Fulvestrant, Ipatasertib and CDK4/6 Inhibition in Metastatic ER+/HER2- Breast Cancer Patients Without ctDNA Suppression (FAIM)

Randomised Open-label Phase II Study of Induction Standard of Care Fulvestrant and CDK4/6 Inhibition With the Addition of Ipatasertib in Metastatic ER+/HER2- Breast Cancer Patients Without ctDNA Suppression

Analysis of circulating tumour DNA (ctDNA) found in a patient's peripheral blood can identify cancer progression and predict a patient's response to therapy. By using ctDNA analysis and imaging techniques, the FAIM trial aims to determine whether the addition of the experimental drug ipatasertib to a standard combination of the hormone treatment fulvestrant and the targeted agent palbociclib increases progression free survival (PFS) for patients with hormone-receptor positive and human epidermal growth factor receptor 2 negative (HR+/HER2-) breast cancer.

Study Overview

• Status: Active, not recruiting
• Conditions: Advanced Breast Cancer; Metastatic Breast Cancer; ER+ Breast Cancer
• Intervention / Treatment: Drug: Ipatasertib 300mg; Drug: Fulvestrant 500g; Drug: Palbociclib 75mg-125mg; Drug: CDK4/6 Inhibitor

Detailed Description

Circulating tumour DNA (ctDNA) can be found in the peripheral blood of patients with cancer. ctDNA analysis provides a readily available, serial source of tumour DNA which can be used to monitor disease and predict a patients response to therapy.

Relative changes in ctDNA after 15 days of treatment with palbociclib and fulvestrant has been found to strongly predict progression free survival (PFS) in hormone-receptor positive and human epidermal growth factor receptor 2 negative (HR+/HER2-) breast cancer patients: patients without ctDNA suppression after 2 weeks of treatment had a significantly shorter PFS compared to those with ctDNA suppression, identifying a group of patients who require additional therapy to prevent early progression.

The FAIM trial is a randomised, open-label study which will aim to determine whether the addition of ipatasertib to standard of care CDK4/6 inhibitors + fulvestrant increases PFS in patients who lack ctDNA suppression after 15 days of treatment. Patients starting standard of care CDK4/6 inhibitors + fulvestrant will have a ctDNA assessment on cycle 1 day 1 (C1D1) and cycle 1 day 15 (C1D15). Those with high ctDNA levels at C1D15 will be randomised on a 1:1 basis to either standard of care (CDK4/6 inhibitors + fulvestrant) or standard of care plus the experimental drug ipatasertib (CDK4/6 inhibitor + fulvestrant + ipatasertib). Patients with ctDNA suppression at C1D15 will continue standard of care (fulvestrant+CDK4/6 inhibitor); the first 100 patients of this group will be followed for PFS and ctDNA collection. Patients without detectable ctDNA on C1D1 will be followed and treated according standard of care; the first 50 patients of this group will be followed for PFS, overall survival (OS), time to next treatment, and time to chemotherapy. Progression free survival will be monitored using RECIST 1.1.

• Study Type: Interventional
• Enrollment (Actual): 57
• Phase: Phase 2

Contacts and Locations

Study Locations

• United Kingdom
  • Edinburgh, United Kingdom, EH4 2XU
    • Western General Hospital
  • Glasgow, United Kingdom
    • Beatson West of Scotland Cancer Centre
  • London, United Kingdom
    • University College London Hospital
  • London, United Kingdom, NW3 2QC
    • Royal Free Hospital
  • London, United Kingdom, SW3 6JJ
    • Royal Marsden NHS Foundation Trust
  • London, United Kingdom, W2 1NY
    • Imperial College University Hospitals NHS Trust
  • Manchester, United Kingdom, M20 4BX
    • The Christie NHS Foundation Trust
  • Nottingham, United Kingdom
    • Nottingham City Hospital
  • Oxford, United Kingdom, OX3 7LE
    • Oxford University Hospitals
  • Cambridgeshire
    • Cambridge, Cambridgeshire, United Kingdom, CB2 0QQ
      • Addenbrookes Hospital
  • Cornwall
    • Truro, Cornwall, United Kingdom, TR1 3LQ
      • Royal Cornwall Hospital
  • Surrey
    • London, Surrey, United Kingdom, HA6 2RN
      • Mount Vernon Cancer Centre
  • Wales
    • Cardiff, Wales, United Kingdom, CF14 2TL
      • Velindre Cancer Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Histological diagnosis of metastatic or inoperable locally advanced ER positive/HER2 negative breast cancer. Assessment of ER and HER2 status as per local assessment. Histologically proven primary ER+ (Allred score 3/8 or greater, or stain in more than 1% of cancer cells) and HER2- (immunohistochemistry 0/1+ or negative by in situ hybridization) breast cancer as determined by local laboratory.
2. Willingness to consent for an archival tumour tissue sample (of advanced disease) to be requested for transfer to the Royal Marsden during study screening for future analysis. Patients without a metastatic biopsy are eligible if archival tumour from the breast primary tumour is available, but only after discussion with the Chief Investigator (see section 7.3.1). (PI assessment that a biopsy is not clinically appropriate will be required as evidence before discussion with the CI).
3. Previously treated with no more than one prior line of chemotherapy for advanced disease.
4. Patients eligible according to standard of care for fulvestrant in combination with a CDK4/6 inhibitor (abemaciclib, palbociclib, or ribociclib).
5. Patients must have progressed on or within 1 month from stopping prior endocrine therapy for advanced disease, or relapsed on or within 12 months of completing adjuvant endocrine therapy.
6. Measurable disease according to RECIST 1.1 or assessable bone disease (lytic or mixed lytic/sclerotic).
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.

8. Adequate bone marrow, renal, and liver function within 14 days prior to the first study treatment on Day 1 of Cycle 1, defined as:

   • Neutrophils (ANC >= 2000/uL), haemoglobin >= 90 g/L, platelet count >= 100 x 10^9/L
   • Serum albumin >= 3 g/dL
   • Total bilirubin <= 1.5 times the upper limit of normal (ULN). Patients with known Gilbert syndrome may be enrolled if bilirubin <= 3 times ULN
   • AST and ALT <= 2.5 times ULN. Patients with documented liver or bone metastases may have AST and ALT <= 5 times ULN
   • ALP <= 2 times ULN. Patients with known liver involvement may have ALP <= 5 times ULN. Patients with known bone involvement may have ALP <= 7 times ULN
   • Serum creatinine <= 1.5 times ULN or creatinine clearance >= 50 mL/min using the Cockcroft-Gault formula
   • INR < 1.5 times ULN and aPTT < 1.5 times ULN. Patients requiring anticoagulation should receive low-molecular-weight heparin or a direct oral anticoagulant
9. Fasting glucose <= 150 mg/dL and HbA1c <= 7.5%.
10. Negative serum pregnancy test at screening for females of childbearing potential.
11. Patients able to have children must agree to use a highly effective method of contraception (failure rate less than 1% per year) throughout the study and for at least two years after the last dose of fulvestrant and 90 days after the last dose of palbociclib or ipatasertib. Patients must also agree to refrain from donating eggs or sperm during this period.
12. Pre- or peri-menopausal patients must be treated with licensed GnRH analogues as per standard of care.
13. Aged 18 years or older.
14. Written informed consent has been provided, signed and dated.

Exclusion Criteria:

1. Prior exposure to adjuvant CDK4/6 inhibitors (abemaciclib, palbociclib, or ribociclib) for early breast cancer less than 12 months (52 weeks or 365 days) prior to breast cancer recurrence.
2. Prior treatment with fulvestrant for advanced breast cancer.
3. Prior treatment with an AKT inhibitor, PIK3CA inhibitor, or mTOR inhibitor in any setting.
4. History of malabsorption syndrome or other condition that would interfere with enteral absorption, or inability or unwillingness to swallow oral medication.
5. Systemic chemotherapy within 14 days or endocrine therapy within 7 days prior to registration.
6. Major surgery within 4 weeks prior to registration.
7. Palliative radiotherapy within 14 days prior to registration.
8. Known leptomeningeal disease, untreated brain metastases, spinal cord compression, or symptomatic brain metastases requiring steroids.

9. Clinically significant, uncontrolled cardiac disease or cardiac repolarization abnormality, including but not limited to:

   • Angina pectoris, symptomatic pericarditis, coronary artery bypass graft, or myocardial infarction within 12 months prior to study entry
   • Symptomatic cardiac failure (NYHA class II to IV or LVEF < 50%), uncontrolled hypertension, cardiac dysrhythmia requiring medication, significant or symptomatic bradycardia, long QT syndrome, family history of congenital long QT syndrome or idiopathic sudden death
   • Cerebrovascular accident or transient ischemic attack within 12 months
   • Known risk factors for prolonged QT interval or Torsade de Pointes
   • Uncorrected hypomagnesaemia or hypokalaemia of Grade 3 or higher
   • Systolic blood pressure > 160 mmHg or < 90 mmHg
   • Resting heart rate < 50 beats per minute
   • Screening QTcF > 470 ms based on the mean of three ECGs
10. Lung disease including any history of pneumonitis, interstitial lung disease, idiopathic pulmonary fibrosis, cystic fibrosis, aspergillosis, active tuberculosis, or opportunistic infections such as pneumocystis pneumonia or cytomegalovirus pneumonia.
11. Uncontrolled pleural effusion, pericardial effusion, or ascites as judged by the investigator.
12. Type I or II diabetes requiring insulin therapy.
13. Use of potent CYP3A4 inducers or inhibitors within 2 weeks or five elimination half-lives (whichever is longer) prior to the first dose of palbociclib with or without ipatasertib.
14. Known HIV infection or AIDS-related illness.
15. Active infection requiring systemic therapy.

16. Known acute or chronic hepatitis B or C infection.

    • Patients with resolved hepatitis B infection (HBsAg negative, HBcAb positive, and HBV DNA negative) are eligible
    • Patients positive for HCV antibody are eligible only if HCV RNA by PCR is negative
17. Clinically significant liver disease consistent with Child-Pugh class B or C.
18. Administration of a live vaccine within 4 weeks prior to study entry.
19. Diagnosis of another malignancy within 5 years, except for adequately treated basal cell carcinoma, squamous cell carcinoma of the skin, or carcinoma in situ of the breast or cervix.
20. Participation in another study involving investigational drugs within 4 weeks prior to study entry or during study participation.
21. Persisting toxicity related to prior therapy greater than Grade 1, except stable peripheral neuropathy Grade 2 or alopecia Grade 2.
22. Other severe acute or chronic medical condition or laboratory abnormality that may increase the risk associated with study participation or interfere with interpretation of results, including colitis, inflammatory bowel disease, active bowel inflammation (for example diverticulitis), psychiatric illness, recent or active suicidal ideation or behaviour, or end-stage renal disease requiring haemodialysis.
23. Known allergy or hypersensitivity to ipatasertib, palbociclib, fulvestrant, or any of their components.
24. Pregnancy or breastfeeding.
25. Requirement for chronic corticosteroid therapy greater than 10 mg prednisolone per day, or equivalent doses of other systemic corticosteroids or immunosuppressants for chronic disease.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Palbociclib + Fulvestrant + Ipatasertib (Interventional arm); Where high ctDNA is detected in screening, patients to be randomised on a 1:1 basis to interventional arm or comparison arm. Patients randomised to interventional arm receive Palbociclib + Fulvestrant + Ipatasertib. n = 87.	Drug: Ipatasertib 300mg; Ipatasertib 300mg once daily. Oral administration. Treatment is continuous daily for 21 days, followed by 7 days off, to complete a 28 day cycle.; Other Names: RG7440; Drug: Fulvestrant 500g; Fulvestrant 500mg administered intramuscularly in the buttocks slowly (1-2 minutes per injection) as two 5-mL injections (one in each buttock). Administered days 1 and 15 of Cycle 1. For subsequent cycles, patients will receive fulvestrant as described above in the clinic on Day 1 of each cycle or approximately every 4 weeks.; Other Names: Faslodex; Drug: Palbociclib 75mg-125mg; Palboclicib 75mg-125mg once daily, dependent on toxicities. Oral administration. Treatment is continuous daily for 21 days, followed by 7 days off, to complete a 28 day cycle.; Other Names: Ibrance
Active Comparator: Palbociclib + Fulvestrant (Comparison arm); Where high ctDNA is detected in screening, patients to be randomised on a 1:1 basis to interventional arm or comparison arm. Patients randomised to Comparison arm receive Palbociclib + Fulvestrant. n = 87.	Drug: Fulvestrant 500g; Fulvestrant 500mg administered intramuscularly in the buttocks slowly (1-2 minutes per injection) as two 5-mL injections (one in each buttock). Administered days 1 and 15 of Cycle 1. For subsequent cycles, patients will receive fulvestrant as described above in the clinic on Day 1 of each cycle or approximately every 4 weeks.; Other Names: Faslodex; Drug: Palbociclib 75mg-125mg; Palboclicib 75mg-125mg once daily, dependent on toxicities. Oral administration. Treatment is continuous daily for 21 days, followed by 7 days off, to complete a 28 day cycle.; Other Names: Ibrance
Active Comparator: Standard of Care (No ctDNA observational arm); Where no ctDNA is detected in screening, patients to be allocated to the observational arm and receive standard of care (Abemaciclib / Ribociclib / Palbociclib + fulvestrant). n = 50.	Drug: Fulvestrant 500g; Fulvestrant 500mg administered intramuscularly in the buttocks slowly (1-2 minutes per injection) as two 5-mL injections (one in each buttock). Administered days 1 and 15 of Cycle 1. For subsequent cycles, patients will receive fulvestrant as described above in the clinic on Day 1 of each cycle or approximately every 4 weeks.; Other Names: Faslodex; Drug: CDK4/6 Inhibitor; CDK4/6 inhibitor. As per current standard of care regime for ER+/HER2- breast cancer.; Other Names: Abemaciclib / Ribociclib / Palbociclib
Active Comparator: Standard of Care (Low ctDNA observational arm); Where low ctDNA is detected in screening, patients to be allocated to the observational arm and receive standard of care (Abemaciclib / Ribociclib / Palbociclib + fulvestrant). n = 100.	Drug: Fulvestrant 500g; Fulvestrant 500mg administered intramuscularly in the buttocks slowly (1-2 minutes per injection) as two 5-mL injections (one in each buttock). Administered days 1 and 15 of Cycle 1. For subsequent cycles, patients will receive fulvestrant as described above in the clinic on Day 1 of each cycle or approximately every 4 weeks.; Other Names: Faslodex; Drug: CDK4/6 Inhibitor; CDK4/6 inhibitor. As per current standard of care regime for ER+/HER2- breast cancer.; Other Names: Abemaciclib / Ribociclib / Palbociclib

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Assess progression free survival (PFS)	To compare PFS in patients randomised between SOC palbociclib/fulvestrant + ipatasertib and SOC CDK4/6 inhibitor/fulvestrant alone, in advanced ER+/HER2- breast cancer patients with trackable mutations and high ctDNA after 2 weeks of CDK4/6 inhibitor/fulvestrant.	Time from date of randomisation until the date of first documented progression or date of death from any cause, whichever comes first, assessed up to 51 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To assess the AEs/SAEs for patients on palbociclib/fulvestrant/ipatasertib compared to palbociclib/fulvestrant alone	To assess the overall safety and tolerability of standard of care palbociclib/fulvestrant + ipatasertib compared to standard of care CDK4/6 inhibitor/fulvestrant alone. Safety will be evaluated continuously by monitoring adverse events and serious adverse events, graded according to NCI CTCAE Version 5.0. SAEs will be collected from registration until 30 days post last trial treatment administration. AEs will be collected from Cycle 2 day 1 until 30 days post last trial treatment administration.	51 months (treatment duration + follow-up duration)
Assess overall survival	• To assess Overall Survival (OS) in patients receiving standard of care palbociclib/fulvestrant + ipatasertib compared to SOC CDK4/6 inhibitor/fulvestrant alone.	51 months (treatment duration + follow-up duration)
Assess objective response rate	• To assess the objective response rate in patients receiving SOC palbociclib/fulvestrant + ipatasertib compared to SOC CDK4/6 inhibitor/fulvestrant alone.	51 months (treatment duration + follow-up duration)
Report progression free survival (PFS) in patients with low ctDNA and high ctDNA	• To report progression free survival (PFS) in patients with suppressed ctDNA on standard of care CDK4/6 inhibitor/fulvestrant within the observational arm.	Time from date of randomisation until the date of first documented progression or date of death from any cause, whichever comes first, assessed up to 51 months
Compare progression free survival (PFS) in the subgroup of advanced ER+/HER2- breast cancer patients	To report PFS in patients randomised between standard of care palbociclib/fulvestrant + ipatasertib and standard of care CDK4/6 inhibitor/fulvestrant alone, in the subgroup of advanced ER+/HER2- breast cancer patients with PIK3CA/PTEN/AKT1 mutations or PTEN loss.	Time from date of randomisation until the date of first documented progression or date of death from any cause, whichever comes first, assessed up to 51 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Report progression-free survival by ctDNA genomic alterations	• To report progression-free survival (PFS) in patients with genetic alterations identified through ctDNA sequencing data.	51 months (treatment duration + follow-up duration)
Report progression free survival (PFS) in patients with undetectable ctDNA and those with detected ctDNA at C1D1 with and without suppression at C1D15.	• To report PFS in patients with undetectable ctDNA at Cycle 1 Day 1 and those with detectable ctDNA with and without ctDNA suppression at Day 15.	51 months (treatment duration + follow-up duration)
Report overall survival (OS) by early ctDNA status at C1D1 and C1D15	To report overall survival (OS) in patients with undetectable ctDNA at C1D1 and in patients with suppressed ctDNA at C1D15.	51 months (treatment duration + follow-up duration)
Evaluate changes in ctDNA in patients with high ctDNA C1D15	• To evaluate changes in ctDNA and CTC enumeration in patients randomised to standard of care palbociclib/fulvestrant + ipatasertib or standard of care CDK4/6 inhibitor/fulvestrant alone.	51 months (treatment duration + follow-up duration)
Evaluate changes in ctDNA levels and circulating tumor cell (CTC) enumeration in patients with suppressed ctDNA	To evaluate changes in ctDNA levels and circulating tumor cell (CTC) enumeration in patients with suppressed ctDNA in the observation arm.	51 months (treatment duration + follow-up duration)
Report time to next chemotherapy	To report time to next chemotherapy in all study participants.	From Cycle 1 Day 1 (each cycle is 28 days) until initiation of next chemotherapy, end of of study participation, or study completion, whichever occurs first (up to 51 months)

Collaborators and Investigators

• Sponsor: Royal Marsden NHS Foundation Trust
• Collaborators: Pfizer; Hoffmann-La Roche
• Investigators: Principal Investigator: Alicia Okines, Royal Marsden NHS Foundation Trust

Publications and helpful links

General Publications

• Turner NC, Ro J, Andre F, Loi S, Verma S, Iwata H, Harbeck N, Loibl S, Huang Bartlett C, Zhang K, Giorgetti C, Randolph S, Koehler M, Cristofanilli M; PALOMA3 Study Group. Palbociclib in Hormone-Receptor-Positive Advanced Breast Cancer. N Engl J Med. 2015 Jul 16;373(3):209-19. doi: 10.1056/NEJMoa1505270. Epub 2015 Jun 1.
• Turner NC, Slamon DJ, Ro J, Bondarenko I, Im SA, Masuda N, Colleoni M, DeMichele A, Loi S, Verma S, Iwata H, Harbeck N, Loibl S, Andre F, Puyana Theall K, Huang X, Giorgetti C, Huang Bartlett C, Cristofanilli M. Overall Survival with Palbociclib and Fulvestrant in Advanced Breast Cancer. N Engl J Med. 2018 Nov 15;379(20):1926-1936. doi: 10.1056/NEJMoa1810527. Epub 2018 Oct 20.
• O'Leary B, Hrebien S, Morden JP, Beaney M, Fribbens C, Huang X, Liu Y, Bartlett CH, Koehler M, Cristofanilli M, Garcia-Murillas I, Bliss JM, Turner NC. Early circulating tumor DNA dynamics and clonal selection with palbociclib and fulvestrant for breast cancer. Nat Commun. 2018 Mar 1;9(1):896. doi: 10.1038/s41467-018-03215-x.
• Bettegowda C, Sausen M, Leary RJ, Kinde I, Wang Y, Agrawal N, Bartlett BR, Wang H, Luber B, Alani RM, Antonarakis ES, Azad NS, Bardelli A, Brem H, Cameron JL, Lee CC, Fecher LA, Gallia GL, Gibbs P, Le D, Giuntoli RL, Goggins M, Hogarty MD, Holdhoff M, Hong SM, Jiao Y, Juhl HH, Kim JJ, Siravegna G, Laheru DA, Lauricella C, Lim M, Lipson EJ, Marie SK, Netto GJ, Oliner KS, Olivi A, Olsson L, Riggins GJ, Sartore-Bianchi A, Schmidt K, Shih lM, Oba-Shinjo SM, Siena S, Theodorescu D, Tie J, Harkins TT, Veronese S, Wang TL, Weingart JD, Wolfgang CL, Wood LD, Xing D, Hruban RH, Wu J, Allen PJ, Schmidt CM, Choti MA, Velculescu VE, Kinzler KW, Vogelstein B, Papadopoulos N, Diaz LA Jr. Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med. 2014 Feb 19;6(224):224ra24. doi: 10.1126/scitranslmed.3007094.
• Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, Rosso S, Coebergh JW, Comber H, Forman D, Bray F. Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012. Eur J Cancer. 2013 Apr;49(6):1374-403. doi: 10.1016/j.ejca.2012.12.027. Epub 2013 Feb 26.
• Telli ML, Gradishar WJ, Ward JH. NCCN Guidelines Updates: Breast Cancer. J Natl Compr Canc Netw. 2019 May 1;17(5.5):552-555. doi: 10.6004/jnccn.2019.5006.
• Johnston SR. Enhancing the efficacy of hormonal agents with selected targeted agents. Clin Breast Cancer. 2009 Jun;9 Suppl 1:S28-36. doi: 10.3816/CBC.2009.s.003.
• Musgrove EA, Sutherland RL. Biological determinants of endocrine resistance in breast cancer. Nat Rev Cancer. 2009 Sep;9(9):631-43. doi: 10.1038/nrc2713.
• Zardavas D, Irrthum A, Swanton C, Piccart M. Clinical management of breast cancer heterogeneity. Nat Rev Clin Oncol. 2015 Jul;12(7):381-94. doi: 10.1038/nrclinonc.2015.73. Epub 2015 Apr 21.
• Meyerson M, Harlow E. Identification of G1 kinase activity for cdk6, a novel cyclin D partner. Mol Cell Biol. 1994 Mar;14(3):2077-86. doi: 10.1128/mcb.14.3.2077-2086.1994.
• Coudreuse D, Nurse P. Driving the cell cycle with a minimal CDK control network. Nature. 2010 Dec 23;468(7327):1074-9. doi: 10.1038/nature09543.
• O'Leary B, Finn RS, Turner NC. Treating cancer with selective CDK4/6 inhibitors. Nat Rev Clin Oncol. 2016 Jul;13(7):417-30. doi: 10.1038/nrclinonc.2016.26. Epub 2016 Mar 31.
• Sledge GW Jr, Toi M, Neven P, Sohn J, Inoue K, Pivot X, Burdaeva O, Okera M, Masuda N, Kaufman PA, Koh H, Grischke EM, Frenzel M, Lin Y, Barriga S, Smith IC, Bourayou N, Llombart-Cussac A. MONARCH 2: Abemaciclib in Combination With Fulvestrant in Women With HR+/HER2- Advanced Breast Cancer Who Had Progressed While Receiving Endocrine Therapy. J Clin Oncol. 2017 Sep 1;35(25):2875-2884. doi: 10.1200/JCO.2017.73.7585. Epub 2017 Jun 3.
• Cardoso F, Senkus E, Costa A, Papadopoulos E, Aapro M, Andre F, Harbeck N, Aguilar Lopez B, Barrios CH, Bergh J, Biganzoli L, Boers-Doets CB, Cardoso MJ, Carey LA, Cortes J, Curigliano G, Dieras V, El Saghir NS, Eniu A, Fallowfield L, Francis PA, Gelmon K, Johnston SRD, Kaufman B, Koppikar S, Krop IE, Mayer M, Nakigudde G, Offersen BV, Ohno S, Pagani O, Paluch-Shimon S, Penault-Llorca F, Prat A, Rugo HS, Sledge GW, Spence D, Thomssen C, Vorobiof DA, Xu B, Norton L, Winer EP. 4th ESO-ESMO International Consensus Guidelines for Advanced Breast Cancer (ABC 4)dagger. Ann Oncol. 2018 Aug 1;29(8):1634-1657. doi: 10.1093/annonc/mdy192. No abstract available.
• Cristofanilli M, Turner NC, Bondarenko I, Ro J, Im SA, Masuda N, Colleoni M, DeMichele A, Loi S, Verma S, Iwata H, Harbeck N, Zhang K, Theall KP, Jiang Y, Bartlett CH, Koehler M, Slamon D. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncol. 2016 Apr;17(4):425-439. doi: 10.1016/S1470-2045(15)00613-0. Epub 2016 Mar 3.

Study record dates

Study Major Dates

• Study Start (Actual): December 28, 2022
• Primary Completion (Estimated): June 1, 2027
• Study Completion (Estimated): June 1, 2027

Study Registration Dates

• First Submitted: May 27, 2021
• First Submitted That Met QC Criteria: June 3, 2021
• First Posted (Actual): June 10, 2021

Study Record Updates

• Last Update Posted (Actual): April 14, 2026
• Last Update Submitted That Met QC Criteria: April 8, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: ctDNA; Fulvestrant; Palbociclib; Ipatasertib
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Skin Diseases; Breast Diseases; Skin and Connective Tissue Diseases; Breast Neoplasms; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Polycyclic Compounds; Steroids; Fused-Ring Compounds; Estradiol; Estrenes; Estranes; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Fulvestrant; abemaciclib; ipatasertib; ribociclib; palbociclib
• Other Study ID Numbers: CCR5214

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: The confidentiality of patients participating in this trial will be protected and each participant will be assigned a unique trial number at the point of registration which will be used to identify eCRFs and anything else sent to the sponsor or other third parties. No patient identifiable data will be shared outside of the participating site.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No