Trial Title:
Liquid-biopsy Informed Platform Trial to Evaluate CDK4/6-inhibitor Resistant ER+/HER2- Metastatic Breast Cancer
NCT ID:
NCT05601440
Condition:
Breast Cancer
Conditions: Official terms:
Breast Neoplasms
Gemcitabine
Fulvestrant
Niraparib
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Recruiting
Study design:
Allocation:
Non-Randomized
Intervention model:
Parallel Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
RP-6306
Description:
Dose and schedule will be assigned at enrolment
Arm group label:
Substudy B - RP-6306 + Gemcitabine
Intervention type:
Drug
Intervention name:
Gemcitabine
Description:
Dose and schedule will be assigned at enrolment
Arm group label:
Substudy B - RP-6306 + Gemcitabine
Intervention type:
Other
Intervention name:
Observation
Description:
Monitoring arm
Arm group label:
Substudy A - Monitoring
Intervention type:
Drug
Intervention name:
Niraparib
Description:
Dose and schedule will be assigned at enrolment
Arm group label:
Substudy C - Niraparib + Fulvestrant
Intervention type:
Drug
Intervention name:
Fulvestrant
Description:
Dose and schedule will be assigned at enrolment
Arm group label:
Substudy C - Niraparib + Fulvestrant
Summary:
This study is being done to answer the following question: Can testing breast cancer for
DNA abnormalities or "biomarkers" help predict which patients are most likely to be
helped by certain treatments? The pre-study screening is being done to test a sample of
blood (or tumour tissue) for biomarkers to see if patients can participate in the study
Detailed description:
This is a 2-stage master protocol with multiple substudies testing investigational
drugs/drug combinations in patients with CDK4/6-inhibitor resistant ER+/HER2- metastatic
breast cancer. First line endocrine therapy (1LET, aromatase inhibitors; AI) improve
clinical outcomes, but are not curative, and acquired resistance develops (median ~2
years). CDK4/6i-resistant MBC is a clinical unmet need, and is marked by numerous
potential resistance alterations / mechanisms. Currently, most patients receive second
line (2L) ET (e.g., fulvestrant) which has a median progression-free survival (PFS) of ~2
months in this setting. Circulating tumour DNA (ctDNA) and circulating tumour cells
(CTCs) are detectable in peripheral blood in >90% of patients with MBC.
Patients who wish to participate but progression has not yet occurred may be enrolled in
the monitoring substudy and followed until progression. This monitoring component of
IND.241 aims to characterize the molecular and clinical features of CDK4/6i resistance as
it occurs after first line CDK4/6i + AI. Besides addressing the principal objectives
described above (ctDNA genotyping and evaluation of dynamic changes in ctDNA and CTC
levels), banked samples will create a biorepository for interrogation of emerging assays
(e.g., DNA methylation, CTC protein or single cell analyses) that may have prognostic or
predictive application. These data will inform future efforts that may consider
intervention prior to clinical treatment failure.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
- Patients must have histologically and/or cytologically confirmed, advanced /
metastatic breast cancer, ER ≥10% and not HER2 overexpressing/amplified as per
ASCO/CAP criteria. Patients with locally advanced or inflammatory disease without
distant metastases that is potentially resectable or treatable with curative intent
are not eligible
- All patients must have a formalin fixed paraffin embedded tissue block (from primary
or metastatic tumour) available and must have provided informed consent for the
release of the block
- Patients must have had objective disease progression demonstrated on (defined as
while taking or within 8 weeks of the last dose) first line CDK4/6i + ET for MBC.
Patients who discontinued CDK4/6i + ET without disease progression more than 8 weeks
prior to objective disease progression (toxicity, patient request) are not eligible.
Patients must have received at least 24 weeks of first line CDK4/6i + ET therapy
- Presence of clinically and/or radiologically documented disease. All radiology
studies must be performed within 21 days prior to enrollment (within 28 days if
negative). All patients must have measurable disease as defined by RECIST 1.1.
- The criteria for defining measurable disease are as follows:
- Chest x-ray ≥ 20 mm
- CT scan (with slice thickness of 5 mm) ≥ 10 mm: longest diameter
- Physical exam (using calipers) ≥ 10 mm
- Lymph nodes by CT scan ≥ 15 mm: measured in short axis
- Patients must be ≥ 18 years of age
- Patients must have an ECOG performance status 0 or 1
- Patients must have a life expectancy ≥ 3 months.
- Hemoglobin ≥90 g/L*
- Absolute neutrophils ≥ 1.5 x 10^9/L (1500/µL)
- Platelets ≥ 100 x 109/L (100 x 10^3/µL)
- Bilirubin ≤ 1.5 x ULN (upper limit of normal)**
- AST & ALT ≤ 2.5 x ULN
- ≤ 5.0 x ULN if patient has liver metastases
- Serum creatinine ≤ 1.5 x ULN, Creatinine clearance >50 mL/min
- All patients must have received at least 24 weeks of prior CDK4/6i in combination
with first line ET for advanced or metastatic disease and have had disease
progression on or within 8 weeks of the last dose of CDK4/6i. Patients who have
progressed on, or within 12 months of completion of adjuvant therapy with an
aromatase inhibitor may be treated with fulvestrant instead of an aromatase
inhibitor combined with CDK4/6 inhibitor.
In addition, the following prior systemic therapies are allowed:
- A single second-line endocrine therapy+/- targeted therapy (e.g. alpelisib) in
combination with endocrine therapy is permitted but patients must then be enrolled
to non-fulvestrant containing substudies.
- Patients may also have received adjuvant/neoadjuvant systemic therapies; however
cytotoxic chemotherapy or antibody drug conjugates (ADC) in the palliative setting
are not permissible.
- Patients receiving LHRH agonists (for example premenopausal patients) may continue,
but may not start LHRH agonist within 12 weeks of enrollment.
- Consult CCTG for other scenarios (for example where short course of other ET is
given prior to CDKi + ET, patients who have received investigational drugs, vaccines
or immunotherapies) as certain patients may be eligible.
- All reversible prior toxicity related to prior therapies must have recovered to
grade ≤ 1 (consult CCTG in the case of irreversible toxicity) and have adequate
washout as follows (screening may occur during the washout period): Longest of the
following (for questions or any proposed variance, please discuss with CCTG prior to
patient enrollment): Two weeks; 5 half-lives for investigational agents; standard
cycle length of standard therapies
- Patients must not have received a transfusion (platelets or red blood cells) or
colony stimulating factors ≤ 4 weeks prior to initiating treatment substudy therapy.
- Surgery: Prior surgery is permitted provided that a minimum of at least 28 days have
elapsed between any major surgical procedure and date of enrollment, and that wound
healing has occurred.
- Radiation: Prior external beam radiation is permitted provided a minimum of 28 days
(4 weeks) have elapsed between the last dose of radiation and date of enrollment.
Exceptions may be made for low-dose, non-myelosuppressive radiotherapy after
consultation with CCTG. Concurrent radiotherapy is not permitted.
- Patients must be registered and provide consent prior to blood collection for
screening. The screening blood sample cannot be sent for analysis prior to screening
registration.
- Patient consent must be appropriately obtained in accordance with applicable local
and regulatory requirements. Each patient must sign a consent form prior to both
screening registration as well as enrollment to a specific substudy to document
their willingness to participate.
- Patients must be accessible for treatment and follow up. Patients enrolled on this
trial must be treated and followed at the participating centre
- In accordance with CCTG policy, substudy treatment is to begin within 2 working days
of patient enrollment.
- Women/men of childbearing potential must have agreed to use a highly effective
contraceptive method.
Exclusion Criteria:
- Patients with a history of other malignancies, including Myelodysplastic syndrome
(MDS) or Acute myeloid leukemia (AML) except: adequately treated non-melanoma skin
cancer, curatively treated in-situ cancer of the cervix, or other malignancies
curatively treated with no evidence of disease for ˃ 2 years and which do not
require ongoing treatment.
- Patients with active or uncontrolled infections or with serious illnesses or medical
conditions which would not permit the patient to be managed according to protocol.
- Infection includes but is not limited to active infection requiring systemic
therapy and active or known human immunodeficiency virus (HIV) with detectable
viral load, known hepatitis B surface antigen or positive hepatitis C antibody
- Pneumonitis or any history of pneumonitis requiring steroids (any dose)
- Participant has received a live vaccine within 30 days of planned start of
study therapy. COVID19 vaccines that do not contain live viruses are allowed.
- Known primary immunodeficiency
- Patients with recent clinically significant cardiac disease, including:
- angina pectoris, symptomatic pericarditis, coronary artery bypass grafting,
coronary angioplasty, or stenting, or myocardial infarction in the previous 12
months;
- history of documented congestive heart failure (New York Heart Association
functional classification III-IV) or cardiomyopathy
- uncontrolled hypertension (per Canadian guidelines)
- All patients should have a LVEF ≥ 50%.
- Patients with HER2 positive breast cancer (based on the most recent assessment,
according to ASCO/CAP criteria).
- History of hypersensitivity to any of the study drugs or their components.
- Patients may not receive concurrent treatment with other anti-cancer therapy (other
than bone-targeted therapy, if already taking and stable) or investigational agents
while on protocol therapy.
- Patients with prior allogenic bone marrow transplant or double umbilical cord blood
transplantation (dUCBT).
- Pregnant or breastfeeding women.
- Patients with history of central nervous system metastases or spinal cord
compression unless they have received definitive treatment such as resection or
radiation, are clinically stable and do not require corticosteroids; corticosteroids
must have been discontinued at least 7 days prior to enrollment.
- Patients who are unable to swallow oral medication and/or have impairment of
gastrointestinal (GI) function or GI disease that may significantly alter the
absorption of the study drugs (e.g. Crohn's disease, ulcerative diseases,
uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, active bowel
inflammation (e.g. diverticulitis) or small bowel resection), unless agreed with
CCTG (exceptions may be given if a parenteral treatment substudy is
available/appropriate).
- Patients with a history of non-compliance to medical regimens.
- See Section 7.3 and individual treatment substudies for a list of concomitant
medications that are not permitted.
- Many substudies include drugs that have a risk for thrombocytopenia; therefore,
participants should be advised to use caution when taking oral anticoagulants (e.g.
warfarin) and antiplatelet drugs (e.g. aspirin).
Gender:
All
Minimum age:
N/A
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Tom Baker Cancer Centre
Address:
City:
Calgary
Zip:
T2N 4N2
Country:
Canada
Status:
Recruiting
Contact:
Last name:
Patricia Tang
Phone:
403 521-3490
Facility:
Name:
BCCA - Kelowna
Address:
City:
Kelowna
Zip:
V1Y 5L3
Country:
Canada
Status:
Recruiting
Contact:
Last name:
Sara Kristina Taylor
Phone:
250 712-3996
Facility:
Name:
BCCA - Vancouver
Address:
City:
Vancouver
Zip:
V5Z 4E6
Country:
Canada
Status:
Recruiting
Contact:
Last name:
Nathalie Levasseur
Phone:
604 877-6000
Facility:
Name:
QEII Health Sciences Centre
Address:
City:
Halifax
Zip:
B3H 1V7
Country:
Canada
Status:
Recruiting
Contact:
Last name:
Daniel Rayson
Phone:
902 473-6106
Facility:
Name:
Juravinski Cancer Centre at Hamilton Health Sciences
Address:
City:
Hamilton
Zip:
L8V 5C2
Country:
Canada
Status:
Recruiting
Contact:
Last name:
Nidhi Kumar Tyagi
Phone:
905 387-9495
Facility:
Name:
Kingston Health Sciences Centre
Address:
City:
Kingston
Zip:
K7L 2V7
Country:
Canada
Status:
Recruiting
Contact:
Last name:
Brooke Wilson
Facility:
Name:
Ottawa Hospital Research Institute
Address:
City:
Ottawa
Zip:
K1H 8L6
Country:
Canada
Status:
Recruiting
Contact:
Last name:
Moira Rushton
Facility:
Name:
Odette Cancer Centre
Address:
City:
Toronto
Zip:
M4N 3M5
Country:
Canada
Status:
Recruiting
Contact:
Last name:
Rossanna Pezo
Phone:
416 480-4757
Facility:
Name:
University Health Network
Address:
City:
Toronto
Zip:
M5G 2M9
Country:
Canada
Status:
Recruiting
Contact:
Last name:
David Cescon
Phone:
416 946-2245
Facility:
Name:
The Jewish General Hospital
Address:
City:
Montreal
Zip:
H3T 1E2
Country:
Canada
Status:
Recruiting
Contact:
Last name:
Parvaneh Fallah
Phone:
614 340-8222
Start date:
June 13, 2023
Completion date:
June 30, 2028
Lead sponsor:
Agency:
Canadian Cancer Trials Group
Agency class:
Other
Source:
Canadian Cancer Trials Group
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05601440
