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Olaparib, Palbociclib, and Fulvestrant in Treating Patients with BRCA Mutation-Associated, Hormone Receptor-Positive, and HER2-Negative Advanced Breast Cancer

Trial Status: Approved

This phase I / II trial studies the best dose and side effects of palbociclib when given together with olaparib and fulvestrant, and to see how well they work in treating patients with BRCA mutation-associated, hormone receptor-positive, HER2-negative breast cancer that has spread from its original site of growth to nearby tissues or lymph nodes and cannot be removed by surgery, or has spread to other places in the body (advanced). Palbociclib and olaparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Anti-hormone therapy consisting of fulvestrant may prevent breast cancer cell growth by blocking estrogen and progesterone receptor stimulation. This trial studies the effectiveness of the combination of palbociclib, olaparib and fulvestrant.

Inclusion Criteria

  • The ability to understand and willingness to sign a written informed consent document. A legally authorized representative signature in the event that the subject is not able to sign themselves is permitted
  • Confirmation of a germline or somatic mutation in BRCA1 or BRCA2 that is predicted to be deleterious or suspected deleterious (known or predicted to be detrimental / lead to loss of function). Results from a local laboratory are acceptable for study entry
  • Metastatic or locally advanced unresectable breast cancer (together termed “advanced”) that is histologically confirmed as estrogen receptor (ER) and/or progesterone receptor (PR) positive (> 1%), HER2 negative. Results from a local laboratory are acceptable. Results from either a primary or metastatic site are acceptable
  • Prior cancer treatment with 0-2 lines of chemotherapy for metastatic breast cancer. Regarding prior platinum-based chemotherapy: * 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 study entry * 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 * 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 candidates for endocrine therapy. Patients may have previously received any or no prior endocrine therapy
  • Hemoglobin >= 10.0 g/dL with no blood transfusion in the past 28 days (within 28 days prior to administration of study treatment)
  • Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (within 28 days prior to administration of study treatment)
  • Platelet count >= 100 x 10^9/L (within 28 days prior to administration of study treatment)
  • Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (within 28 days prior to administration of study treatment)
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) / alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal unless liver metastases are present in which case they must be =< 5 x ULN (within 28 days prior to administration of study treatment)
  • Creatinine clearance of >= 51 mL/min using the Cockcroft-Gault equation (within 28 days prior to administration of study treatment)
  • Eastern Cooperative Oncology Group (ECOG) performance status 0-1
  • At least one lesion (measurable and/or non-measurable) that can be accurately assessed at baseline by standard imaging techniques and is suitable for repeated assessment
  • A 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 within 28 days of study treatment and one on day 1 of the study run-in period prior to commencing treatment. Postmenopausal is defined as: * Amenorrheic for 1 year or more following cessation of exogenous hormonal treatments * Luteinizing hormone (LH) and 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 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
  • Willingness and ability to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations
  • Willingness to discontinue all herbal preparations / medications throughout the study
  • Availability of archived tumor tissue or willingness / ability to undergo tumor biopsy. Specific quantity of tissue available will not impact eligibility

Exclusion Criteria

  • Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site)
  • Any previous treatment with PARP inhibitor, including olaparib, or a CDK4/6 inhibitor
  • Participation in another clinical study with an investigational product during the last 3 weeks
  • Receipt of any systemic chemotherapy or radiotherapy (except for palliative reasons) within 3 weeks prior to study treatment
  • Major surgery within 2 weeks of starting study treatment. Patients must have recovered from any effects of any major surgery
  • Other malignancy within the last 5 years except: adequately treated non-melanoma skin cancer, curatively treated in situ cancer of the cervix, ductal carcinoma in situ (DCIS), stage 1, grade 1 endometrial carcinoma, or other solid tumors including lymphomas (without bone marrow involvement) curatively treated with no evidence of disease for >= 5 years. Patients with a history of localized triple negative breast cancer may be eligible, provided they completed their adjuvant chemotherapy more than three years prior to registration, and that the patient remains free of recurrent or metastatic disease
  • Concomitant use of known strong CYP3A inhibitors (e.g. itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (e.g. ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout period prior to starting olaparib is 2 weeks
  • Concomitant use of known strong (e.g. phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John’s wort) or moderate CYP3A inducers (e.g. bosentan, efavirenz, modafinil). The required washout period prior to starting olaparib is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents
  • Persistent toxicities (> Common Terminology Criteria for Adverse Event [CTCAE] grade 2) caused by previous cancer therapy, excluding alopecia and neuropathy
  • Presence of myelodysplastic syndrome/acute myeloid leukemia or with features suggestive of myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML)
  • Patients with symptomatic uncontrolled brain metastases. A scan to confirm the absence of brain metastases is not required. The patient can receive a stable dose of corticosteroids before and during the study as long as these were started at least 4 weeks prior to treatment. Patients with spinal cord compression unless considered to have received definitive treatment for this and evidence of clinically stable disease for 28 days
  • Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, extensive interstitial bilateral lung disease on high resolution computed tomography (HRCT) scan or any psychiatric disorder that prohibits obtaining informed consent
  • Resting electrocardiogram (ECG) with corrected QT (QTc) > 470 msec on 2 or more time points within a 24 hour period or family history of long QT syndrome
  • Inability to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication
  • Immunocompromised patients, e.g., patients who are known to be serologically positive for human immunodeficiency virus (HIV)
  • Pregnant or breast-feeding women
  • Known hypersensitivity to olaparib, palbociclib, or fulvestrant, or any of the excipients of the products
  • Known active hepatitis (i.e. hepatitis B or C) or HIV
  • Previous allogenic bone marrow transplant or double umbilical cord blood transplantation (dUCBT)
  • Previous enrollment in the present study
  • Whole blood transfusions in the last 120 days prior to signing consent for the study (packed red blood cells and platelet transfusions are acceptable as long as consistent with timing in inclusion criterion above)

New York

New York
Memorial Sloan Kettering Cancer Center
Status: APPROVED
Contact: Mark Emerson Robson
Phone: 646-888-5434

Pennsylvania

Philadelphia
University of Pennsylvania / Abramson Cancer Center
Status: APPROVED
Contact: Payal D. Shah
Phone: 215-349-5730

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) of palbociclib when given in combination with olaparib and fulvestrant in patients with germline or somatic mutations in BRCA1 or BRCA2 and metastatic, hormone receptor-positive, HER2-negative breast cancer. (Phase I)

II. To assess the efficacy of the combination of olaparib, fulvestrant and palbociclib in patients with BRCA1/2-associated, hormone receptor-positive, HER2-negative metastatic breast cancer, using Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 to evaluate progression-free survival (PFS), objective response rate (ORR), 24-week clinical benefit rate (CBR). (Phase II)

SECONDARY OBJECTIVES:

I. To preliminarily assess the efficacy of the combination of olaparib, fulvestrant and palbociclib in patients with BRCA1/2-associated, hormone receptor-positive, HER2-negative metastatic breast cancer, using RECIST v1.1 to evaluate the efficacy endpoints. (Phase I)

II. To describe the safety and tolerability of olaparib plus fulvestrant and palbociclib in patients with BRCA1/2-associated, hormone receptor-positive, HER2-negative metastatic breast cancer based on Common Terminology Criteria for Adverse Events (CTCAE) v5.0. (Phase I/II)

III. To describe the safety and tolerability of olaparib and fulvestrant in patients with BRCA1/2-associated, hormone receptor-positive, HER2-negative metastatic breast cancer based on CTCAE v5.0, in patients unable to tolerate combination therapy with palbociclib. (Phase I/II)

IV. To describe the efficacy of olaparib and fulvestrant in patients with BRCA1/2-associated, hormone receptor-positive, HER2-negative metastatic breast cancer based on CTCAE v5.0, in patients unable to tolerate combination therapy with palbociclib. (Phase I/II)

EXPLORATORY OBJECTIVES:

I. To correlate potential PARP inhibitor predictive biomarkers, below, in pre-treatment tumor samples with measures of treatment effectiveness:

Ia. BRCA1/2 gene-specific loss of heterozygosity (LOH).

Ib. Measures of homologous recombination deficiency (HRD), including genomic LOH, telomeric allelic imbalance, and large-state transitions.

Ic. Stratton mutational signatures.

II. To characterize the immunogenicity of BRCA1/2-associated metastatic breast cancer by measuring:

IIa. CD8 T-cell infiltration and function.

IIb. Mutational burden.

IIc. Neoantigen load.

IId. Cytolytic index.

IIe. Immune ESTIMATE scores.

III. To serially evaluate circulating tumor deoxyribonucleic acid (DNA) in the peripheral blood of patients on study treatment.

OUTLINE: This is a phase I, dose-escalation study of palbociclib followed by a phase II study.

Patients receive olaparib orally (PO) twice daily (BID) on days 1-28, fulvestrant intramuscularly (IM) over 1-2 minutes on day 1 (days 1 and 15 for cycle 1 of phase II), and palbociclib PO once daily (QD) on days 1-21. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days.

Trial Phase Phase I/II

Trial Type Treatment

Lead Organization
University of Pennsylvania / Abramson Cancer Center

Principal Investigator
Payal D. Shah

  • Primary ID UPCC 21118
  • Secondary IDs NCI-2019-04210
  • Clinicaltrials.gov ID NCT03685331