A Phase II Study of Triple Combination of Atezolizumab + Cobimetinib + Eribulin (ACE) or Atezolizumab + Eribulin (AE) in Patients With Recurrent/Metastatic Inflammatory Breast Cancer
Overview
- Phase
- Phase 2
- Intervention
- Eribulin
- Conditions
- Recurrent Breast Inflammatory Carcinoma
- Sponsor
- M.D. Anderson Cancer Center
- Enrollment
- 37
- Locations
- 1
- Primary Endpoint
- Overall response rate (ORR)
- Status
- Active, not recruiting
- Last Updated
- 4 months ago
Overview
Brief Summary
This phase II trial studies how well atezolizumab, cobimetinib, and eribulin work in treating patients with inflammatory breast cancer that has spread to other places in the body (metastatic). Immunotherapy with monoclonal antibodies, such as atezolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Cobimetinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as eribulin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving atezolizumab, cobimetinib, and eribulin may work better in treating patients with inflammatory breast cancer.
Detailed Description
PRIMARY OBJECTIVES: I. To determine ORR (overall response rate) of metastatic inflammatory breast cancer (BC) (mIBC) patients treated with this proposed combinatorial atezolizumab, cobimetinib, and eribulin (ACE) therapy via phase II. (ACE, Cohort I) II. To determine ORR (overall response rate) for double combination of atezolizumab and eribulin (AE). (AE, cohort II) SECONDARY OBJECTIVES: I. To further characterize the safety and tolerability of atezolizumab + cobimetinib + eribulin. II. To further characterize the safety and tolerability of atezolizumab + eribulin. III. To determine CBR (clinical benefit rate): (stable disease \[SD\] + complete response \[CR\] + partial response \[PR\] \>= 24 weeks). III. To determine the duration of response (DOR). IV. To determine progression free survival (PFS). V. To determine 2 years overall survival (OS). EXPLORATORY OBJECTIVES: I. To determine the progressive disease (PD) biomarker changes induced by combinatorial therapy using liquid and tissue based assays to investigate microenvironment via multiplex imaging, proportional study of T cells: CD3, CD8 composition and change, macrophage (M1 and M2), PD-L1 expression on circulating tumor cell (CTC). II. To determine the immune pathway related biomarker changes induced by combinatorial therapy via multiplex serum cytokine assays. III. This translational biomarker assays will be done based on collaboration with plasma based ribonucleic acid (RNA) sequencing (RNA-seq) in collaboration with Lambowitz laboratory (lab) (University of Texas at Austin \[UT Austin\]), Oncomine next-generation sequencing (NGS) study on tumor/circulating tumor deoxyribonucleic acid (ctDNA) with Wistuba lab, and bioinformatics with Futreal lab. OUTLINE: COHORT I: Patients receive atezolizumab intravenously (IV) over about 30-60 minutes every 2 weeks, cobimetinib orally (PO) daily for 3 weeks on, 1 week off for 4 weeks of the safety lead-in course. Patients then receive atezolizumab IV over about 30-60 minutes every 2 weeks, cobimetinib PO daily for 3 weeks on, 1 week off, and eribulin IV over 2-5 minutes on days 1 and 8 of cycles 1-4. Cycles 1-4 repeat every 21 days and subsequent cycles with atezolizumab and cobimetinib repeat every 28 days in the absence of disease progression or unacceptable toxicity. COHORT II: Patients receive atezolizumab IV over about 30-60 minutes every 3 weeks for cycles 1-6 and every 4 weeks for subsequent cycles, and eribulin IV over 2-5 minutes on days 1 and 8 of cycles 1-6. Cycles 1-6 repeat every 21 days and subsequent cycles with atezolizumab repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of the study treatment, patients are followed for 3 months and then every 6 months for 2 years.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Signed informed consent form (ICF) and comply with the requirements of the study protocol
- •Eastern Cooperative Oncology Group (ECOG) performance status 0-1
- •Confirmed diagnosis of inflammatory breast cancer according to international consensus criteria: (1) onset: rapid onset of breast erythema, edema, and/or peau d'orange, and/or warm breast, with or without an underlying breast mass (2) duration: history of such findings no more than 6 months (3) extent: erythema occupying at least 1/3 of whole breast (4) pathology: pathologic confirmation of invasive carcinoma
- •Patients with recurrent or metastatic IBC after standard systemic therapy are eligible; patients who have disease progression while receiving standard anthracycline or taxane based neoadjuvant therapy are also eligible. a. patients with HER2-positive disease must have had at least 2 lines of anti-HER2 therapy, including Perjeta and Kadcyla; b. prior eribulin treatment is allowed
- •At least one metastatic lesion amendable for biopsy (core, punch, or fine needle aspiration \[FNA\]); if the patient only has lymph nodes, these are considered amenable but will not be biopsied
- •At least one site of measurable disease (per Response Evaluation Criteria in Solid Tumors \[RECIST\] 1.1), local or distant
- •Any estrogen receptor (ER), progesterone receptor (PR), HER2 status
- •Absolute neutrophil count (ANC) \>= 1500 cells/uL (obtained within 14 days prior to the first study treatment \[PD window day 1\])
- •White blood cell (WBC) counts \> 2500/uL (obtained within 14 days prior to the first study treatment \[PD window, day 1\])
- •Lymphocyte count \>= 300/uL (obtained within 14 days prior to the first study treatment \[PD window day 1\])
Exclusion Criteria
- •Any approved anticancer therapy for treatment purpose is not allowed, or need to be stopped at least 2 weeks prior to initiation of study treatment; however, the following are allowed: a. endocrine therapy (selective estrogen receptor modulator \[SERM\], aromatase inhibitor, fulvestrant) b. palliative radiotherapy for bone metastases \> 1 week prior to study treatment c. stable brain metastasis and asymptomatic treated central nervous system (CNS) metastases are allowed, patient must show stable disease by CNS radiographic study \>= 4 weeks from completion of radiotherapy and \>= 2 weeks from discontinuation of corticosteroids
- •Adverse events (AEs) from prior anticancer therapy that have not resolved to grade =\< 1 except for alopecia and neuropathy
- •Grade 3 or above neuropathy induced from prior treatment, that is not resolved to grade 2 or below despite best supportive care
- •Known clinically significant liver disease, including active viral, alcoholic, or other hepatitis; cirrhosis; fatty liver; and inherited liver disease
- •Pregnancy, lactation, or breastfeeding
- •Known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies
- •Inability to comply with study and follow-up procedures
- •Active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjogren's syndrome, Guillain-Barre syndrome, or multiple sclerosis, with the following exception: a. patients with a history of autoimmune hypothyroidism who are on thyroid replacement hormone are eligible for the study; b. patients with controlled type 1 diabetes mellitus who are on an insulin regimen are eligible for the study; c. 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 are met: i. rash must cover \< 10% of body surface area.; ii. disease is well controlled at baseline and requires only low-potency topical corticosteroids; iii. no occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high potency or oral corticosteroids within the previous 12 months
- •Acute exacerbations of underlying condition within the last 12 months (requiring psoralen plus ultraviolet A radiation \[PUVA\], methotrexate, retinoids, biologic agents, oral calcineurin inhibitors; high potency or oral steroids)
- •Known 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:
Arms & Interventions
Cohort II (atezolizumab, eribulin)
Patients receive atezolizumab IV over about 30-60 minutes every 3 weeks for cycles 1-6 and every 4 weeks for subsequent cycles, and eribulin IV over 2-5 minutes on days 1 and 8 of cycles 1-6. Cycles 1-6 repeat every 21 days and subsequent cycles with atezolizumab repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention: Eribulin
Cohort II (atezolizumab, eribulin)
Patients receive atezolizumab IV over about 30-60 minutes every 3 weeks for cycles 1-6 and every 4 weeks for subsequent cycles, and eribulin IV over 2-5 minutes on days 1 and 8 of cycles 1-6. Cycles 1-6 repeat every 21 days and subsequent cycles with atezolizumab repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention: Laboratory Biomarker Analysis
Cohort II (atezolizumab, eribulin)
Patients receive atezolizumab IV over about 30-60 minutes every 3 weeks for cycles 1-6 and every 4 weeks for subsequent cycles, and eribulin IV over 2-5 minutes on days 1 and 8 of cycles 1-6. Cycles 1-6 repeat every 21 days and subsequent cycles with atezolizumab repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention: Pharmacological Study
Cohort I (atezolizumab, cobimetinib, eribulin)
Patients receive atezolizumab IV over about 30-60 minutes every 2 weeks, cobimetinib PO daily for 3 weeks on, 1 week off for 4 weeks of the safety lead-in course. Patients then receive atezolizumab IV over about 30-60 minutes every 2 weeks, cobimetinib PO daily for 3 weeks on, 1 week off, and eribulin IV over 2-5 minutes on days 1 and 8 of cycles 1-4. Cycles 1-4 repeat every 21 days and subsequent cycles with atezolizumab and cobimetinib repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention: Atezolizumab
Cohort I (atezolizumab, cobimetinib, eribulin)
Patients receive atezolizumab IV over about 30-60 minutes every 2 weeks, cobimetinib PO daily for 3 weeks on, 1 week off for 4 weeks of the safety lead-in course. Patients then receive atezolizumab IV over about 30-60 minutes every 2 weeks, cobimetinib PO daily for 3 weeks on, 1 week off, and eribulin IV over 2-5 minutes on days 1 and 8 of cycles 1-4. Cycles 1-4 repeat every 21 days and subsequent cycles with atezolizumab and cobimetinib repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention: Cobimetinib
Cohort I (atezolizumab, cobimetinib, eribulin)
Patients receive atezolizumab IV over about 30-60 minutes every 2 weeks, cobimetinib PO daily for 3 weeks on, 1 week off for 4 weeks of the safety lead-in course. Patients then receive atezolizumab IV over about 30-60 minutes every 2 weeks, cobimetinib PO daily for 3 weeks on, 1 week off, and eribulin IV over 2-5 minutes on days 1 and 8 of cycles 1-4. Cycles 1-4 repeat every 21 days and subsequent cycles with atezolizumab and cobimetinib repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention: Eribulin
Cohort I (atezolizumab, cobimetinib, eribulin)
Patients receive atezolizumab IV over about 30-60 minutes every 2 weeks, cobimetinib PO daily for 3 weeks on, 1 week off for 4 weeks of the safety lead-in course. Patients then receive atezolizumab IV over about 30-60 minutes every 2 weeks, cobimetinib PO daily for 3 weeks on, 1 week off, and eribulin IV over 2-5 minutes on days 1 and 8 of cycles 1-4. Cycles 1-4 repeat every 21 days and subsequent cycles with atezolizumab and cobimetinib repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention: Laboratory Biomarker Analysis
Cohort I (atezolizumab, cobimetinib, eribulin)
Patients receive atezolizumab IV over about 30-60 minutes every 2 weeks, cobimetinib PO daily for 3 weeks on, 1 week off for 4 weeks of the safety lead-in course. Patients then receive atezolizumab IV over about 30-60 minutes every 2 weeks, cobimetinib PO daily for 3 weeks on, 1 week off, and eribulin IV over 2-5 minutes on days 1 and 8 of cycles 1-4. Cycles 1-4 repeat every 21 days and subsequent cycles with atezolizumab and cobimetinib repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention: Pharmacological Study
Cohort II (atezolizumab, eribulin)
Patients receive atezolizumab IV over about 30-60 minutes every 3 weeks for cycles 1-6 and every 4 weeks for subsequent cycles, and eribulin IV over 2-5 minutes on days 1 and 8 of cycles 1-6. Cycles 1-6 repeat every 21 days and subsequent cycles with atezolizumab repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention: Atezolizumab
Outcomes
Primary Outcomes
Overall response rate (ORR)
Time Frame: Up to 2 years
Calculated per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. ORR is defined as the rate of patients who achieved partial response or complete response as the best response. All tumor response will be evaluated by RECIST 1.1. The ORR will be estimated along with 95% confidence intervals. Logistic regression model will be used to assess other variables' effect on the best ORR.
Secondary Outcomes
- Pharmacodynamic markers(Up to 2 years)
- Incidence of dose limiting toxicity (DLT) of cobimetinib and atezolizumab (safety lead-in)(Up to 7 weeks)
- Progression free survival (PFS)(From date of treatment start until date of first documented disease progression or death, whichever occurs first, assessed up to 2 years)
- Overall survival (OS)(At 2 years)
- Clinical benefit rate (CBR)(Up to 2 years)
- Incidence of adverse events(Up to 2 years)
- Duration of response (DOR)(Up to 2 years)