Breast Cancer
Conditions
Keywords
ctDNA, Early breast cancer, HR-positive/HER2-negative, MRD, Minimal Residual Disease
Brief summary
This trial is a multicenter, open-label, non-comparative, phase II, biomarker-driven adjuvant treatment study involving the periodic collection and analysis of blood samples from patients with HR-positive/HER2-negative early-stage BC at higher risk of relapse, who have undergone surgery within the previous five years, with no evidence of locoregional, contralateral, or distant disease. The study design is composed by an initial pre-screening phase, a molecular follow-up phase (ctDNA surveillance phase), and an interventional therapeutic phase (treatment phase). After informed consent is obtained, a total of 976 eligible patients will enter a ctDNA surveillance in which primary tumor tissue and matched normal blood will be collected from each patient to obtain a patient-specific somatic mutations panel (tumor signature). At the event of ctDNA positivity, patients will be screened to enter the treatment phase of the study. Upon confirmed eligibility, a total of 40 patients will be allocated in one of the following trial's arms adopting a sequential recruitment strategy: Arm A: Control Arm (N=10) Arm B: Experimental Arm with giredestrant (N=10) Arm C: Experimental Arm with giredestrant + abemaciclib (N=10) Arm D: Experimental Arm with giredestrant + inavolisib (N=10) If the strategy of ctDNA monitoring enables physicians to identify patients at high risk of relapse and assess whether treatment at molecular relapse can improve outcome, new cohorts may be added to the study.
Detailed description
This is a multicenter, open-label, non-comparative, phase II, biomarker-driven adjuvant treatment Study involving the periodic collection and analysis of blood samples from patients with HR-positive/HER2- negative early-stage BC at higher risk of relapse, who have undergone surgery, have received radiotherapy if indicated as per local guidelines, with no evidence of locoregional, contralateral, or distant disease. Patients must be on adjuvant treatment with ET for at least two years and no more than seven years at the time of Study enrolment with an additional three years of ET planned. At least 6 months prior to enrolment on the same ET treatment (AI or tamoxifen). LHRH is mandatory for men and premenopausal women receiving AI, as well as for premenopausal women treated with tamoxifen, except in cases of bilateral oophorectomy). The trial design entails an initial pre-screening phase, a molecular follow-up phase (ctDNA surveillance phase), and an interventional therapeutic phase (treatment phase). After informed consent is obtained, 976 eligible patients will enter a ctDNA surveillance in which primary tumor tissue and matched normal blood will be collected from each patient to obtain a patient-specific somatic mutations panel (tumor signature). Note: Additional patients may enter the ctDNA surveillance phase if needed, for example if additional arms are opened. Then, blood will be collected, processed, and analyzed to detect the presence or absence of ctDNA at predefined time points for longitudinal surveillance. ctDNA analysis will occur every three months from Study inclusion during the first year and every six months thereafter until positive result or end of accrual. At the event of ctDNA positivity, patients will be screened to enter the treatment phase of the Study. Upon confirmed eligibility, a total of 40 patients will be allocated in one of the following trial's arms adopting a sequential recruitment strategy. Arm A: Experimental Arm with standard treatment followed by change in treatment (N=10) Arm B: Experimental Arm with giredestrant (N=10) Arm C: Experimental Arm with giredestrant + abemaciclib (N=10) Arm D: Experimental Arm with giredestrant + inavolisib (N=10) Note I: In addition to the treatments described on each of the treatment arms, LHRH agonist will be administered to male participants and pre-menopausal/perimenopausal participants according to local prescribing information. The patient should be supplied with the previous LHRH they were taking. Note II: During the length of the study, additional treatment arms may open to stay up to date with the most recent advances in oncology, and to be able to provide the best treatment options to patients in this study. Because of that, the N of patients screened to enter the treatment phase may increase. Note III: For patients eligible to receive inavolisib with a creatinine clearance between 30 and \<60 mL/min, as estimated by the 2021 CKD-EPI creatinine equation (National Kidney Foundation, 2021), the starting dose is 6 mg orally once daily (PO QD) on Days 1-28 of each 28-day cycle. In the meanwhile, serial assessment of ctDNA will be continuously performed every three months during the first year and every six months thereafter until EoS to correlate any ctDNA variations with response. Patients discontinuing the Study treatment period will enter a post-treatment follow-up period during which survival and new anti-cancer therapy information will be collected every three months (±14 days) from the last dose of Study treatment up to the EoS. Telephone contact is acceptable (in some countries medical information can only be shared directly in person with the patient). Arm extensions After initiation of Study treatments, data obtained from serial assessment of ctDNA will also be used to confirm feasibility of eventual arms extensions, with maximum two arms that could be expanded (10 additional patients will be enrolled in each of the selected arms). The expansion will be approved when the arm complies with the following criteria: * If at three months, a 90% ctDNA decrease is observed in at least 30% patients and if after three additional months, a 90% ctDNA decrease is maintained in at least 20% patients In this case, 10 additional patients will be enrolled in the specific experimental arms that meet these requirements (N=20). * If all three experimental arms fulfill the criteria, the two arms with the highest proportion of patients with the highest proportion of 90% decrease will be the ones expanded. * If cohorts remain too similar (no clear "winners"), the decision will be taken by the Steering Committee based on the duration of the response and the safety and toxicity of each specific treatment. * If none of the arms fulfill the specific expansion criteria, the Steering Committee will evaluate the data further and may nominate the two arms with the strongest signal of ctDNA decreases for further expansion. If the strategy of ctDNA monitoring enables physicians to identify patients at high risk of relapse and assess whether treatment at molecular relapse can improve outcome, new cohorts may be added to the study
Interventions
DRUGGiredestrant
Giredestrant is a highly potent, non-steroidal, oral selective ER antagonist and degrader (SERD)
DRUGAbemaciclib
Abemaciclib is an orally administered CDK4/6 inhibitor
DRUGInavolisib
Inavolisib is a potent, selective inhibitor of the Class I phosphatidylinositol 3-kinase α (PI3K-alpha isoform (p110-alpha)
Sponsors
MedSIR
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Eligibility criteria for the surveillance phase: Note: Patients who have not participated in the surveillance phase but have a positive ctDNA test (conducted under other circumstances) will be allowed to enter directly into the treatment phase after confirmation of ctDNA positivity by the study test. Therefore, these patients will not need to meet all the inclusion criteria for the surveillance phase but will need to meet all the inclusion criteria for the treatment phase. Inclusion criteria for surveillance phase: 1. Signed informed consent form (ICF) prior to participation in any Studyrelated activities. 2. Male or female patients aged 18 years or older. 3. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. 4. Histologically proven primary HR-positive according to the updated American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) 2020 guidelines and HER2-negative BC as per ASCO/CAP 2018 criteria based on local testing on the most recent analyzed biopsy. 5. Patients with high-risk early-stage BC according to at least one of the following criteria: a. If there is no previous neoadjuvant chemotherapy: i. pN2-N3 or ii. pN1 (including micrometastasis - pN1mi) if: 1\. pT3-T4, or 2. pT2 and high genomic risk and/or histological grade III and/or Ki 67≥30%. b. If patients have received previous neoadjuvant chemotherapy, they must have had residual invasive disease defined as at least one of the following: i. Residual invasive disease in lymph nodes (ypN+, including ypN1mi) ii. ypN0 with residual invasive disease in breast if: 1. cT3-4, or 2. cT2 and high genomic risk and / or histological grade III and / or Ki67≥30%. Note: Genomic risk using platforms such as Oncotype Dx, Prosigna or Mammaprint won't be assessed for the screening to participate in the Study. However, patients with the detailed scores assessed prior to Study inclusion, may be eligible. 6\. On adjuvant treatment with ET for at least two years and no more than seven years at the time of Study enrolment with an additional three years of ET planned, and at least 6 months prior to enrolment on the same ET treatment with AI or tamoxifen (LHRH is mandatory for men and premenopausal women receiving AI, as well as for premenopausal women treated with tamoxifen, except in cases of bilateral oophorectomy.) Note: Pre-menopausal patients treated with tamoxifen alone are excluded. 7\. Prior treatment with cyclin-dependent kinases 4/6 (CDK4/6) inhibitors will be allowed in the case of an interval of at least 12 months between the last dose and inclusion in the trial. 8\. No prior treatment with SERDs will be allowed. 9\. Willingness and ability to provide tissue from one archival tumor tissue sample (either from diagnostic biopsy, primary surgery, or where available from a residual disease post-neoadjuvant therapy). Note: Patients with multifocal BC may be enrolled, if archival tissue samples from at least two tumors are available and after histopathological examination, all tumors meet pathologic criteria for HR-positive and HER2-negative BC. 10\. Absence of metastatic disease by routine clinical assessment (computed tomography \[CT\] scan of the thorax and abdomen, and bone scan or positron emission tomography \[PET\] scan). confirmed no longer than three months prior to Study inclusion. 11\. Patients must have had surgery for their primary BC with documented clear margins (as per local guidelines) and they must have received radiotherapy if indicated (as per local guidelines). 12\. Patients must be able and willing to adhere to Study procedures.
Exclusion criteria
for surveillance phase: 1. Patients with pathological complete response (pCR) after neoadjuvant treatment. 2. Any concurrent or planned treatment for the current diagnosis of BC other than adjuvant ET except for denosumab or zoledronic acid, which are allowed. 3. Diagnosis of an alternative cancer in the five years prior to primary BC diagnosis other than for non-melanoma carcinoma of the skin or cervical carcinoma in situ. Other stage I tumors will be discussed case by case prior to inclusion with the Medical Monitor of the Study. 4. Active or prior documented inflammatory bowel disease (i.e., Crohn's disease, ulcerative colitis, or a preexisting chronic condition resulting in baseline grade ≥1 diarrhea) that may significantly alter the absorption of oral drugs. 5. Active cardiac disease or history of cardiac dysfunction including any of the following: 1. History (within two years from screening) or presence of idiopathic bradycardia or resting heart rate \<50 beats per minute at screening. 2. History of angina pectoris or symptomatic coronary heart disease within 12 months prior to Study entry. 3. QT interval corrected through use of Fridericia's formula (QTcF) \> 450 ms for women and \> 470 ms for men by at least three electrocardiograms (ECGs) \> 30 minutes apart. 4. History or presence of an abnormal ECG that is clinically significant in the investigator's opinion, 5. History of ventricular dysrhythmias or risk factors for ventricular dysrhythmias such as structural heart disease (e.g., severe left ventricular systolic dysfunction, left ventricular hypertrophy cardiomyopathy, infiltrative cardiomyopathy, moderate-to-severe valve disease), coronary heart disease (symptomatic or with ischemia demonstrated by diagnostic testing), clinically significant electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia, hypocalcemia), or family history of long QT syndrome within 12 months. 6. History of pneumonitis, interstitial lung disease (ILD), or pulmonary fibrosis. 7. Known history of Human Immunodeficiency Virus (HIV) infection (testing not required as part of Study screening). 8. Clinically significant liver disease consistent with Child-Pugh C, including active hepatitis (e.g., hepatitis B virus \[HBV\] or hepatitis C virus \[HCV\]), current alcohol abuse, cirrhosis, or positive test for viral hepatitis 9. Active bleeding diathesis venous thrombo-embolism, previous history of bleeding diathesis, or chronic anti-coagulation treatment, or any indications or history of Disseminated Intravascular Coagulation (DIC) or Deep vein thrombosis (DVT). Low molecular weight heparin (LMWH), low dose aspirin or clopidogrel are permitted. 10. Creatinine clearance \< 30mL/min. 11. Participants with renal dysfunction who require dialysis. 12. Patient who has any other concurrent severe and/or uncontrolled medical condition that would, in the Investigator' opinion cause unacceptable safety risks, contraindicate patient participation in the clinical trial or compromise compliance with the protocol. 13. Females who are known to be breastfeeding or pregnant as determined by a serum pregnancy test, Human chorionic gonadotropin (β-HCG), prior to the administration of any trial treatment (once during the treatment phase). Since β-HCG over expression can also be elevated in some tumor types, a positive result should be confirmed with a validated alternative test (e.g., ultrasound). 14. Female or male participants planning a pregnancy. Eligibility criteria for the treatment phase: Patients will be considered eligible to enter to the treatment phase and to be allocated to standard ET only followed by change in treatment after a 90-day period , giredestrant monotherapy, giredestrant plus abemaciclib, or giredestrant plus inavolisib if they fulfill all the inclusion and none of the
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Evaluation of decrease or clearance in baseline ctDNA at three months after initiation of study treatment | Treatment phase (three months after treatment initiation) | To evaluate the treatment efficacy -in terms of rate of patients with a 90% decrease or clearance in baseline ctDNA at three months- of the different arms. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Total ctDNA detection and breakdown by incidence at first ctDNA test versus incidence at subsequent ctDNA tests. | Surveillance phase (up to two years after study start date) | To assess the incidence of ctDNA detection in patients with HR-positive/HER2-negative breast cancer. |
| Proportion of patients with at least a 90% decrease in baseline ctDNA at six, nine, and 12 months after initiation of study treatment. | Treatment phase (at six, nine, and 12 months after study treatment initiation) | To evaluate the treatment efficacy -in terms of a 90% decrease in baseline ctDNA at six, nine, and 12 months- of the different experimental arms. |
| Proportion of patients with at least a 90% decrease in baseline ctDNA at three months maintained at six months and 12 months after initiation of study treatment. | Treatment phase (at six and 12 months after study treatment initiation) | To evaluate the treatment efficacy -in terms of a 90% decrease in baseline ctDNA at three months and maintained at six months and 12 months- of the different treatment arms. |
| Proportion of patients with 50% and 70% decrease in baseline ctDNA at three, six, nine, and 12 months after initiation of study treatment. | Treatment phase (at three, six, nine, and 12 months after study treatment initiation) | To evaluate the treatment efficacy -in terms of a 50% and 70% decrease in baseline ctDNA at three, six, nine, and 12 months- of the treatment different arms. |
| Time to rising ctDNA defined as time to first ctDNA increase compared to baseline | Treatment phase (up to five years after study treatment initiation) | To evaluate the treatment efficacy -in terms of time to rising ctDNA during the study follow-up- of the different arms. |
| Duration of at least a 90% decrease in baseline ctDNA after initiation of study treatment. | Treatment phase (up to five years after study treatment initiation) | To evaluate the duration of treatment efficacy -in terms of time with at least a 90% decrease in baseline ctDNA- of the treatment different arms. |
| Best percentage of ctDNA decrease relative to baseline at six, nine, and 12 months after initiation of study treatment. | Treatment phase (up to five years) | To evaluate the ctDNA decrease relative to baseline -at three, six, nine, and 12 months- of the different arms. |
| Number of participants with treatment-related adverse events as assessed by NCI-CTCAE v5.0. | Treatment phase (up to five years after study treatment initiation) | National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0 will performed to evaluate the safety and tolerability of the different treatments. The occurrence and maximum grade of AEs observed throughout the study will be listed and tabulated according to type and dose level. Any AEs that the investigator reports as unrelated to the drug will also be reported. In this study, side effects will be assessed according to the NCI-CTCAE v.5.0. |
Countries
Spain, United Kingdom
Contacts
CONTACTMedsir
PRINCIPAL_INVESTIGATORAntonio Llombart, MD
Arnau de Vilanova Hospital, Valencia (Spain)
Outcome results
None listed