Trial Outcomes & Findings for TAK-228 and TAK-117 Followed by Cisplatin and Nab Paclitaxel for Metastatic Triple Negative Breast Cancer (NCT NCT03193853)

NCT ID: NCT03193853

Last Updated: 2023-08-07

Results Overview

To assess the objective response rate associated with sequential treatment of the oral combination TAK 228 and 117 followed by nab-paclitaxel plus cisplatin in metastatic TNBC. Objective response is measured as prolonged clinical benefit; clinical benefit is defined as progression free survival on study therapy for at least 6 months.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

12 participants

Primary outcome timeframe

Through study completion, up to 2 years 8 months

Results posted on

2023-08-07

Participant Flow

Two patients are not included in the results as they screen failed before begin assigned to a study group.

Participant milestones

Participant milestones
Measure	Tak + Cisplatin and Nab Paclitaxel Patients with metastatic TNBC who meet the enrollment criteria will receive TAK-228 and TAK-117 until disease progression followed by nab paclitaxel plus cisplatin for six cycles. Patients who did not progress may continue nab paclitaxel under treating physicians discretion. Tak-228 \& Tak-117: Patients will receive 4mg oral TAK-228 and 200mg oral TAK-117 tablets until disease progression. Cisplatin \& Nab Paclitaxel: following Tak-228 \& Tak-117 standard 175-220 mg/m2 nab paclitaxel plus 60-75 mg/m2 cisplatin infusion for six cycles. Patients who did not progress may continue nab paclitaxel under treating physicians discretion
Overall Study STARTED	10
Overall Study COMPLETED	4
Overall Study NOT COMPLETED	6

Reasons for withdrawal

Reasons for withdrawal
Measure	Tak + Cisplatin and Nab Paclitaxel Patients with metastatic TNBC who meet the enrollment criteria will receive TAK-228 and TAK-117 until disease progression followed by nab paclitaxel plus cisplatin for six cycles. Patients who did not progress may continue nab paclitaxel under treating physicians discretion. Tak-228 \& Tak-117: Patients will receive 4mg oral TAK-228 and 200mg oral TAK-117 tablets until disease progression. Cisplatin \& Nab Paclitaxel: following Tak-228 \& Tak-117 standard 175-220 mg/m2 nab paclitaxel plus 60-75 mg/m2 cisplatin infusion for six cycles. Patients who did not progress may continue nab paclitaxel under treating physicians discretion
Overall Study Death	6

Baseline Characteristics

TAK-228 and TAK-117 Followed by Cisplatin and Nab Paclitaxel for Metastatic Triple Negative Breast Cancer

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Tak + Cisplatin and Nab Paclitaxel n=10 Participants Patients with metastatic TNBC who meet the enrollment criteria will receive TAK-228 and TAK-117 until disease progression followed by nab paclitaxel plus cisplatin for six cycles. Patients who did not progress may continue nab paclitaxel under treating physicians discretion. Tak-228 \& Tak-117: Patients will receive oral TAK-228 and TAK-117 tablets until disease progression. Cisplatin \& Nab Paclitaxel: following Tak-228 \& Tak-117 standard nab paclitaxel plus cisplatin infusion for six cycles. Patients who did not progress may continue nab paclitaxel under treating physicians discretion
Age, Continuous	52 years n=5 Participants
Sex: Female, Male Female	10 Participants n=5 Participants
Sex: Female, Male Male	0 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	9 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants
Race (NIH/OMB) Asian	1 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	1 Participants n=5 Participants
Race (NIH/OMB) White	8 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants
Region of Enrollment United States	10 participants n=5 Participants

PRIMARY outcome

Timeframe: Through study completion, up to 2 years 8 months

Population: All participants who received at least one dose of treatment.

Outcome measures

Outcome measures
Measure	Tak + Cisplatin and Nab Paclitaxel n=10 Participants Patients with metastatic TNBC who meet the enrollment criteria will receive TAK-228 and TAK-117 until disease progression followed by nab paclitaxel plus cisplatin for six cycles. Patients who did not progress may continue nab paclitaxel under treating physicians discretion. Tak-228 \& Tak-117: Patients will receive oral TAK-228 and TAK-117 tablets until disease progression. Cisplatin \& Nab Paclitaxel: following Tak-228 \& Tak-117 standard nab paclitaxel plus cisplatin infusion for six cycles. Patients who did not progress may continue nab paclitaxel under treating physicians discretion
Efficacy (Objective Response Rate)	1 Participants

SECONDARY outcome

Timeframe: Through study completion, up to 2 years 8 months

To assess duration of response associated with sequential treatment of the oral combination Tak 228 and 117 followed by nab-paclitaxel plus cisplatin. Duration of response is measured as prolonged clinical benefit; clinical benefit is defines as progression free survival on study therapy for at least 6 months.

Outcome measures

Outcome measures
Measure	Tak + Cisplatin and Nab Paclitaxel n=1 Participants Patients with metastatic TNBC who meet the enrollment criteria will receive TAK-228 and TAK-117 until disease progression followed by nab paclitaxel plus cisplatin for six cycles. Patients who did not progress may continue nab paclitaxel under treating physicians discretion. Tak-228 \& Tak-117: Patients will receive oral TAK-228 and TAK-117 tablets until disease progression. Cisplatin \& Nab Paclitaxel: following Tak-228 \& Tak-117 standard nab paclitaxel plus cisplatin infusion for six cycles. Patients who did not progress may continue nab paclitaxel under treating physicians discretion
Efficacy (Duration of Response)	28 weeks

SECONDARY outcome

Timeframe: For up to 30 days following last dose, approximately 7 months

To assess safety associated with sequential treatment of the oral combination Tak 228 and 117 followed by nab-paclitaxel plus cisplatin

Outcome measures

Outcome measures
Measure	Tak + Cisplatin and Nab Paclitaxel n=10 Participants Patients with metastatic TNBC who meet the enrollment criteria will receive TAK-228 and TAK-117 until disease progression followed by nab paclitaxel plus cisplatin for six cycles. Patients who did not progress may continue nab paclitaxel under treating physicians discretion. Tak-228 \& Tak-117: Patients will receive oral TAK-228 and TAK-117 tablets until disease progression. Cisplatin \& Nab Paclitaxel: following Tak-228 \& Tak-117 standard nab paclitaxel plus cisplatin infusion for six cycles. Patients who did not progress may continue nab paclitaxel under treating physicians discretion
Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.0".	10 Participants

SECONDARY outcome

Timeframe: For up to 30 days following last dose, approximately 7 months

To assess safety associated with sequential treatment of the oral combination TAK 228 and TAK 117 followed by nab-paclitaxel plus cisplatin per CTCAE v4.0 criteria.

Outcome measures

Outcome measures
Measure	Tak + Cisplatin and Nab Paclitaxel n=10 Participants Patients with metastatic TNBC who meet the enrollment criteria will receive TAK-228 and TAK-117 until disease progression followed by nab paclitaxel plus cisplatin for six cycles. Patients who did not progress may continue nab paclitaxel under treating physicians discretion. Tak-228 \& Tak-117: Patients will receive oral TAK-228 and TAK-117 tablets until disease progression. Cisplatin \& Nab Paclitaxel: following Tak-228 \& Tak-117 standard nab paclitaxel plus cisplatin infusion for six cycles. Patients who did not progress may continue nab paclitaxel under treating physicians discretion
Number of Treatment-Emergent Adverse Events (Safety and Tolerability)	64 adverse events

Adverse Events

Tak + Cisplatin and Nab Paclitaxel

Serious events: 4 serious events

Other events: 10 other events

Deaths: 6 deaths

Serious adverse events

Serious adverse events
Measure	Tak + Cisplatin and Nab Paclitaxel n=10 participants at risk Patients with metastatic TNBC who meet the enrollment criteria will receive TAK-228 and TAK-117 until disease progression followed by nab paclitaxel plus cisplatin for six cycles. Patients who did not progress may continue nab paclitaxel under treating physicians discretion. Tak-228 \& Tak-117: Patients will receive oral TAK-228 and TAK-117 tablets until disease progression. Cisplatin \& Nab Paclitaxel: following Tak-228 \& Tak-117 standard nab paclitaxel plus cisplatin infusion for six cycles. Patients who did not progress may continue nab paclitaxel under treating physicians discretion
Renal and urinary disorders Renal Injury	10.0% 1/10 • Number of events 1 • For up to 30 days following last dose, approximately 7 months All AEs are recorded for up to 30 days following the last dose of study treatment, approximately 7 months
Respiratory, thoracic and mediastinal disorders Acute Respiratory Failure	10.0% 1/10 • Number of events 1 • For up to 30 days following last dose, approximately 7 months All AEs are recorded for up to 30 days following the last dose of study treatment, approximately 7 months
Vascular disorders Transient ischemic attack	10.0% 1/10 • Number of events 1 • For up to 30 days following last dose, approximately 7 months All AEs are recorded for up to 30 days following the last dose of study treatment, approximately 7 months
Respiratory, thoracic and mediastinal disorders Pleural Effusion	10.0% 1/10 • Number of events 1 • For up to 30 days following last dose, approximately 7 months All AEs are recorded for up to 30 days following the last dose of study treatment, approximately 7 months
General disorders Sepsis	10.0% 1/10 • Number of events 1 • For up to 30 days following last dose, approximately 7 months All AEs are recorded for up to 30 days following the last dose of study treatment, approximately 7 months

Other adverse events

Other adverse events
Measure	Tak + Cisplatin and Nab Paclitaxel n=10 participants at risk Patients with metastatic TNBC who meet the enrollment criteria will receive TAK-228 and TAK-117 until disease progression followed by nab paclitaxel plus cisplatin for six cycles. Patients who did not progress may continue nab paclitaxel under treating physicians discretion. Tak-228 \& Tak-117: Patients will receive oral TAK-228 and TAK-117 tablets until disease progression. Cisplatin \& Nab Paclitaxel: following Tak-228 \& Tak-117 standard nab paclitaxel plus cisplatin infusion for six cycles. Patients who did not progress may continue nab paclitaxel under treating physicians discretion
Gastrointestinal disorders Abdominal Pain	10.0% 1/10 • Number of events 1 • For up to 30 days following last dose, approximately 7 months All AEs are recorded for up to 30 days following the last dose of study treatment, approximately 7 months
Renal and urinary disorders Acute Renal Failure	10.0% 1/10 • Number of events 1 • For up to 30 days following last dose, approximately 7 months All AEs are recorded for up to 30 days following the last dose of study treatment, approximately 7 months
Skin and subcutaneous tissue disorders Alopecia	20.0% 2/10 • Number of events 2 • For up to 30 days following last dose, approximately 7 months All AEs are recorded for up to 30 days following the last dose of study treatment, approximately 7 months
Blood and lymphatic system disorders Anemia	30.0% 3/10 • Number of events 3 • For up to 30 days following last dose, approximately 7 months All AEs are recorded for up to 30 days following the last dose of study treatment, approximately 7 months
Musculoskeletal and connective tissue disorders Axilla Pain	20.0% 2/10 • Number of events 2 • For up to 30 days following last dose, approximately 7 months All AEs are recorded for up to 30 days following the last dose of study treatment, approximately 7 months
Musculoskeletal and connective tissue disorders Back Pain	40.0% 4/10 • Number of events 4 • For up to 30 days following last dose, approximately 7 months All AEs are recorded for up to 30 days following the last dose of study treatment, approximately 7 months
Infections and infestations Bacterial Vaginosis	10.0% 1/10 • Number of events 1 • For up to 30 days following last dose, approximately 7 months All AEs are recorded for up to 30 days following the last dose of study treatment, approximately 7 months
General disorders Blurred Vision	20.0% 2/10 • Number of events 2 • For up to 30 days following last dose, approximately 7 months All AEs are recorded for up to 30 days following the last dose of study treatment, approximately 7 months
Musculoskeletal and connective tissue disorders Bone Pain	10.0% 1/10 • Number of events 1 • For up to 30 days following last dose, approximately 7 months All AEs are recorded for up to 30 days following the last dose of study treatment, approximately 7 months
Respiratory, thoracic and mediastinal disorders Bronchitis	10.0% 1/10 • Number of events 1 • For up to 30 days following last dose, approximately 7 months All AEs are recorded for up to 30 days following the last dose of study treatment, approximately 7 months
Musculoskeletal and connective tissue disorders Cervicalgia	20.0% 2/10 • Number of events 2 • For up to 30 days following last dose, approximately 7 months All AEs are recorded for up to 30 days following the last dose of study treatment, approximately 7 months
Musculoskeletal and connective tissue disorders Chest Wall Pain	30.0% 3/10 • Number of events 4 • For up to 30 days following last dose, approximately 7 months All AEs are recorded for up to 30 days following the last dose of study treatment, approximately 7 months
Respiratory, thoracic and mediastinal disorders Congestion	20.0% 2/10 • Number of events 2 • For up to 30 days following last dose, approximately 7 months All AEs are recorded for up to 30 days following the last dose of study treatment, approximately 7 months
Respiratory, thoracic and mediastinal disorders Cough	40.0% 4/10 • Number of events 6 • For up to 30 days following last dose, approximately 7 months All AEs are recorded for up to 30 days following the last dose of study treatment, approximately 7 months
General disorders Decreased Appetite	10.0% 1/10 • Number of events 1 • For up to 30 days following last dose, approximately 7 months All AEs are recorded for up to 30 days following the last dose of study treatment, approximately 7 months
General disorders Dehydration	20.0% 2/10 • Number of events 2 • For up to 30 days following last dose, approximately 7 months All AEs are recorded for up to 30 days following the last dose of study treatment, approximately 7 months
Gastrointestinal disorders Diarrhea	70.0% 7/10 • Number of events 8 • For up to 30 days following last dose, approximately 7 months All AEs are recorded for up to 30 days following the last dose of study treatment, approximately 7 months
General disorders Dizziness	30.0% 3/10 • Number of events 3 • For up to 30 days following last dose, approximately 7 months All AEs are recorded for up to 30 days following the last dose of study treatment, approximately 7 months
General disorders Dry Throat	10.0% 1/10 • Number of events 1 • For up to 30 days following last dose, approximately 7 months All AEs are recorded for up to 30 days following the last dose of study treatment, approximately 7 months
General disorders Dysgeusia	20.0% 2/10 • Number of events 2 • For up to 30 days following last dose, approximately 7 months All AEs are recorded for up to 30 days following the last dose of study treatment, approximately 7 months
General disorders Dysphagia	10.0% 1/10 • Number of events 1 • For up to 30 days following last dose, approximately 7 months All AEs are recorded for up to 30 days following the last dose of study treatment, approximately 7 months
General disorders Dysphonia	10.0% 1/10 • Number of events 1 • For up to 30 days following last dose, approximately 7 months All AEs are recorded for up to 30 days following the last dose of study treatment, approximately 7 months
Respiratory, thoracic and mediastinal disorders Dyspnea	20.0% 2/10 • Number of events 2 • For up to 30 days following last dose, approximately 7 months All AEs are recorded for up to 30 days following the last dose of study treatment, approximately 7 months
General disorders Earache	20.0% 2/10 • Number of events 2 • For up to 30 days following last dose, approximately 7 months All AEs are recorded for up to 30 days following the last dose of study treatment, approximately 7 months
General disorders Fatigue	90.0% 9/10 • Number of events 9 • For up to 30 days following last dose, approximately 7 months All AEs are recorded for up to 30 days following the last dose of study treatment, approximately 7 months
General disorders Fever	40.0% 4/10 • Number of events 5 • For up to 30 days following last dose, approximately 7 months All AEs are recorded for up to 30 days following the last dose of study treatment, approximately 7 months
Skin and subcutaneous tissue disorders Folliculitis	10.0% 1/10 • Number of events 1 • For up to 30 days following last dose, approximately 7 months All AEs are recorded for up to 30 days following the last dose of study treatment, approximately 7 months
General disorders Hoarseness	20.0% 2/10 • Number of events 2 • For up to 30 days following last dose, approximately 7 months All AEs are recorded for up to 30 days following the last dose of study treatment, approximately 7 months
General disorders Hot Flashes	10.0% 1/10 • Number of events 1 • For up to 30 days following last dose, approximately 7 months All AEs are recorded for up to 30 days following the last dose of study treatment, approximately 7 months
Endocrine disorders Hyperglycemia	30.0% 3/10 • Number of events 3 • For up to 30 days following last dose, approximately 7 months All AEs are recorded for up to 30 days following the last dose of study treatment, approximately 7 months
General disorders Hyperopia	10.0% 1/10 • Number of events 1 • For up to 30 days following last dose, approximately 7 months All AEs are recorded for up to 30 days following the last dose of study treatment, approximately 7 months
Blood and lymphatic system disorders Hypokalemia	10.0% 1/10 • Number of events 1 • For up to 30 days following last dose, approximately 7 months All AEs are recorded for up to 30 days following the last dose of study treatment, approximately 7 months
Hepatobiliary disorders Ictericia	10.0% 1/10 • Number of events 1 • For up to 30 days following last dose, approximately 7 months All AEs are recorded for up to 30 days following the last dose of study treatment, approximately 7 months
General disorders Increased Forgetfulness	10.0% 1/10 • Number of events 1 • For up to 30 days following last dose, approximately 7 months All AEs are recorded for up to 30 days following the last dose of study treatment, approximately 7 months
General disorders Insomnia	30.0% 3/10 • Number of events 3 • For up to 30 days following last dose, approximately 7 months All AEs are recorded for up to 30 days following the last dose of study treatment, approximately 7 months
Musculoskeletal and connective tissue disorders Jaw Pain	10.0% 1/10 • Number of events 1 • For up to 30 days following last dose, approximately 7 months All AEs are recorded for up to 30 days following the last dose of study treatment, approximately 7 months
Musculoskeletal and connective tissue disorders Leg Cramps	30.0% 3/10 • Number of events 3 • For up to 30 days following last dose, approximately 7 months All AEs are recorded for up to 30 days following the last dose of study treatment, approximately 7 months
General disorders Lethargy	10.0% 1/10 • Number of events 1 • For up to 30 days following last dose, approximately 7 months All AEs are recorded for up to 30 days following the last dose of study treatment, approximately 7 months
Musculoskeletal and connective tissue disorders Myalgia	20.0% 2/10 • Number of events 2 • For up to 30 days following last dose, approximately 7 months All AEs are recorded for up to 30 days following the last dose of study treatment, approximately 7 months
Gastrointestinal disorders Nausea	90.0% 9/10 • Number of events 10 • For up to 30 days following last dose, approximately 7 months All AEs are recorded for up to 30 days following the last dose of study treatment, approximately 7 months
Respiratory, thoracic and mediastinal disorders Pleural Effusion	20.0% 2/10 • Number of events 2 • For up to 30 days following last dose, approximately 7 months All AEs are recorded for up to 30 days following the last dose of study treatment, approximately 7 months
Nervous system disorders Neuropathy	20.0% 2/10 • Number of events 2 • For up to 30 days following last dose, approximately 7 months All AEs are recorded for up to 30 days following the last dose of study treatment, approximately 7 months
Nervous system disorders Neuropathy in Lower Extremities	50.0% 5/10 • Number of events 5 • For up to 30 days following last dose, approximately 7 months All AEs are recorded for up to 30 days following the last dose of study treatment, approximately 7 months
Nervous system disorders Neuropathy in Upper Extremities	20.0% 2/10 • Number of events 2 • For up to 30 days following last dose, approximately 7 months All AEs are recorded for up to 30 days following the last dose of study treatment, approximately 7 months
Skin and subcutaneous tissue disorders Pruritus	10.0% 1/10 • Number of events 1 • For up to 30 days following last dose, approximately 7 months All AEs are recorded for up to 30 days following the last dose of study treatment, approximately 7 months
Skin and subcutaneous tissue disorders Rash	30.0% 3/10 • Number of events 3 • For up to 30 days following last dose, approximately 7 months All AEs are recorded for up to 30 days following the last dose of study treatment, approximately 7 months
Skin and subcutaneous tissue disorders Scalp Tenderness	10.0% 1/10 • Number of events 1 • For up to 30 days following last dose, approximately 7 months All AEs are recorded for up to 30 days following the last dose of study treatment, approximately 7 months
Musculoskeletal and connective tissue disorders Shin Pain	10.0% 1/10 • Number of events 1 • For up to 30 days following last dose, approximately 7 months All AEs are recorded for up to 30 days following the last dose of study treatment, approximately 7 months
Infections and infestations Shingles	10.0% 1/10 • Number of events 1 • For up to 30 days following last dose, approximately 7 months All AEs are recorded for up to 30 days following the last dose of study treatment, approximately 7 months
Musculoskeletal and connective tissue disorders Shoulder Pain	10.0% 1/10 • Number of events 1 • For up to 30 days following last dose, approximately 7 months All AEs are recorded for up to 30 days following the last dose of study treatment, approximately 7 months
Infections and infestations Sore Throat	10.0% 1/10 • Number of events 1 • For up to 30 days following last dose, approximately 7 months All AEs are recorded for up to 30 days following the last dose of study treatment, approximately 7 months
Gastrointestinal disorders Stomatitis	50.0% 5/10 • Number of events 5 • For up to 30 days following last dose, approximately 7 months All AEs are recorded for up to 30 days following the last dose of study treatment, approximately 7 months
Infections and infestations Strep Throat	20.0% 2/10 • Number of events 2 • For up to 30 days following last dose, approximately 7 months All AEs are recorded for up to 30 days following the last dose of study treatment, approximately 7 months
Blood and lymphatic system disorders Thrombus	10.0% 1/10 • Number of events 1 • For up to 30 days following last dose, approximately 7 months All AEs are recorded for up to 30 days following the last dose of study treatment, approximately 7 months
Ear and labyrinth disorders Tinnitus	30.0% 3/10 • Number of events 3 • For up to 30 days following last dose, approximately 7 months All AEs are recorded for up to 30 days following the last dose of study treatment, approximately 7 months
Hepatobiliary disorders Transaminitis	20.0% 2/10 • Number of events 2 • For up to 30 days following last dose, approximately 7 months All AEs are recorded for up to 30 days following the last dose of study treatment, approximately 7 months
Nervous system disorders Tremors	10.0% 1/10 • Number of events 1 • For up to 30 days following last dose, approximately 7 months All AEs are recorded for up to 30 days following the last dose of study treatment, approximately 7 months
Respiratory, thoracic and mediastinal disorders Upper Respiratory Infection	50.0% 5/10 • Number of events 5 • For up to 30 days following last dose, approximately 7 months All AEs are recorded for up to 30 days following the last dose of study treatment, approximately 7 months
Renal and urinary disorders Urinary Tract Infection	20.0% 2/10 • Number of events 3 • For up to 30 days following last dose, approximately 7 months All AEs are recorded for up to 30 days following the last dose of study treatment, approximately 7 months
Infections and infestations Viral Gastroenteritis	10.0% 1/10 • Number of events 1 • For up to 30 days following last dose, approximately 7 months All AEs are recorded for up to 30 days following the last dose of study treatment, approximately 7 months
Eye disorders Vision Changes	10.0% 1/10 • Number of events 1 • For up to 30 days following last dose, approximately 7 months All AEs are recorded for up to 30 days following the last dose of study treatment, approximately 7 months
General disorders Vitamin D Deficiency	10.0% 1/10 • Number of events 1 • For up to 30 days following last dose, approximately 7 months All AEs are recorded for up to 30 days following the last dose of study treatment, approximately 7 months
Gastrointestinal disorders Vomiting	10.0% 1/10 • Number of events 1 • For up to 30 days following last dose, approximately 7 months All AEs are recorded for up to 30 days following the last dose of study treatment, approximately 7 months
General disorders Weight Loss	20.0% 2/10 • Number of events 2 • For up to 30 days following last dose, approximately 7 months All AEs are recorded for up to 30 days following the last dose of study treatment, approximately 7 months

Additional Information

Joyce O'Shaughnessy

Baylor Scott and White Health

Phone: 214-818-8472

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place