Comparative study of ribociclib and palbociclib in patients with advanced hormone receptor-positive/HER2-negative/HER2-Enriched breast cancer - HARMONIA trial

Phase 1

Conditions: Patients with advanced hormone receptor-positive/HER2-negative/HER2-Enriched breast cancer
Therapeutic area: Diseases [C] - Cancer [C04]

Registration Number: EUCTR2021-002027-38-PT

Lead Sponsor: SOLTI

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Authorised-recruitment may be ongoing or finished

Sex: All

Target Recruitment: 306

Inclusion Criteria

1. Signed informed consent must be obtained prior to any trial-specific screening procedure. Signed informed molecular pre-screening consent must be obtained prior to PAM50 test.
2. Male/female patients =18 years of age
3. HR-positive and HER2-negative breast cancer by local testing
4. ECOG performance status of 0 to 1.
5. Prior radiation therapy for metastatic disease is permitted. Patients must have recovered from radiotherapy toxicities prior to inclusion.
6. Patient has advanced (loco regionally recurrent not amenable to curative therapy or metastatic) breast cancer.
7. Availability of FFPE tumor block for biomarker analysis, obtained during metastatic period.
8. HER2-E or Basal-like subtype as per central PAM50 analysis.
9. Measurable disease or non-measurable (but evaluable), as defined by RECIST v1.1.
10. Adequate hematologic and end-organ function
11. Patient must be willing and able to comply with scheduled visits, treatment plans, laboratory tests, and other trial procedures.
12. Women of childbearing potential must have confirmed negative serum pregnancy test.
13. Women of CBP must be willing to use highly effective methods of contraception.
14. Postmenopausal OR Pre/perimenopausal status as defined in protocol
15. Patients must have the ability to swallow oral medication.
16. Patient must have a 6-lead or 12-lead ECG at screening
For Basal-like cohort only:
17.Non-sterile males must be willing to use a highly effective method of birth control for the duration of the study and for = 120 days after the last dose of tislelizumab
- A sterile male is defined as one for whom azoospermia has been previously demonstrated in a semen sample examination as definitive evidence of infertility.
- Males with known low sperm counts (consistent with sub-fertility) are not to be considered sterile for purposes of this study.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 350
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 16

Exclusion Criteria

1. Prior therapy with any CDK4/6 inhibitors.
2. Patient has received prior treatment with chemotherapy for advanced / metastatic breast cancer (neoadjuvant/ adjuvant chemotherapy for early breast cancer is allowed).
3. Patient has received extended-field radiotherapy = 4 weeks or limited field radiotherapy = 2 weeks prior to enrollment and has not recovered to grade 1 or better from related side effects of such therapy. Patients in whom = 25% of the bone marrow has been previously irradiated are also excluded.
4. Any ongoing acute toxic effects of prior anti-cancer therapy or major surgical procedures to NCI CTCAE version 4.03 Grade = 1 at day of inclusion.
5. Uncontrolled pleural effusion, pericardial effusion, or ascites.
6. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years.
7. Known active central nervous system metastases and/or carcinomatous meningitis.
8. Known history of Human Immunodeficiency Virus (HIV).
9. Patient has known active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection
10. Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality
11. Patient has any other concurrent severe and/or uncontrolled medical condition that would, in the Investigator’s judgment, cause unacceptable safety risks, contraindicate patient participation in the clinical trial or compromise compliance with the protocol or limit life expectancy to =6 months.
12. Participation in other studies involving investigational drug(s) within 30 days prior to randomization or within 5 half-lives of the investigational drug(s)
13. Pregnant or breast-feeding women or women who plan to become pregnant or breast-feed during the trial.
14. Not able to understand and to comply with study instructions and requirements according to investigator criteria.
15.Patient is currently receiving or has received systemic corticosteroids (>10 mg daily of prednisone or equivalent) = 2 weeks prior to starting trial treatment, or has not fully recovered from side effects of such treatment.

For HER2-E cohort only:
16. Patient with a known hypersensitivity to any of the excipients of ribociclib, palbociclib and/or endocrine therapy
17. Patient is currently receiving any protocol-prohibited substances within 7 days before randomization
18. Patient has impairment of GI function or GI disease that may significantly alter the absorption of the oral trial treatments
For Basal-like cohort only:
19. History of hypersensitivity reactions to paclitaxel or other drugs formulated in the same solvent as paclitaxel (polyoxyethylated castor oil).
20.A history of severe hypersensitivity reactions to other monoclonal antibodies.
21.Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2 or any other antibody or drug specifically targeting T-cell costimulation or checkpoint pathways.
22.Active autoimmune diseases or history of autoimmune diseases that may relapse. (refer to Appendix 3 for a list of conditions).
23.History of interstitial lung disease, non-infectious pneumonitis or uncontrolled lung diseases including pulmonary fibrosis, acute lung diseases, etc. Patients with significantly impaired pulmonary function, or who require supplemental oxygen at baseline must undergo an assessment of pulmonary function at screening.
24. Infection (including tuberculosis infection, etc.) requiring systemic antibacterial, antifungal or antiviral therapy within 14 days prior to first dose of study