otherwise, up to a further 31 patients may be evaluated,for a maximum total of 46 evaluable patients. If a total of 19 or more responses are seen at the end of the second stage, then the null will have been rejected in favor of the alternative; and further investigation of the combination is warranted.

Recruitment will not be halted during the interim analysis period. Therefore, no interruption in the accrual will be done during the interim analysis in order to maintain the dynamic of accrual in the trial.

After confirmation of all eligibility criteria, eligible patients will receive pembrolizumab 200 mg every 3 weeks (on D1 of each 21-day cycle, beginning in Cycle 1) in combination with paclitaxel 80 mg/m2 administered at days 1, 8, 15 of each 21-day cycle beginning at cycle 2. Treatment will continue until disease progression, the development of unacceptable toxicity, withdrawal of consent, 24 months from the date of the first dose of pembrolizumab or end of study, whichever occurs first.

All patients will be followed for survival from screening until the last patient recruited has been followed for 12 months, has progressed or has died, whichever occurs first. The patient will be followed for survival approximately every 3 months ( 21 days) until death, withdrawal of consent, loss to follow-up, or study termination by the sponsor. In addition, information regarding use of subsequent anti-cancer agents for metastatic HR+/HER2- during the survival follow-up period will be collected.

Tumor assessments per Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 and Immune-Related Response Evaluation Criteria In Solid Tumors (iRECIST) will be performed every 9 weeks (63 days 5 days) until disease progression, treatment discontinuation, the start of new anti-cancer treatment, withdrawal of consent, death, or the end of the study, whichever occurs first. Tumor assessments will be performed on the specified schedule regardless of treatment delays.

Safety assessments will include the incidence, nature, and severity of adverse events (AEs) and laboratory abnormalities graded per the NCI CTCAE v.5.

Laboratory safety assessments will include the regular monitoring of hematology, blood chemistry and pregnancy test

Condition Metastatic Breast Cancer, Stage IV Breast Cancer
Treatment Paclitaxel, Pembrolizumab
Clinical Study IdentifierNCT04251169
SponsorSOLTI Breast Cancer Research Group
Last Modified on1 August 2021


Yes No Not Sure

Inclusion Criteria

Male/female participants who are at least 18 years of age on the day of signing informed consent with histologically confirmed diagnosis of locally advanced or metastatic, histologically documented hormone receptor positive (ER and/or PR expression >1%) and HER2- breast cancer by local testing, not amenable to surgical therapy will be enrolled in this study
HER2 negativity is defined as either of the following by local laboratory assessment: Immunohistochemistry (IHC) 0, IHC 1+ or IHC 2+/in situ hybridisation (ISH) negative as per American Society of Clinical Oncology (ASCO)-College of American Pathologists Guideline (CAP) guideline (ISH negative is defined as a ratio of HER2 to chromosome 17 centromere (CEP17) <2.0)117
ER and/or PR positivity are defined as >1% of cells expressing HR via IHC analysis as per ASCO-CAP guideline118
The participant (or legally acceptable representative if applicable) provides written informed consent for the trial
Eligible for taxane therapy
No prior chemotherapy for inoperable locally advanced or metastatic breast cancer
Prior radiation therapy for metastatic disease is permitted. Subjects who were treated with radiation therapy may participate as long as at least 2 weeks have elapsed since the last dose of radiation therapy or have recovered from the effects of radiation before allocation whichever is the latest
Disease refractory to CDK4/6 inhibitors, defined as recurrence during or within 12 months after the end of adjuvant treatment or progression during or within 6 months after the end of treatment for advanced/metastatic disease
Notes: CDK4/6 inhibitors do not have to be the last treatment prior to
randomization. Other prior anticancer endocrine therapy, e.g. aromatase
inhibitors, fulvestrant or tamoxifen, are also allowed
\. Previous chemotherapy with a taxane for early breast cancer (neoadjuvant
or adjuvant setting) is permitted
\. Availability of formalin-fixed paraffin-embedded (FFPE) tumor block
collected during advanced/metastatic disease, with an associated pathology
report. The tumor tissue should be of good quality based on total and viable
tumor content and must be evaluated centrally for PAM50 analysis prior to
enrollment. Patients whose tumor tissue is not evaluable for central testing
are not eligible. If PAM50 analysis of tumor sample has alredy been performed
Acceptable samples include core needle biopsies for deep tumor tissue or excisional, incisional, punch, or forceps biopsies for cutaneous, subcutaneous, or mucosal lesions or biopsies from bone metastases
at central lab (i.e analysis from other SOLTI clinical trial) PAM50 result can
Fine needle aspiration, brushing, cell pellet from pleural effusion and lavage samples are not acceptable
be valid for this study
Non-Luminal subtype as per PAM50 analysis (i.e. HER2-enriched or Basal-like)
Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Evaluation of ECOG is to be performed within 10 days prior to the date of allocation/randomization
Life expectancy 12 weeks
Measurable disease, as defined by RECIST v1.1. (Note: Previously irradiated lesions can be considered as measurable disease only if disease progression has been unequivocally documented at that site since radiation.)
Adequate hematologic and end-organ function, defined by the study protocol with results obtained within 10 days prior to the first study treatment at Cycle 1, Day 1 (C1D1)
Male participants
\. A male participant must agree to use contraception as detailed in
Appendix 3 of this protocol during the treatment period and for at least 180
days after the last dose of paclitaxel and 120 days form the last doses of
pembrolizumab and refrain from donating sperm during this period
Female participants
\. A female participant is eligible to participate if she is not pregnant
(see Appendix 3), not breastfeeding, and at least one of the following
conditions applies: a.) Not a woman of childbearing potential (WOCBP) as
defined in Appendix 3 OR b.) A WOCBP who agrees to follow the contraceptive
guidance in Appendix 3 during the treatment period and for at least 180 days
after the last dose of paclitaxel and 120 days from the last dose of

Exclusion Criteria

A WOCBP who has a positive urine pregnancy test within 72 hours prior to C1D1 (see Appendix 3). If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
Has received prior therapy with an anti-PD1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor
History of hypersensitivity reactions to paclitaxel or other drugs formulated in the same solvent as paclitaxel (polyoxyethylated castor oil)
Resolution of all acute toxic effects of prior anti-cancer therapy or major surgical procedures to NCI CTCAE version 5.0 Grade 1 (except alopecia or other toxicities not considered a safety risk for the patient at investigators discretion)
Note: Placement of central venous access catheter(s) (e.g., port or similar)
is not considered a major surgical procedure and is therefore permitted
\. Has received a live vaccine within 30 days prior to the first dose of
study drug. Examples of live vaccines include, but are not limited to, the
following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow
fever, rabies, Bacillus Calmette-Gurin (BCG), and typhoid vaccine. Seasonal
influenza vaccines for injection are generally killed virus vaccines and are
allowed; however, intranasal influenza vaccines (eg, FluMist) are live
\. Uncontrolled pleural effusion, pericardial effusion, or ascites (Note
patients with indwelling catheters, such as PleurX are allowed)
attenuated vaccines and are not allowed. Note: It is not recommended the use
\. Uncontrolled hypercalcemia (>1.5 mmol/L [>6 mg/dL] ionized calcium or
of live or attenuated COVID-19 vaccines within 30 days of initiation or during
serum calcium [uncorrected for albumin] >3 mmol/L [>12 mg/dL] or corrected
study treatment. However, if vaccination with these vaccines is required
serum calcium >ULN) or clinically significant (symptomatic) hypercalcemia
please ask for advice on how to proceed the Medical Monitor
\. Has a diagnosis of immunodeficiency or is receiving chronic systemic
steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or
any other form of immunosuppressive therapy within 7 days prior to the first
dose of study drug
\. Has a known additional malignancy that is progressing or has required
active treatment within the past 3 years. Note: Participants with basal cell
carcinoma of the skin, squamous cell carcinoma of the skin or carcinoma in
situ (e.g. breast carcinoma, cervical cancer in situ) that have undergone
potentially curative therapy are not excluded
\. Has known active Central Nervous System metastases and/or carcinomatous
meningitis. Participants with previously treated brain metastases may
participate provided they are radiologically stable, i.e. without evidence of
progression for at least 4 weeks by repeat imaging (note that the repeat
imaging should be performed during study screening), clinically stable and
without requirement of steroid treatment for at least 14 days prior to first
dose of study treatment
\. Has severe hypersensitivity (Grade 3) to pembrolizumab and/or any of its
\. Has 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 (eg., thyroxine, insulin, or
physiologic corticosteroid replacement therapy for adrenal or pituitary
insufficiency, etc.) is not considered a form of systemic treatment
\. Prior allogeneic stem cell or solid organ transplantation
\. Has an active infection requiring systemic therapy
\. Has a known history of Human Immunodeficiency Virus (HIV)
\. Has a known history of Hepatitis B (defined as Hepatitis B surface
\. Has a history of (non-infectious) pneumonitis/interstitial lung disease
antigen [HBsAg] reactive) or known active Hepatitis C virus (HCV) (defined as
that required steroids or has current pneumonitis/interstitial lung disease
HCV RNA [qualitative] is detected) infection. Note: no testing for Hepatitis B
and Hepatitis C is required unless mandated by local health authority
\. Has a known history of active Tuberculosis Bacillus
\. Has a history or current evidence of any condition, therapy, or
laboratory abnormality that might confound the results of the study, interfere
with the subject's participation for the full duration of the study, or is not
in the best interest of the subject to participate, in the opinion of the
treating investigator
\. Has known psychiatric or substance abuse disorders that would interfere
with cooperation with the requirements of the trial
\. Is pregnant or breastfeeding or expecting to conceive or father children
within the projected duration of the study, starting with the screening visit
through 120 days after the last dose of pembrolizumab or 180 days after the
last dose of paclitaxel
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