Clinical Trials /

A Study Of Ipatasertib in Combination With Atezolizumab and Paclitaxel as a Treatment for Participants With Locally Advanced or Metastatic Triple-Negative Breast Cancer.

NCT04177108

Description:

This study will evaluate the efficacy and safety of ipatasertib in combination with atezolizumab and paclitaxel in locally advanced or metastatic Triple-Negative Breast Cancer (TNBC) previously untreated in this setting.

Related Conditions:
  • Breast Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: A Study Of Ipatasertib in Combination With Atezolizumab and Paclitaxel as a Treatment for Participants With Locally Advanced or Metastatic Triple-Negative Breast Cancer.
  • Official Title: A Phase III, Double-blind, Placebo-controlled, Randomized Study Of Ipatasertib in Combination With Atezolizumab and Paclitaxel as a Treatment for Participants With Locally Advanced Unresectable or Metastatic Triple-Negative Breast Cancer.

Clinical Trial IDs

  • ORG STUDY ID: CO41101
  • SECONDARY ID: 2019-000810-12
  • NCT ID: NCT04177108

Conditions

  • Triple-Negative Breast Cancer

Interventions

DrugSynonymsArms
AtezolizumabCohort 1 Arm A
IpatasertibCohort 1 Arm A
PaclitaxelCohort 1 Arm A
Placebo for AtezolizumabCohort 1 Arm B
Placebo for IpatasertibCohort 1 Arm C

Purpose

This study will evaluate the efficacy and safety of ipatasertib in combination with atezolizumab and paclitaxel in locally advanced or metastatic Triple-Negative Breast Cancer (TNBC) previously untreated in this setting.

Detailed Description

      This study will evaluate the efficacy, safety and pharmacokinetics of ipatasertib in
      combination with atezolizumab and paclitaxel in locally advanced unresectable or metastatic
      triple-negative breast cancer (TNBC) previously untreated in this setting. Participants with
      Programmed Death-Ligand 1 (PD-L1) non-positive and PD-L1 positive tumors will be
      independently enrolled in Cohorts 1 and 2, respectively. The combination of ipatasertib,
      atezolizumab and paclitaxel will be evaluated in Cohorts 1 and 2 and the combination of
      ipatasertib and paclitaxel will be evaluated in Cohort 1.
    

Trial Arms

NameTypeDescriptionInterventions
Cohort 1 Arm AExperimentalPD-L1 Non-Positive Participants receiving Paclitaxel, Atezolizumab and Ipatasertib. Participants will be randomised in a 1:1:1 ratio.
  • Atezolizumab
  • Ipatasertib
  • Paclitaxel
Cohort 1 Arm BExperimentalPD-L1 Non-Positive Participants receiving Paclitaxel, Ipatasertib and Placebo for Atezolizumab. Participants will be randomised in a 1:1:1 ratio.
  • Ipatasertib
  • Paclitaxel
  • Placebo for Atezolizumab
Cohort 1 Arm CActive ComparatorPD-L1 Non-Positive Participants receiving Paclitaxel, Placebo for Ipatasertib and Placebo for Atezolizumab. Participants will be randomised in a 1:1:1 ratio.
  • Paclitaxel
  • Placebo for Atezolizumab
  • Placebo for Ipatasertib
Cohort 2 Arm AExperimentalPD-L1 Positive Participants receiving Paclitaxel, Atezolizumab and Ipatasertib. Participants will be randomised in a 1:1 ratio.
  • Atezolizumab
  • Ipatasertib
  • Paclitaxel
Cohort 2 Arm BActive ComparatorPD-L1 Positive Participants receiving Paclitaxel, Atezolizumab and Placebo for Ipatasertib. Participants will be randomised in a 1:1 ratio.
  • Atezolizumab
  • Paclitaxel
  • Placebo for Ipatasertib

Eligibility Criteria

        Inclusion Criteria:

          1. Willingness and ability to complete all study-related assessments, including PRO
             assessments, in the investigator's judgement.

          2. Adequate hematologic and organ function within 14 days before the first study
             treatment on Day 1 of Cycle 1.

          3. Life expectancy of at least 6 months.

          4. Measurable disease according to RECIST v1.1.

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

          6. For women of childbearing potential: agreement to remain abstinent (refrain from
             heterosexual intercourse) or use contraception, and agreement to refrain from donating
             eggs.

          7. For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use
             contraceptive methods, and agreement to refrain from donating sperm.

          8. Appropriate candidate for paclitaxel monotherapy if tumor PD-L1 status is unknown or
             non-positive; appropriate candidate for paclitaxel and atezolizumab if tumor PD-L1
             status is positive.

          9. Histologically documented triple-negative adenocarcinoma of the breast that is locally
             advanced or metastatic and is not amenable to resection with curative intent.

        Exclusion Criteria:

          1. Inability to comply with study and follow-up procedures.

          2. History of malabsorption syndrome or other condition that would interfere with enteral
             absorption or results in the inability or unwillingness to swallow pills.

          3. Active infection requiring systemic anti-microbial treatment (including antibiotics,
             anti-fungal agents, and anti-viral agents).

          4. Known HIV infection (there must be a negative HIV test at screening).

          5. Known clinically significant history of liver disease consistent with Child-Pugh Class
             B or C.

          6. Current treatment with anti-viral therapy for HBV.

          7. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
             prior to Day 1 of Cycle 1 or anticipation of need for a major surgical procedure
             during the study.

          8. Pregnancy or breastfeeding, or intention to become pregnant during the study or within
             28 days after the final dose of ipatasertib/placebo, 5 months after the final dose of
             atezolizumab/placebo, and 6 months after the final dose of paclitaxel whichever occurs
             later.

          9. New York Heart Association Class II, III, or IV heart failure, left ventricular
             ejection fraction < 50%, or active ventricular arrhythmia requiring medication.

         10. Current unstable angina or history of myocardial infarction within 6 months prior to
             Day 1 of Cycle 1.

         11. Congenital long QT syndrome or screening QT interval corrected through use
             Fridericia's formula (QTcF) > 480 ms.

         12. Current treatment with medications used at doses known to cause clinically relevant
             prolongation of QT/QTc interval.

         13. History or presence of an abnormal ECG that is clinically significant in the
             investigator's opinion (including complete left bundle branch block, second- or
             third-degree heart block, or evidence of prior myocardial infarction).

         14. Requirement for chronic corticosteroid therapy of > 10 mg of prednisone per day or an
             equivalent dose of other anti-inflammatory corticosteroids or immunosuppressant agents
             for a chronic disease.

         15. Treatment with approved or investigational cancer therapy within 14 days prior to Day
             1 of Cycle 1.

         16. Any other disease, metabolic dysfunction, physical examination finding, or clinical
             laboratory finding that, in the investigator's opinion, gives 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 renders the participant at high risk
             from treatment complications.

         17. History of or known presence of spinal cord metastases, as determined by computed
             tomography (CT) or magnetic resonance imaging (MRI) evaluation during screening or
             prior radiographic assessments.

         18. Known CNS disease, except for treated asymptomatic CNS metastases.

         19. Known germline BRCA1/2 deleterious mutation, unless the participant is not an
             appropriate candidate for a PARP-inhibitor.

         20. Any previous systemic therapy for inoperable locally advanced or metastatic
             triple-negative adenocarcinoma of the breast.

         21. Unresolved, clinically significant toxicity from prior therapy, except for alopecia
             and Grade 1 peripheral neuropathy.

         22. Participants who have received palliative radiotherapy to peripheral sites (e.g., bone
             metastases) for pain control and whose last treatment was completed 14 days prior to
             Day 1 of Cycle 1 may be enrolled in the study if they have recovered from all acute,
             reversible effects (e.g., to Grade 1 or resolved by enrolment).

         23. Uncontrolled pleural effusion, pericardial effusion or ascites.

         24. Uncontrolled tumor-related pain.

         25. Malignancies other than breast cancer within 5 years prior to Day 1 of Cycle 1, except
             for appropriately treated carcinoma in situ of the cervix, non-melanoma skin
             carcinoma, or Stage I uterine cancer.

         26. Known hypersensitivity or contraindication to any component of the study treatments,
             including the paclitaxel excipient, macrogolglycerol ricinoleate.

         27. Grade >= 2 peripheral neuropathy.

         28. History of Type I or Type II diabetes mellitus requiring insulin.

         29. Grade >= 2 uncontrolled or untreated hypercholesterolemia or hypertriglyceridemia.

         30. History of or active inflammatory bowel disease (e.g., Crohn disease and ulcerative
             colitis) or active bowel inflammation (e.g., diverticulitis).

         31. Lung disease: pneumonitis, interstitial lung disease, idiopathic pulmonary fibrosis,
             cystic fibrosis, Aspergillosis, active tuberculosis, or history of opportunistic
             infections (pneumocystis pneumonia or cytomegalovirus pneumonia).

         32. Treatment with strong CYP3A inhibitors or strong CYP3A inducers within 2 weeks or 5
             drug-elimination half-lives, whichever is longer, prior to initiation of study drug.

         33. Prior treatment with an Akt inhibitor.

         34. Active or history of autoimmune disease or immune deficiency.

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

         36. Prior allogeneic stem cell or solid organ transplantation.

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

         38. History of severe allergic anaphylactic reactions to chimeric or humanized antibodies
             or fusion proteins.

         39. Known hypersensitivity to Chinese hamster ovary cell products or recombinant human
             antibodies.

         40. Treatment with systemic immunostimulatory agents (including, but not limited to,
             interferon and interleukin-2) within 4 weeks or 5 half-lives of the drug (whichever is
             longer) prior to initiation of study treatment.

         41. Treatment with systemic immunosuppressive medication (including, but not limited to
             corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and
             anti-tumor necrosis factor-alpha agents) within 2 weeks prior to initiation of study
             treatment, or anticipation of need for systemic immunosuppressive medication during
             the study.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Investigator-assessed Progression Free Survival (PFS)
Time Frame:Up to 76 months
Safety Issue:
Description:Defined as the time from randomisation to the first occurrence of disease progression, as determined locally according to Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1), or death from any cause, whichever occurs first.

Secondary Outcome Measures

Measure:Overall Response Rate (ORR)
Time Frame:Up to 76 months
Safety Issue:
Description:Defined as the proportion of participants with a complete response (CR) or partial response (PR) on two consecutive occasions >= 4 weeks apart, as determined by the investigator according to RECIST v1.1.
Measure:Duration of Response (DOR)
Time Frame:Up to 76 months
Safety Issue:
Description:Defined as the time from the first occurrence of a documented objective response to the first occurrence of disease progression, as determined by the investigator according to RECIST v1.1, or death from any cause, whichever occurs first.
Measure:Clinical Benefit Rate (CBR)
Time Frame:Up to 76 months
Safety Issue:
Description:Defined as the proportion of participants who have a CR, PR, or stable disease for >= 24 weeks, as determined by the investigator according to RECIST v1.1.
Measure:Mean and mean changes from baseline score in participant-reported function (role, physical)
Time Frame:Up to 76 months
Safety Issue:
Description:Assessed by EORTC QLC-C30 Selected Scales: Physical Function (Questions 1-5) and Role Function (Questions 6 and 7).
Measure:Mean and mean changes from baseline score in function in participant-reported Global Health Status (GHS)/Quality of Life (QoL) by assessment timepoint and between treatment arms
Time Frame:Up to 76 months
Safety Issue:
Description:Assessed by EORTC QLC-C30 Selected Scale: GHS/QoL (Questions 29 and 30).
Measure:Progression Free Survival (PFS) for participants with Programmed Death-Ligand 1 (PD-L1)-non-positive tumors
Time Frame:Up to 76 months
Safety Issue:
Description:Participants administered with atezolizumab in combination with ipatasertib and paclitaxel (Arm A vs. Arm B in Cohort 1).
Measure:Overall Survival (OS) for participants with PD-L1-non-positive tumors
Time Frame:Up to 76 months
Safety Issue:
Description:Participants administered with atezolizumab in combination with ipatasertib and paclitaxel (Arm A vs. Arm B in Cohort 1).
Measure:Overall Response Rate (ORR) for participants with PD-L1-non-positive tumors
Time Frame:Up to 76 months
Safety Issue:
Description:Participants administered with atezolizumab in combination with ipatasertib and paclitaxel (Arm A vs. Arm B in Cohort 1).
Measure:Progression Free Survival (PFS) for participants with PIK3CA/AKT1/PTEN-altered tumors
Time Frame:Up to 76 months
Safety Issue:
Description:Participants in experimental treatment arm will be compared with participants in control treatment arm.
Measure:Overall Survival (OS) for participants with PIK3CA/AKT1/PTEN-altered tumors
Time Frame:Up to 76 months
Safety Issue:
Description:Participants in experimental treatment arm will be compared with participants in control treatment arm.
Measure:Overall Response Rate (ORR) for participants with PIK3CA/AKT1/PTEN-altered tumors
Time Frame:Up to 76 months
Safety Issue:
Description:Participants in experimental treatment arm will be compared with participants in control treatment arm.
Measure:Duration of Response (DOR) for participants with PIK3CA/AKT1/PTEN-altered tumors
Time Frame:Up to 76 months
Safety Issue:
Description:Participants in experimental treatment arm will be compared with participants in control treatment arm.
Measure:Number of Participants with Adverse Events (AEs)
Time Frame:Up to 79 months
Safety Issue:
Description:Severity determined by the investigator according to the NCI Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0).
Measure:Plasma concentration of ipatasertib and its metabolite (G037720) (ng/mL) at specified timepoints
Time Frame:Up to 77 months
Safety Issue:
Description:
Measure:Serum concentration of atezolizumab (µg/mL) at specified timepoints
Time Frame:Up to 77 months
Safety Issue:
Description:
Measure:Level of Anti-Drug Antibodies (ADAs) (%) to Atezolizumab
Time Frame:Up to 76 months
Safety Issue:
Description:

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Hoffmann-La Roche

Trial Keywords

  • Breast Neoplasms
  • Triple Negative Breast Neoplasms
  • Neoplasms by Site
  • Neoplasms
  • Breast Diseases
  • Skin Diseases
  • Paclitaxel
  • Atezolizumab
  • Ipatasertib
  • Antibodies, Monoclonal
  • Antineoplastic Agents, Phytogenic
  • Antineoplastic Agents
  • Tubulin Modulators
  • Antimitotic Agents
  • Mitosis Modulators

Last Updated

November 22, 2019