Trial Outcomes & Findings for CPX-351 in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome (NCT NCT02019069)
NCT ID: NCT02019069
Last Updated: 2019-01-22
Results Overview
The response rate was determined as the sum of complete response calculated by adding the total complete response (CR) and complete response with incomplete count recovery (CRi). The outcome is reported as the total number without dispersion. * CR = less than 5% blasts; no blasts with auer rods; and no persistence of extramedullary disease, with blood count recovery to platelets ≥ 100,000/uL and ANC \> 1000/uL, with transfusion independence. * CRi = all the parameters for CR, but platelets \< 100,000/uL and/or ANC ≤ 1000/uL.
COMPLETED
PHASE2
11 participants
Day 42
2019-01-22
Participant Flow
Participant milestones
| Measure |
Liposomal Cytarabine-daunorubicin CPX-351
* 1st INDUCTION: Patients receive liposomal cytarabine-daunorubicin CPX-351 IV at a dose of 65 units/m2/day over 90 minutes on days 1, 3, and 5.
* 2nd INDUCTION: Patients receive liposomal cytarabine-daunorubicin CPX-351 IV a dose of 65 units/m2/day over 90 minutes on days 1 and 3.
* CONSOLIDATION: Beginning on day 28, patients receive liposomal cytarabine-daunorubicin CPX-351 IV a dose of 65 units/m2/day over 90 minutes on days 1 and 3.
liposomal cytarabine-daunorubicin CPX-351: Given IV
|
|---|---|
|
Overall Study
STARTED
|
11
|
|
Overall Study
COMPLETED
|
11
|
|
Overall Study
NOT COMPLETED
|
0
|
Reasons for withdrawal
Withdrawal data not reported
Baseline Characteristics
CPX-351 in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome
Baseline characteristics by cohort
| Measure |
Liposomal Cytarabine-daunorubicin CPX-351
n=11 Participants
* 1st INDUCTION: Patients receive liposomal cytarabine-daunorubicin CPX-351 IV at a dose of 65 units/m2/day over 90 minutes on days 1, 3, and 5.
* 2nd INDUCTION: Patients receive liposomal cytarabine-daunorubicin CPX-351 IV a dose of 65 units/m2/day over 90 minutes on days 1 and 3.
* CONSOLIDATION: Beginning on day 28, patients receive liposomal cytarabine-daunorubicin CPX-351 IV a dose of 65 units/m2/day over 90 minutes on days 1 and 3.
liposomal cytarabine-daunorubicin CPX-351: Given IV
|
|---|---|
|
Age, Categorical
<=18 years
|
0 Participants
n=5 Participants
|
|
Age, Categorical
Between 18 and 65 years
|
0 Participants
n=5 Participants
|
|
Age, Categorical
>=65 years
|
11 Participants
n=5 Participants
|
|
Age, Continuous
|
74 years
STANDARD_DEVIATION 4.9 • n=5 Participants
|
|
Sex: Female, Male
Female
|
2 Participants
n=5 Participants
|
|
Sex: Female, Male
Male
|
9 Participants
n=5 Participants
|
|
Ethnicity (NIH/OMB)
Hispanic or Latino
|
2 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
|
0 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
|
2 Participants
n=5 Participants
|
|
Region of Enrollment
United States
|
11 participants
n=5 Participants
|
PRIMARY outcome
Timeframe: Day 42The response rate was determined as the sum of complete response calculated by adding the total complete response (CR) and complete response with incomplete count recovery (CRi). The outcome is reported as the total number without dispersion. * CR = less than 5% blasts; no blasts with auer rods; and no persistence of extramedullary disease, with blood count recovery to platelets ≥ 100,000/uL and ANC \> 1000/uL, with transfusion independence. * CRi = all the parameters for CR, but platelets \< 100,000/uL and/or ANC ≤ 1000/uL.
Outcome measures
| Measure |
Liposomal Cytarabine-daunorubicin CPX-351
n=11 Participants
* 1st INDUCTION: Patients receive liposomal cytarabine-daunorubicin CPX-351 IV at a dose of 65 units/m2/day over 90 minutes on days 1, 3, and 5.
* 2nd INDUCTION: Patients receive liposomal cytarabine-daunorubicin CPX-351 IV a dose of 65 units/m2/day over 90 minutes on days 1 and 3.
* CONSOLIDATION: Beginning on day 28, patients receive liposomal cytarabine-daunorubicin CPX-351 IV a dose of 65 units/m2/day over 90 minutes on days 1 and 3.
liposomal cytarabine-daunorubicin CPX-351: Given IV
|
|---|---|
|
Response Rate (RR)
|
3 Participants
|
SECONDARY outcome
Timeframe: Day 42Complete response (CR) with incomplete count recovery (CRi) was determined as the number of participants who achieved CRi after induction therapy. The outcome is reported as the total number or participants without dispersion. * CR = less than 5% blasts; no blasts with auer rods; and no persistence of extramedullary disease, with blood count recovery to platelets ≥ 100,000/uL and ANC \> 1000/uL, with transfusion independence. * CRi = all the parameters for CR, but platelets \< 100,000/uL and/or ANC ≤ 1000/uL.
Outcome measures
| Measure |
Liposomal Cytarabine-daunorubicin CPX-351
n=11 Participants
* 1st INDUCTION: Patients receive liposomal cytarabine-daunorubicin CPX-351 IV at a dose of 65 units/m2/day over 90 minutes on days 1, 3, and 5.
* 2nd INDUCTION: Patients receive liposomal cytarabine-daunorubicin CPX-351 IV a dose of 65 units/m2/day over 90 minutes on days 1 and 3.
* CONSOLIDATION: Beginning on day 28, patients receive liposomal cytarabine-daunorubicin CPX-351 IV a dose of 65 units/m2/day over 90 minutes on days 1 and 3.
liposomal cytarabine-daunorubicin CPX-351: Given IV
|
|---|---|
|
Complete Response With Incomplete Count Recovery (CRi)
|
1 Participants
|
SECONDARY outcome
Timeframe: Day 42Complete response (CR) was determined the number of participants who achieved CR by Day 42 after induction treatment. The outcome is reported as the total number of participants without dispersion. • CR = less than 5% blasts; no blasts with auer rods; and no persistence of extramedullary disease, with blood count recovery to platelets ≥ 100,000/uL and ANC \> 1000/uL, with transfusion independence.
Outcome measures
| Measure |
Liposomal Cytarabine-daunorubicin CPX-351
n=11 Participants
* 1st INDUCTION: Patients receive liposomal cytarabine-daunorubicin CPX-351 IV at a dose of 65 units/m2/day over 90 minutes on days 1, 3, and 5.
* 2nd INDUCTION: Patients receive liposomal cytarabine-daunorubicin CPX-351 IV a dose of 65 units/m2/day over 90 minutes on days 1 and 3.
* CONSOLIDATION: Beginning on day 28, patients receive liposomal cytarabine-daunorubicin CPX-351 IV a dose of 65 units/m2/day over 90 minutes on days 1 and 3.
liposomal cytarabine-daunorubicin CPX-351: Given IV
|
|---|---|
|
Complete Response (CR)
|
2 Participants
|
SECONDARY outcome
Timeframe: Up to 1 yearDuration of remission (DOR) was assessed as the length of time from documented complete response (CR) or complete response with incomplete count recovery (CRi) until documented lost of response, relapse, or death. The outcome is reported as the median with full range. * CR = less than 5% blasts; no blasts with auer rods; and no persistence of extramedullary disease, with blood count recovery to platelets ≥ 100,000/uL and ANC \> 1000/uL, with transfusion independence. * CRi = all the parameters for CR, but platelets \< 100,000/uL and/or ANC ≤ 1000/uL. For patients remaining alive, duration of remission (DOR) is reported as the length of time from documented complete response (CR) or complete response with incomplete count recovery (CRi) until the most recent assessment.
Outcome measures
| Measure |
Liposomal Cytarabine-daunorubicin CPX-351
n=11 Participants
* 1st INDUCTION: Patients receive liposomal cytarabine-daunorubicin CPX-351 IV at a dose of 65 units/m2/day over 90 minutes on days 1, 3, and 5.
* 2nd INDUCTION: Patients receive liposomal cytarabine-daunorubicin CPX-351 IV a dose of 65 units/m2/day over 90 minutes on days 1 and 3.
* CONSOLIDATION: Beginning on day 28, patients receive liposomal cytarabine-daunorubicin CPX-351 IV a dose of 65 units/m2/day over 90 minutes on days 1 and 3.
liposomal cytarabine-daunorubicin CPX-351: Given IV
|
|---|---|
|
Duration of Remission (DOR) Following Induction With CPX-351
|
185 days
Interval 25.0 to 329.0
|
SECONDARY outcome
Timeframe: At 12 monthsOverall survival (OS) was assessed as the number of participants remaining alive 12 months, starting from date of entry into trial. The outcome is reported as the number of participants (without dispersion).
Outcome measures
| Measure |
Liposomal Cytarabine-daunorubicin CPX-351
n=11 Participants
* 1st INDUCTION: Patients receive liposomal cytarabine-daunorubicin CPX-351 IV at a dose of 65 units/m2/day over 90 minutes on days 1, 3, and 5.
* 2nd INDUCTION: Patients receive liposomal cytarabine-daunorubicin CPX-351 IV a dose of 65 units/m2/day over 90 minutes on days 1 and 3.
* CONSOLIDATION: Beginning on day 28, patients receive liposomal cytarabine-daunorubicin CPX-351 IV a dose of 65 units/m2/day over 90 minutes on days 1 and 3.
liposomal cytarabine-daunorubicin CPX-351: Given IV
|
|---|---|
|
Overall Survival (OS)
|
1 Participants
|
SECONDARY outcome
Timeframe: 30 daysEarly induction mortality was assessed as the number of participants who died within 30 days of completing the 1st cycle of CPX-351 (1st induction). The outcome is reported as the number of participants without dispersion.
Outcome measures
| Measure |
Liposomal Cytarabine-daunorubicin CPX-351
n=11 Participants
* 1st INDUCTION: Patients receive liposomal cytarabine-daunorubicin CPX-351 IV at a dose of 65 units/m2/day over 90 minutes on days 1, 3, and 5.
* 2nd INDUCTION: Patients receive liposomal cytarabine-daunorubicin CPX-351 IV a dose of 65 units/m2/day over 90 minutes on days 1 and 3.
* CONSOLIDATION: Beginning on day 28, patients receive liposomal cytarabine-daunorubicin CPX-351 IV a dose of 65 units/m2/day over 90 minutes on days 1 and 3.
liposomal cytarabine-daunorubicin CPX-351: Given IV
|
|---|---|
|
Early Induction Mortality (Day 30 After 1st Induction)
|
2 Participants
|
SECONDARY outcome
Timeframe: 60 daysMortality at Day 60 after 1st induction was assessed as the number of participants who died within 60 days of completing the 1st cycle of CPX-351 (1st induction). The outcome is reported as the number of participants without dispersion.
Outcome measures
| Measure |
Liposomal Cytarabine-daunorubicin CPX-351
n=11 Participants
* 1st INDUCTION: Patients receive liposomal cytarabine-daunorubicin CPX-351 IV at a dose of 65 units/m2/day over 90 minutes on days 1, 3, and 5.
* 2nd INDUCTION: Patients receive liposomal cytarabine-daunorubicin CPX-351 IV a dose of 65 units/m2/day over 90 minutes on days 1 and 3.
* CONSOLIDATION: Beginning on day 28, patients receive liposomal cytarabine-daunorubicin CPX-351 IV a dose of 65 units/m2/day over 90 minutes on days 1 and 3.
liposomal cytarabine-daunorubicin CPX-351: Given IV
|
|---|---|
|
Mortality at Day 60 After 1st Induction
|
3 Participants
|
SECONDARY outcome
Timeframe: Up to 4 weeks after completion of treatmentSerious adverse events per participant were assessed as serious adverse events per 21CFR§312.32 that were Grade 3 or greater, and independent of relationship to CPX-351. The outcome is reported as the number of participants that experienced any defined SAE, a number without dispersion.
Outcome measures
| Measure |
Liposomal Cytarabine-daunorubicin CPX-351
n=11 Participants
* 1st INDUCTION: Patients receive liposomal cytarabine-daunorubicin CPX-351 IV at a dose of 65 units/m2/day over 90 minutes on days 1, 3, and 5.
* 2nd INDUCTION: Patients receive liposomal cytarabine-daunorubicin CPX-351 IV a dose of 65 units/m2/day over 90 minutes on days 1 and 3.
* CONSOLIDATION: Beginning on day 28, patients receive liposomal cytarabine-daunorubicin CPX-351 IV a dose of 65 units/m2/day over 90 minutes on days 1 and 3.
liposomal cytarabine-daunorubicin CPX-351: Given IV
|
|---|---|
|
Participants Experiencing of Serious Adverse Events
|
5 Participants
|
SECONDARY outcome
Timeframe: Up to 4 weeks after completion of treatmentPopulation: Per protocol, the outcome only includes SAEs that are Grade 3 or greater. Adverse events that were Grade 2 or less, (eg, Grade 2 event with hospitalization) are not included.
Serious adverse events were assessed as serious adverse events per 21CFR§312.32 that were Grade 3 or greater, and independent of relationship to CPX-351. The outcome is reported as the total number of the defined SAEs, a number without dispersion.
Outcome measures
| Measure |
Liposomal Cytarabine-daunorubicin CPX-351
n=11 Participants
* 1st INDUCTION: Patients receive liposomal cytarabine-daunorubicin CPX-351 IV at a dose of 65 units/m2/day over 90 minutes on days 1, 3, and 5.
* 2nd INDUCTION: Patients receive liposomal cytarabine-daunorubicin CPX-351 IV a dose of 65 units/m2/day over 90 minutes on days 1 and 3.
* CONSOLIDATION: Beginning on day 28, patients receive liposomal cytarabine-daunorubicin CPX-351 IV a dose of 65 units/m2/day over 90 minutes on days 1 and 3.
liposomal cytarabine-daunorubicin CPX-351: Given IV
|
|---|---|
|
Serious Adverse Events
|
8 Adverse events
|
Adverse Events
Liposomal Cytarabine-daunorubicin CPX-351
Serious adverse events
| Measure |
Liposomal Cytarabine-daunorubicin CPX-351
n=11 participants at risk
* 1st INDUCTION: Patients receive liposomal cytarabine-daunorubicin CPX-351 IV at a dose of 65 units/m2/day over 90 minutes on days 1, 3, and 5.
* 2nd INDUCTION: Patients receive liposomal cytarabine-daunorubicin CPX-351 IV a dose of 65 units/m2/day over 90 minutes on days 1 and 3.
* CONSOLIDATION: Beginning on day 28, patients receive liposomal cytarabine-daunorubicin CPX-351 IV a dose of 65 units/m2/day over 90 minutes on days 1 and 3.
liposomal cytarabine-daunorubicin CPX-351: Given IV
|
|---|---|
|
Respiratory, thoracic and mediastinal disorders
Pneumonia
|
18.2%
2/11 • Number of events 2 • Up to 4 weeks after completion of treatment]
|
|
Respiratory, thoracic and mediastinal disorders
Adult repiratory distress syndrome (ARDS)
|
9.1%
1/11 • Number of events 1 • Up to 4 weeks after completion of treatment]
|
|
Cardiac disorders
Cardio-pulmonary arrest
|
9.1%
1/11 • Number of events 1 • Up to 4 weeks after completion of treatment]
|
|
Blood and lymphatic system disorders
Febrile neutropenia
|
36.4%
4/11 • Number of events 5 • Up to 4 weeks after completion of treatment]
|
|
Respiratory, thoracic and mediastinal disorders
Respiratory failure
|
9.1%
1/11 • Number of events 1 • Up to 4 weeks after completion of treatment]
|
|
General disorders
Chills
|
9.1%
1/11 • Number of events 1 • Up to 4 weeks after completion of treatment]
|
|
Blood and lymphatic system disorders
Anemia
|
9.1%
1/11 • Number of events 1 • Up to 4 weeks after completion of treatment]
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms - Other, Acute myelogenous leukemia
|
9.1%
1/11 • Number of events 1 • Up to 4 weeks after completion of treatment]
|
Other adverse events
| Measure |
Liposomal Cytarabine-daunorubicin CPX-351
n=11 participants at risk
* 1st INDUCTION: Patients receive liposomal cytarabine-daunorubicin CPX-351 IV at a dose of 65 units/m2/day over 90 minutes on days 1, 3, and 5.
* 2nd INDUCTION: Patients receive liposomal cytarabine-daunorubicin CPX-351 IV a dose of 65 units/m2/day over 90 minutes on days 1 and 3.
* CONSOLIDATION: Beginning on day 28, patients receive liposomal cytarabine-daunorubicin CPX-351 IV a dose of 65 units/m2/day over 90 minutes on days 1 and 3.
liposomal cytarabine-daunorubicin CPX-351: Given IV
|
|---|---|
|
Blood and lymphatic system disorders
Blood and lymphatic system disorders, other - clot in cheek
|
9.1%
1/11 • Number of events 1 • Up to 4 weeks after completion of treatment]
|
|
Blood and lymphatic system disorders
Febrile neutropenia
|
72.7%
8/11 • Number of events 8 • Up to 4 weeks after completion of treatment]
|
|
Blood and lymphatic system disorders
Thrombotic thrombocytopenic purpura
|
18.2%
2/11 • Number of events 2 • Up to 4 weeks after completion of treatment]
|
|
Cardiac disorders
Atrial fibrillation
|
9.1%
1/11 • Number of events 1 • Up to 4 weeks after completion of treatment]
|
|
Cardiac disorders
Cardiac disorders, other - tachycardia
|
9.1%
1/11 • Number of events 1 • Up to 4 weeks after completion of treatment]
|
|
Cardiac disorders
Sinus tachycardia
|
9.1%
1/11 • Number of events 1 • Up to 4 weeks after completion of treatment]
|
|
Eye disorders
Eye disorders, other - eye itching
|
9.1%
1/11 • Number of events 1 • Up to 4 weeks after completion of treatment]
|
|
Eye disorders
Papilledema
|
9.1%
1/11 • Number of events 1 • Up to 4 weeks after completion of treatment]
|
|
Gastrointestinal disorders
Abdominal pain
|
27.3%
3/11 • Number of events 3 • Up to 4 weeks after completion of treatment]
|
|
Gastrointestinal disorders
Colitis
|
27.3%
3/11 • Number of events 3 • Up to 4 weeks after completion of treatment]
|
|
Gastrointestinal disorders
Constipation
|
36.4%
4/11 • Number of events 4 • Up to 4 weeks after completion of treatment]
|
|
Gastrointestinal disorders
Diarrhea
|
63.6%
7/11 • Number of events 7 • Up to 4 weeks after completion of treatment]
|
|
Gastrointestinal disorders
Mucositis oral
|
54.5%
6/11 • Number of events 6 • Up to 4 weeks after completion of treatment]
|
|
Gastrointestinal disorders
Nausea
|
9.1%
1/11 • Number of events 1 • Up to 4 weeks after completion of treatment]
|
|
Gastrointestinal disorders
Rectal hemorrhage
|
9.1%
1/11 • Number of events 1 • Up to 4 weeks after completion of treatment]
|
|
General disorders
Pain, hip
|
9.1%
1/11 • Number of events 1 • Up to 4 weeks after completion of treatment]
|
|
General disorders
Pain, leg
|
9.1%
1/11 • Number of events 1 • Up to 4 weeks after completion of treatment]
|
|
General disorders
Fatigue
|
9.1%
1/11 • Number of events 1 • Up to 4 weeks after completion of treatment]
|
|
General disorders
Fever
|
36.4%
4/11 • Number of events 4 • Up to 4 weeks after completion of treatment]
|
|
Infections and infestations
Lung infection
|
18.2%
2/11 • Number of events 2 • Up to 4 weeks after completion of treatment]
|
|
Investigations
Alanine aminotransferase increased
|
18.2%
2/11 • Number of events 2 • Up to 4 weeks after completion of treatment]
|
|
Investigations
Investigations, other - fluid overload
|
9.1%
1/11 • Number of events 1 • Up to 4 weeks after completion of treatment]
|
|
Metabolism and nutrition disorders
Hepatobiliary disorders, other - hyperbilirubinemia
|
9.1%
1/11 • Number of events 1 • Up to 4 weeks after completion of treatment]
|
|
Metabolism and nutrition disorders
Anorexia (decreased food consumption)
|
9.1%
1/11 • Number of events 1 • Up to 4 weeks after completion of treatment]
|
|
Metabolism and nutrition disorders
Hypertriglyceridemia
|
9.1%
1/11 • Number of events 1 • Up to 4 weeks after completion of treatment]
|
|
Musculoskeletal and connective tissue disorders
Bone pain
|
9.1%
1/11 • Number of events 1 • Up to 4 weeks after completion of treatment]
|
|
Musculoskeletal and connective tissue disorders
Musculoskeletal and connective tissue disorder, other - broken leg
|
9.1%
1/11 • Number of events 1 • Up to 4 weeks after completion of treatment]
|
|
Nervous system disorders
Brachial plexopathy
|
9.1%
1/11 • Number of events 1 • Up to 4 weeks after completion of treatment]
|
|
Nervous system disorders
Dizziness
|
18.2%
2/11 • Number of events 2 • Up to 4 weeks after completion of treatment]
|
|
Nervous system disorders
Headache
|
9.1%
1/11 • Number of events 1 • Up to 4 weeks after completion of treatment]
|
|
Nervous system disorders
Peripheral motor neuropathy
|
9.1%
1/11 • Number of events 1 • Up to 4 weeks after completion of treatment]
|
|
Psychiatric disorders
Hallucinations
|
36.4%
4/11 • Number of events 4 • Up to 4 weeks after completion of treatment]
|
|
Renal and urinary disorders
Hematuria
|
27.3%
3/11 • Number of events 3 • Up to 4 weeks after completion of treatment]
|
|
Renal and urinary disorders
Renal and urinary disorders, other - urinary discomfort
|
9.1%
1/11 • Number of events 1 • Up to 4 weeks after completion of treatment]
|
|
Respiratory, thoracic and mediastinal disorders
Aspiration
|
9.1%
1/11 • Number of events 1 • Up to 4 weeks after completion of treatment]
|
|
Respiratory, thoracic and mediastinal disorders
Cough
|
27.3%
3/11 • Number of events 3 • Up to 4 weeks after completion of treatment]
|
|
Respiratory, thoracic and mediastinal disorders
Epistaxis (nose bleed)
|
9.1%
1/11 • Number of events 1 • Up to 4 weeks after completion of treatment]
|
|
Respiratory, thoracic and mediastinal disorders
Hypoxia
|
9.1%
1/11 • Number of events 1 • Up to 4 weeks after completion of treatment]
|
|
Respiratory, thoracic and mediastinal disorders
Respiratory, thoracic and mediastinal disorders, other - chest tightness
|
9.1%
1/11 • Number of events 1 • Up to 4 weeks after completion of treatment]
|
|
Respiratory, thoracic and mediastinal disorders
Pneumothorax
|
9.1%
1/11 • Number of events 1 • Up to 4 weeks after completion of treatment]
|
|
Skin and subcutaneous tissue disorders
Rash
|
27.3%
3/11 • Number of events 3 • Up to 4 weeks after completion of treatment]
|
|
Skin and subcutaneous tissue disorders
Skin and subcutaneous tissue disorders, other - multiple subcutaneous nodules
|
9.1%
1/11 • Number of events 1 • Up to 4 weeks after completion of treatment]
|
|
Vascular disorders
Thromboembolic event
|
9.1%
1/11 • Number of events 1 • Up to 4 weeks after completion of treatment]
|
Additional Information
Results disclosure agreements
- Principal investigator is a sponsor employee
- Publication restrictions are in place