Clinical Trials /

Olaparib With or Without Atezolizumab in Treating Patients With Locally Advanced or Metastatic Non-HER2-Positive Breast Cancer

NCT02849496

Description:

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 to other places in the body. Olaparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. 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.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Olaparib With or Without Atezolizumab in Treating Patients With Locally Advanced or Metastatic Non-HER2-Positive Breast Cancer
  • Official Title: A Phase II Open-Label, Randomized Study of PARP Inhibition (Olaparib) Either Alone or in Combination With Anti-PD-L1 Therapy (Atezolizumab; MPDL3280A) in Homologous DNA Repair (HDR) Deficient, Locally Advanced or Metastatic Non-HER2-Positive Breast Cancer

Clinical Trial IDs

  • ORG STUDY ID: NCI-2016-01130
  • SECONDARY ID: NCI-2016-01130
  • SECONDARY ID: 1608018258
  • SECONDARY ID: 10020
  • SECONDARY ID: 10020
  • SECONDARY ID: UM1CA186644
  • SECONDARY ID: UM1CA186686
  • SECONDARY ID: UM1CA186688
  • SECONDARY ID: UM1CA186689
  • SECONDARY ID: UM1CA186691
  • SECONDARY ID: UM1CA186709
  • NCT ID: NCT02849496

Conditions

  • BRCA1 Gene Mutation
  • BRCA2 Gene Mutation
  • Metastatic Breast Carcinoma
  • Stage III Breast Cancer AJCC v7
  • Stage IIIA Breast Cancer AJCC v7
  • Stage IIIB Breast Cancer AJCC v7
  • Stage IIIC Breast Cancer AJCC v7
  • Stage IV Breast Cancer AJCC v6 and v7

Interventions

DrugSynonymsArms
AtezolizumabMPDL 3280A, MPDL 328OA, MPDL-3280A, MPDL3280A, MPDL328OA, RG7446, RO5541267, TecentriqArm II (olaparib, atezolizumab)
OlaparibAZD2281, KU-0059436, Lynparza, PARP Inhibitor AZD2281Arm I (olaparib)

Purpose

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 to other places in the body. Olaparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. 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.

Detailed Description

      PRIMARY OBJECTIVES:

      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.

      TERTIARY 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.

      OUTLINE: Patients are randomized to 1 of 2 arms.

      ARM I: Patients receive olaparib orally (PO) twice daily (BID) on days 1-21. 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. Cycles repeat every 21 days in the absence of disease progression or
      unacceptable toxicity.

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

Trial Arms

NameTypeDescriptionInterventions
Arm I (olaparib)ExperimentalPatients receive olaparib PO BID on days 1-21. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients with disease progression may cross-over to Arm II.
  • Olaparib
Arm II (olaparib, atezolizumab)ExperimentalPatients receive olaparib as Arm I and atezolizumab IV over 30-60 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
  • Atezolizumab
  • Olaparib

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

          -  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 6 weeks 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

          -  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

          -  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
             28 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 or 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

          -  Patients with active seizures or a history of uncontrolled seizure disorder, including
             focal or generalized seizure within the past year

          -  Patients requiring treatment with a RANKL inhibitor (e.g. denosumab) who cannot
             discontinue it before treatment with atezolizumab

          -  Resting electrocardiogram (ECG) with corrected QT (QTc) > 470 msec or family history
             of long QT syndrome

          -  Concomitant use of known strong CYP3A inhibitors (eg. itraconazole, telithromycin,
             clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir,
             saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (eg.
             ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil); the required washout
             per
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression-free survival (PFS)
Time Frame:Time measured from randomization, assessed up to 3 years
Safety Issue:
Description:The study arms will be compared for duration of response survival with Kaplan-Meier estimates and log-rank tests. The Rothman confidence interval (CI), which is based on Greenwood's variance, Thomas and Grunkemeier CI, and the simultaneous confidence bands by Nair and Hall and Wellner, will be reported. In addition, the possible risk factors will be compared for survival with log-rank test. For multivariate analysis, the proportional hazards Cox model will be applied to investigate potential prognostic factors, such as age and stage of disease of the PFS data. The adjusted p-values of the hazard ratios and the adjusted 95% confidence interval will be reported.

Secondary Outcome Measures

Measure:Overall response rate (ORR) evaluated by immune response criteria and normal Response Evaluation Criteria in Solid Tumors criteria
Time Frame:Up to 3 years
Safety Issue:
Description:The ORR will be estimated using the 95% CI based on Wilson's method. The Fisher's exact test will be applied to examine the difference between two arms. The Wilcoxon rank sum test and Fisher's exact test will be applied to study the association between the response status and the continuous and categorical variables, respectively. The generalized non-linear model and logistic regression will be applied for multivariable data analysis. The adjusted p-value and 95% CI of the odds ratios (OR) will be reported.
Measure:Duration of response (DoR)
Time Frame:Time from documentation of tumor response to disease progression, assessed up to 3 years
Safety Issue:
Description:The study arms will be compared for duration of response survival with Kaplan-Meier estimates and log-rank tests. The Rothman CI, which is based on Greenwood's variance, Thomas and Grunkemeier CI, and the simultaneous confidence bands by Nair and Hall and Wellner, will be reported. In addition, the possible risk factors will be compared for survival with log-rank test. For multivariate analysis, the proportional hazards Cox model will be applied to investigate potential prognostic factors, such as age and stage of disease of the DoR data. The adjusted p-values of the hazard ratios and the adjusted 95% confidence interval will be reported.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

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