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

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ClinicalTrials.gov Identifier: NCT04177108
Recruitment Status : Recruiting
First Posted : November 26, 2019
Last Update Posted : November 26, 2019
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Triple-Negative Breast Cancer Drug: Atezolizumab Drug: Ipatasertib Drug: Paclitaxel Drug: Placebo for Atezolizumab Drug: Placebo for Ipatasertib Phase 3

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 1155 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
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.
Estimated Study Start Date : December 18, 2019
Estimated Primary Completion Date : October 10, 2025
Estimated Study Completion Date : October 10, 2025

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arm Intervention/treatment
Experimental: Cohort 1 Arm A
PD-L1 Non-Positive Participants receiving Paclitaxel, Atezolizumab and Ipatasertib. Participants will be randomised in a 1:1:1 ratio.
Drug: Atezolizumab
Atezolizumab will be administered to participants by intravenous (IV) infusion at a fixed dose of 840 mg on Days 1 and 15 of each 28-day cycle until unacceptable toxicity.

Drug: Ipatasertib
Ipatasertib will be administered to participants at a starting dose of 400 mg QD PO (one tablet a day orally) for 21 days of each 28-day cycle on Days 1 - 21 unless held for management of adverse events.

Drug: Paclitaxel
Paclitaxel will be administered to participants at a starting dose of 80 mg/m^2 by IV infusion for 3 of 4 weeks on Days 1, 8, and 15 of each 28-day cycle unless deferred to Day 22 because of an adverse event.

Experimental: Cohort 1 Arm B
PD-L1 Non-Positive Participants receiving Paclitaxel, Ipatasertib and Placebo for Atezolizumab. Participants will be randomised in a 1:1:1 ratio.
Drug: Ipatasertib
Ipatasertib will be administered to participants at a starting dose of 400 mg QD PO (one tablet a day orally) for 21 days of each 28-day cycle on Days 1 - 21 unless held for management of adverse events.

Drug: Paclitaxel
Paclitaxel will be administered to participants at a starting dose of 80 mg/m^2 by IV infusion for 3 of 4 weeks on Days 1, 8, and 15 of each 28-day cycle unless deferred to Day 22 because of an adverse event.

Drug: Placebo for Atezolizumab
Placebo will be administered to participants at a fixed dose of 840 mg IV infusion for Atezolizumab on Days 1 and 15 of each 28-day cycle until unacceptable toxicity.

Active Comparator: Cohort 1 Arm C
PD-L1 Non-Positive Participants receiving Paclitaxel, Placebo for Ipatasertib and Placebo for Atezolizumab. Participants will be randomised in a 1:1:1 ratio.
Drug: Paclitaxel
Paclitaxel will be administered to participants at a starting dose of 80 mg/m^2 by IV infusion for 3 of 4 weeks on Days 1, 8, and 15 of each 28-day cycle unless deferred to Day 22 because of an adverse event.

Drug: Placebo for Atezolizumab
Placebo will be administered to participants at a fixed dose of 840 mg IV infusion for Atezolizumab on Days 1 and 15 of each 28-day cycle until unacceptable toxicity.

Drug: Placebo for Ipatasertib
Placebo will be administered to participants at a starting dose of 400 mg QD PO (one tablet a day orally) for Ipatasertib for 21 days of each 28-day cycle on Days 1 - 21 unless held for management of adverse events.

Experimental: Cohort 2 Arm A
PD-L1 Positive Participants receiving Paclitaxel, Atezolizumab and Ipatasertib. Participants will be randomised in a 1:1 ratio.
Drug: Atezolizumab
Atezolizumab will be administered to participants by intravenous (IV) infusion at a fixed dose of 840 mg on Days 1 and 15 of each 28-day cycle until unacceptable toxicity.

Drug: Ipatasertib
Ipatasertib will be administered to participants at a starting dose of 400 mg QD PO (one tablet a day orally) for 21 days of each 28-day cycle on Days 1 - 21 unless held for management of adverse events.

Drug: Paclitaxel
Paclitaxel will be administered to participants at a starting dose of 80 mg/m^2 by IV infusion for 3 of 4 weeks on Days 1, 8, and 15 of each 28-day cycle unless deferred to Day 22 because of an adverse event.

Active Comparator: Cohort 2 Arm B
PD-L1 Positive Participants receiving Paclitaxel, Atezolizumab and Placebo for Ipatasertib. Participants will be randomised in a 1:1 ratio.
Drug: Atezolizumab
Atezolizumab will be administered to participants by intravenous (IV) infusion at a fixed dose of 840 mg on Days 1 and 15 of each 28-day cycle until unacceptable toxicity.

Drug: Paclitaxel
Paclitaxel will be administered to participants at a starting dose of 80 mg/m^2 by IV infusion for 3 of 4 weeks on Days 1, 8, and 15 of each 28-day cycle unless deferred to Day 22 because of an adverse event.

Drug: Placebo for Ipatasertib
Placebo will be administered to participants at a starting dose of 400 mg QD PO (one tablet a day orally) for Ipatasertib for 21 days of each 28-day cycle on Days 1 - 21 unless held for management of adverse events.




Primary Outcome Measures :
  1. Investigator-assessed Progression Free Survival (PFS) [ Time Frame: Up to 76 months ]
    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.

  2. Overall Survival (OS) [ Time Frame: Up to 76 months ]
    Defined as the time from randomisation to death from any cause.


Secondary Outcome Measures :
  1. Overall Response Rate (ORR) [ Time Frame: Up to 76 months ]
    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.

  2. Duration of Response (DOR) [ Time Frame: Up to 76 months ]
    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.

  3. Clinical Benefit Rate (CBR) [ Time Frame: Up to 76 months ]
    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.

  4. Mean and mean changes from baseline score in participant-reported function (role, physical) [ Time Frame: Up to 76 months ]
    Assessed by EORTC QLC-C30 Selected Scales: Physical Function (Questions 1-5) and Role Function (Questions 6 and 7).

  5. 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 ]
    Assessed by EORTC QLC-C30 Selected Scale: GHS/QoL (Questions 29 and 30).

  6. Progression Free Survival (PFS) for participants with Programmed Death-Ligand 1 (PD-L1)-non-positive tumors [ Time Frame: Up to 76 months ]
    Participants administered with atezolizumab in combination with ipatasertib and paclitaxel (Arm A vs. Arm B in Cohort 1).

  7. Overall Survival (OS) for participants with PD-L1-non-positive tumors [ Time Frame: Up to 76 months ]
    Participants administered with atezolizumab in combination with ipatasertib and paclitaxel (Arm A vs. Arm B in Cohort 1).

  8. Overall Response Rate (ORR) for participants with PD-L1-non-positive tumors [ Time Frame: Up to 76 months ]
    Participants administered with atezolizumab in combination with ipatasertib and paclitaxel (Arm A vs. Arm B in Cohort 1).

  9. Progression Free Survival (PFS) for participants with PIK3CA/AKT1/PTEN-altered tumors [ Time Frame: Up to 76 months ]
    Participants in experimental treatment arm will be compared with participants in control treatment arm.

  10. Overall Survival (OS) for participants with PIK3CA/AKT1/PTEN-altered tumors [ Time Frame: Up to 76 months ]
    Participants in experimental treatment arm will be compared with participants in control treatment arm.

  11. Overall Response Rate (ORR) for participants with PIK3CA/AKT1/PTEN-altered tumors [ Time Frame: Up to 76 months ]
    Participants in experimental treatment arm will be compared with participants in control treatment arm.

  12. Duration of Response (DOR) for participants with PIK3CA/AKT1/PTEN-altered tumors [ Time Frame: Up to 76 months ]
    Participants in experimental treatment arm will be compared with participants in control treatment arm.

  13. Number of Participants with Adverse Events (AEs) [ Time Frame: Up to 79 months ]
    Severity determined by the investigator according to the NCI Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0).

  14. Plasma concentration of ipatasertib and its metabolite (G037720) (ng/mL) at specified timepoints [ Time Frame: Up to 77 months ]
  15. Serum concentration of atezolizumab (µg/mL) at specified timepoints [ Time Frame: Up to 77 months ]
  16. Level of Anti-Drug Antibodies (ADAs) (%) to Atezolizumab [ Time Frame: Up to 76 months ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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

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): NCT04177108


Contacts
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Contact: Reference Study ID: CO41101 http://www.roche.com/about_roche/roche_worldwide.htm 888-662-6728 (U.S. and Canada) global-roche-genentech-trials@gene.com

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Sponsors and Collaborators
Hoffmann-La Roche
Investigators
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Study Director: Clinical Trials Hoffmann-La Roche

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Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT04177108     History of Changes
Other Study ID Numbers: CO41101
2019-000810-12 ( EudraCT Number )
First Posted: November 26, 2019    Key Record Dates
Last Update Posted: November 26, 2019
Last Verified: November 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: "Qualified researchers may request access to individual patient level data through the clinical study data request platform (www.clinicalstudydatarequest.com). Further details on Roche's criteria for eligible studies are available here (https://clinicalstudydatarequest.com/Study-Sponsors/Study-Sponsors-Roche.aspx). For further details on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here (https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm)."

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Hoffmann-La Roche:
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
Additional relevant MeSH terms:
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Breast Neoplasms
Triple Negative Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Paclitaxel
Albumin-Bound Paclitaxel
Atezolizumab
Antineoplastic Agents
Antibodies, Monoclonal
Antineoplastic Agents, Phytogenic
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Immunologic Factors
Physiological Effects of Drugs