Trial Outcomes & Findings for Gamma-Secretase/Notch Signalling Pathway Inhibitor RO4929097 in Treating Patients With Recurrent or Progressive Glioblastoma (NCT NCT01122901)
NCT ID: NCT01122901
Last Updated: 2017-05-03
Results Overview
Time to event endpoints for Group A will be measured from the date of first dose. All patients who receive at least one dose of study drug will be included in the analysis. Time to event endpoints for Group B will be measured from the first post-surgical date (this will be considered start date of treatment). Progression defined as: \>25% increase sum of products of perpendicular diameters (bi-dimensional measurements) of enhancing lesions (over baseline (BL) if no decrease) on stable or increasing doses of corticosteroids. and/or b) Significant increase in T2/FLAIR nonenhancing lesion on stable or increasing doses of corticosteroids compared to BL scan or best response following initiation of therapy c) Any new lesion. d) Clear clinical deterioration not attributable to other causes apart from the tumor e) Failure to return for evaluation due to death or deteriorating condition.
TERMINATED
PHASE2
47 participants
At 6 months
2017-05-03
Participant Flow
Patients enrolled between April 2011 and May 2012 Patients enrolled in outpatient setting
Participant milestones
| Measure |
Group A RO4929097 PO
Patients receive gamma-secretase/Notch signalling pathway inhibitor RO4929097 PO QD on days 1-3, 8-10, 15-17, and 22-24. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
gamma-secretase/Notch signalling pathway inhibitor RO4929097: Given PO
pharmacological study: Correlative studies
|
Group B RO4929097 Pre Surgery
Patients receive gamma-secretase/Notch signalling pathway inhibitor RO4929097 PO QD on days -6 to -1. Patients undergo surgical resection on day 0. Within 30 days after surgical resection, patients receive gamma-secretase inhibitor RO4929097 as in group A.
gamma-secretase/Notch signalling pathway inhibitor RO4929097: Given PO
therapeutic conventional surgery: Undergo surgery
pharmacological study: Correlative studies
laboratory biomarker analysis: Correlative studies
|
|---|---|---|
|
Overall Study
STARTED
|
40
|
7
|
|
Overall Study
COMPLETED
|
40
|
7
|
|
Overall Study
NOT COMPLETED
|
0
|
0
|
Reasons for withdrawal
Withdrawal data not reported
Baseline Characteristics
Gamma-Secretase/Notch Signalling Pathway Inhibitor RO4929097 in Treating Patients With Recurrent or Progressive Glioblastoma
Baseline characteristics by cohort
| Measure |
Group A RO4929097 PO
n=40 Participants
Patients receive gamma-secretase/Notch signalling pathway inhibitor RO4929097 PO QD on days 1-3, 8-10, 15-17, and 22-24. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
gamma-secretase/Notch signalling pathway inhibitor RO4929097: Given PO
pharmacological study: Correlative studies
|
Group B RO4929097 Pre Surgery
n=7 Participants
Patients receive gamma-secretase/Notch signalling pathway inhibitor RO4929097 PO QD on days -6 to -1. Patients undergo surgical resection on day 0. Within 30 days after surgical resection, patients receive gamma-secretase inhibitor RO4929097 as in group A.
gamma-secretase/Notch signalling pathway inhibitor RO4929097: Given PO
therapeutic conventional surgery: Undergo surgery
pharmacological study: Correlative studies
laboratory biomarker analysis: Correlative studies
|
Total
n=47 Participants
Total of all reporting groups
|
|---|---|---|---|
|
Age, Continuous
|
58 years
n=5 Participants
|
56 years
n=7 Participants
|
57 years
n=5 Participants
|
|
Sex: Female, Male
Female
|
13 Participants
n=5 Participants
|
2 Participants
n=7 Participants
|
15 Participants
n=5 Participants
|
|
Sex: Female, Male
Male
|
27 Participants
n=5 Participants
|
5 Participants
n=7 Participants
|
32 Participants
n=5 Participants
|
|
Karnofsky Performance Status Scale
|
80 units on a scale
n=5 Participants
|
80 units on a scale
n=7 Participants
|
80 units on a scale
n=5 Participants
|
|
Debulking
Yes
|
30 Participants
n=5 Participants
|
6 Participants
n=7 Participants
|
36 Participants
n=5 Participants
|
|
Debulking
No
|
10 Participants
n=5 Participants
|
1 Participants
n=7 Participants
|
11 Participants
n=5 Participants
|
PRIMARY outcome
Timeframe: At 6 monthsTime to event endpoints for Group A will be measured from the date of first dose. All patients who receive at least one dose of study drug will be included in the analysis. Time to event endpoints for Group B will be measured from the first post-surgical date (this will be considered start date of treatment). Progression defined as: \>25% increase sum of products of perpendicular diameters (bi-dimensional measurements) of enhancing lesions (over baseline (BL) if no decrease) on stable or increasing doses of corticosteroids. and/or b) Significant increase in T2/FLAIR nonenhancing lesion on stable or increasing doses of corticosteroids compared to BL scan or best response following initiation of therapy c) Any new lesion. d) Clear clinical deterioration not attributable to other causes apart from the tumor e) Failure to return for evaluation due to death or deteriorating condition.
Outcome measures
| Measure |
Group A (Post Surgery) & Group B (Pre-surgery) RO4929097 PO
n=40 Participants
GROUP A Patients receive gamma-secretase/Notch signalling pathway inhibitor RO4929097 PO QD on days 1-3, 8-10, 15-17, and 22-24. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
gamma-secretase/Notch signalling pathway inhibitor RO4929097: Given PO
pharmacological study: Correlative studies
GROUP B Patients receive gamma-secretase/Notch signalling pathway inhibitor RO4929097 PO QD on days -6 to -1. Patients undergo surgical resection on day 0. Within 30 days after surgical resection, patients receive gamma-secretase inhibitor RO4929097 as in group A.
gamma-secretase/Notch signalling pathway inhibitor RO4929097: Given PO
therapeutic conventional surgery: Undergo surgery
pharmacological study: Correlative studies
laboratory biomarker analysis: Correlative studies
|
Group B RO4929097 Pre Surgery
n=7 Participants
Patients receive gamma-secretase/Notch signalling pathway inhibitor RO4929097 PO QD on days -6 to -1. Patients undergo surgical resection on day 0. Within 30 days after surgical resection, patients receive gamma-secretase inhibitor RO4929097 as in group A.
gamma-secretase/Notch signalling pathway inhibitor RO4929097: Given PO
therapeutic conventional surgery: Undergo surgery
pharmacological study: Correlative studies
laboratory biomarker analysis: Correlative studies
|
Group B RO4929097 Pre Surgery
Patients receive gamma-secretase/Notch signalling pathway inhibitor RO4929097 PO QD on days -6 to -1. Patients undergo surgical resection on day 0. Within 30 days after surgical resection, patients receive gamma-secretase inhibitor RO4929097 as in group A.
gamma-secretase/Notch signalling pathway inhibitor RO4929097: Given PO
therapeutic conventional surgery: Undergo surgery
pharmacological study: Correlative studies
laboratory biomarker analysis: Correlative studies
|
|---|---|---|---|
|
Overall Median Progression-free Survival (6-month PFS)
|
1.7 months
Interval 1.1 to 1.8
|
1.6 months
Interval 0.8 to 2.3
|
—
|
PRIMARY outcome
Timeframe: At time of surgeryPopulation: This outcome could not be analyzed as the n was too small. Only had 7 samples. The study was terminated prematurely by Hoffman-La Roche Company due to their decision to terminate drug supply for further development of this drug
This outcome could not be analyzed as the n was too small. The study was terminated prematurely by Hoffman-La Roche Company due to their decision to terminate drug supply for further development of this drug. All CTEP-sponsored trials using RO4929097 were closed to accrual and all patients had to be off treatment by 7/31/12.
Outcome measures
Outcome data not reported
SECONDARY outcome
Timeframe: Up to 6 months after completion of treatmentRANO: Measurable: Bidimensionally measurable lesions w/ clearly defined margins by MRI Evaluable: Unidimensionally measurable lesions, masses w/margins not clearly defined. Complete Response (CR): Complete disappearance of all measurable/evaluable disease. No new lesions. No evidence of non-evaluable disease. Patients on minimal/no steroids. Partial Response (PR): \>/= to 50% decrease under baseline in the sum of products of perpendicular diameters of all measurable lesions. No progression of evaluable disease. Responders must be on same/decreasing doses of dexamethasone. Stable/No Response: Does not qualify for CR, PR, or progression. Progression: 25% increase in the sum of products of all measurable lesions over smallest sum observed (over BL if no decrease), OR clear worsening of any evaluable disease, OR appearance of any new lesion/site, OR failure to return for evaluation due to death or deteriorating condition (unless clearly unrelated to this cancer).
Outcome measures
| Measure |
Group A (Post Surgery) & Group B (Pre-surgery) RO4929097 PO
n=40 Participants
GROUP A Patients receive gamma-secretase/Notch signalling pathway inhibitor RO4929097 PO QD on days 1-3, 8-10, 15-17, and 22-24. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
gamma-secretase/Notch signalling pathway inhibitor RO4929097: Given PO
pharmacological study: Correlative studies
GROUP B Patients receive gamma-secretase/Notch signalling pathway inhibitor RO4929097 PO QD on days -6 to -1. Patients undergo surgical resection on day 0. Within 30 days after surgical resection, patients receive gamma-secretase inhibitor RO4929097 as in group A.
gamma-secretase/Notch signalling pathway inhibitor RO4929097: Given PO
therapeutic conventional surgery: Undergo surgery
pharmacological study: Correlative studies
laboratory biomarker analysis: Correlative studies
|
Group B RO4929097 Pre Surgery
n=7 Participants
Patients receive gamma-secretase/Notch signalling pathway inhibitor RO4929097 PO QD on days -6 to -1. Patients undergo surgical resection on day 0. Within 30 days after surgical resection, patients receive gamma-secretase inhibitor RO4929097 as in group A.
gamma-secretase/Notch signalling pathway inhibitor RO4929097: Given PO
therapeutic conventional surgery: Undergo surgery
pharmacological study: Correlative studies
laboratory biomarker analysis: Correlative studies
|
Group B RO4929097 Pre Surgery
Patients receive gamma-secretase/Notch signalling pathway inhibitor RO4929097 PO QD on days -6 to -1. Patients undergo surgical resection on day 0. Within 30 days after surgical resection, patients receive gamma-secretase inhibitor RO4929097 as in group A.
gamma-secretase/Notch signalling pathway inhibitor RO4929097: Given PO
therapeutic conventional surgery: Undergo surgery
pharmacological study: Correlative studies
laboratory biomarker analysis: Correlative studies
|
|---|---|---|---|
|
Radiographic Response Rate According to the Radiographic Assessment in Neuro-Oncology Criteria (Group A) and Group (B)
Complete Response
|
1 Participants
|
0 Participants
|
—
|
|
Radiographic Response Rate According to the Radiographic Assessment in Neuro-Oncology Criteria (Group A) and Group (B)
Partial Response
|
0 Participants
|
0 Participants
|
—
|
|
Radiographic Response Rate According to the Radiographic Assessment in Neuro-Oncology Criteria (Group A) and Group (B)
Stable Disease
|
3 Participants
|
0 Participants
|
—
|
|
Radiographic Response Rate According to the Radiographic Assessment in Neuro-Oncology Criteria (Group A) and Group (B)
Progression
|
33 Participants
|
5 Participants
|
—
|
|
Radiographic Response Rate According to the Radiographic Assessment in Neuro-Oncology Criteria (Group A) and Group (B)
Not Evaluable
|
3 Participants
|
2 Participants
|
—
|
SECONDARY outcome
Timeframe: Up to 30 days after completion of study treatmentassessed by the National Cancer Institute CTCAE version 4.0 assessed if patient received at least one dose of study drug Grade 3-5 toxicities grade 3 -severe grade 4 - life threatening grade 5 - death
Outcome measures
| Measure |
Group A (Post Surgery) & Group B (Pre-surgery) RO4929097 PO
n=40 Participants
GROUP A Patients receive gamma-secretase/Notch signalling pathway inhibitor RO4929097 PO QD on days 1-3, 8-10, 15-17, and 22-24. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
gamma-secretase/Notch signalling pathway inhibitor RO4929097: Given PO
pharmacological study: Correlative studies
GROUP B Patients receive gamma-secretase/Notch signalling pathway inhibitor RO4929097 PO QD on days -6 to -1. Patients undergo surgical resection on day 0. Within 30 days after surgical resection, patients receive gamma-secretase inhibitor RO4929097 as in group A.
gamma-secretase/Notch signalling pathway inhibitor RO4929097: Given PO
therapeutic conventional surgery: Undergo surgery
pharmacological study: Correlative studies
laboratory biomarker analysis: Correlative studies
|
Group B RO4929097 Pre Surgery
n=7 Participants
Patients receive gamma-secretase/Notch signalling pathway inhibitor RO4929097 PO QD on days -6 to -1. Patients undergo surgical resection on day 0. Within 30 days after surgical resection, patients receive gamma-secretase inhibitor RO4929097 as in group A.
gamma-secretase/Notch signalling pathway inhibitor RO4929097: Given PO
therapeutic conventional surgery: Undergo surgery
pharmacological study: Correlative studies
laboratory biomarker analysis: Correlative studies
|
Group B RO4929097 Pre Surgery
Patients receive gamma-secretase/Notch signalling pathway inhibitor RO4929097 PO QD on days -6 to -1. Patients undergo surgical resection on day 0. Within 30 days after surgical resection, patients receive gamma-secretase inhibitor RO4929097 as in group A.
gamma-secretase/Notch signalling pathway inhibitor RO4929097: Given PO
therapeutic conventional surgery: Undergo surgery
pharmacological study: Correlative studies
laboratory biomarker analysis: Correlative studies
|
|---|---|---|---|
|
Number of Participants With Toxicities Associated With Study Drug (Group A and Group B)
Cognitive Disturbance gr 3
|
1 Participants
|
0 Participants
|
—
|
|
Number of Participants With Toxicities Associated With Study Drug (Group A and Group B)
Fatigue gr 3
|
1 Participants
|
0 Participants
|
—
|
|
Number of Participants With Toxicities Associated With Study Drug (Group A and Group B)
Hypophosphatemia gr 3
|
4 Participants
|
0 Participants
|
—
|
|
Number of Participants With Toxicities Associated With Study Drug (Group A and Group B)
Skin Infection gr 3
|
1 Participants
|
0 Participants
|
—
|
|
Number of Participants With Toxicities Associated With Study Drug (Group A and Group B)
AST increase gr 3
|
1 Participants
|
0 Participants
|
—
|
SECONDARY outcome
Timeframe: 2 yearstime to event endpoints for Group A will be measured from date of first dose. All patients who receive at least one dose will be included in analysis. Time to event endpoints for Group B will be measured from the first post-surgical date (this will be considered start date of treatment).
Outcome measures
| Measure |
Group A (Post Surgery) & Group B (Pre-surgery) RO4929097 PO
n=40 Participants
GROUP A Patients receive gamma-secretase/Notch signalling pathway inhibitor RO4929097 PO QD on days 1-3, 8-10, 15-17, and 22-24. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
gamma-secretase/Notch signalling pathway inhibitor RO4929097: Given PO
pharmacological study: Correlative studies
GROUP B Patients receive gamma-secretase/Notch signalling pathway inhibitor RO4929097 PO QD on days -6 to -1. Patients undergo surgical resection on day 0. Within 30 days after surgical resection, patients receive gamma-secretase inhibitor RO4929097 as in group A.
gamma-secretase/Notch signalling pathway inhibitor RO4929097: Given PO
therapeutic conventional surgery: Undergo surgery
pharmacological study: Correlative studies
laboratory biomarker analysis: Correlative studies
|
Group B RO4929097 Pre Surgery
n=7 Participants
Patients receive gamma-secretase/Notch signalling pathway inhibitor RO4929097 PO QD on days -6 to -1. Patients undergo surgical resection on day 0. Within 30 days after surgical resection, patients receive gamma-secretase inhibitor RO4929097 as in group A.
gamma-secretase/Notch signalling pathway inhibitor RO4929097: Given PO
therapeutic conventional surgery: Undergo surgery
pharmacological study: Correlative studies
laboratory biomarker analysis: Correlative studies
|
Group B RO4929097 Pre Surgery
Patients receive gamma-secretase/Notch signalling pathway inhibitor RO4929097 PO QD on days -6 to -1. Patients undergo surgical resection on day 0. Within 30 days after surgical resection, patients receive gamma-secretase inhibitor RO4929097 as in group A.
gamma-secretase/Notch signalling pathway inhibitor RO4929097: Given PO
therapeutic conventional surgery: Undergo surgery
pharmacological study: Correlative studies
laboratory biomarker analysis: Correlative studies
|
|---|---|---|---|
|
Overall Survival
|
6.6 months
Interval 5.3 to 10.5
|
6.7 months
Interval 5.1 to 12.0
|
—
|
SECONDARY outcome
Timeframe: At the time of surgeryPopulation: This outcome could not be analyzed as the n was too small. The study was terminated prematurely by Hoffman-La Roche Company due to their decision to terminate drug supply for further development of this drug.
This outcome could not be analyzed as the n was too small. The study was terminated prematurely by Hoffman-La Roche Company due to their decision to terminate drug supply for further development of this drug. All CTEP-sponsored trials using RO4929097 were closed to accrual and all patients had to be off treatment by 7/31/12.
Outcome measures
Outcome data not reported
SECONDARY outcome
Timeframe: At the time of surgeryPopulation: This outcome could not be analyzed as the n was too small. The study was terminated prematurely by Hoffman-La Roche Company due to their decision to terminate drug supply for further development of this drug.
This outcome could not be analyzed as the n was too small. The study was terminated prematurely by Hoffman-La Roche Company due to their decision to terminate drug supply for further development of this drug. All CTEP-sponsored trials using RO4929097 were closed to accrual and all patients had to be off treatment by 7/31/12.
Outcome measures
Outcome data not reported
SECONDARY outcome
Timeframe: 2 yearsTime to event endpoints for Group A will be measured from the date of first dose. All patients who receive at least one dose of study drug will be included in the analysis. Time to event endpoints for Group B will be measured from the first post-surgical date (this will be considered start date of treatment). Progression defined as: \>25% increase sum of products of perpendicular diameters (bi-dimensional measurements) of enhancing lesions (over baseline (BL) if no decrease) on stable or increasing doses of corticosteroids. and/or b) Significant increase in T2/FLAIR nonenhancing lesion on stable or increasing doses of corticosteroids compared to BL scan or best response following initiation of therapy c) Any new lesion. d) Clear clinical deterioration not attributable to other causes apart from the tumor e) Failure to return for evaluation due to death or deteriorating condition.
Outcome measures
| Measure |
Group A (Post Surgery) & Group B (Pre-surgery) RO4929097 PO
n=47 Participants
GROUP A Patients receive gamma-secretase/Notch signalling pathway inhibitor RO4929097 PO QD on days 1-3, 8-10, 15-17, and 22-24. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
gamma-secretase/Notch signalling pathway inhibitor RO4929097: Given PO
pharmacological study: Correlative studies
GROUP B Patients receive gamma-secretase/Notch signalling pathway inhibitor RO4929097 PO QD on days -6 to -1. Patients undergo surgical resection on day 0. Within 30 days after surgical resection, patients receive gamma-secretase inhibitor RO4929097 as in group A.
gamma-secretase/Notch signalling pathway inhibitor RO4929097: Given PO
therapeutic conventional surgery: Undergo surgery
pharmacological study: Correlative studies
laboratory biomarker analysis: Correlative studies
|
Group B RO4929097 Pre Surgery
n=40 Participants
Patients receive gamma-secretase/Notch signalling pathway inhibitor RO4929097 PO QD on days -6 to -1. Patients undergo surgical resection on day 0. Within 30 days after surgical resection, patients receive gamma-secretase inhibitor RO4929097 as in group A.
gamma-secretase/Notch signalling pathway inhibitor RO4929097: Given PO
therapeutic conventional surgery: Undergo surgery
pharmacological study: Correlative studies
laboratory biomarker analysis: Correlative studies
|
Group B RO4929097 Pre Surgery
n=7 Participants
Patients receive gamma-secretase/Notch signalling pathway inhibitor RO4929097 PO QD on days -6 to -1. Patients undergo surgical resection on day 0. Within 30 days after surgical resection, patients receive gamma-secretase inhibitor RO4929097 as in group A.
gamma-secretase/Notch signalling pathway inhibitor RO4929097: Given PO
therapeutic conventional surgery: Undergo surgery
pharmacological study: Correlative studies
laboratory biomarker analysis: Correlative studies
|
|---|---|---|---|
|
Progression Free Survival
|
1.7 months
Interval 1.2 to 1.8
|
1.7 months
Interval 1.1 to 1.8
|
1.6 months
Interval 0.8 to 2.3
|
Adverse Events
Group A RO4929097 PO
Group B RO4929097 Pre Surgery
Serious adverse events
Adverse event data not reported
Other adverse events
| Measure |
Group A RO4929097 PO
n=40 participants at risk
Patients receive gamma-secretase/Notch signalling pathway inhibitor RO4929097 PO QD on days 1-3, 8-10, 15-17, and 22-24. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
gamma-secretase/Notch signalling pathway inhibitor RO4929097: Given PO
pharmacological study: Correlative studies
|
Group B RO4929097 Pre Surgery
n=7 participants at risk
Patients receive gamma-secretase/Notch signalling pathway inhibitor RO4929097 PO QD on days -6 to -1. Patients undergo surgical resection on day 0. Within 30 days after surgical resection, patients receive gamma-secretase inhibitor RO4929097 as in group A.
gamma-secretase/Notch signalling pathway inhibitor RO4929097: Given PO
therapeutic conventional surgery: Undergo surgery
pharmacological study: Correlative studies
laboratory biomarker analysis: Correlative studies
|
|---|---|---|
|
Investigations
white blood cell decrease
|
7.5%
3/40 • Number of events 3 • 2 year
|
14.3%
1/7 • Number of events 1 • 2 year
|
|
Investigations
Alanine aminotransferase increase
|
7.5%
3/40 • Number of events 3 • 2 year
|
0.00%
0/7 • 2 year
|
|
Blood and lymphatic system disorders
anemia
|
7.5%
3/40 • Number of events 3 • 2 year
|
0.00%
0/7 • 2 year
|
|
Metabolism and nutrition disorders
anorexia
|
7.5%
3/40 • Number of events 3 • 2 year
|
0.00%
0/7 • 2 year
|
|
Investigations
Aspartate aminotransferase increase
|
7.5%
3/40 • Number of events 3 • 2 year
|
0.00%
0/7 • 2 year
|
|
Gastrointestinal disorders
constipation
|
10.0%
4/40 • Number of events 4 • 2 year
|
0.00%
0/7 • 2 year
|
|
Gastrointestinal disorders
diarrhea
|
7.5%
3/40 • Number of events 3 • 2 year
|
0.00%
0/7 • 2 year
|
|
General disorders
edema face
|
7.5%
3/40 • Number of events 3 • 2 year
|
0.00%
0/7 • 2 year
|
|
General disorders
fatigue
|
27.5%
11/40 • Number of events 11 • 2 year
|
14.3%
1/7 • Number of events 1 • 2 year
|
|
Investigations
electrocardiogram QT corrected interval prolonged
|
5.0%
2/40 • Number of events 2 • 2 year
|
0.00%
0/7 • 2 year
|
|
Metabolism and nutrition disorders
Hypomagnesemia
|
12.5%
5/40 • Number of events 5 • 2 year
|
0.00%
0/7 • 2 year
|
|
Investigations
platelet count decrease
|
10.0%
4/40 • Number of events 4 • 2 year
|
14.3%
1/7 • Number of events 1 • 2 year
|
|
Skin and subcutaneous tissue disorders
Pruritus
|
5.0%
2/40 • Number of events 2 • 2 year
|
0.00%
0/7 • 2 year
|
|
Gastrointestinal disorders
vomiting
|
5.0%
2/40 • Number of events 2 • 2 year
|
0.00%
0/7 • 2 year
|
|
Investigations
weight loss
|
5.0%
2/40 • Number of events 2 • 2 year
|
0.00%
0/7 • 2 year
|
Additional Information
Results disclosure agreements
- Principal investigator is a sponsor employee
- Publication restrictions are in place
Restriction type: LTE60