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

Study Overview
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Brief Summary
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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).

Detailed Description
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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

Official Title
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Targeting Non-Luminal Disease by PAM50 With Pembrolizumab + Paclitaxel in Hormone Receptor-positive/HER2-negative Advanced/Metastatic Breast Cancer, Who Have Progressed on or After CDK 4/6 Inhibitor Treatment

Conditions
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Metastatic Breast Cancer

Intervention / Treatment
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* Drug: Pembrolizumab
* Drug: Paclitaxel


Participation Criteria
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Eligibility Criteria
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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 at central lab (i.e analysis from other SOLTI clinical trial) PAM50 result can be valid for this study. 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. Fine needle aspiration, brushing, cell pellet from pleural effusion and lavage samples are not acceptable. 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 pembrolizumab. 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 investigator´s 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-Guérin (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 attenuated vaccines and are not allowed. Note: It is not recommended the use of live or attenuated COVID-19 vaccines within 30 days of initiation or during study treatment. However, if vaccination with these vaccines is required, please ask for advice on how to proceed the Medical Monitor. Uncontrolled pleural effusion, pericardial effusion, or ascites (Note: patients with indwelling catheters, such as PleurX® are allowed). Uncontrolled hypercalcemia (>1.5 mmol/L [>6 mg/dL] ionized calcium or serum calcium [uncorrected for albumin] >3 mmol/L [>12 mg/dL] or corrected serum calcium >ULN) or clinically significant (symptomatic) hypercalcemia 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 excipients. 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. Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease. 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 antigen [HBsAg] reactive) or known active Hepatitis C virus (HCV) (defined as 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pembrolizumab + Paclitaxel<br>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. | Drug: Pembrolizumab<br>* Pembrolizumab 200 mg will be administered as 30 minutes IV infusion every 3 weeks beginning in Cycle 1<br>* Other names: Keytruda;Drug: Paclitaxel<br>* Paclitaxel will be administered at the 80 mg/m2 dose via 1-hour IV infusion on Days 1, 8, and 15 of every 21-day cycle (beginning in Cycle 2). On days of scheduled infusions of pembrolizumab and paclitaxel (i.e., Day 1 of every cycle), paclitaxel is to be administered after infusion of pembrolizumab<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response rate of pembrolizumab in combination with paclitaxel in HR+/HER2- non-luminal subtype advanced breast cancer defined by the PAM50 assay | ORR defined as the proportion of patients with best overall response of complete response (CR) or partial response (PR), as per local investigator´s assessment and according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria | From date of randomization to disease progression, death, unacceptable toxicity, consent withdrawal or study termination, whichever came first, assessed up to approximately 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Benefit Rate (CBR) | Proportion of patients with a best overall response of CR, PR or an overall lesion response of Stable Disease (SD) or Non-PR/Non-progression disease (PD) lasting ≥ 24 weeks, based on local investigator´s assessment according to RECIST v1.1. The CBR and its exact 90% confidence interval (CI). | From date of randomization to disease progression, death, unacceptable toxicity, consent withdrawal or study termination, whichever came first, assessed up to approximately 24 months | 
| Progression free survival (PFS) | PFS is defined as the time from the date of allocation to the date of the first documented progression or death due to any cause occurring in the study. PFS will be assessed based on local investigator's assessment according to RECIST v1.1. PFS will be censored if no PFS event is observed before the cut-off date. The censoring date will be the date of last adequate tumor assessment before the cut-off date. If a PFS event is observed after two or more missing or non-adequate tumor assessments, then PFS will be censored at the last adequate tumor assessment. If a PFS event is observed after a single missing or non-adequate tumor assessment, the actual date of event will be used. It is not intended to censor patients for new anticancer therapy prior to documented disease progression in the primary analysis. | From date of randomization to disease progression, death, unacceptable toxicity, consent withdrawal or study termination, whichever came first, assessed up to approximately 24 months | 
| Duration of response (DoR) | Time from the first occurrence of a documented objective response to disease progression, as determined locally by the investigator through use of RECIST v.1.1, or death from any cause, whichever occurs first. DOR only applies to patients whose best overall response is CR or PR according to RECIST v1.1 based on tumor response data per local investigator's assessment. The start date is the date of first documented response of CR or PR (i.e., the start date of response, not the date when response was confirmed), and the end date is defined as the date of the first documented progression or death due to underlying cancer. Patients continuing without progression or death due to underlying cancer will be censored at the date of their last adequate tumor assessment. | From date of randomization to disease progression, death, unacceptable toxicity, consent withdrawal or study termination, whichever came first, assessed up to approximately 24 months | 
| Time to response (TtR) | Time from allocation to the first objective tumor response (tumor shrinkage of ≥30%) observed for patients who achieved a CR or PR. TtR only applies to patients whose best overall response is CR or PR according to RECIST v1.1 based on tumor response data per local investigator's assessment. | From date of randomization to disease progression, death, unacceptable toxicity, consent withdrawal or study termination, whichever came first, assessed up to approximately 24 months | 
| Overall survival (OS) | Time from allocation to death from any cause. Data for patients who are alive at the time of the analysis data cutoff will be censored at the last date they were known to be alive. Data from patients without post-baseline information will be censored at the date of allocation. The results from log-rank test will be provided. The OS curve will be estimated by the Kaplan-Meier methodology, and the 95% CI will be estimated by the Cox proportional-hazards models. | From date of randomization to death, unacceptable toxicity, consent withdrawal or study termination, whichever came first, assessed up to approximately 24 months | 
| PFS on study treatment compared to PFS on prior line of therapy (pre-PFS) | Time from allocation to the first occurrence of disease progression, as determined locally by the investigator through the use of RECIST v.1.1, or death from any cause, whichever occurs first compared to PFS on prior line of therapy. Pre-PFS only applies to patients whose received have previous treatment for metastatic disease | From date of randomization to disease progression, death, unacceptable toxicity, consent withdrawal or study termination, whichever came first, assessed up to approximately 24 months | 
| ORR according to PD1 messenger ribonucleic acid (mRNA) expression. | To evaluate the direct association of PD1 FFPE-based mRNA expression with ORR we evaluate the PD1 mRNA pre-established cutoff (median or tertiles) and a continuous variable. Median: Cutoff points are calculated according to the median value for the mRNA expression. Samples with mRNA expression above or equal to the median were considered as samples with high expression, while those with value below the median as samples with low expression. Tertiles: Cutoff points are calculated according to the tertiles value for the mRNA expression. Samples with mRNA expression above or equal to the tertile-1 (PD1-high) were considered as samples with high expression, samples with mRNA expression above or equal to the tertile-2 (PD1-high) were considered as samples with intermediate expression, while those with value below the tertile-2 as samples with low expression. | From date of randomization to disease progression, death, unacceptable toxicity, consent withdrawal or study termination, whichever came first, assessed up to approximately 24 months | 
| ORR according to early dynamic changes in circulating tumor DNA (ctDNA) | Correlation between ORR and ctDNA dynamic changes between baseline and after 1 cycle of pembrolizumab. The circulating tumor DNA response is defined as the ratio of mutant copies/ml of plasma at day 1 cycle 2 and day 1 cycle 1. | From date of randomization to disease progression, death, unacceptable toxicity, consent withdrawal or study termination, whichever came first, assessed up to approximately 24 months | 
| PFS according to early dynamic changes in ctDNA | Correlation between PFS and ctDNA dynamic changes between baseline and after 1 cycle of pembrolizumab. The circulating tumor DNA response is defined as the ratio of mutant copies/ml of plasma at day 1 cycle 2 and day 1 cycle 1. | From date of randomization to disease progression, death, unacceptable toxicity, consent withdrawal or study termination, whichever came first, assessed up to approximately 24 months | 
| Incidence, duration and severity of Adverse Events (AEs) of the combination of pembrolizumab with paclitaxel | Incidence, duration and severity of AEs assessed by the NCI Common Terminology for Classification of Adverse Events (CTCAE) version 5, | Toxicities will be assessed during the whole treatment period (from baseline until 90 days after a patients' final treatment which is defined as the end of the Treatment Phase of the study | 
| Number of patients with dose interruptions, reductions, delays and treatment discontinuation of the combination of pembrolizumab with paclitaxel | Quantification of dose interruptions, reductions, dose intensity, delays and treatment discontinuation will be recorded in the electronic case report form (eCRF) | Tolerability will be assessed during the whole treatment period (from baseline until patients' final treatment which is defined as the end of the Treatment Phase of the study, an average of 10 months |