Evaluation of Pembrolizumab and Paclitaxel in HR+/HER2- Advanced Breast Cancer Post-CDK 4/6 Inhibitor Progression

Trial ID: 2023-508546-17-00
Protocol: SOLTI-1716
Sponsor: Solti Group

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Diseases & Conditions

Hormone receptor positive HER2 negative breast cancer

Objectives

The primary objective of this clinical trial is to evaluate the **overall response rate (ORR)** in patients with hormone receptor-positive/HER2-negative advanced or metastatic breast cancer who have progressed on or after CDK 4/6 inhibitor treatment. The ORR is defined as the proportion of patients achieving a best overall response of complete response (CR) or partial response (PR), assessed by local investigators according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. This measure is clinically relevant as it provides insight into the efficacy of the treatment regimen involving pembrolizumab and paclitaxel in this specific patient population.

Secondary objectives include determining the clinical benefit of pembrolizumab and paclitaxel through various metrics:

Clinical Benefit Rate (CBR), defined as the proportion of patients with a best overall response of CR, PR, or stable disease (SD) or non-progression disease (PD) lasting ≥ 24 weeks.
Progression-free survival (PFS).
Duration of response (DoR).
Time to response (TtR).
Overall survival (OS).
Comparison of PFS on study treatment to PFS on prior therapy (pre-PFS).
ORR according to PD1 mRNA expression.
ORR and PFS according to early dynamic changes in circulating tumor DNA (ctDNA) between baseline and after one cycle of pembrolizumab.
Assessment of the safety and tolerability of the combination therapy.

These secondary objectives aim to provide a comprehensive evaluation of the treatment's impact on disease progression, response duration, and overall survival, as well as its safety profile.

Participants

The clinical trial involves a study population comprising **pre and post-menopausal women** and men aged 18 years and older, diagnosed with locally advanced or metastatic hormone receptor-positive (HR+) and HER2-negative breast cancer. The trial does not specify the total number of participants, as this information was not provided by the sponsor. Participants were selected based on their histologically confirmed diagnosis of HR+/HER2-negative breast cancer, with the condition being refractory to CDK4/6 inhibitors. Both male and female participants are included, and they must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. The study excludes vulnerable populations and requires participants to have a life expectancy of at least 12 weeks. Relevant lifestyle considerations include the requirement for male participants to use contraception during the treatment period and for a specified duration after the last dose of treatment. Female participants must not be pregnant or breastfeeding and must adhere to contraceptive guidance if they are of childbearing potential. The trial population is not limited by specific dietary or physical activity requirements, and prior chemotherapy with a taxane for early breast cancer is permitted. Participants must have measurable disease as defined by RECIST v1.1 criteria and adequate hematologic and end-organ function.

Plans and Procedures

The clinical trial is designed to evaluate the efficacy of **pembrolizumab** in combination with paclitaxel for patients with hormone receptor-positive, HER2-negative advanced or metastatic breast cancer who have shown resistance to CDK 4/6 inhibitors. This is a Phase II, randomized, double-blind, controlled trial. The trial commenced on July 1, 2020, and is expected to conclude by April 30, 2024, with an estimated end date for the entire study on May 1, 2025. The trial involves multiple study visits, beginning with an inclusion (screening) visit to assess eligibility based on specific criteria, including histologically confirmed diagnosis and prior treatment history.

Participants will undergo regular follow-up visits to monitor treatment response and safety, with assessments conducted according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. The primary endpoint is the overall response rate, while secondary endpoints include clinical benefit rate, progression-free survival, and overall survival. The end-of-study visit will occur after the final treatment cycle or upon early termination, which may result from disease progression, unacceptable toxicity, or withdrawal of consent. Participant involvement is expected to last up to 10 treatment cycles, with each cycle corresponding to a maximum daily dose of 200 mg of pembrolizumab administered via intravenous infusion.

Conditions that may lead to early termination include non-compliance with the protocol, adverse events, or investigator discretion based on clinical judgment. The trial aims to provide comprehensive data on the efficacy and safety of the treatment regimen, contributing to the understanding of therapeutic options for this patient population. The study is conducted under strict adherence to ethical guidelines and regulatory requirements, ensuring the integrity and reliability of the collected data.

Treatment

The clinical trial involves the administration of **pembrolizumab**, marketed under the name **KEYTRUDA 25 mg/mL concentrate for solution for infusion**. This experimental medication is provided in the form of a concentrate for solution for infusion, specifically designed for intravenous infusion. The active substance, pembrolizumab, is a protein-based therapeutic agent. The maximum daily dose is set at 200 mg, with the same limit for the total dose per administration. The treatment period is capped at 10 cycles, with each cycle administered every three weeks. The pharmaceutical product is manufactured by Merck Sharp & Dohme B.V. and is authorized for use in the European Union under the marketing authorization number EU/1/15/1024/002.

In addition to the experimental treatment, the study protocol includes the administration of **paclitaxel**, a standard-of-care chemotherapy agent, as a non-experimental treatment. Paclitaxel is commonly used in the treatment of advanced or metastatic breast cancer and serves as a comparator treatment in this trial. The dosing schedule and administration route for paclitaxel are consistent with standard clinical practice, ensuring that participants receive a comprehensive treatment regimen. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol and to assess the overall response rate as per the study's main objective.

Efficacy

Efficacy in the clinical trial will be assessed using the **Overall Response Rate (ORR)** as the primary endpoint. ORR is defined as the proportion of patients achieving a best overall response of complete response (CR) or partial response (PR), evaluated by local investigators according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Secondary endpoints include the Clinical Benefit Rate (CBR), which measures the proportion of patients with CR, PR, or stable disease (SD) lasting at least 24 weeks, and Progression-Free Survival (PFS), defined as the time from allocation to disease progression or death from any cause. Additional secondary endpoints are Duration of Response (DoR), Time to Response (TtR), Overall Survival (OS), and comparisons of PFS on study treatment to prior therapy.

Assessments will be conducted at specified intervals throughout the trial, with efficacy parameters collected and analyzed based on local investigator assessments. The trial will also evaluate ORR and PFS in relation to PD1 mRNA expression and early dynamic changes in circulating tumor DNA (ctDNA) between baseline and after one cycle of pembrolizumab. These assessments will provide comprehensive insights into the treatment's efficacy in patients with hormone receptor-positive/HER2-negative advanced/metastatic breast cancer who have progressed following CDK 4/6 inhibitor treatment.

Inclusion and Exclusion 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. a) HER2 negativity is defined as either of the following by local laboratory assessment: IHC 0, IHC 1+ or IHC2+/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 CEP17 <2.0). b) ER and/or PR positivity are defined as >1% of cells expressing HR via IHC analysis as per ASCO-CAP guideline
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 following laboratory results (Table 4) obtained within 10 days prior to the first study treatment (Cycle 1, Day 1):
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
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.
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. a) 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. b) 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).

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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 (eg, CTLA-4, OX-40, CD137).
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
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
Has known active CNS 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
Has severe hypersensitivity (grado ≥ 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. 13.
Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease. 14.
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 (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 TB (Bacillus Tuberculosis).
Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study􀀏􀀃􀁌􀁑􀁗􀁈􀁕􀁉􀁈􀁕􀁈􀀃􀁚􀁌􀁗􀁋􀀃􀁗􀁋􀁈􀀃􀁖􀁘􀁅􀁍􀁈􀁆􀁗􀂶􀁖􀀃􀁓􀁄􀁕􀁗􀁌􀁆􀁌􀁓􀁄􀁗􀁌􀁒􀁑􀀃􀁉􀁒􀁕􀀃􀁗􀁋􀁈􀀃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 exepectin 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. Lifestyle restrictions Meals and dietary restrictions