Advanced Breast Cancer, BRCA1 Mutation, BRCA2 Mutation, Locally Advanced Breast Cancer, Metastatic Breast Cancer
Conditions
Keywords
HER2-negative
Brief summary
The main purpose of this research study is to learn whether the investigational combination of olaparib, palbociclib, and fulvestrant is safe in patients with estrogen receptor-positive breast cancer and BRCA1 or BRCA2 mutations.
Interventions
DRUGPalbociclib
Combination of palbociclib, olaparib, and fulvestrant.
DRUGOlaparib
Combination of palbociclib, olaparib, and fulvestrant.
DRUGFulvestrant
Combination of palbociclib, olaparib, and fulvestrant.
Sponsors
Abramson Cancer Center at Penn Medicine
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
The phase I component is a dose-escalation study. Dose escalation will follow a 3+3 design. An additional cohort of at least 36 patients (total number of patients in phase I and phase II = 54) will be included on the single-arm, non-randomized phase II portion of this clinical trial.
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Females/males ≥ age 18 * Germline or somatic deleterious or suspected deleterious mutation in BRCA1 or BRCA2 * Metastatic or locally advanced unresectable breast cancer that is ER and/or PR positive (\>1%) and HER2 nonamplified * Prior treatment with 0-2 prior lines of chemotherapy for metastatic breast cancer * Regarding prior platinum-based chemotherapy: 1. Patients who received prior platinum-based chemotherapy in the adjuvant or neoadjuvant setting for breast cancer are eligible if treatment was completed at least 12 months prior to diagnosis of metastatic disease. 2. Patients who received platinum for advanced breast cancer are eligible to enter the study provided there was no evidence of disease progression during the platinum chemotherapy. 3. Patients who received prior platinum-based as a potentially curative treatment for a prior non-breast cancer (e.g., ovarian cancer) with no evidence of disease for 5 years or greater prior to study entry are permitted. * Deemed a candidate for endocrine therapy (any prior endocrine therapy is permitted; no prior endocrine therapy is also permitted) * Adequate organ and bone marrow function * ECOG performance status 0-1 * At least one measurable disease or disease that can be assessed by CT or MRI * Life expectancy ≥ 16 weeks * Postmenopausal as defined below. Women who are on pharmacologic ovarian suppression must have two negative urine or serum pregnancy tests: one during screening (within 28 days prior to study treatment) and one within 7 days prior to commencing treatment. Postmenopausal is defined as one of the below: * Amenorrheic for 1 year or more following cessation of exogenous hormonal treatments * Follicle stimulating hormone (FSH) levels in the post-menopausal range for women under 50 * radiation-induced oophorectomy with last menses \>1 year ago * chemotherapy-induced menopause with \>1 year interval since last menses * bilateral oophorectomy or hysterectomy * on luteinizing hormone-releasing hormone (LHRH) agonists according to current clinical practice standards as pharmacologic ovarian suppression * Female patients of childbearing potential (not post-menopausal as defined above) must agree to the use of two highly effective forms of contraception in combination throughout the period of taking study treatment and for 1 month after last dose of study drug(s) to prevent pregnancy. * Male patients and their sexual partners of childbearing potential must agree to the use of two highly effective forms of contraception in combination throughout the period of taking study treatment and for 3 months after last dose of study drug(s) to prevent pregnancy in a partner. * Willing to comply with study requirements and procedures including use of appropriate contraception, willingness to discontinue herbal preparations / medications, and study biopsy if archival tissue is not available
Exclusion criteria
* Involvement in study planning or conduct * Regarding prior olaparib or palbociclib, a) Phase II: Patients who previously progressed on olaparib or palbociclib for metastatic breast cancer treatment are excluded * Participation in another clinical study with an investigational product during the last 3 weeks * Systemic chemotherapy or radiotherapy (except palliative) within 3 weeks of start of study treatment * Major surgery within 2 weeks of start of study treatment * Other malignancy within the last 5 years with exceptions listed in the protocol * Concomitant strong or moderate CYP3A inhibitors/ inducers * Persistent toxicity of prior cancer therapy that is grade ≥ 2 except for alopecia or neuropathy * MDS or features suggestive of MDS/AML * Symptomatic uncontrolled brain metastases * Patients considered to be at poor medical risk * QTc \>470 msec on 2 or more time points or a family history of long QT syndrome * Unable to swallow or absorb oral medication * Immunocompromised patients * Pregnant or breast-feeding * Hypersensitivity to olaparib, palbociclib, fulvestrant, or any excipients of these products * Known active hepatitis * Prior bone marrow transplant * Whole blood transfusions 120 days prior to signing consent
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Progression-free survival | From first dose of protocol therapy to progression or death due to any cause, whichever comes first, an estimated average of 7 months |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective response rate | From first dose of protocol therapy to progression or death due to any cause, whichever comes first, an estimated average of 7 months | Includes complete and partial response as per RECIST 1.1 criteria. Overall response rate will be defined as the proportion of patients within the efficacy analysis set that experience a complete or partial response. |
| 24-week clinical benefit rate | From the date of study treatment until the date of progression, an estimated average of 7 months | Defined as the proportion of patients within the efficacy analysis set that experience clinical benefit ≥24 weeks. |
Countries
United States
Outcome results
None listed