Clinical Trials /

First Line Atezolizumab, Paclitaxel, and Bevacizumab (Avastin®) in mTNBC

NCT04408118

Description:

This is a multicenter, open-label, single-arm, phase II clinical trial to evaluate to evaluate the efficacy and safety of first line atezolizumab in combination with paclitaxel and bevacizumab (Avastin®) in patients with advanced or metastatic triple-negative breast cancer (mTNBC)

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: First Line Atezolizumab, Paclitaxel, and Bevacizumab (Avastin®) in mTNBC
  • Official Title: Phase II Clinical Trial to Evaluate the Efficacy and Safety of First Line Atezolizumab in Combination With Paclitaxel and Bevacizumab (Avastin®) in Patients With Advanced or Metastatic Triple-negative Breast Cancer

Clinical Trial IDs

  • ORG STUDY ID: MedOPP150
  • SECONDARY ID: 2019-001503-20
  • NCT ID: NCT04408118

Conditions

  • Metastatic Breast Cancer
  • Advanced Breast Cancer
  • Triple Negative Breast Cancer

Interventions

DrugSynonymsArms
AtezolizumabAtezolizumab + Paclitaxel + Bevacizumab (Avastin®)
PaclitaxelAtezolizumab + Paclitaxel + Bevacizumab (Avastin®)
BevacizumabAvastinAtezolizumab + Paclitaxel + Bevacizumab (Avastin®)

Purpose

This is a multicenter, open-label, single-arm, phase II clinical trial to evaluate to evaluate the efficacy and safety of first line atezolizumab in combination with paclitaxel and bevacizumab (Avastin®) in patients with advanced or metastatic triple-negative breast cancer (mTNBC)

Detailed Description

      Men and women age ≥ 18 years with previously untreated unresectable locally advanced or
      metastatic triple-negative breast cancer (TNBC) that is not amenable to resection with
      curative intent regardless of programmed death-ligand 1 (PD-L1) status.

      The number of patients to be included is 100 patients. The primary objective is to evaluate
      the efficacy -in terms of progression-free survival (PFS)- of first line atezolizumab in
      combination with paclitaxel and bevacizumab (Avastin®) in patients with unresectable locally
      advanced or metastatic TNBC.

      After signing the ICF and confirmed eligibility, patients will begin treatment on 28 days
      cycles: Atezolizumab (840 mg) intravenously on days 1 and 15; Paclitaxel (90 mg/m2) via IV
      infusion on days 1, 8 and 15; Bevacizumab (Avastin® 10mg/kg) intravenously on days 1 and 15.

      Patients will receive treatment until disease progression, unacceptable toxicity, death, or
      discontinuation from the study treatment for any other reason.

      Patients discontinuing the study treatment will enter a post- treatment follow-up period
      until death, withdrawal of consent, patient is lost to follow-up, or study termination.
    

Trial Arms

NameTypeDescriptionInterventions
Atezolizumab + Paclitaxel + Bevacizumab (Avastin®)ExperimentalAll eligible patients will be treated with atezolizumab (840 mg) intravenously on days 1 and 15, Paclitaxel (90 mg/m2) on days 1, 8 and 15 via IV infusion and Bevacizumab (Avastin® 10mg/kg) intravenously on days 1 and 15. Treatment cycles and patient visits are organized in scheduled cycles of 28 days.
  • Atezolizumab
  • Paclitaxel
  • Bevacizumab

Eligibility Criteria

        Inclusion Criteria:

          1. Signed informed consent form (ICF) prior to participation in any study-related
             activities.

          2. Male or female patients ≥ 18 years at the time of signing ICF.

          3. Ability to comply with the study protocol, in the investigator's judgment.

          4. Histologically confirmed TNBC -regardless of PD-L1 status- per American Society of
             Clinical Oncology (ASCO)/College of American Pathologists (CAP) criteria based on
             local testing on the most recent analyzed biopsy. Triple-negative is defined as <1%
             expression for estrogen receptor (ER) and progesterone receptor (PgR) as determined by
             immunohistochemistry (IHC) and negative for HER2 (0-1+ by immunohistochemistry [IHC]
             or 2+ and negative by in situ hybridization [ISH] test).

          5. Unresectable locally advanced or metastatic disease documented by computerized
             tomography (CT) scan or magnetic resonance imaging (MRI) that is not amenable to
             resection with curative intent.

          6. No prior chemotherapy and/or targeted therapy and/or immunotherapy and/or
             antiangiogenic agent for MBC. Patients who have received (neo)adjuvant taxane-based
             chemotherapy and/or immunotherapy and/or an antiangiogenic agent are required to have
             a disease-free interval (DFI) of at least 12 months after completion of each of these
             treatments. For (neo)adjuvant non-taxane-based chemotherapy, a DFI of at least 6
             months is required.

          7. Resolution of all acute toxic effects of prior anti-cancer therapy to grade ≤ 1 as
             determined by the NCI-CTCAE v.5.0 (except for alopecia, grade ≤ 2 peripheral
             neuropathy, or other toxicities not considered a safety risk for the patient at
             investigator's discretion).

          8. Evidence of measurable disease or non-measurable disease as per RECIST v.1.1. Patients
             with only bone lesions are also eligible.

          9. Willingness and ability to provide the most recent tumor biopsy since last progression
             from either metastatic or primary tissues at the time of the inclusion to perform
             exploratory studies. If not feasible, patient eligibility should be evaluated by a
             Sponsor's qualified designee. An additional tumor biopsy from either metastatic or
             primary (only if metastatic biopsies cannot be obtained for inaccessible lesion or
             subject safety concern) tissues would be collected at disease progression or study
             termination whenever it is feasible.

             Note: Patients for whom tumor biopsies cannot be obtained (e.g., inaccessible tumor or
             safety concern) may submit archived pathological material from either metastatic or
             primary sites, but the most recent tumor biopsy from the patient should be obtained
             when available.

         10. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.

         11. Life expectancy of ≥12 weeks.

         12. Adequate hematologic and organ function within 14 days before the first study
             treatment on Cycle 1 Day 1 (C1D1), defined by the following parameters:

               1. Hematological: White blood cell (WBC) count > 3.0 x 109/L; Absolute neutrophil
                  count (ANC) > 1.5 X 109/L (without granulocyte colony- stimulating factor [G-CSF]
                  support within 2 weeks prior to Cycle 1 Day1); Lymphocyte count 3 0.5 x 109/L
                  (500μL); Platelet count 3 75.0 x 109/L (without transfusion within 2 weeks prior
                  to Cycle 1 Day 1); Hemoglobin > 9.0 g/dL (Patients may be transfused or receive
                  erythropoietic treatment to meet this criterion).

                  Note: Patients cannot be transfused platelets within 14 days prior to C1D1 to
                  meet this criterion. The use of G-CSF within 14 days prior to C1D1 is also
                  prohibited.

               2. Hepatic: Bilirubin ≤ 1.5 times the upper limit of normal (× ULN) (≤ 3 x ULN in
                  the case of Gilbert's disease); aspartate transaminase (AST) and alanine
                  transaminase (ALT) ≤ 2.5 × ULN (in the case of liver metastases ≤ 5 × ULN);
                  alkaline phosphatase (ALP) ≤ 2.5 × ULN (≤ 5 × ULN in the case of liver and/or
                  bone metastases).

               3. Serum albumin ≥ 2.5 g/dL

               4. Renal: Serum creatinine < 1.5 × ULN or creatinine clearance ≥ 50 mL/min based on
                  Cockcroft−Gault glomerular filtration rate estimation. No proteinuria by dipstick
                  urinalysis (trace proteinuria is allowed). In cases of proteinuria at least 1+ by
                  urinalysis, proteinuria should be less than 500 mg by 24-hour urine collection.

               5. Coagulation: For patients not receiving therapeutic anticoagulation: Partial
                  Thromboplastin Time (PTT) (or activated Partial Thromboplastin Time [aPTT]) and
                  International Normalized Ratio (INR) ≤ 1.5 × ULN. For patients receiving
                  therapeutic anticoagulation: stable anticoagulant regimen.

         13. Negative human immunodeficiency virus (HIV) test at screening. Patients with a
             positive HIV test at screening are eligible provided they are stable on
             anti-retroviral therapy, have a CD4 count 3 200/μL, and have an undetectable viral
             load.

         14. Negative hepatitis B surface antigen (HBsAg) test and negative total hepatitis B core
             antibody (HBcAb) tests at screening, or positive total HBcAb test followed by a
             negative hepatitis B virus (HBV) DNA test at screening. Current treatment with
             anti-viral therapy for HBV is not allowed.

             Note: HBV DNA test only to be performed for patients with a positive total HBcAb test.

         15. Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV antibody
             test followed by a negative HCV RNA test at screening.

             Note: HCV RNA test only to be performed for patients with a positive HCV antibody
             test.

         16. Women of childbearing potential must have a negative serum pregnancy test within 14
             days before study treatment initiation and agree to remain abstinent (refrain from
             heterosexual intercourse) or use one highly effective contraceptive method, or two
             effective contraceptive methods, as defined in the protocol during the treatment
             period for at least 5 months after the last dose of atezolizumab, and for at least 6
             months after the last dose of paclitaxel and bevacizumab (Avastin®).

        Exclusion Criteria:

          1. Known active uncontrolled or symptomatic central nervous system (CNS) metastases as
             indicated by clinical symptoms, cerebral edema, and/or progressive growth. Patients
             with a history of CNS metastases are eligible if they meet the following criteria:

               -  Evidence of measurable disease or non-measurable disease as per RECIST v.1.1.

               -  The patient has no history of intracranial hemorrhage.

               -  The patient has not undergone stereotactic radiotherapy within 7 days prior to
                  initiation of study treatment, whole-brain radiotherapy within 14 days prior to
                  initiation of study treatment, or neurosurgical resection within 28 days prior to
                  initiation of study treatment. The patient has no ongoing requirement for
                  corticosteroids as therapy for CNS disease. Anticonvulsant therapy at a stable
                  dose is permitted.

          2. History of leptomeningeal disease.

          3. Uncontrolled tumor-related pain.

             Note 1: Patients requiring pain medication must be on a stable regimen at study entry.

             Note 2: Symptomatic lesions (e.g., bone metastases or metastases causing nerve
             impingement) amenable to palliative radiotherapy should be treated prior to enrolment.
             Patients should be recovered from the effects of radiation.

          4. 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 syndrome, Guillain-Barré syndrome,
             or multiple sclerosis for a more comprehensive list of autoimmune diseases and immune
             deficiencies, with the following exceptions:

               -  Patients with a history of autoimmune-related hypothyroidism who are on thyroid
                  replacement hormone are eligible for the study.

               -  Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen
                  are eligible for the study.

               -  Patients with eczema, psoriasis, lichen simplex chronicum, or vitiligo with
                  dermatologic manifestations only (e.g., patients with psoriatic arthritis are
                  excluded) are eligible for the study provided all of following conditions are
                  met:

               -  Rash must cover < 10% of body surface area.

               -  Disease is well controlled at baseline and requires only low-potency topical
                  corticosteroids.

               -  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.

          5. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent
             drainage procedures.

             Note: Patients with indwelling catheters (e.g., PleurX®) are allowed.

          6. Uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L; calcium > 12
             mg/dL).

          7. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis
             obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of
             active pneumonitis on screening chest computed tomography (CT) scan.

             Note: History of radiation pneumonitis in the radiation field (fibrosis) is permitted.

          8. Active tuberculosis.

          9. Significant cardiovascular disease 6 months prior to initiation of study treatment.
             These include New York Heart Association Class II or greater cardiac disease,
             myocardial infarction, unstable arrhythmia, or unstable angina, symptomatic
             pericarditis, ventricular arrhythmias - except for benign premature ventricular
             contractions-, arrhythmias or conduction abnormalities requiring a pacemaker or not
             controlled with medication, and prior peripheral vascular disease including any
             cerebrovascular accident including transient ischemic attack, any pulmonary embolism,
             any prior deep vein thrombosis, and/or any grade ≥ 2 peripheral vascular disease.

         10. Left ventricular ejection fraction (LVEF) < 50% as determined by multiple gated
             acquisition (MUGA) scan or echocardiogram (ECHO).

         11. Uncontrolled hypertension (systolic blood pressure greater than 160 mmHg and diastolic
             blood pressure greater than 100 mmHg).

         12. Major surgical procedure (defined as requiring general anesthesia) or significant
             traumatic injury within 28 days of start of study drug, or patients who have not
             recovered from the side effects of any major surgery.

         13. Concurrent malignancy(ies) or malignancy(ies) within 5 years of study enrollment
             except for carcinoma in situ of the cervix, non-melanoma skin carcinoma, or stage I
             uterine cancer. For other cancers considered to have a low risk of recurrence,
             discussion with the Medical Monitor is required.

         14. Treatment with therapeutic oral or IV antibiotics or severe infection 2 weeks prior to
             initiation of study treatment. Patients receiving prophylactic antibiotics (e.g., to
             prevent a urinary tract infection or chronic obstructive pulmonary disease
             exacerbation) are eligible for the study.

         15. Prior allogeneic stem cell or solid organ transplantation.

         16. Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study
             treatment, or anticipation of need for such a vaccine during atezolizumab treatment or
             within 5 months after the final dose of atezolizumab.

         17. Extracranial radiotherapy or limited-field palliative radiotherapy within seven days
             prior to study enrolment, or patients who have not recovered from radiotherapy-related
             toxicities to baseline or grade ≤ 1.

         18. Treatment with investigational therapy within 28 days prior to initiation of study
             treatment.

         19. Treatment with systemic immunosuppressive medication within 2 weeks prior to
             initiation of study treatment (including, but not limited to, corticosteroids,
             cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-TNF-a agents) or
             anticipation of need for systemic immunosuppressive medication during study treatment,
             with the following exceptions:

             Note 1: Patients who have received acute, low-dose systemic immunosuppressant
             medication or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48
             hours of corticosteroids for a contrast allergy) are eligible for the study after
             Medical Monitor approval has been obtained.

             Note 2: Patients who are receiving mineralocorticoids (e.g., fludrocortisone), inhaled
             corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma, or
             low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency are
             eligible for the study.

         20. Chronic daily intake of antiplatelet drugs (e.g., aspirin doses of 325 mg/day or
             higher or non-steroidal anti-inflammatory medication known to inhibit platelet
             function).

         21. History of severe allergic anaphylactic reactions to chimeric or humanized antibodies
             or

         22. Any other concurrent severe and/or uncontrolled medical condition that would, in the
             investigator's judgement, contraindicate patient participation in the clinical study.

         23. Concurrent participation in other interventional clinical trials.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:PFS (Progression-free Survival)
Time Frame:24 months
Safety Issue:
Description:From a clinical point of view, the primary endpoint for this study is the PFS (progression-free survival) defined as the period of time from treatment initiation to the first occurrence of disease progression or death from any cause, whichever occurs first, as determined locally by the investigator using RECIST v.1.1.

Secondary Outcome Measures

Measure:Efficacy (TTR)
Time Frame:24 months
Safety Issue:
Description:TTR is defined as the time from the treatment initiation to time of the first objective tumor response (tumor shrinkage of ≥30%) observed for patients who achieved a complete response (CR) or partial response (PR).
Measure:Efficacy (ORR)
Time Frame:24 months
Safety Issue:
Description:Objective response rate (ORR) is defined as the sum of CR and PR relative to the number of patients in the analysis set with measurable disease at baseline.
Measure:Efficacy (CBR)
Time Frame:24 months
Safety Issue:
Description:Clinical benefit rate (CBR) is defined as the proportion of participants with CR, PR or SD ≥24 weeks relative to the number of patients in the analysis set.
Measure:Efficacy (DoR)
Time Frame:24 months
Safety Issue:
Description:Duration of response (DoR) is defined as the time from the first documentation of objective tumor response (CR or PR) to the first documentation of disease progression, death due to any cause or treatment discontinuation, whichever occurs first.
Measure:Efficacy (OS)
Time Frame:24 months
Safety Issue:
Description:Overall survival (OS) is defined as the time from date of treatment initiation to date of death due to any cause. In the absence of confirmation of death, survival time will be censored to last date the participant was known to be alive.
Measure:Efficacy (Best percentage of change of target tumor lesions)
Time Frame:24 months
Safety Issue:
Description:Best percentage of change from baseline in the size of target tumor lesions is defined as the biggest decrease, or smallest increase if no decrease will be observed.
Measure:Safety AEs and SAEs
Time Frame:24 months
Safety Issue:
Description:Incidence and severity of adverse events (AEs), serious adverse events (SAEs) according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE) v.5.0, including dose reductions, delays, and treatment discontinuations.
Measure:Exploratory objectives (irPFS)
Time Frame:24 months
Safety Issue:
Description:Immune-related progression-free survival (irPFS) is defined as the period of time from the date of treatment initiation to the date of the first documentation of objective progression of disease (irPD) or death due to any cause in absence of documented irPD.
Measure:Exploratory objectives (irORR)
Time Frame:24 months
Safety Issue:
Description:Immune-related objective response (irORR) is defined as the proportion of participants with irCR or irPR relative to the number of patients in the analysis set with measurable disease at baseline.
Measure:Exploratory objectives (molecular markers)
Time Frame:24 months
Safety Issue:
Description:Changes in mutation and copy number in oncogenes, tumor suppressors, and/or other genes associated with disease progression assessed in liquid biopsy.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:MedSIR

Trial Keywords

  • breast cancer
  • metastatic breast cancer
  • triple negative breast cancer
  • HER2 negative
  • HR negative

Last Updated

May 25, 2020