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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT03800836




Registration number
NCT03800836
Ethics application status
Date submitted
7/01/2019
Date registered
11/01/2019
Date last updated
30/10/2024

Titles & IDs
Public 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
Scientific 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
Secondary ID [1] 0 0
2017-001957-15
Secondary ID [2] 0 0
CO40151
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Breast Cancer 0 0
Condition category
Condition code
Cancer 0 0 0 0
Breast

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Ipatasertib
Treatment: Drugs - Paclitaxel
Treatment: Drugs - Atezolizumab
Treatment: Drugs - Nab-Paclitaxel
Treatment: Drugs - AC

Experimental: Arm A1: Ipat + Atezo + Pacl - Safety 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.

Experimental: Arm A2: Ipat + Atezo + Pacl - Expansion (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.

Experimental: Arm A3: Ipat + Atezo + Pacl - Expansion (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.

Experimental: Arm B1: Ipat + Atezo + Nab-Pacl - Safety 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.

Experimental: Arm B2: Ipat + Atezo + Nab-Pacl - Expansion (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.

Experimental: Arm C1: (Ipat + Pacl) (2 weeks) + Atezo - Safety 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.

Experimental: Arm C2 (Ipat + Pacl) (2 weeks) + Atezo - Expansion (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.

Experimental: Arm D1: (Atezo + Pacl) (2 weeks) + Ipat - Safety 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.

Experimental: Arm D2: (Atezo + Pacl) (2 weeks) + Ipat - Expansion (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.

Experimental: Arm E: Ipat + Atezo - Participants (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.

Experimental: Arm F1: Ipat + Atezol + AC / Ipat + Atezo + Pacl - Safety 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.

Experimental: Arm F2: Ipat + Atezol + AC / Ipat + Atezo + Pacl - Expansion (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.

Experimental: Arm G1: Ipat + Atezol + AC / Ipat + Atezo + Pacl - Safety 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.

Experimental: Arm G2: Ipat + Atezol + AC / Ipat + Atezo + Pacl - Expansion (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.

Experimental: Arm H: Ipat + Atezo + Pacl - Participants (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.


Treatment: Drugs: Ipatasertib
Ipatasertib will be administered at a dose of 400 milligrams (mg) orally daily on Days 1-21 of each 28 day cycle for all arms except for arms F1/F2 where it will be administered at a dose of 300 milligrams (mg) orally daily for the first two cycles and 400 mg for the remaining three cycles.

Treatment: Drugs: Paclitaxel
Paclitaxel will be administered at a dose of 80 milligrams per square meter (mg/m\^2) as IV infusion on Days 1, 8, and 15 of each 28 day cycle for all arms, with the exceptions of Arms F1, F2, G1 and G2, where it will be also administered on Day 22 as well, of each 28 day cycle.

Treatment: Drugs: Atezolizumab
Atezolizumab will be administered by IV infusion at a fixed dose of 840 mg on Days 1 and 15 of each 28 day cycle for all arms, although in Arms C1/C2, it will be administered on Day 15 of Cycle 1 followed by Days 1 and 15 in subsequent cycles.

Treatment: Drugs: Nab-Paclitaxel
Nab-paclitaxel will be administered by IV infusion at a dose of 100 mg/m\^2 on Days 1, 8, and 15 of each 28 day cycle.

Treatment: Drugs: AC
AC (Doxorubicin and Cyclophosphamide) will be administered by IV infusion at 60 mg/m\^2 and 600 mg/m\^2 respectively on Days 1 and 15 of Cycles 1 and 2 for Arms F1, F2, G1 and G2.
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Cohort 1 and Cohort 4: Percentage of Participants With Objective Response (OR) as Assessed by Investigator Based on Response Evaluation Criteria in Solid Tumors (RECIST), Version (v) 1.1
Timepoint [1] 0 0
From screening up to approximately 43.6 months
Primary outcome [2] 0 0
Cohort 3: Pathological Complete Response (pCR) Rate
Timepoint [2] 0 0
2-6 weeks following last dose of study treatment (up to 69 weeks)
Primary outcome [3] 0 0
Cohort 1, Cohort 2, Cohort 3 and Cohort 4: Number of Participants With Adverse Events (AEs)
Timepoint [3] 0 0
Up until 90 days after the last dose of study treatment or until initiation of new systemic anti-cancer therapy, whichever occurs first (up to 4 years 1 month)
Secondary outcome [1] 0 0
Cohort 1 and Cohort 4: Duration of Response (DOR), as Determined by the Investigator According to RECIST v1.1
Timepoint [1] 0 0
From the date of first documented confirmed response (CR or PR) to disease progression or death due to any cause (up to approximately 43.6 months)
Secondary outcome [2] 0 0
Cohort 1 and Cohort 4: Progression-Free Survival (PFS), as Assessed by Investigator Based on RECIST v1.1
Timepoint [2] 0 0
From enrollment up to disease progression or death due to any cause whichever occurs first (up to approximately 43.6 months)
Secondary outcome [3] 0 0
Cohort 1 and Cohort 4: Overall Survival (OS)
Timepoint [3] 0 0
From enrollment up to death due to any cause (up to approximately 43.6 months).
Secondary outcome [4] 0 0
Cohort 1 and Cohort 4: Plasma Concentration of Ipatasertib
Timepoint [4] 0 0
Day 15 Cycle 1: pre-dose and 1, 2, 4 and 6 hours post-dose, Day 15 Cycle2: predose and 1, 2, 4 and 6 hours post-dose and Day 15 Cycle 3 - post dose up to - 3 hours (each cycle is of 28 days)
Secondary outcome [5] 0 0
Cohort 1 and Cohort 4: Plasma Concentration of Ipatasertib Metabolite M1 (G-037720)
Timepoint [5] 0 0
Day 15 Cycle 1 - pre-dose and 1 hour, 2 hours, 4 hours and 6 hours post-dose, Day 15 Cycle2: predose and 1 hour, 2 hours, 4 hours and 6 hours post-dose and Day 15 Cycle 3 - post dose up to - 3 hours (each cycle is of 28 days)
Secondary outcome [6] 0 0
Cohort 1 and Cohort 4: Number of Participants With Anti-Drug Antibodies (ADAs) for Atezolizumab During Study Treatment
Timepoint [6] 0 0
From baseline up to 30 days from the last dose of atezolizumab (to approximately 4 years 1.1 month)
Secondary outcome [7] 0 0
Cohort 1 and Cohort 4: Plasma Concentration of Atezolizumab
Timepoint [7] 0 0
Cycle 1 Day 1 and 15: predose and 30 mins post dose; Cycle 2: Day 1 and 15 predose, Cycle 3, 4, 8, 12, and 16 Day 1: predose; treatment discontinuation visit
Secondary outcome [8] 0 0
Cohort 1 and Cohort 4: Clinical Benefit Rate (CBR) as Assessed by Investigator Based on RECIST v1.1
Timepoint [8] 0 0
From screening up to confirmed SD or CR or PR (up to approximately 43.6 months)

Eligibility
Key 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.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
13/02/2018
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
16/03/2022
Sample size
Target
Accrual to date
Final
139
Recruitment in Australia
Recruitment state(s)
NSW,VIC
Recruitment hospital [1] 0 0
St Vincents Hospital; Cardiopulmonary transplant Ambulatory Care Dept - Darlinghurst
Recruitment hospital [2] 0 0
Austin Hospital - Heidelberg
Recruitment hospital [3] 0 0
Peter MacCallum Cancer Center - North Melbourne
Recruitment postcode(s) [1] 0 0
2010 - Darlinghurst
Recruitment postcode(s) [2] 0 0
3084 - Heidelberg
Recruitment postcode(s) [3] 0 0
3051 - North Melbourne
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
California
Country [2] 0 0
France
State/province [2] 0 0
Angers
Country [3] 0 0
France
State/province [3] 0 0
Bordeaux
Country [4] 0 0
France
State/province [4] 0 0
Dijon
Country [5] 0 0
France
State/province [5] 0 0
Paris
Country [6] 0 0
France
State/province [6] 0 0
Villejuif
Country [7] 0 0
Spain
State/province [7] 0 0
Barcelona
Country [8] 0 0
Spain
State/province [8] 0 0
Madrid
Country [9] 0 0
Spain
State/province [9] 0 0
Sevilla
Country [10] 0 0
United Kingdom
State/province [10] 0 0
London
Country [11] 0 0
United Kingdom
State/province [11] 0 0
Nottingham

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
Hoffmann-La Roche
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Clinical Trials
Address 0 0
Hoffmann-La Roche
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

No information has been provided regarding IPD availability


What supporting documents are/will be available?




Results publications and other study-related documents

No documents have been uploaded by study researchers.

Results are available at https://clinicaltrials.gov/study/NCT03800836