A Proof of Concept Study to Evaluate Treatments' Efficacy by Monitoring Minimal Residual Disease Using ctDNA in HR-positive/HER2-negative Early Breast Cancer Population
Overview
- Phase
- Phase 2
- Intervention
- Giredestrant
- Conditions
- Breast Cancer
- Sponsor
- MedSIR
- Enrollment
- 976
- Locations
- 41
- Primary Endpoint
- Evaluation of decrease or clearance in baseline ctDNA at three months after initiation of study treatment
- Status
- Recruiting
- Last Updated
- last month
Overview
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
Investigators
Eligibility Criteria
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:
- •Signed informed consent form (ICF) prior to participation in any Studyrelated activities.
- •Male or female patients aged 18 years or older.
- •Eastern Cooperative Oncology Group (ECOG) performance status 0 or
- •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.
- •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
- •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:
Exclusion Criteria
- •for surveillance phase:
- •Patients with pathological complete response (pCR) after neoadjuvant treatment.
- •Any concurrent or planned treatment for the current diagnosis of BC other than adjuvant ET except for denosumab or zoledronic acid, which are allowed.
- •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.
- •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.
- •Active cardiac disease or history of cardiac dysfunction including any of the following:
- •History (within two years from screening) or presence of idiopathic bradycardia or resting heart rate \<50 beats per minute at screening.
- •History of angina pectoris or symptomatic coronary heart disease within 12 months prior to Study entry.
- •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.
- •History or presence of an abnormal ECG that is clinically significant in the investigator's opinion,
Arms & Interventions
Arm B: Experimental Arm with giredestrant
Giredestrant: 30 mg will be taken orally (PO) once a day (QD) on Days 1 to 28 of each 28-day cycle up to five years or until disease recurrence, unacceptable toxicity, or treatment/study discontinuation (whichever occurs first).
Intervention: Giredestrant
Arm C: Experimental Arm with giredestrant + abemaciclib
* Giredestrant: 30 mg will be taken PO QD on Days 1to 28 of each 28-day cycle up to five years or until disease recurrence, unacceptable toxicity, or treatment/study discontinuation (whichever occurs first). * Abemaciclib 150mg will be taken PO twice daily (BID) (two intakes for a total daily dose of 300 mg) during each 28-day cycle up to two years or until disease recurrence, unacceptable toxicity, or treatment/study discontinuation (whichever occurs first).
Intervention: Giredestrant
Arm C: Experimental Arm with giredestrant + abemaciclib
* Giredestrant: 30 mg will be taken PO QD on Days 1to 28 of each 28-day cycle up to five years or until disease recurrence, unacceptable toxicity, or treatment/study discontinuation (whichever occurs first). * Abemaciclib 150mg will be taken PO twice daily (BID) (two intakes for a total daily dose of 300 mg) during each 28-day cycle up to two years or until disease recurrence, unacceptable toxicity, or treatment/study discontinuation (whichever occurs first).
Intervention: Abemaciclib
Arm D: Experimental Arm with giredestrant + inavolisib
* Giredestrant: 30 mg will be administered PO QD on Days 1-28 of each 28-day cycle up to five years or until disease recurrence, unacceptable toxicity, or treatment/study discontinuation (whichever occurs first). * Inavolisib: 9 mg will be administered PO QD on Days 1-28 of each 28-day cycle up to two years or until disease recurrence, unacceptable toxicity, or treatment/study discontinuation (whichever occurs first).
Intervention: Giredestrant
Arm D: Experimental Arm with giredestrant + inavolisib
* Giredestrant: 30 mg will be administered PO QD on Days 1-28 of each 28-day cycle up to five years or until disease recurrence, unacceptable toxicity, or treatment/study discontinuation (whichever occurs first). * Inavolisib: 9 mg will be administered PO QD on Days 1-28 of each 28-day cycle up to two years or until disease recurrence, unacceptable toxicity, or treatment/study discontinuation (whichever occurs first).
Intervention: Inavolisib
Arm A: Control Arm
Patients will continue receiving the same standard ET that was prescribed during the surveillance phase for a period of 90 days. This will be done in accordance with standard clinical practice and until the analysis of the primary endpoint.No changes to the prescribed ET are permitted during the 90-day period.
Outcomes
Primary Outcomes
Evaluation of decrease or clearance in baseline ctDNA at three months after initiation of study treatment
Time Frame: 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 Outcomes
- 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))
- 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))
- 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))
- 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))
- 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))
- Time to rising ctDNA defined as time to first ctDNA increase compared to baseline(Treatment phase (up to five years after study treatment initiation))
- 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))
- 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))