Trial Outcomes & Findings for Phase II Trial of Alisertib (MLN8237) in Salvage Malignant Mesothelioma (NCT NCT02293005)

Last Updated: 2022-10-04

Results Overview

Patients who are free of disease progression at 4 months. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

28 participants

Primary outcome timeframe

4 months from treatment started

Results posted on

2022-10-04

Participant Flow

Recruitment Period: May 2015 - February 2017. The patients were recruited in the Thoracic clinic at MD Anderson Cancer Center.

28 participants signed consent, 2 participants inevaluable.

Participant milestones

Participant milestones
Measure	Alisertib Alisertib was administered PO at 50 mg BID for 7 days in each treatment cycle, followed by a 14-day, treatment-free period, for a 21-day cycle.
Overall Study STARTED	26
Overall Study COMPLETED	0
Overall Study NOT COMPLETED	26

Reasons for withdrawal

Reasons for withdrawal
Measure	Alisertib Alisertib was administered PO at 50 mg BID for 7 days in each treatment cycle, followed by a 14-day, treatment-free period, for a 21-day cycle.
Overall Study Adverse Event	2
Overall Study Death	4
Overall Study Lost to Follow-up	1
Overall Study Withdrawal by Subject	2
Overall Study Progression	17

Baseline Characteristics

Phase II Trial of Alisertib (MLN8237) in Salvage Malignant Mesothelioma

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Alisertib n=26 Participants Alisertib was administered PO at 50 mg BID for 7 days in each treatment cycle, followed by a 14-day, treatment-free period, for a 21-day cycle.
Age, Categorical <=18 years	0 Participants n=99 Participants
Age, Categorical Between 18 and 65 years	8 Participants n=99 Participants
Age, Categorical >=65 years	18 Participants n=99 Participants
Age, Continuous	69 years n=99 Participants
Sex: Female, Male Female	2 Participants n=99 Participants
Sex: Female, Male Male	24 Participants n=99 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=99 Participants
Race (NIH/OMB) Asian	0 Participants n=99 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=99 Participants
Race (NIH/OMB) Black or African American	3 Participants n=99 Participants
Race (NIH/OMB) White	23 Participants n=99 Participants
Race (NIH/OMB) More than one race	0 Participants n=99 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=99 Participants
Region of Enrollment United States	26 participants n=99 Participants
Number of Participants with Prior Systemic Therapies	1 Participants n=99 Participants

PRIMARY outcome

Timeframe: 4 months from treatment started

Population: 1 patient did not complete one cycle of treatment and 25 patients were evaluable for efficacy.

Outcome measures

Outcome measures
Measure	Alisertib n=25 Participants Alisertib was administered PO at 50 mg BID for 7 days in each treatment cycle, followed by a 14-day, treatment-free period, for a 21-day cycle.
Disease Control Rate at 4 Months	8 Participants

SECONDARY outcome

Timeframe: From treatment start, every 6 weeks until progression, death, withdrawal of consent or study completion an average of 25 months

Population: 1 patient did not complete one cycle of treatment and 25 patients were evaluable for efficacy.

Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.

Outcome measures

Outcome measures
Measure	Alisertib n=25 Participants Alisertib was administered PO at 50 mg BID for 7 days in each treatment cycle, followed by a 14-day, treatment-free period, for a 21-day cycle.
Overall Response Rate	1 Participants

SECONDARY outcome

Timeframe: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 35 months

Population: 1 patient did not complete one cycle of treatment and 25 patients were evaluable for efficacy.

Overall Survival is defined as the time from the date of randomization to the date of death due to any cause.

Outcome measures

Outcome measures
Measure	Alisertib n=25 Participants Alisertib was administered PO at 50 mg BID for 7 days in each treatment cycle, followed by a 14-day, treatment-free period, for a 21-day cycle.
Overall Survival	6.3 months Interval 5.7 to 11.1

SECONDARY outcome

Timeframe: From treatment start to death/progression or last follow-up, whichever come first assessed up to 25 months.

Population: 1 patient did not complete one cycle of treatment and 25 patients were evaluable for efficacy.

PFS is defined as the time from the date of randomization to the date of the first documentation of progressive disease (PD) or date of death, whichever occurs first. Progression is defined using modified Response Evaluation Criteria In Solid Tumors Criteria (mRECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions or RECIST 1.1 if mRECIST cannot be used.

Outcome measures

Outcome measures
Measure	Alisertib n=25 Participants Alisertib was administered PO at 50 mg BID for 7 days in each treatment cycle, followed by a 14-day, treatment-free period, for a 21-day cycle.
Progression Free Survival (PFS)	2.8 months Interval 1.3 to 4.0

Adverse Events

Alisertib

Serious events: 6 serious events

Other events: 26 other events

Deaths: 7 deaths

Serious adverse events

Serious adverse events
Measure	Alisertib n=26 participants at risk Alisertib was administered PO at 50 mg BID for 7 days in each treatment cycle, followed by a 14-day, treatment-free period, for a 21-day cycle.
Gastrointestinal disorders Abdominal pain	3.8% 1/26 • Number of events 1 • Deaths, Serious Adverse Events and Other (Not Including Serious) Adverse events will be captured from the time of the first protocol-specific intervention, until 30 days after the last dose of drug, unless the participant withdraws consent, through study completion an average of 25 months.
Blood and lymphatic system disorders Anemia	3.8% 1/26 • Number of events 1 • Deaths, Serious Adverse Events and Other (Not Including Serious) Adverse events will be captured from the time of the first protocol-specific intervention, until 30 days after the last dose of drug, unless the participant withdraws consent, through study completion an average of 25 months.
Gastrointestinal disorders Diarrhea	3.8% 1/26 • Number of events 1 • Deaths, Serious Adverse Events and Other (Not Including Serious) Adverse events will be captured from the time of the first protocol-specific intervention, until 30 days after the last dose of drug, unless the participant withdraws consent, through study completion an average of 25 months.
Respiratory, thoracic and mediastinal disorders Dyspnea	3.8% 1/26 • Number of events 1 • Deaths, Serious Adverse Events and Other (Not Including Serious) Adverse events will be captured from the time of the first protocol-specific intervention, until 30 days after the last dose of drug, unless the participant withdraws consent, through study completion an average of 25 months.
General disorders Fever	3.8% 1/26 • Number of events 1 • Deaths, Serious Adverse Events and Other (Not Including Serious) Adverse events will be captured from the time of the first protocol-specific intervention, until 30 days after the last dose of drug, unless the participant withdraws consent, through study completion an average of 25 months.
Infections and infestations Lung infection	7.7% 2/26 • Number of events 2 • Deaths, Serious Adverse Events and Other (Not Including Serious) Adverse events will be captured from the time of the first protocol-specific intervention, until 30 days after the last dose of drug, unless the participant withdraws consent, through study completion an average of 25 months.
Gastrointestinal disorders Mucositis oral	3.8% 1/26 • Number of events 1 • Deaths, Serious Adverse Events and Other (Not Including Serious) Adverse events will be captured from the time of the first protocol-specific intervention, until 30 days after the last dose of drug, unless the participant withdraws consent, through study completion an average of 25 months.
Respiratory, thoracic and mediastinal disorders Pulmonary hypertension	3.8% 1/26 • Number of events 1 • Deaths, Serious Adverse Events and Other (Not Including Serious) Adverse events will be captured from the time of the first protocol-specific intervention, until 30 days after the last dose of drug, unless the participant withdraws consent, through study completion an average of 25 months.
Respiratory, thoracic and mediastinal disorders Respiratory failure	3.8% 1/26 • Number of events 1 • Deaths, Serious Adverse Events and Other (Not Including Serious) Adverse events will be captured from the time of the first protocol-specific intervention, until 30 days after the last dose of drug, unless the participant withdraws consent, through study completion an average of 25 months.
Investigations White blood cell decreased	3.8% 1/26 • Number of events 1 • Deaths, Serious Adverse Events and Other (Not Including Serious) Adverse events will be captured from the time of the first protocol-specific intervention, until 30 days after the last dose of drug, unless the participant withdraws consent, through study completion an average of 25 months.

Other adverse events

Other adverse events
Measure	Alisertib n=26 participants at risk Alisertib was administered PO at 50 mg BID for 7 days in each treatment cycle, followed by a 14-day, treatment-free period, for a 21-day cycle.
Gastrointestinal disorders Abdominal pain	7.7% 2/26 • Number of events 2 • Deaths, Serious Adverse Events and Other (Not Including Serious) Adverse events will be captured from the time of the first protocol-specific intervention, until 30 days after the last dose of drug, unless the participant withdraws consent, through study completion an average of 25 months.
Investigations Alanine aminotransferase increased	7.7% 2/26 • Number of events 2 • Deaths, Serious Adverse Events and Other (Not Including Serious) Adverse events will be captured from the time of the first protocol-specific intervention, until 30 days after the last dose of drug, unless the participant withdraws consent, through study completion an average of 25 months.
Immune system disorders Allergic reaction	3.8% 1/26 • Number of events 1 • Deaths, Serious Adverse Events and Other (Not Including Serious) Adverse events will be captured from the time of the first protocol-specific intervention, until 30 days after the last dose of drug, unless the participant withdraws consent, through study completion an average of 25 months.
Skin and subcutaneous tissue disorders Alopecia	53.8% 14/26 • Number of events 15 • Deaths, Serious Adverse Events and Other (Not Including Serious) Adverse events will be captured from the time of the first protocol-specific intervention, until 30 days after the last dose of drug, unless the participant withdraws consent, through study completion an average of 25 months.
Blood and lymphatic system disorders Anemia	23.1% 6/26 • Number of events 13 • Deaths, Serious Adverse Events and Other (Not Including Serious) Adverse events will be captured from the time of the first protocol-specific intervention, until 30 days after the last dose of drug, unless the participant withdraws consent, through study completion an average of 25 months.
Metabolism and nutrition disorders Anorexia	11.5% 3/26 • Number of events 3 • Deaths, Serious Adverse Events and Other (Not Including Serious) Adverse events will be captured from the time of the first protocol-specific intervention, until 30 days after the last dose of drug, unless the participant withdraws consent, through study completion an average of 25 months.
Psychiatric disorders Anxiety	7.7% 2/26 • Number of events 2 • Deaths, Serious Adverse Events and Other (Not Including Serious) Adverse events will be captured from the time of the first protocol-specific intervention, until 30 days after the last dose of drug, unless the participant withdraws consent, through study completion an average of 25 months.
Investigations Aspartate aminotransferase increased	3.8% 1/26 • Number of events 1 • Deaths, Serious Adverse Events and Other (Not Including Serious) Adverse events will be captured from the time of the first protocol-specific intervention, until 30 days after the last dose of drug, unless the participant withdraws consent, through study completion an average of 25 months.
Musculoskeletal and connective tissue disorders Back pain	3.8% 1/26 • Number of events 1 • Deaths, Serious Adverse Events and Other (Not Including Serious) Adverse events will be captured from the time of the first protocol-specific intervention, until 30 days after the last dose of drug, unless the participant withdraws consent, through study completion an average of 25 months.
Gastrointestinal disorders Bloating	3.8% 1/26 • Number of events 1 • Deaths, Serious Adverse Events and Other (Not Including Serious) Adverse events will be captured from the time of the first protocol-specific intervention, until 30 days after the last dose of drug, unless the participant withdraws consent, through study completion an average of 25 months.
Eye disorders Blurred vision	3.8% 1/26 • Number of events 2 • Deaths, Serious Adverse Events and Other (Not Including Serious) Adverse events will be captured from the time of the first protocol-specific intervention, until 30 days after the last dose of drug, unless the participant withdraws consent, through study completion an average of 25 months.
Cardiac disorders Chest pain - cardiac	3.8% 1/26 • Number of events 1 • Deaths, Serious Adverse Events and Other (Not Including Serious) Adverse events will be captured from the time of the first protocol-specific intervention, until 30 days after the last dose of drug, unless the participant withdraws consent, through study completion an average of 25 months.
Psychiatric disorders Confusion	3.8% 1/26 • Number of events 1 • Deaths, Serious Adverse Events and Other (Not Including Serious) Adverse events will be captured from the time of the first protocol-specific intervention, until 30 days after the last dose of drug, unless the participant withdraws consent, through study completion an average of 25 months.
Gastrointestinal disorders Constipation	19.2% 5/26 • Number of events 8 • Deaths, Serious Adverse Events and Other (Not Including Serious) Adverse events will be captured from the time of the first protocol-specific intervention, until 30 days after the last dose of drug, unless the participant withdraws consent, through study completion an average of 25 months.
Respiratory, thoracic and mediastinal disorders Cough	15.4% 4/26 • Number of events 4 • Deaths, Serious Adverse Events and Other (Not Including Serious) Adverse events will be captured from the time of the first protocol-specific intervention, until 30 days after the last dose of drug, unless the participant withdraws consent, through study completion an average of 25 months.
Investigations Creatinine increased	3.8% 1/26 • Number of events 1 • Deaths, Serious Adverse Events and Other (Not Including Serious) Adverse events will be captured from the time of the first protocol-specific intervention, until 30 days after the last dose of drug, unless the participant withdraws consent, through study completion an average of 25 months.
Psychiatric disorders Depression	3.8% 1/26 • Number of events 1 • Deaths, Serious Adverse Events and Other (Not Including Serious) Adverse events will be captured from the time of the first protocol-specific intervention, until 30 days after the last dose of drug, unless the participant withdraws consent, through study completion an average of 25 months.
Gastrointestinal disorders Diarrhea	19.2% 5/26 • Number of events 5 • Deaths, Serious Adverse Events and Other (Not Including Serious) Adverse events will be captured from the time of the first protocol-specific intervention, until 30 days after the last dose of drug, unless the participant withdraws consent, through study completion an average of 25 months.
Skin and subcutaneous tissue disorders Dry skin	3.8% 1/26 • Number of events 1 • Deaths, Serious Adverse Events and Other (Not Including Serious) Adverse events will be captured from the time of the first protocol-specific intervention, until 30 days after the last dose of drug, unless the participant withdraws consent, through study completion an average of 25 months.
Respiratory, thoracic and mediastinal disorders Dyspnea	7.7% 2/26 • Number of events 2 • Deaths, Serious Adverse Events and Other (Not Including Serious) Adverse events will be captured from the time of the first protocol-specific intervention, until 30 days after the last dose of drug, unless the participant withdraws consent, through study completion an average of 25 months.
Injury, poisoning and procedural complications Fall	3.8% 1/26 • Number of events 1 • Deaths, Serious Adverse Events and Other (Not Including Serious) Adverse events will be captured from the time of the first protocol-specific intervention, until 30 days after the last dose of drug, unless the participant withdraws consent, through study completion an average of 25 months.
General disorders Fatigue	42.3% 11/26 • Number of events 12 • Deaths, Serious Adverse Events and Other (Not Including Serious) Adverse events will be captured from the time of the first protocol-specific intervention, until 30 days after the last dose of drug, unless the participant withdraws consent, through study completion an average of 25 months.
General disorders Fever	3.8% 1/26 • Number of events 1 • Deaths, Serious Adverse Events and Other (Not Including Serious) Adverse events will be captured from the time of the first protocol-specific intervention, until 30 days after the last dose of drug, unless the participant withdraws consent, through study completion an average of 25 months.
Gastrointestinal disorders Gastrointestinal disorders - (Other), specify	3.8% 1/26 • Number of events 1 • Deaths, Serious Adverse Events and Other (Not Including Serious) Adverse events will be captured from the time of the first protocol-specific intervention, until 30 days after the last dose of drug, unless the participant withdraws consent, through study completion an average of 25 months.
General disorders General disorders and administration site conditions - (Other), specify	11.5% 3/26 • Number of events 6 • Deaths, Serious Adverse Events and Other (Not Including Serious) Adverse events will be captured from the time of the first protocol-specific intervention, until 30 days after the last dose of drug, unless the participant withdraws consent, through study completion an average of 25 months.
Musculoskeletal and connective tissue disorders Generalized muscle weakness	3.8% 1/26 • Number of events 1 • Deaths, Serious Adverse Events and Other (Not Including Serious) Adverse events will be captured from the time of the first protocol-specific intervention, until 30 days after the last dose of drug, unless the participant withdraws consent, through study completion an average of 25 months.
Psychiatric disorders Hallucinations	3.8% 1/26 • Number of events 1 • Deaths, Serious Adverse Events and Other (Not Including Serious) Adverse events will be captured from the time of the first protocol-specific intervention, until 30 days after the last dose of drug, unless the participant withdraws consent, through study completion an average of 25 months.
Nervous system disorders Headache	3.8% 1/26 • Number of events 1 • Deaths, Serious Adverse Events and Other (Not Including Serious) Adverse events will be captured from the time of the first protocol-specific intervention, until 30 days after the last dose of drug, unless the participant withdraws consent, through study completion an average of 25 months.
Nervous system disorders Hypersomnia	3.8% 1/26 • Number of events 1 • Deaths, Serious Adverse Events and Other (Not Including Serious) Adverse events will be captured from the time of the first protocol-specific intervention, until 30 days after the last dose of drug, unless the participant withdraws consent, through study completion an average of 25 months.
Metabolism and nutrition disorders Hypokalemia	7.7% 2/26 • Number of events 2 • Deaths, Serious Adverse Events and Other (Not Including Serious) Adverse events will be captured from the time of the first protocol-specific intervention, until 30 days after the last dose of drug, unless the participant withdraws consent, through study completion an average of 25 months.
Psychiatric disorders Insomnia	3.8% 1/26 • Number of events 1 • Deaths, Serious Adverse Events and Other (Not Including Serious) Adverse events will be captured from the time of the first protocol-specific intervention, until 30 days after the last dose of drug, unless the participant withdraws consent, through study completion an average of 25 months.
Investigations Lymphocyte count decreased	3.8% 1/26 • Number of events 1 • Deaths, Serious Adverse Events and Other (Not Including Serious) Adverse events will be captured from the time of the first protocol-specific intervention, until 30 days after the last dose of drug, unless the participant withdraws consent, through study completion an average of 25 months.
Gastrointestinal disorders Mucositis oral	26.9% 7/26 • Number of events 9 • Deaths, Serious Adverse Events and Other (Not Including Serious) Adverse events will be captured from the time of the first protocol-specific intervention, until 30 days after the last dose of drug, unless the participant withdraws consent, through study completion an average of 25 months.
Musculoskeletal and connective tissue disorders Musculoskeletal and connective tissue disorder - Specify (Other)	3.8% 1/26 • Number of events 1 • Deaths, Serious Adverse Events and Other (Not Including Serious) Adverse events will be captured from the time of the first protocol-specific intervention, until 30 days after the last dose of drug, unless the participant withdraws consent, through study completion an average of 25 months.
Musculoskeletal and connective tissue disorders Myalgia	3.8% 1/26 • Number of events 1 • Deaths, Serious Adverse Events and Other (Not Including Serious) Adverse events will be captured from the time of the first protocol-specific intervention, until 30 days after the last dose of drug, unless the participant withdraws consent, through study completion an average of 25 months.
Gastrointestinal disorders Nausea	26.9% 7/26 • Number of events 10 • Deaths, Serious Adverse Events and Other (Not Including Serious) Adverse events will be captured from the time of the first protocol-specific intervention, until 30 days after the last dose of drug, unless the participant withdraws consent, through study completion an average of 25 months.
Investigations Neutrophil count decreased	11.5% 3/26 • Number of events 5 • Deaths, Serious Adverse Events and Other (Not Including Serious) Adverse events will be captured from the time of the first protocol-specific intervention, until 30 days after the last dose of drug, unless the participant withdraws consent, through study completion an average of 25 months.
General disorders Non-cardiac chest pain	3.8% 1/26 • Number of events 2 • Deaths, Serious Adverse Events and Other (Not Including Serious) Adverse events will be captured from the time of the first protocol-specific intervention, until 30 days after the last dose of drug, unless the participant withdraws consent, through study completion an average of 25 months.
Gastrointestinal disorders Oral pain	7.7% 2/26 • Number of events 2 • Deaths, Serious Adverse Events and Other (Not Including Serious) Adverse events will be captured from the time of the first protocol-specific intervention, until 30 days after the last dose of drug, unless the participant withdraws consent, through study completion an average of 25 months.
Investigations Platelet count decreased	19.2% 5/26 • Number of events 7 • Deaths, Serious Adverse Events and Other (Not Including Serious) Adverse events will be captured from the time of the first protocol-specific intervention, until 30 days after the last dose of drug, unless the participant withdraws consent, through study completion an average of 25 months.
Reproductive system and breast disorders Reproductive system and breast disorders - (Other), specify	3.8% 1/26 • Number of events 1 • Deaths, Serious Adverse Events and Other (Not Including Serious) Adverse events will be captured from the time of the first protocol-specific intervention, until 30 days after the last dose of drug, unless the participant withdraws consent, through study completion an average of 25 months.
Infections and infestations Sinusitis	3.8% 1/26 • Number of events 1 • Deaths, Serious Adverse Events and Other (Not Including Serious) Adverse events will be captured from the time of the first protocol-specific intervention, until 30 days after the last dose of drug, unless the participant withdraws consent, through study completion an average of 25 months.
Skin and subcutaneous tissue disorders Skin and subcutaneous tissue disorders - (Other), specify	7.7% 2/26 • Number of events 2 • Deaths, Serious Adverse Events and Other (Not Including Serious) Adverse events will be captured from the time of the first protocol-specific intervention, until 30 days after the last dose of drug, unless the participant withdraws consent, through study completion an average of 25 months.
Nervous system disorders Somnolence	15.4% 4/26 • Number of events 5 • Deaths, Serious Adverse Events and Other (Not Including Serious) Adverse events will be captured from the time of the first protocol-specific intervention, until 30 days after the last dose of drug, unless the participant withdraws consent, through study completion an average of 25 months.
Vascular disorders Thromboembolic event	3.8% 1/26 • Number of events 1 • Deaths, Serious Adverse Events and Other (Not Including Serious) Adverse events will be captured from the time of the first protocol-specific intervention, until 30 days after the last dose of drug, unless the participant withdraws consent, through study completion an average of 25 months.
Infections and infestations Upper respiratory infection	3.8% 1/26 • Number of events 1 • Deaths, Serious Adverse Events and Other (Not Including Serious) Adverse events will be captured from the time of the first protocol-specific intervention, until 30 days after the last dose of drug, unless the participant withdraws consent, through study completion an average of 25 months.
Ear and labyrinth disorders Vertigo	3.8% 1/26 • Number of events 1 • Deaths, Serious Adverse Events and Other (Not Including Serious) Adverse events will be captured from the time of the first protocol-specific intervention, until 30 days after the last dose of drug, unless the participant withdraws consent, through study completion an average of 25 months.
Gastrointestinal disorders Vomiting	19.2% 5/26 • Number of events 7 • Deaths, Serious Adverse Events and Other (Not Including Serious) Adverse events will be captured from the time of the first protocol-specific intervention, until 30 days after the last dose of drug, unless the participant withdraws consent, through study completion an average of 25 months.
Investigations Weight loss	3.8% 1/26 • Number of events 1 • Deaths, Serious Adverse Events and Other (Not Including Serious) Adverse events will be captured from the time of the first protocol-specific intervention, until 30 days after the last dose of drug, unless the participant withdraws consent, through study completion an average of 25 months.
Investigations White blood cell decreased	7.7% 2/26 • Number of events 3 • Deaths, Serious Adverse Events and Other (Not Including Serious) Adverse events will be captured from the time of the first protocol-specific intervention, until 30 days after the last dose of drug, unless the participant withdraws consent, through study completion an average of 25 months.

Additional Information

Dr. Anne Tsao, MD- VP, Academic Affairs, CAO Office

UT MD Anderson Cancer Center

Phone: (713) 792-6363

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place