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Clinical Trial 18979

Cancer Type: Breast
Study Type: Treatment
NCT#: NCT02849496

Phase: Phase II
Principal Investigator: Han, Heather

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Overview

Study Title

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

Summary

This randomized phase II trial studies how well veliparib and atezolizumab work either alone or in combination in treating patients with stage III-IV triple negative breast cancer. Veliparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as atezolizumab, may interfere with the ability of tumor cells to grow and spread. It is not known whether giving veliparib and atezolizumab either alone or in combination would work better in patients with triple negative breast cancer.

Objective

Primary Objectives: To compare the progression free survival (PFS) among three study arms, i.e., ABT-888 monotherapy (arm 1), atezolizumab monotherapy (arm 2), and ABT-888 + atezolizumab in combination (arm 3) based on normal RECIST criteria in patients with advanced triple negative breast cancer (TNBC) harboring homologous DNA repair (HDR) through BRCA 1/2 mutation.

Treatments

Therapies

Immunotherapy; Therapy (NOS)

Medications

Atezolizumab (Tecentriq); Olaparib (Lynparza)

Inclusion Criteria

  • Must have histologically documented unresectable locally advanced or metastatic non-HER-2 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 tumor sequencing and not blood.
  • Measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension as >= 20 mm (>= 2 cm) with conventional techniques or as >= 10 mm (>= 1 cm) with spiral computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam
  • Prior chemotherapy allowed, including platinum therapy; must not have received chemotherapy for 4 weeks prior to the initiation of study treatment and must have recovery less than or equal to grade 1 from any adverse events from any prior chemotherapy (other than alopecia); must not have had nitrosoureas or mitomycin C for 6 weeks prior to the initiation of study treatment
  • Prior radiation therapy is allowed; must not have received minimal radiation therapy within 3 weeks prior to initiation of study treatment; otherwise, 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 immunospressive agents is allowed, provided the following is met: minimum of 6 weeks or five half-lives of the drug (whichever is shorter) prior to cycle 1, day 1
  • Treatment with systemic immunostimulatory medications 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 may be enrolled; the use of corticosteroids and mineralocorticoids for patients with orthostatic hypotension or adrenocortical insufficiency is allowed
  • 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.
  • Prior experimental (non-FDA approved) therapies and immunotherapies are allowed; must not have received these therapies for 4 weeks prior to initiation of study treatment (or within five half-lives of the investigational product, whichever is longer), must have recovery less than or equal to grade1 from any adverse events of these therapies (other than alopecia); prior treatment with any PARP inhibitor or any anti-programmed cell death protein 1 (PD-1)/anti-PD-L1 antibody is NOT allowed
  • Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2 (Karnofsky >= 60%)
  • Life expectancy of greater than 12 weeks
  • Adequate organ and marrow function
  • International normalized ratio (INR) and activated partial thromboplastin time (aPTT) less than/equal to 1.5 x ULN (applies only to those who do not receive therapeutic anticoagulation; patients receiving therapeutic anticoagulation such as low-molecular-weight heparin or warfarin, should be on a stable dose)
  • Must have tumors determined to be easily accessible for biopsy and be willing to have serial biopsies (third biopsy if cross-over occurs to combination arm)
  • Women of child-bearing potential must agree to use adequate contraception prior to study entry, for of study participation, and for 90 days after the last dose of study agent
  • Additional criteria may apply

    • Exclusion Criteria

  • Prior: allogeneic bone marrow transplantation, solid organ transplantation
  • Known brain metastases
  • Known primary central nervous system (CNS) malignancy or symptomatic CNS metastases. EXCEPTION - asymptomatic untreated CNS disease - may be enrolled, provided all of 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 (C1,D1). EXCEPTION - asymptomatic treated CNS metastases - may enroll, if all criteria above are met and: Radiographic demonstration of improvement upon completion of CNS directed therapy and no evidence of interim progression between completion of CNS directed therapy and screening radiographic study; No stereotactic radiation or whole-brain radiation within 28 days prior to C1,D1; Screening CNS radiographic study >= 4 weeks from completion of radiotherapy and >= 2 weeks from discontinuation of corticosteroids.
  • Known hypersensitivity: Chinese hamster ovary cell products or other recombinant human antibodies
  • History: severe allergic, anaphylactic, other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
  • History: allergic reactions attributed to compounds of similar chemical or biologic composition to ABT-888 and MPDL3280A
  • Prior treatment with any: PARP inhibitor, anti-PD-1/anti-PD-L1 antibody
  • Known clinically significant liver disease, including active viral, alcoholic/other hepatitis; cirrhosis; fatty liver; and inherited liver disease. Patients with past or resolved hepatitis B infection may be eligible. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA.
  • History/risk of autoimmune disease. History of autoimmune hypothyroidism on a stable dose of thyroid replacement hormone: may be eligible. Controlled Type 1 diabetes mellitus on a stable insulin regimen: may be eligible. Eczema, psoriasis, lichen simplex chronicus of vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis would be excluded): permitted provided they meet the following conditions: Psoriasis - must have a baseline ophthalmologic exam to rule out ocular manifestations; Rash must cover less than 10% of body surface area (BSA); Disease well controlled at baseline and only requiring low potency topical steroids; No acute exacerbations of underlying condition within 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, organizing pneumonia, 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
  • Active tuberculosis (TB)
  • Severe infections within 4 weeks prior to C1,D1
  • Signs/symptoms of severe infection within 2 weeks prior to C1,D1
  • Oral or intravenous (IV) antibiotics within 2 weeks prior to C1,D1; those receiving prophylactic antibiotics are eligible
  • Major surgical procedure within 28 days prior to C1,D1/anticipation of need for major surgical procedure during course of study
  • Live, attenuated vaccine within 4 weeks before cycle 1, day 1/anticipation of need for live, attenuated vaccine during the study
  • Uncontrolled intercurrent illness that would limit study compliance
  • Additional criteria may apply

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