Breast Cancer Clinical Trial

Testing Olaparib Either Alone or in Combination With Atezolizumab in BRCA Mutant Non-HER2-positive Breast Cancer

Summary

This randomized phase II trial studies how well olaparib with or without atezolizumab work in treating patients with non-HER2-positive breast cancer that has spread from its original site of growth to nearby tissues or lymph nodes and is not amenable to surgical resection (locally advanced unresectable) or has spread to other places in the body (metastatic). Olaparib is an inhibitor of PARP, an enzyme that helps repair deoxyribonucleic acid (DNA) when it becomes damaged. Blocking PARP may help keep cancer cells from repairing their damaged DNA, causing them to die. PARP inhibitors are a type of targeted therapy. Immunotherapy with monoclonal antibodies, such as atezolizumab, may help the body's immune system attack the tumor, and may interfere with the ability of tumor cells to grow and spread. It is not known whether giving olaparib with or without atezolizumab will work better in patients with non-HER2-positive breast cancer.

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Full Description

PRIMARY OBJECTIVE:

I. To compare the progression free survival (PFS) between two study arms, i.e., olaparib monotherapy (arm 1) and olaparib + atezolizumab in combination (arm 2) based on normal Response Evaluation Criteria in Solid Tumors (RECIST) criteria in patients with locally advanced or metastatic non-HER2-positive breast cancer harboring homologous deoxyribonucleic acid (DNA) repair (HDR) through BRCA 1/2 mutation.

SECONDARY OBJECTIVES:

I. To compare the progression free survival (PFS) between the two study arms based on immune response criteria.

II. To compare the time to treatment failure (TTF) between the two study arms based on immune response criteria and normal RECIST.

III. To compare the overall response rate (ORR) between the two study arms based on immune response criteria and normal RECIST.

IV. To compare the duration of response (DoR) between the two study arms based on immune response criteria and normal RECIST.

V. Determine the changes in extent of mutational burden in BRCA 1/2 mutated tumors at baseline and at progression.

VI. Evaluate and characterize changes in the extent of PD-L1 expression and tumor immune infiltrates.

VII. Retrospectively evaluate tumors with limited immune infiltrate (e.g. "non-inflamed") to determine if PARPi increased immune infiltration.

VIII. Determine the immune-related best overall response (irBOR) of olaparib in combination with atezolizumab in locally advanced or metastatic non-HER2+ breast cancer harboring HDR through BRCA 1/2 mutation.

EXPLORATORY OBJECTIVES:

I. Evaluate changes in candidate neoantigen profiles and immune/inflammation signatures using DNA and ribonucleic acid (RNA)-sequencing in serial tumor biopsies.

II. Evaluate and characterize circulating tumor DNA (ctDNA) and immune parameters in blood.

III. Test the hypothesis that DNA repair status affects the tumor-immune interaction.

IV. Characterize mechanism of action of the PARP inhibitor olaparib. V. To explore the inclusion of patient reported symptomatic adverse events. VI. To use anti-Kynurenine antibodies for immunohistochemistry (IHC) as well as unbiased metabolome studies on plasma to understand the metabolic consequences of PARP-inhibition and their effects on immune infiltrates.

VII. To explore pharmacodynamic transcriptional changes induced by treatment in different immune cell populations and with high resolution in single cell RNA sequencing of peripheral blood mononuclear cell (PBMC) preparations.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive olaparib orally (PO) twice daily (BID) on days 1-21 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients with disease progression may cross-over to Arm II.

ARM II: Patients receive olaparib as Arm I and atezolizumab intravenously (IV) over 30-60 minutes on day 1 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up monthly.

View Eligibility Criteria

Eligibility Criteria

Inclusion Criteria:

Patients must have histologically documented unresectable locally advanced or metastatic non-HER2-positive breast cancer and a known BRCA 1/2 mutation present; both germline and somatic mutations are acceptable, however somatic mutations must be identified by either tumor sequencing of tumor tissue or ctDNA in plasma; patients with BRCA mutations of unknown significance are not allowed
Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >= 20 mm (>= 2 cm) by chest x-ray or as >= 10 mm (>= 1 cm) with computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam
Prior chemotherapy is allowed, including platinum therapy; patients must not have received chemotherapy for 4 weeks prior to the initiation of study treatment and must have recovery =< grade 1 from any adverse events from any prior chemotherapy (other than alopecia); patients must not have had nitrosoureas or mitomycin C for 6 weeks prior to the initiation of study treatment
Prior radiation therapy is allowed; patients must not have received minimal radiation therapy (=< 5% of their total marrow volume) within 3 weeks prior to the initiation of study treatment; otherwise, patients must not have received radiation therapy (> 5% of their total marrow volume) within 4 weeks prior to the initiation of study treatment; patients who have received prior radiation to 50% or more of their total marrow volume will be excluded
Patients who have received prior treatment with anti-CTLA-4 may be enrolled, provided the following requirements are met: minimum of 12 weeks from the first dose of anti-CTLA-4 and > 6 weeks from the last dose, and no history of severe immune-related adverse effects from anti-CTLA-4 (National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] grade 3 and 4)
Treatment with systemic immunosuppressive medications (including, but not limited to, prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor [anti-TNF] agents) is allowed, provided the following is met: minimum of 2 weeks prior to cycle 1, day 1; patients who have received acute, low dose, systemic immunosuppressant medications (e.g., a one-time dose of dexamethasone for nausea) may be enrolled; the use of corticosteroids and mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension or adrenocortical insufficiency is allowed
Prior treatment with systemic immunostimulatory agents (including, but not limited to, interferon [IFN]-alpha or interleukin [IL]-2) is allowed, provided the following is met: minimum of 4 weeks or 5 half-lives of the drug (whichever is longer) prior to cycle 1, day 1
Patients taking bisphosphonate therapy for symptomatic hypercalcemia are NOT allowed; use of bisphosphonate therapy for other reasons (e.g., bone metastasis or osteoporosis) is allowed
Prior hormone therapy is allowed; patients must not have received hormone therapy for breast cancer for 2 weeks prior to the initiation of study treatment and must have recovery =< grade 1 from any adverse events related to these therapies (other than alopecia)
Prior experimental (non-Food and Drug Administration [FDA] approved) therapies and immunotherapies are allowed; patients must not have received these therapies for 4 weeks prior to the initiation of study treatment and must have recovery =< grade 1 from any adverse events of these therapies (other than alopecia); prior treatment with any PARP inhibitor or any anti-PD-1/anti-PD-L1 antibody is NOT allowed
Other therapies (e.g. targeted therapy such as cyclin-dependent kinase [CDK] inhibitors): patients should have recovered to =< grade 1 drug related toxicity; they must have completed therapy for either a total of duration equivalent to 5 half-lives of the drug or 28 days, whichever is shorter
Age >= 18 years. No dosing or adverse event data are currently available on the use of olaparib in combination with atezolizumab in patients < 18 years of age; hence, children are excluded from this study, but will be eligible for future pediatric trials
Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
Life expectancy of greater than 6 months
Absolute neutrophil count >= 1,500/mcL
Leukocytes >= 3,000/mcL
Platelets >= 100,000/mcL
Hemoglobin >= 8 g/dL
Total bilirubin =< 1.5 x upper limit of normal (ULN) (however, patients with known Gilbert disease who have serum bilirubin level =< 3 x ULN may be enrolled)
Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2.5 x upper limit of normal (ULN) if no liver metastasis; =< 5 x upper ULN if liver metastasis present
Alkaline phosphatase =< 2.5 x ULN (=< 5 x ULN for patients with documented liver involvement or bone metastases)
Creatinine clearance >= 51 mL/min/1.73 m^2 by Cockcroft-Gault
International normalized ratio (INR) and activated partial thromboplastin time (aPTT) =< 1.5 x ULN (this applies only to patients who do not receive therapeutic anticoagulation; patients receiving therapeutic anticoagulation, such as low-molecular-weight heparin or warfarin, should be on a stable dose)
No features suggestive of myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) on peripheral blood smear when performed as clinically indicated
Patients must have tumors determined to be easily accessible for biopsy and must be willing to have serial biopsies (with a third biopsy upon evidence of disease progression)

Administration of atezolizumab and/or olaparib may have an adverse effect on pregnancy and poses a risk to the human fetus, including embryo-lethality; women of child-bearing potential and men must agree to use highly effective contraception prior to study entry, for the duration of study participation, and for at least 5 months (150 days) after the last dose of study agent; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately; men treated or enrolled on this protocol must also agree to use two highly effective forms of contraception in combination prior to the study, for the duration of study participation, and for at least 5 months (150 days) after completion of atezolizumab and/or olaparib administration; women of child-bearing potential: negative serum pregnancy test within 14 days of study treatment and confirmed prior to treatment on day 1; postmenopausal or evidence of non-childbearing status for women of childbearing potential; 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
Surgical sterilization (bilateral oophorectomy or hysterectomy)
Ability to understand and the willingness to sign a written informed consent document
Subject is able to swallow and retain oral medication and does not have uncontrolled emesis or gastrointestinal disorders likely to interfere with absorption of the study medication
Patients crossing over from monotherapy to combination therapy do not have to be fully rescreened; however, they do need to meet performance status, organ function, and blood parameters and not meet any of the exclusion criteria

Patients positive for human immunodeficiency virus (HIV) are NOT excluded from this study, but HIV-positive patients must have:

A stable regimen of highly active anti-retroviral therapy (HAART)
No requirement for concurrent antibiotics or antifungal agents for the prevention of opportunistic infections
A CD4 count above 250 cells/mcL and an undetectable HIV viral load on standard polymerase chain reaction (PCR)-based test

Exclusion Criteria:

Patients with prior allogeneic bone marrow transplantation, double umbilical cord blood transplantation (dUCBT) or prior solid organ transplantation
Patients with known brain metastases should be excluded from this clinical trial except as those described below, because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events

Patients with known primary central nervous system (CNS) malignancy or symptomatic CNS metastases are excluded, with the following exceptions:

Patients with asymptomatic untreated CNS disease may be enrolled, provided all of the following criteria are met:

Evaluable or measurable disease outside the CNS
No metastases to brain stem, midbrain, pons, medulla, cerebellum, or within 10 mm of the optic apparatus (optic nerves and chiasm)
No history of intracranial hemorrhage unless it is confined within a lesion previously noted and secondary to gamma knife or another equivalent radiologic therapeutic
No history of spinal cord hemorrhage
No ongoing requirement for dexamethasone for CNS disease; patients on a stable dose of anticonvulsants are permitted
No neurosurgical resection or brain biopsy within 28 days prior to cycle 1, day 1

Patients with asymptomatic treated CNS metastases may be enrolled, provided all the criteria listed above are met as well as the following:

Radiographic demonstration of improvement upon the completion of CNS directed therapy and no evidence of interim progression between the completion of CNS directed therapy and the screening radiographic study
No stereotactic radiation or whole-brain radiation within 28 days prior to cycle 1, day 1
Screening CNS radiographic study >= 4 weeks from completion of radiotherapy and >= 2 weeks from discontinuation of corticosteroids
Known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies
History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
History of allergic reactions attributed to compounds of similar chemical or biologic composition to olaparib and atezolizumab; patients with a known hypersensitivity to olaparib or any of the excipients of the product
Prior treatment with any PARP inhibitor or any anti-PD-1/anti-PD-L1 antibody

Known clinically significant liver disease, including active viral, alcoholic, or other hepatitis; cirrhosis; fatty liver; and inherited liver disease

Patients with past or resolved hepatitis B infection (defined as having a negative hepatitis B surface antigen [HBsAg] test and a positive anti-HBc [antibody to hepatitis B core antigen] antibody test) are eligible
Patients positive for hepatitis C virus (HCV) antibody are eligible only if PCR is negative for HCV RNA

History or risk of autoimmune disease, including, but not limited to, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjogren's syndrome, Bell's palsy, Guillain-Barre syndrome, multiple sclerosis, autoimmune thyroid disease, vasculitis, lichen sclerosis, or glomerulonephritis

Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid replacement hormone may be eligible
Patients with controlled type 1 diabetes mellitus on a stable insulin regimen may be eligible

Patients with eczema, psoriasis, lichen simplex chronicus of vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis would be excluded) are permitted provided that they meet the following conditions:

Patients with psoriasis must have a baseline ophthalmologic exam to rule out ocular manifestations
Rash must cover less than 10% of body surface area (BSA)
Disease is well controlled at baseline and only requiring low potency topical steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%, fluocinolone 0.01%, desonide 0.05%, alclometasone dipropionate 0.05%)
No acute exacerbations of underlying condition within the last 12 months (not requiring psoralen plus ultraviolet A radiation [PUVA], methotrexate, retinoids, biologic agents, oral calcineurin inhibitors; high potency or oral steroids)
History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced), organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia, etc.), or evidence of active pneumonitis on screening chest computed tomography (CT) scan; history of radiation pneumonitis in the radiation field (fibrosis) is permitted if recovered
Major surgical procedure within 28 days prior to cycle 1, day 1 and patients must have recovered from any effects of any major surgery; anticipation of need for a major surgical procedure during the course of the study

Administration of a live, attenuated vaccine within 4 weeks before cycle 1, day 1 or anticipation that such a live, attenuated vaccine will be required during the study and up to 5 months after the last dose of atezolizumab

Influenza vaccination should be given during influenza season only (approximately October to March); patients must not receive live, attenuated influenza vaccine within 4 weeks prior to cycle 1, day 1 or at any time during the study
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, unstable spinal cord compression, superior vena cava syndrome, symptomatic congestive heart failure, unstable angina pectoris, extensive interstitial bilateral lung disease on high resolution computed tomography (HRCT) scan or any psychiatric disorder that prohibits obtaining informed consent and would limit compliance with study requirements
Pregnant women are excluded from this study because olaparib and atezolizumab are have the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with olaparib and atezolizumab, breastfeeding should be discontinued if the mother is treated with olaparib and atezolizumab
Any prior grade >= 3 immune-related adverse event (irAE) while receiving any previous immunotherapy agent, or any unresolved irAE > grade 1

Study is for people with:

Breast Cancer

Phase:

Phase 2

Estimated Enrollment:

81

Study ID:

NCT02849496

Recruitment Status:

Active, not recruiting

Sponsor:

National Cancer Institute (NCI)

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There are 56 Locations for this study

See Locations Near You

Mayo Clinic Hospital in Arizona
Phoenix Arizona, 85054, United States
Mayo Clinic in Arizona
Scottsdale Arizona, 85259, United States
UC San Diego Moores Cancer Center
La Jolla California, 92093, United States
University of California Davis Comprehensive Cancer Center
Sacramento California, 95817, United States
UC San Diego Medical Center - Hillcrest
San Diego California, 92103, United States
UCSF Medical Center-Mount Zion
San Francisco California, 94115, United States
University of Colorado Hospital
Aurora Colorado, 80045, United States
Smilow Cancer Hospital-Derby Care Center
Derby Connecticut, 06418, United States
Smilow Cancer Hospital Care Center-Fairfield
Fairfield Connecticut, 06824, United States
Smilow Cancer Hospital Care Center - Guiford
Guilford Connecticut, 06437, United States
Smilow Cancer Hospital Care Center at Saint Francis
Hartford Connecticut, 06105, United States
Smilow Cancer Center/Yale-New Haven Hospital
New Haven Connecticut, 06510, United States
Yale University
New Haven Connecticut, 06520, United States
Smilow Cancer Hospital-Orange Care Center
Orange Connecticut, 06477, United States
Smilow Cancer Hospital-Torrington Care Center
Torrington Connecticut, 06790, United States
Smilow Cancer Hospital Care Center-Trumbull
Trumbull Connecticut, 06611, United States
Smilow Cancer Hospital-Waterbury Care Center
Waterbury Connecticut, 06708, United States
Mayo Clinic in Florida
Jacksonville Florida, 32224, United States
Moffitt Cancer Center-International Plaza
Tampa Florida, 33607, United States
Moffitt Cancer Center
Tampa Florida, 33612, United States
University of Chicago Comprehensive Cancer Center
Chicago Illinois, 60637, United States
UC Comprehensive Cancer Center at Silver Cross
New Lenox Illinois, 60451, United States
University of Chicago Medicine-Orland Park
Orland Park Illinois, 60462, United States
University of Kansas Clinical Research Center
Fairway Kansas, 66205, United States
Johns Hopkins University/Sidney Kimmel Cancer Center
Baltimore Maryland, 21287, United States
Massachusetts General Hospital Cancer Center
Boston Massachusetts, 02114, United States
Brigham and Women's Hospital
Boston Massachusetts, 02115, United States
Beth Israel Deaconess Medical Center
Boston Massachusetts, 02215, United States
Dana-Farber Cancer Institute
Boston Massachusetts, 02215, United States
Wayne State University/Karmanos Cancer Institute
Detroit Michigan, 48201, United States
Weisberg Cancer Treatment Center
Farmington Hills Michigan, 48334, United States
Mayo Clinic in Rochester
Rochester Minnesota, 55905, United States
Siteman Cancer Center at West County Hospital
Creve Coeur Missouri, 63141, United States
Washington University School of Medicine
Saint Louis Missouri, 63110, United States
Siteman Cancer Center-South County
Saint Louis Missouri, 63129, United States
Siteman Cancer Center at Christian Hospital
Saint Louis Missouri, 63136, United States
Siteman Cancer Center at Saint Peters Hospital
Saint Peters Missouri, 63376, United States
Nebraska Medicine-Bellevue
Bellevue Nebraska, 68123, United States
Nebraska Medicine-Village Pointe
Omaha Nebraska, 68118, United States
University of Nebraska Medical Center
Omaha Nebraska, 68198, United States
Rutgers Cancer Institute of New Jersey
New Brunswick New Jersey, 08903, United States
Montefiore Medical Center-Einstein Campus
Bronx New York, 10461, United States
Montefiore Medical Center-Weiler Hospital
Bronx New York, 10461, United States
Montefiore Medical Center - Moses Campus
Bronx New York, 10467, United States
NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center
New York New York, 10032, United States
UNC Lineberger Comprehensive Cancer Center
Chapel Hill North Carolina, 27599, United States
Duke University Medical Center
Durham North Carolina, 27710, United States
Case Western Reserve University
Cleveland Ohio, 44106, United States
Ohio State University Comprehensive Cancer Center
Columbus Ohio, 43210, United States
University of Pittsburgh Cancer Institute (UPCI)
Pittsburgh Pennsylvania, 15232, United States
Vanderbilt Breast Center at One Hundred Oaks
Nashville Tennessee, 37204, United States
Vanderbilt University/Ingram Cancer Center
Nashville Tennessee, 37232, United States
UT Southwestern/Simmons Cancer Center-Dallas
Dallas Texas, 75390, United States
Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center
Houston Texas, 77030, United States
Farmington Health Center
Farmington Utah, 84025, United States
University of Utah Sugarhouse Health Center
Salt Lake City Utah, 84106, United States
Huntsman Cancer Institute/University of Utah
Salt Lake City Utah, 84112, United States
South Jordan Health Center
South Jordan Utah, 84009, United States

How clear is this clinincal trial information?

Study is for people with:

Breast Cancer

Phase:

Phase 2

Estimated Enrollment:

81

Study ID:

NCT02849496

Recruitment Status:

Active, not recruiting

Sponsor:


National Cancer Institute (NCI)

How clear is this clinincal trial information?

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