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A Study to Evaluate the Safety and Efficacy of Ipatasertib in Combination With Atezolizumab and Paclitaxel or Nab-Paclitaxel in Participants With Locally Advanced or Metastatic Triple-Negative Breast Cancer

NCT03800836

Description:

This is a study consisting of four cohorts in this setting. In Cohort 1, the safety and efficacy of ipatasertib (ipat) in combination with atezolizumab (atezo) and paclitaxel (pac) or nab-paclitaxel will be evaluated for participants with locally advanced or metastatic triple-negative breast cancer (TNBC) who have not previously received chemotherapy. In Cohort 2, ipatasertib and atezolizumab (with no chemotherapy), will be administered to participants with locally advanced or metastatic TNBC. In Cohort 3, the safety and efficacy of neoadjuvant ipatasertib, atezolizumab, doxorubicin and cyclophosphamide (AC) (Ipat + Atezo + AC) followed by Ipat + Atezo + Pac will be evaluated in participants with locally advanced Type 2-4 (T2-4) TNBC. In Cohort 4, the safety and efficacy of Ipat + Atezo + Pac will be evaluated in participants with PD-L1 (Programmed Death-Ligand-1) positive locally advanced or metastatic TNBC that is not amenable to resection and who have not previously received chemotherapy in the advanced setting.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: A Study to Evaluate the Safety and Efficacy of Ipatasertib in Combination With Atezolizumab and Paclitaxel or Nab-Paclitaxel in Participants With Locally Advanced or Metastatic Triple-Negative Breast Cancer
  • Official Title: A Phase Ib, Open-Label, Multicenter Study Evaluating the Safety and Efficacy of Ipatasertib in Combination With Atezolizumab and Paclitaxel or Nab-Paclitaxel in Patients With Locally Advanced or Metastatic Triple-Negative Breast Cancer

Clinical Trial IDs

  • ORG STUDY ID: CO40151
  • SECONDARY ID: 2017-001957-15
  • NCT ID: NCT03800836

Conditions

  • Breast Cancer

Interventions

DrugSynonymsArms
IpatasertibArm A1: Ipat + Atezo + Pacl
PaclitaxelArm A1: Ipat + Atezo + Pacl
AtezolizumabArm A1: Ipat + Atezo + Pacl
Nab-PaclitaxelArm B1: Ipat + Atezo + Nab-Pacl
ACArm F1: Ipat + Atezol + AC / Ipat + Atezo + Pacl

Purpose

This is a study consisting of four cohorts in this setting. In Cohort 1, the safety and efficacy of ipatasertib (ipat) in combination with atezolizumab (atezo) and paclitaxel (pac) or nab-paclitaxel will be evaluated for participants with locally advanced or metastatic triple-negative breast cancer (TNBC) who have not previously received chemotherapy. In Cohort 2, ipatasertib and atezolizumab (with no chemotherapy), will be administered to participants with locally advanced or metastatic TNBC. In Cohort 3, the safety and efficacy of neoadjuvant ipatasertib, atezolizumab, doxorubicin and cyclophosphamide (AC) (Ipat + Atezo + AC) followed by Ipat + Atezo + Pac will be evaluated in participants with locally advanced Type 2-4 (T2-4) TNBC. In Cohort 4, the safety and efficacy of Ipat + Atezo + Pac will be evaluated in participants with PD-L1 (Programmed Death-Ligand-1) positive locally advanced or metastatic TNBC that is not amenable to resection and who have not previously received chemotherapy in the advanced setting.

Trial Arms

NameTypeDescriptionInterventions
Arm A1: Ipat + Atezo + PaclExperimentalSafety Run-In (Cohort 1): Participants will receive ipatasertib orally daily on Days 1-21 of each 28 day cycle, and atezolizumab will be administered by intravenous (IV) infusion on Days 1 and 15 of each 28 day cycle. Paclitaxel will be administered by IV infusion on Days 1, 8, and 15 of each 28 day cycle. All participants in this cohort will continue to be treated until loss of clinical benefit, unacceptable toxicity, or withdrawal of consent.
  • Ipatasertib
  • Paclitaxel
  • Atezolizumab
Arm A2: Ipat + Atezo + PaclExperimentalExpansion (Cohort 1): Participants will receive ipatasertib orally daily on Days 1-21 of each 28 day cycle, and atezolizumab will be administered by intravenous (IV) infusion on Days 1 and 15 of each 28 day cycle. Paclitaxel will be administered by IV infusion on Days 1, 8, and 15 of each 28 day cycle. All participants in this cohort will continue to be treated until loss of clinical benefit, unacceptable toxicity, or withdrawal of consent.
  • Ipatasertib
  • Paclitaxel
  • Atezolizumab
Arm A3: Ipat + Atezo + PaclExperimentalExpansion (Cohort 1): Participants will receive ipatasertib orally daily on Days 1-21 of each 28 day cycle, and atezolizumab will be administered by intravenous (IV) infusion on Days 1 and 15 of each 28 day cycle. Paclitaxel will be administered by IV infusion on Days 1, 8, and 15 of each 28 day cycle. All participants in this cohort will continue to be treated until loss of clinical benefit, unacceptable toxicity, or withdrawal of consent.
  • Ipatasertib
  • Paclitaxel
  • Atezolizumab
Arm B1: Ipat + Atezo + Nab-PaclExperimentalSafety Run-In (Cohort 1): Participants will receive ipatasertib orally daily on Days 1-21 of each 28 day cycle, and atezolizumab will be administered by IV infusion on Days 1 and 15 of each 28 day cycle. Nab-paclitaxel will be administered by IV infusion on Days 1, 8, and 15 of each 28 day cycle. All participants in this cohort will continue to be treated until loss of clinical benefit, unacceptable toxicity, or withdrawal of consent.
  • Ipatasertib
  • Atezolizumab
  • Nab-Paclitaxel
Arm B2: Ipat + Atezo + Nab-PaclExperimentalExpansion (Cohort 1): Participants will receive ipatasertib orally daily on Days 1-21 of each 28 day cycle, and atezolizumab will be administered by IV infusion on Days 1 and 15 of each 28 day cycle. Nab-paclitaxel will be administered by IV infusion on Days 1, 8, and 15 of each 28 day cycle. All participants in this cohort will continue to be treated until loss of clinical benefit, unacceptable toxicity, or withdrawal of consent.
  • Ipatasertib
  • Atezolizumab
  • Nab-Paclitaxel
Arm C1: (Ipat + Pacl) (2 weeks) + AtezoExperimentalSafety Run-In (Cohort 1): Participants will receive a 2-week lead in of ipatasertib in combination with paclitaxel, followed by atezolizumab in an initial 28-day (1 cycle) period. Ipatasertib will be administered orally daily on Days 1-21, with paclitaxel administered by IV infusion on Days 1, 8 and 15. Atezolizumab will be administered by IV infusion on Day 15. In all subsequent treatment cycles, ipatasertib will be administered orally daily on Days 1-21, paclitaxel will be administered by IV infusion on Days 1, 8, and 15 and atezolizumab will be administered by IV infusion on Days 1 and 15. All participants in this cohort will continue to be treated until loss of clinical benefit, unacceptable toxicity, or withdrawal of consent.
  • Ipatasertib
  • Paclitaxel
  • Atezolizumab
Arm C2 (Ipat + Pacl) (2 weeks) + AtezoExperimentalExpansion (Cohort 1): Participants will receive a 2-week lead in of ipatasertib in combination with paclitaxel, followed by atezolizumab in an initial 28-day (1 cycle) period. Ipatasertib will be administered orally daily on Days 1-21, with paclitaxel administered by IV infusion on Days 1, 8 and 15. Atezolizumab will be administered by IV infusion on Day 15. In all subsequent treatment cycles, ipatasertib will be administered orally daily on Days 1-21, paclitaxel will be administered by IV infusion on Days 1, 8, and 15 and atezolizumab will be administered by IV infusion on Days 1 and 15. All participants in this cohort will continue to be treated until loss of clinical benefit, unacceptable toxicity, or withdrawal of consent.
  • Ipatasertib
  • Paclitaxel
  • Atezolizumab
Arm D1: (Atezo + Pacl) (2 weeks) + IpatExperimentalSafety Run-In (Cohort 1): Participants will receive a 2-week lead in of atezolizumab in combination with paclitaxel, followed by ipatasertib in an initial 28-day (1 cycle) period. Atezolizumab will be administered via IV infusion on Days 1 and 15, with paclitaxel administered by IV infusion on Days 1, 8 and 15. Ipatasertib will be administered orally daily on Days 15-21. In all subsequent treatment cycles, ipatasertib will be administered orally daily on Days 1-21, paclitaxel will be administered by IV infusion on Days 1, 8, and 15 and atezolizumab will be administered by IV infusion on Days 1 and 15. All participants in this cohort will continue to be treated until loss of clinical benefit, unacceptable toxicity, or withdrawal of consent.
  • Ipatasertib
  • Paclitaxel
  • Atezolizumab
Arm D2: (Atezo + Pacl) (2 weeks) + IpatExperimentalExpansion (Cohort 1): Participants will receive a 2-week lead in of atezolizumab in combination with paclitaxel, followed by ipatasertib in an initial 28-day (1 cycle) period. Atezolizumab will be administered via IV infusion on Days 1 and 15, with paclitaxel administered by IV infusion on Days 1, 8 and 15. Ipatasertib will be administered orally daily on Days 15-21. In all subsequent treatment cycles, ipatasertib will be administered orally daily on Days 1-21, paclitaxel will be administered by IV infusion on Days 1, 8, and 15 and atezolizumab will be administered by IV infusion on Days 1 and 15. All participants in this cohort will continue to be treated until loss of clinical benefit, unacceptable toxicity, or withdrawal of consent.
  • Ipatasertib
  • Paclitaxel
  • Atezolizumab
Arm E: Ipat + AtezoExperimentalParticipants (Cohort 2) will receive Ipatasertib orally daily on Days 1-28 of Cycle 1 (35-day cycle) and on Days 1-21 of subsequent cycles (28-day cycles). Atezolizumab will be administered by IV infusion on Days 8 and 22 of Cycle 1 and on Days 1 and 15 of subsequent cycles. All participants in this cohort will continue to be treated until loss of clinical benefit, unacceptable toxicity, or withdrawal of consent.
  • Ipatasertib
  • Atezolizumab
Arm F1: Ipat + Atezol + AC / Ipat + Atezo + PaclExperimentalSafety Run-In (Cohort 3): Participants will receive in Cycles 1 and 2 (28 day cycles), Ipatasertib orally daily on Days 1-21, Atezolizumab via IV infusion on Days 1 and 15 and AC (Doxorubicin and Cyclophosphamide) via IV infusion on Days 1 and 15. In Cycles 3-5, participants will receive Ipatasertib orally daily on Days 1-21, Atezolizumab via IV infusion on Days 1 and 15, with Paclitaxel administered by IV infusion on Days 1, 8, 15 and 22. All participants in this cohort will continue to be treated for five cycles (28-day cycles; 20 weeks) or until disease progression or unacceptable toxicity, whichever occurs first.
  • Ipatasertib
  • Paclitaxel
  • Atezolizumab
  • AC
Arm F2: Ipat + Atezol + AC / Ipat + Atezo + PaclExperimentalExpansion (Cohort 3): Participants will receive in Cycles 1 and 2 (28 day cycles), Ipatasertib orally daily on Days 1-21, Atezolizumab via IV infusion on Days 1 and 15 and AC (Doxorubicin and Cyclophosphamide) via IV infusion on Days 1 and 15. In Cycles 3-5, participants will receive Ipatasertib orally daily on Days 1-21, Atezolizumab via IV infusion on Days 1 and 15, with Paclitaxel administered by IV infusion on Days 1, 8, 15 and 22. All participants in this cohort will continue to be treated for five cycles (28-day cycles; 20 weeks) or until disease progression or unacceptable toxicity, whichever occurs first.
  • Ipatasertib
  • Paclitaxel
  • Atezolizumab
  • AC
Arm G1: Ipat + Atezol + AC / Ipat + Atezo + PaclExperimentalSafety Run-In (Cohort 3): Participants will receive in Cycles 1 and 2 (28 day cycles), Ipatasertib orally daily on Days 1-21, Atezolizumab via IV infusion on Days 1 and 15 and AC (Doxorubicin and Cyclophosphamide) via IV infusion on Days 1 and 15. In Cycles 3-5, participants will receive Ipatasertib orally daily on Days 1-21, Atezolizumab via IV infusion on Days 1 and 15, with Paclitaxel administered by IV infusion on Days 1, 8, 15 and 22. All participants in this cohort will continue to be treated for five cycles (28-day cycles; 20 weeks) or until disease progression or unacceptable toxicity, whichever occurs first.
  • Ipatasertib
  • Paclitaxel
  • Atezolizumab
  • AC
Arm G2: Ipat + Atezol + AC / Ipat + Atezo + PaclExperimentalExpansion (Cohort 3): Participants will receive in Cycles 1 and 2 (28 day cycles), Ipatasertib orally daily on Days 1-21, Atezolizumab via IV infusion on Days 1 and 15 and AC (Doxorubicin and Cyclophosphamide) via IV infusion on Days 1 and 15. In Cycles 3-5, participants will receive Ipatasertib orally daily on Days 1-21, Atezolizumab via IV infusion on Days 1 and 15, with Paclitaxel administered by IV infusion on Days 1, 8, 15 and 22. All participants in this cohort will continue to be treated for five cycles (28-day cycles; 20 weeks) or until disease progression or unacceptable toxicity, whichever occurs first.
  • Ipatasertib
  • Paclitaxel
  • Atezolizumab
  • AC
Arm H: Ipat + Atezo + PaclExperimentalParticipants (Cohort 4) will receive ipatasertib orally daily on Days 1-21 of each 28 day cycle, and atezolizumab will be administered by intravenous (IV) infusion on Days 1 and 15 of each 28 day cycle. Paclitaxel will be administered by IV infusion on Days 1, 8, and 15 of each 28 day cycle. All participants in this cohort will continue to be treated until loss of clinical benefit, unacceptable toxicity, or withdrawal of consent.
  • Ipatasertib
  • Paclitaxel
  • Atezolizumab

Eligibility Criteria

        Inclusion Criteria:

        General:

          -  Eastern Cooperative Oncology Group Performance Status of 0 or 1.

          -  Adequate hematologic and organ function.

          -  For Cohorts 1, 2 and 4: Life expectancy of at least 6 months.

          -  For men and women of child bearing potential: agreement to remain abstinent or use
             protocol defined contraceptive measures during the treatment period and for at least
             28 days after the last dose of ipatasertib, 6 months after the last dose of
             paclitaxel, nab-paclitaxel, or doxorubicin, and 12 months after the last dose of
             cyclophosphamide, and 5 months after the last dose of atezolizumab, whichever occurs
             later along with refraining from donating sperm or eggs during this same period.

        Disease-specific:

          -  For Cohorts 1, 2 and 4: histologically documented TNBC that is locally advanced or
             metastatic and is not amenable to resection with curative intent.

          -  For Cohort 2: disease progression following one or two lines of systemic therapy for
             inoperable locally advanced or metastatic TNBC.

          -  For Cohorts 1, 2 and 4: measurable disease according to RECIST v1.1 criteria.

          -  For Cohort 2: Treated brain or spinal cord metastases are allowed if participants have
             stable disease and are not on steroid treatment.

          -  For Cohort 3: histologically documented TNBC with a primary breast tumour size of > 2
             cm by at least one radiographic or clinical measurement and disease stage at
             presentation of cT2-4 cN0-3 cM0.

          -  For Cohort 3: participant agreement to undergo appropriate surgical management,
             including axillary lymph node surgery and partial or total mastectomy, after
             completion of neoadjuvant treatment.

          -  For Cohort 4: participants must have centrally confirmed PD-L1-positive tumour.

        Exclusion Criteria:

        General:

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

          -  Active infection requiring antibiotics.

          -  History of or current evidence of HIV infection.

          -  Known clinically significant history of liver disease.

          -  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
             (other than anticipated breast surgery for Cohort 3) during the course of the study.

          -  Pregnant or breastfeeding.

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

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

          -  Prior treatment with an Akt inhibitor.

        Disease-specific:

          -  For Cohorts 1 and 4: history of or known presence of brain or spinal cord metastases.

          -  For Cohorts 1 and 4: participants who have received previous systemic therapy for
             inoperable locally advanced or metastatic TNBC, including chemotherapy, immune
             checkpoint inhibitors, or targeted agents.

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

          -  Participants who have received palliative radiation treatment 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 and have recovered from all acute, reversible effects.

          -  Uncontrolled pleural effusion, pericardial effusion, or ascites.

          -  Uncontrolled tumor related complications.

          -  Uncontrolled hypercalcaemia or symptomatic hypercalcaemia requiring continued use of
             bisphosphonate therapy.

          -  Malignancies other than breast cancer within 5 years prior to Day 1 of Cycle 1.

          -  For Cohort 3, participants with the following are excluded: [1] prior history of
             invasive breast cancer; [2] prior systemic therapy for treatment and/or prevention of
             invasive breast cancer; [3] previous therapy with anthracyclines or taxanes for any
             malignancy; [4] bilateral breast cancer; [5] undergone incisional and/or excisional
             biopsy of primary tumor and/or axillary lymph nodes; [6] undergone axillary lymph node
             dissection (ALND) prior to initiation of neoadjuvant therapy; [6] history of other
             malignancy within 5 years prior to screening; [7] history of cerebrovascular accident
             within 12 months prior to initiation of study treatment; [8] cardiopulmonary
             dysfunction; [9] known allergy or hypersensitivity to the components of
             cyclophosphamide/doxorubicin formulations and filgrastim or pegfilgrastim
             formulations; [10] severe infection within 4 weeks prior to initiation of study
             treatment; [11] treatment with therapeutic oral or IV (Intravenous) antibiotics within
             2 weeks prior to initiation of study treatment and [12] prior treatment with CD137
             agonists or immune checkpoint - blockade therapies.

        Ipatasertib-specific:

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

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

          -  History of or active inflammatory bowel disease or active bowel inflammation.

          -  Clinically significant lung disease.

          -  Treatment with strong CYP3A inhibitors or strong CYP3A inducers.

        Atezolizumab-specific:

          -  Active or history of autoimmune disease or immune deficiency.

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

          -  Prior allogeneic stem cell or solid organ transplantation.

          -  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 last dose of atezolizumab.

          -  History of hypersensitivity reactions to study drug or any component of the study drug
             formulation.

          -  Treatment with systemic immunostimulatory agents and immunosuppressive medication
             treatment, or anticipation of need for systemic immunosuppressive medication during
             the course of the study.

        Paclitaxel-specific:

        - Grade >= 2 peripheral neuropathy.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Cohort 1 and Cohort 4: Percentage of Participants with Objective Response (Complete Response [CR] or Partial Response [PR]), as Assessed by Investigator Based on Response Evaluation Criteria in Solid Tumors (RECIST), Version (v) 1.1
Time Frame:Baseline up to disease progression or treatment discontinuation, whichever occurs first (to approximately 12 months)
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Cohort 1 and Cohort 4: Progression-Free Survival, as Assessed by Investigator Based on RECIST v1.1
Time Frame:Baseline up to disease progression or death due to any cause whichever occurs first (up to approximately 12 months)
Safety Issue:
Description:
Measure:Cohort 1 and Cohort 4: Percentage of Participants who have an Objective Response (Complete or Partial), or Stable Disease for at least 24 weeks, as Assessed by Investigator Based on RECIST v1.1
Time Frame:Baseline up to disease progression or death due to any cause whichever occurs first (up to approximately 12 months)
Safety Issue:
Description:
Measure:Cohort 1 and Cohort 4: Overall Survival in All Participants
Time Frame:Baseline up to disease progression or death due to any cause whichever occurs first (up to approximately 12 months)
Safety Issue:
Description:
Measure:Cohort 1 and Cohort 4: Plasma Concentration of Ipatasertib
Time Frame:At Day 15 of Cycles 1-3 (each cycle is 28 days)
Safety Issue:
Description:
Measure:Cohort 1, Cohort 3 and Cohort 4: Plasma Concentration of Ipatasertib's Metabolite (G-037720)
Time Frame:At Day 15 of Cycles 1-3 (each cycle is 28 days)
Safety Issue:
Description:
Measure:Cohort 1, Cohort 3 and Cohort 4: Presence of Anti-Drug Antibody During Study Treatment
Time Frame:At Day 1 and Day 15 of Cycle 1 and Day 1 of succeeding cycles (each cycle is 28 days)
Safety Issue:
Description:
Measure:Cohort 1, Cohort 3 and Cohort 4: Plasma Concentration of Atezolizumab
Time Frame:At Day 1 and Day 15 of Cycle 1 and Day 1 of succeeding cycles (each cycle is 28 days)
Safety Issue:
Description:
Measure:Cohort 1, Cohort 2, Cohort 3 and Cohort 4: Percentage of Participants with Adverse Events
Time Frame:Baseline up to disease progression or death due to any cause whichever occurs first (up to approximately 12 months)
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Hoffmann-La Roche

Last Updated

February 13, 2020