Clinical Trial to evaluate the efficacy of immunotherapy in a subset of Hormonal Receptor-positive/HER2-negative advanced breast cancer patients who have progressed to standard therapy.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Solti Group

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

1 Jul 2020 → 30 Apr 2024

Decision date (initial)

2023-12-11

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

MERCK SHARP & DOHME DE ESPAÑA, S.A

External identifiers

EU CT number

2023-508546-17-00

EudraCT number

2018-003367-58

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Efficacy

Overall response rate (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

Secondary objectives 1

1. To determine the clinical benefit of pembrolizumab and paclitaxel in terms of: •Clinical Benefit Rate (CBR) defined as the 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•Progression free survival (PFS)•Duration of response(DoR)•Time to response(TtR)•Overall survival(OS) •PFS on study treatment compared to PFS on prior line of therapy (pre-PFS).•ORR according to PD1 mRNA expression.•ORR according to early dynamic changes in ctDNA between baseline and after 1 cycle of pembrolizumab.•PFS according to early dynamic changes in ctDNA between baseline and after 1 cycle of pembrolizumab.To assess the safety and tolerability of the combination

Conditions and MedDRA coding

Pre and post-menopausal women with locally advanced or metastatic HR+/HER2-negative endocrine resistant breast cancer

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

1. 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
2. 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.
3. Life expectancy ≥ 12 weeks
4. 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.)
5. 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):
6. 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
7. 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.
8. Eligible for taxane therapy.
9. No prior chemotherapy for inoperable locally advanced or metastatic breast cancer.
10. 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.
11. 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.
12. Previous chemotherapy with a taxane for early breast cancer (neoadjuvant or adjuvant setting) is permitted.
13. 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
14. Non-Luminal subtype as per PAM50 analysis (i.e. HER2-enriched or Basal-like).

Exclusion criteria 21

1. 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
2. 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).
3. History of hypersensitivity reactions to paclitaxel or other drugs formulated in the same solvent as paclitaxel (polyoxyethylated castor oil).
4. 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.
5. 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.
6. Uncontrolled pleural effusion, pericardial effusion, or ascites (Note: patients with indwelling catheters, such as PleurX® are allowed).
7. 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
8. 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
9. 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
10. 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
11. Has severe hypersensitivity (grado ≥ 3) to pembrolizumab and/or any of its excipients.
12. 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.
13. Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease. 14.
14. Prior allogeneic stem cell or solid organ transplantation
15. Has an active infection requiring systemic therapy.
16. Has a known history of Human Immunodeficiency Virus (HIV).
17. 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.
18. Has a known history of active TB (Bacillus Tuberculosis).
19. 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.
20. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
21. 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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Overall Response rate (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 (see Appendix 5).

Secondary endpoints 9

1. Clinical Benefit Rate (CBR) defined as the 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.
2. Progression free survival (PFS) defined as the 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.
3. Duration of response (DoR) defined as the 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
4. Time to response (TtR) defined as the time from allocation to the first objective tumor response (tumor shrinkage of ≥30%) observed for patients who achieved a CR or PR
5. Overall survival (OS) defined as the time from allocation to death from any cause (OS will be determined at the end of the study). 6. PFS on study treatment compared to PFS on prior line of therapy (pre- PFS).
6. PFS on study treatment compared to PFS on prior line of therapy (pre- PFS)
7. ORR according to PD1 mRNA expression
8. ORR according to early dynamic changes in ctDNA between baseline and after 1 cycle of pembrolizumab.
9. PFS according to early dynamic changes in ctDNA between baseline and after 1 cycle of pembrolizumab.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Solti Group

Sponsor organisation

Solti Group

Address

Calle Balmes 89 Planta 1 Puerta 2

City

Barcelona

Postcode

08008

Country

Spain

Scientific contact point

Organisation

Solti Group

Contact name

SOLTI-Start-Up Group

Public contact point

Organisation

Solti Group

Contact name

SOLTI-Start-Up Group

Locations

1 EU/EEA country · 7 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 2 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications