Trial Title:
Levels of Circulating Tumor DNA as a Predictive Marker for Early Switch in Treatment for Patients With Metastatic (Stage IV) Breast Cancer
NCT ID:
NCT05826964
Condition:
Breast Cancer
ER-positive Breast Cancer
HER2-negative Breast Cancer
Metastatic Breast Cancer
Conditions: Official terms:
Breast Neoplasms
Tamoxifen
Sirolimus
Capecitabine
Everolimus
Letrozole
Vinorelbine
Fulvestrant
Palbociclib
Anastrozole
Exemestane
Temsirolimus
MTOR Inhibitors
Elafin
Aromatase Inhibitors
Selective Estrogen Receptor Modulators
Estrogen Receptor Modulators
Estrogens
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Recruiting
Study design:
Allocation:
Randomized
Intervention model:
Sequential Assignment
Intervention model description:
The study will have the following 3 steps:
1. Step 1: All patients (N=450 to 500) will be receiving standard of care (SOC)
frontline treatment regimens.
2. Step 2: A subset of patients in Step 1 (N=160) will be randomized to continue same
treatment (Arm 1) or switch to new treatment (Arm 2).
3. Step 3: A subset of patients in Arm 1 will be switched to new treatment at time of
clinical disease progression (number to be determined).
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
AI+CDK4/6i
Description:
Participants will receive standard of care one of three available AI therapies in
combination with one of three available CDK4/6i therapies:
- AI: Anastrozole, Letrozole or Exemestane
- CDK4/6i: Palbociclib, Ribociclib or Abemaciclib
Arm group label:
Step 2 Arm 1: No Modification of Therapy
Arm group label:
Step 2 Arm 2: Early Switch in Therapy
Arm group label:
Step 3: Optional Treatment for Patients in Arm 1
Other name:
Aromatase Inhibitor (AI) + Cyclin dependent kinase 4 and 6 inhibitor (CDK4/6i)
Other name:
Anastrozole
Other name:
Letrozole
Other name:
Exemestane
Other name:
Palbociclib
Other name:
Ribociclib
Other name:
Abemaciclib
Intervention type:
Drug
Intervention name:
SERD+CDK4/6i
Description:
Participants will receive standard of care SERD therapy in the form of Fulvestrant, in
combination with one of three one of three available CDK4/6i therapies:
- SERD: Fulvestrant
- CDK4/6i: Palbociclib, Ribociclib or Abemaciclib
Arm group label:
Step 2 Arm 1: No Modification of Therapy
Arm group label:
Step 2 Arm 2: Early Switch in Therapy
Arm group label:
Step 3: Optional Treatment for Patients in Arm 1
Other name:
Selective Estrogen Receptor Degrader (SERD) + CDK4/6i
Other name:
Fulvestrant
Other name:
Palbociclib
Other name:
Ribociclib
Other name:
Abemaciclib
Intervention type:
Drug
Intervention name:
mTOR inhibitor + AI
Description:
Participants will receive standard of care mTOR inhibitor therapy (Everolimus) in
combination with AI therapy (Exemestane) in Step 2 Arm 2 and Step 3. mTOR inhibitor + AI
therapy administered as one of the available options for early switch from AI+CDK4/6i or
SERD+CDk4/6i therapy in administered in Step 1.
Arm group label:
Step 2 Arm 2: Early Switch in Therapy
Arm group label:
Step 3: Optional Treatment for Patients in Arm 1
Other name:
Mammalian target of rapamycin (mTOR) inhibitor + Aromatase Inhibitor (AI)
Other name:
Everolimus
Other name:
Exemestane
Intervention type:
Drug
Intervention name:
mTOR inhibitor + SERD
Description:
Participants will receive standard of care mTOR inhibitor therapy (Everolimus) in
combination with SERD therapy (Fulvestrant), in Step 2 Arm 2 and Step 3. mTOR inhibitor +
SERD therapy administered as one of the available options for early switch from
AI+CDK4/6i or SERD+CDk4/6i therapy in administered in Step 1.
Arm group label:
Step 2 Arm 2: Early Switch in Therapy
Arm group label:
Step 3: Optional Treatment for Patients in Arm 1
Other name:
Everolimus
Other name:
Fulvestrant
Intervention type:
Drug
Intervention name:
mTOR inhibitor + Selective estrogen receptor modulator
Description:
Participants will receive standard of care mTOR inhibitor therapy (Everolimus) in
combination with selective estrogen receptor modulator therapy (Tamoxifen) in Step 2 Arm
2 and Step 3. mTOR inhibitor + Selective estrogen receptor modulator therapy administered
as one of the available options for early switch from AI+CDK4/6i or SERD+CDk4/6i therapy
in administered in Step 1.
Arm group label:
Step 2 Arm 2: Early Switch in Therapy
Arm group label:
Step 3: Optional Treatment for Patients in Arm 1
Other name:
Everolimus
Other name:
Tamoxifen
Intervention type:
Drug
Intervention name:
PI3K inhibitor + SERD
Description:
Participants will receive standard of care one PI3K inhibitor therapy (Alpelisib), in
combination with SERD therapy (Fulvestrant) in Step 2 Arm 2 and Step 3. PI3K inhibitor +
SERD therapy administered as one of the available options for early switch from
AI+CDK4/6i or SERD+CDk4/6i therapy in administered in Step 1.
Arm group label:
Step 2 Arm 2: Early Switch in Therapy
Arm group label:
Step 3: Optional Treatment for Patients in Arm 1
Other name:
Phosphoinositide 3-kinase (PI3K) inhibitor + SERD
Other name:
Alpelisib
Other name:
Fulvestrant
Intervention type:
Drug
Intervention name:
PI3K inhibitor + AI
Description:
Participants will receive standard of care a PI3K inhibitor therapy (Alpelisib), in
combination with an AI therapy (Letrozole) in Step 2 Arm 2 and Step 3. PI3K inhibitor +
AI therapy administered as one of the available options for early switch from
SERD+CDk4/6i therapy in administered in Step 1.
Arm group label:
Step 2 Arm 2: Early Switch in Therapy
Arm group label:
Step 3: Optional Treatment for Patients in Arm 1
Other name:
Alpelisib
Other name:
Letrozole
Intervention type:
Drug
Intervention name:
Chemotherapy
Description:
Chemotherapy administered standard of care as an alternative therapy in Step 2 Arm 2 and
Step 3.
Arm group label:
Step 2 Arm 2: Early Switch in Therapy
Arm group label:
Step 3: Optional Treatment for Patients in Arm 1
Other name:
Taxane
Other name:
Eribulin
Other name:
Capecitabine
Other name:
Vinorelbine
Intervention type:
Drug
Intervention name:
Oral SERD
Description:
Participants will receive standard of care oral SERD therapy (Elacestrant) in Step 2 Arm
2 and Step 3. Oral SERD therapy administered as one of the available options for early
switch from AI+CDK4/6i or SERD+CDk4/6i therapy in administered in Step 1.
Arm group label:
Step 2 Arm 2: Early Switch in Therapy
Arm group label:
Step 3: Optional Treatment for Patients in Arm 1
Other name:
Elacestrant
Summary:
The majority of patients (pts) with breast cancer have hormone receptor positive (HR+)
disease, and this holds true for pts with advanced breast cancer (ABC). Currently
frontline therapy for pts with HR+ ABC is antihormonal therapy with an aromatase
inhibitor or selective estrogen receptor degrader plus a CDK4/6i. The proposed trial is a
randomized study to further evaluate the potential benefit of switching a frontline
regimen at the time that a molecular signal, ctDNA, suggests progression prior to
detection of clinical progression using standard methods. The purpose of this study is to
determine whether switching treatment earlier in the disease process, based on molecular
progression, will increase the amount of time that a patient's metastatic breast cancer
is controlled compared to patients with metastatic breast cancer who receive treatment
later based on diagnostic imaging results or other methods currently used in medical
practice.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
1. Men or women age ≥ 18 years.
2. Patients with a diagnosis of ER+, HER2- metastatic (Stage IV) breast cancer.
Positivity status is defined as >10% staining for ER and immunohistochemistry (IHC)
0+ or IHC 1 or 2+ staining for HER-2, and fluorescence in situ hybridization (FISH)
negative with standard pathology staining methods.
3. Archived tumor tissue available.
4. Women and men with proven locally advanced, locoregionally recurrent or metastatic
disease adenocarcinoma of the breast not amenable to curative therapy. Note:
patients relapsing while on adjuvant tamoxifen or AI are eligible for this study.
5. No prior systemic anticancer therapy for metastatic or advanced disease
(chemotherapy targeted therapy or ET).
Note 1: prior endocrine therapy in the metastatic setting is not allowed unless
initiated <30 days from study initiation or Cycle 1, Day 1 (C1D1) (Section 3.2).
Note 2: prior initiation of LHRH agonist or bone-directed agents, however, is
allowed.
6. No visceral crisis. Visceral crisis is defined as advanced, symptomatic, visceral
spread that is at risk of life-threatening complication in the short term and that
requires chemotherapy.
7. Adequate organ and marrow function as defined below:
- Hematological
- Absolute neutrophil count (ANC) ≥1,500 cells/mm³
- Platelets ≥100,000 cells/mm³
- Hemoglobin ≥9.0 g/dL
- Renal
- Serum creatinine or Measured or calculated creatinine clearance
(glomerular filtration rate (GFR) can also be used in place of creatinine
or creatinine clearance (CrCl)) ≤ 1.5 x upper limit of normal (ULN) or
CrCl ≥ 40 mL/min. CrCl should be calculated per institutional standard.
- Hepatic
- Serum total bilirubin < 1.0 ULN
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
(SGOT)) and alanine transaminase (ALT) (serum glutamic-pyruvic
transaminase (SGPT)). Aminotransferase (AST and ALT) ≤ 2.5 x ULN or 5 X
ULN for patients with liver metastases
- Albumin ≥ 2.5 mg/dL
8. Measurable disease as defined by Response Evaluation Criteria in Solid Tumors
version 1.1 (RECIST V.1.1) or non- measurable disease that is evaluable (Eisenhauer
EA, Therasse P, Bogaerts J et al, 2009).
9. Patients with an Eastern Cooperative Oncology Group (ECOG) performance score of 0 or
1. (See APPENDIX A for more information.)
10. Ability to understand and the willingness to sign a written informed consent
document.
11. Life expectancy >3 months.
12. Postmenopausal women, women with suppressed ovarian function, or premenopausal
women, provided they are being treated with monthly LHRH analogues (first injection
performed ≥ 7 days before treatment initiation) and are willing to continue to
receive LHRH agonist therapy for the duration of the trial. Menopausal patients or
patients with suppressed ovarian function are defined as follows:
- Women with bilateral oophorectomy
- Postmenopausal women, as defined by any of the following criteria:
- Age 60 or over
- Age 50-59 years and meets the following criterion:
- Amenorrhea for ≥12 months and follicle-stimulating hormone and estradiol
levels within the postmenopausal range
- Women with hysterectomy or chemotherapy-induced amenorrhea. Note: Patients
with hysterectomy or chemotherapy-induced amenorrhea must display follicle
stimulating hormone and estradiol levels within the postmenopausal range.
13. Resolution of all acute toxic effects from prior anticancer therapy or surgical
procedures as defined by the National Cancer Institute (NCI) Common Terminology
Criteria for Adverse Events (CTCAE) V 5.0 to grade 1 (except alopecia or other
toxicities not considered a safety risk for the patient at Investigator's
discretion)
(https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Q
uick_ Reference_8.5x11.pdf).
Exclusion Criteria:
1. Patients who are currently receiving or have received treatment for a secondary
cancer other than resected non-melanoma skin cancer lesions or in situ cancer within
the past 24 months.
2. Prior exposure to CDK4/6i ≤12 months prior to enrollment.
3. Use of investigational drugs ≤28 days prior to study enrollment and during the
study.
4. History or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the trial, interfere with the patient's
participation for the full duration of the trial, or that makes participation in the
trial to be not in the best interest of the patient in the opinion of the
Investigator.
5. Locally advanced breast cancer or locoregional relapse amenable for any treatment
with curative intent.
6. HER2+ or equivocal tumor status either on the primary or on the recurrent tumor
defined as IHC3+, FISH/CISH (chromogenic in situ hybridization) amplified or
FISH/CISH equivocal according to the American Society of Clinical Oncologists (ASCO)
2015 criteria (Wolff AC, Hammond MEH, Allison KH et al, 2018).
7. Prior endocrine therapy in the metastatic setting is not allowed unless initiated <
30 days from study initiation or Cycle 1, Day 1 (C1D1).
8. Prior treatment with any CDK 4/6 inhibitor in the metastatic setting is not allowed.
9. Patients who are ctDNA negative or with undetectable levels of ctDNA at study entry.
10. Any major surgery (defined as requiring general anesthesia) or significant traumatic
injury within 4 weeks of treatment; however, surgical diagnostic procedure is
allowed (even if under general anesthesia).
11. Known active, bleeding diathesis.
12. Any serious known concomitant systemic disorder incompatible with the study (at the
discretion of the Investigator).
13. Patients unable to swallow tablets.
14. History of malabsorption syndrome or other condition that would interfere with
enteral absorption.
15. Known active uncontrolled or symptomatic central nervous system (CNS) metastases,
carcinomatous meningitis, or leptomeningeal disease as indicated by clinical
symptoms, cerebral edema and/or progressive growth. Patients with a history of CNS
metastases or cord compression are eligible if they have been definitively treated
with local therapy (e.g., radiotherapy, stereotactic surgery) and are clinically
stable and off anticonvulsants and steroids for at least 4 weeks before treatment
initiation.
16. Known hypersensitivity to letrozole, anastrozole, exemestane, fulvestrant, or
CDK4/6i or any of their excipients.
17. Uncontrolled electrolyte disorders that can compound the effects of a QTc prolonging
drug (eg, hypocalcemia, hypokalemia, hypomagnesaemia).
18. Patients treated within the last 7 days prior to treatment start in the study with
medications that are known to be cytochrome (CYP) 3A4 inhibitors or drugs that are
known to be CYP3A4 inducers.
19. Patients requiring palliative radiation within the Screening Period (Section 7.1) or
within the 60 days following C1D1 in Step 1 (Section 4.3.1).
20. Patients already included in another therapeutic trial evaluating an investigational
medicinal product or having received an investigational medicinal product within 3
months.
21. Any stage II, III, or IV cancer within 5 years preceding patient enrollment in the
trial; however, multiple breast cancers (contralateral/ipsilateral cancers/local
relapses) are allowed pending all tumor masses were ER+.
22. Any history of hematologic malignancy.
23. Pregnancy or lactation period. Women of childbearing potential must implement
adequate nonhormonal contraceptive measures (barrier methods, intrauterine
contraceptive devices, sterilization; LHRH agonist cannot be considered as an
efficient contraceptive measure) during study treatment and for 90 days after
discontinuation. A serum pregnancy test must be negative in premenopausal women or
women with amenorrhea of less than 12 months.
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
University of Miami
Address:
City:
Miami
Zip:
33136
Country:
United States
Status:
Recruiting
Contact:
Last name:
Frances Valdes-Albini, MD
Phone:
305-243-5302
Email:
fvalbini@med.miami.edu
Investigator:
Last name:
Frances Valdes-Albini, MD
Email:
Principal Investigator
Start date:
June 12, 2023
Completion date:
July 31, 2029
Lead sponsor:
Agency:
University of Miami
Agency class:
Other
Source:
University of Miami
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05826964
