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Study of Triple Combination of Atezolizumab + Cobimetinib + Eribulin (ACE) in Patients With Recurrent/Metastatic Inflammatory Breast Cancer

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ClinicalTrials.gov Identifier: NCT03202316
Recruitment Status : Recruiting
First Posted : June 28, 2017
Last Update Posted : July 10, 2018
Sponsor:
Collaborator:
Genentech, Inc.
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Brief Summary:

The goal of this clinical research study is to learn if the combination of atezolizumab, cobimetinib, and eribulin (ACE) can help to control inflammatory breast cancer that is metastatic (has spread). The safety of this drug combination will also be studied.

This is an investigational study. Atezolizumab is FDA approved and commercially available for the treatment of patients with locally advanced or metastatic urothelial carcinoma and patients with metastatic non-small cell lung cancer. Cobimetinib is FDA approved and commercially available for the treatment of patients with unresectable (cannot be removed with surgery) or metastatic melanoma. Eribulin is FDA approved and commercially available for the treatment of patients with metastatic breast cancer.

The combination of atezolizumab, cobimetinib and eribulin for the treatment of metastatic inflammatory breast cancer is considered investigational. The study doctor can explain how the study drugs are designed to work.

Up to 33 participants will be enrolled in this study. All will take part at MD Anderson.


Condition or disease Intervention/treatment Phase
Malignant Neoplasm of Breast Drug: Cobimetinib Drug: Atezolizumab Drug: Eribulin Phase 2

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 33 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Study of Triple Combination of Atezolizumab + Cobimetinib + Eribulin (ACE) in Patients With Recurrent/Metastatic Inflammatory Breast Cancer
Actual Study Start Date : August 11, 2017
Estimated Primary Completion Date : August 2020
Estimated Study Completion Date : August 2021


Arm Intervention/treatment
Experimental: Atezolizumab + Cobimetinib + Eribulin

During Safety lead-in cycle, participants receive Atezolizumab and Cobimetinib only. During Cycles 1-4, participants receive all 3 study drugs. Starting at Cycle 5, participants only receive Atezolizumab and Cobimetinib.

Participants receive Atezolizumab every 2 weeks while on study.

Participants receive Eribulin on Days 1 and 8 of Cycles 1-4.

Safety lead-in cycle is 2 weeks, Cycles 1-3 are 21 days (about 3 weeks), Cycle 4 is 35 days (about 5 weeks), and Cycles 5 and beyond are 28 days (about 4 weeks).

Drug: Cobimetinib

Safety Lead-In Starting Dose of Cobimetinib: 60 mg by mouth daily. Participants take Cobimetinib by mouth at the same time every day with or without food on a 3 weeks on, 1 week off schedule.

Phase II Starting Dose of Cobimetinib: Maximum tolerated dose from Safety Lead-In.


Drug: Atezolizumab
840 mg by vein over about 30 minutes every 2 weeks while on study.
Other Name: MPDL3280A

Drug: Eribulin
1.4 mg/m2 by vein over about 5 minutes on Days 1 and 8 of Cycles 1-4.
Other Name: E7389




Primary Outcome Measures :
  1. Maximum Tolerated Dose (MTD) of Cobimetinib Plus Atezolizumab and Eribulin (ACE) in Patients With Chemotherapy Resistant Metastatic Inflammatory Breast Cancer [ Time Frame: 5 weeks ]

    Bayesian optimal interval (BOIN) design used (Liu and Yuan, 2015) to find the MTD.

    Dose limiting toxicity (DLT) defined as any of the following treatment-emergent adverse events (AEs) occurring during the first 5 weeks. Adverse events assessed according to the CTCAE version 4.0.

    Target toxicity rate is 0.3 and the maximum sample size is 9.


  2. Overall Response Rate (ORR) of Cobimetinib Plus Atezolizumab and Eribulin (ACE) in Patients With Chemotherapy Resistant Metastatic Inflammatory Breast Cancer [ Time Frame: 2 years ]
    ORR defined as rate of patients who achieved partial response or complete response as the best response. Tumor response evaluated by RECIST 1.1.


Secondary Outcome Measures :
  1. Clinical Benefit Rate (CBR) of Cobimetinib Plus Atezolizumab and Eribulin (ACE) in Patients With Chemotherapy Resistant Metastatic Inflammatory Breast Cancer [ Time Frame: 24 weeks ]
    CBR defined as complete response (CR) plus partial response (PR) plus stable disease (SD).

  2. Duration of Response (DOR) of Cobimetinib Plus Atezolizumab and Eribulin (ACE) in Patients With Chemotherapy Resistant Metastatic Inflammatory Breast Cancer [ Time Frame: 2 years ]
    DOR defined as the period measured from the date of the first occurrence of a complete response (CR) or partial response (PR) (whichever status is recorded first) until the first date that progressive disease or death is documented.

  3. Progression Free Survival (PFS) of Cobimetinib Plus Atezolizumab and Eribulin (ACE) in Patients With Chemotherapy Resistant Metastatic Inflammatory Breast Cancer [ Time Frame: 2 years ]
    PFS defined as the time between date of treatment start to the date of documented disease progression or death, whichever occurs first.

  4. Overall Survival (OS) of Cobimetinib Plus Atezolizumab and Eribulin (ACE) in Patients With Chemotherapy Resistant Metastatic Inflammatory Breast Cancer [ Time Frame: 2 years ]
    OS estimated using the Kaplan-Meier method.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Signed Informed Consent Form (ICF) and comply with the requirements of the study protocol
  2. Age >/=18 years
  3. ECOG performance status 0-1
  4. 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
  5. 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.
  6. Have at least one metastatic lesion amendable for biopsy (core, punch, or FNA).
  7. At least one site of measurable disease (per RECIST 1.1), local or distant
  8. Any ER, PR, and HER2 status
  9. Adequate hematologic function, defined by the following laboratory results obtained within 14 days prior to the first study treatment (PD window, Day 1): a. ANC >/= 1500 cells/uL b. WBC counts > 2500/uL c. Lymphocyte count >/= 300/uL d. Platelet count >/= 100,000/uL; e. Hemoglobin >/= 9.0 g/dL
  10. Adequate organ function, defined by the following laboratory results obtained within 14 days prior to the first study treatment (Cycle 1, Day 1):f. Total bilirubin </= 1.5 x upper limit of normal (ULN) with the following the exception that patients with known Gilbert disease who have serum bilirubin level </=3 x ULN may be enrolled. g. AST and ALT </= 2.5 x ULN with the exception that patients with liver involvement: AST and/or ALT </= 5 x ULN h. Alkaline phosphatase </= 2.5 x ULN with the exception that patients with documented liver involvement or bone metastases: alkaline phosphatase </= 5 x ULN i. Serum creatinine </= 1.5 x ULN or creatinine clearance >/= 50 mL/min on the basis of the Cockcroft-Gault glomerular filtration rate estimation: (140 - age) x (weight in kg) x (0.85 if female)/72 x (serum creatinine in mg/dL)
  11. For women of childbearing potential or male subjects: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of < 1% per year, during the treatment period and for at least 5 months after the last dose of treatment.
  12. INR and aPTT </= 1.5 x ULN for patients who do not receive therapeutic anticoagulation;
  13. Patients receiving therapeutic anticoagulation (such as low-molecular-weight heparin or warfarin) should be on a stable dose.
  14. Left Ventricular ejection fraction >/= 50% measured by MUGA scan or echocardiogram

Exclusion Criteria:

  1. 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 (SERM, aromatase inhibitor, fulvestrant) b. Palliative radiotherapy for bone metastases > 1 week prior to study treatment c. Stable brain metastasis and asymptomatic treated 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
  2. AEs from prior anticancer therapy that have not resolved to Grade </= 1 except for alopecia and neuropathy (see item below)
  3. Grade 3 or above neuropathy induced from prior treatment, that is not resolved to grade 2 or below despite best supportive care
  4. Known clinically significant liver disease, including active viral, alcoholic, or other hepatitis; cirrhosis; fatty liver; and inherited liver disease.
  5. Pregnancy, lactation, or breastfeeding
  6. Known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies
  7. Inability to comply with study and follow-up procedures
  8. 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, Sjögren's syndrome, Guillain-Barré 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.
  9. (continuing from #8) 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: 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.
  10. 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)
  11. 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. But History of radiation pneumonitis in the radiation field (fibrosis) is permitted.
  12. Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complications
  13. Known history of HIV infection or active hepatitis B (chronic or acute) or hepatitis C infection. But: a. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA. b. 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, but should sample for HBV DNA and referral to virologist to monitor for HBV reactivation
  14. Active tuberculosis based on history, symptoms, physical exam, imaging
  15. Severe infections within 4 weeks prior to study treatment, including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia
  16. Signs or symptoms of infection within 2 weeks prior to study treatment
  17. Received oral or IV antibiotics within 2 weeks prior to study treatment. But patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection or chronic obstructive pulmonary disease) are eligible
  18. Major surgical procedure within 28 days prior to study treatment or anticipation of need for a major surgical procedure during the course of the study
  19. Patients must agree not to receive any live, attenuated influenza vaccine (e.g., FluMist®) within 28 days prior to receiving study treatment, during treatment or within 5 months following the last dose of atezolizumab.
  20. Malignancies other than the disease under study within 5 years prior to study treatment, with the exception of those with a negligible risk of metastasis or death and with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, or ductal carcinoma in situ treated surgically with curative intent) or undergoing active surveillance per standard-of-care management (e.g., chronic lymphocytic leukemia Rai Stage 0)
  21. History of or evidence of retinal pathology on ophthalmologic examination that is considered a risk factor for neurosensory retinal detachment/central serous chorioretinopathy (CSCR), retinal vein occlusion (RVO), or neovascular macular degeneration
  22. Patients will be excluded if they currently have the following risk factors for RVO: (1) Uncontrolled glaucoma with intra-ocular pressures >/=21mmHg (2) Serum cholesterol >/= Grade 2 (3) Hypertriglyceridemia >/=Grade 2 (4) Hyperglycemia (fasting) >/= Grade 2
  23. Patients with congestive heart failure, congenital long QT syndrome. bradyarrhythmias, drugs known to prolong the QT interval.
  24. The following foods/supplements are prohibited at least 7 days prior to initiation of and during study treatment: (1) St. John's wort or hyperforin (potent CYP3A4 enzyme inducer) (2) Grapefruit juice (potent cytochrome P450 CYP3A4 enzyme inhibitor)
  25. Prior treatment with anti-PD-1, or anti-PD-L1 therapeutic antibody or pathway targeting agents. But patients who have received prior treatment with anti-CTLA-4 may be enrolled, provided the following requirements are met: (1). Minimum of 12 weeks from the first dose of anti-CTLA-4 and > 6 weeks from the last dose; (2). No history of severe immune-related adverse effects from anti-CTLA 4 (NCI CTCAE Grade 3 and 4)
  26. Treatment with systemic immunostimulatory agents (including but not limited to interferon [IFN]-a or interleukin [IL]-2) within 6 weeks or five half-lives of the drug (whichever is shorter) prior to study treatment
  27. Treatment with investigational agent within 4 weeks prior to study treatment (or within five half lives of the investigational product, whichever is longer)
  28. Treatment with systemic immunosuppressive medications (including but not limited to prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor [anti-TNF] agents) within 2 weeks prior to study treatment. But: a. Patients who have received acute, low dose, systemic immunosuppressant medications (e.g., a one-time dose of dexamethasone for nausea) may be enrolled. b. The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension or adrenocortical insufficiency is allowed.
  29. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
  30. Patients with prior solid organ transplantation on anti-immunosuppressant

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03202316


Contacts
Contact: Bora Lim, MD 713-792-2817 blim@mdanderson.org
Contact: Angela Alexander, PHD 713-792-9137

Locations
United States, Texas
University of Texas MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Clinical Research Operations       blim@mdanderson.org   
Sponsors and Collaborators
M.D. Anderson Cancer Center
Genentech, Inc.
Investigators
Principal Investigator: Bora Lim, MD M.D. Anderson Cancer Center

Additional Information:
Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT03202316     History of Changes
Other Study ID Numbers: 2016-0890
NCI-2017-01601 ( Registry Identifier: NCI CTRP )
First Posted: June 28, 2017    Key Record Dates
Last Update Posted: July 10, 2018
Last Verified: July 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by M.D. Anderson Cancer Center:
Malignant neoplasm of breast
Metastatic inflammatory breast cancer
mIBC
Cobimetinib
Atezolizumab
MPDL3280A
Eribulin
E7389

Additional relevant MeSH terms:
Breast Diseases
Breast Neoplasms
Neoplasms
Inflammatory Breast Neoplasms
Neoplasms by Site
Skin Diseases
Atezolizumab
Antibodies, Monoclonal
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs