Study of MLN8237 in Combination With Irinotecan and Temozolomide
Sponsor
New Approaches to Neuroblastoma Therapy Consortium (Other)
Overall Status
Completed
CT.gov ID
NCT01601535
Collaborator
(none)
54
13
1
74.8
4.2
0.1
Study Details
Study Description
Brief Summary
The goal of the first part of this clinical trial (Phase I portion) is to study the side effects, drug breakdown (pharmacokinetics), and dosing of the drug MLN8237 when added to standard chemotherapy drugs, irinotecan and temozolomide.
The goal of the second part of this clinical trial (Phase II portion) is to learn how many children and young adults show improvements in their neuroblastoma when treated with the combination of MLN8237, irinotecan, and temozolomide.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 1/Phase 2 |
Detailed Description
The Aurora A kinase has been shown to play an important role in neuroblastoma growth. Inhibition of Aurora A kinase activity attenuates the growth of neuroblastoma cells. MLN8237 is a selective small molecule inhibitor of Aurora A kinase that has completed pediatric single-agent phase I testing, as well as stage 1 phase 2 testing in patients with Neuroblastoma. MLN8237 showed activity against the NCI-sponsored Pediatric Preclinical Testing Program neuroblastoma in vivo panel that exceeded the activity level observed with chemotherapy agents routinely used in the treatment of neuroblastoma. Additional in vitro and in vivo studies have shown that Aurora A kinase inhibitors result in enhanced cytotoxicity when used in combination with chemotherapy. Irinotecan and temozolomide is a commonly used salvage regimen for patients with relapsed or refractory neuroblastoma. This combination has a modest objective response rate (16%) and is well-tolerated, suggesting that it will provide a useful platform for the study of novel compounds in combination with chemotherapy. Preclinical studies demonstrate marked enhancement of anti-neuroblastoma activity with the addition of MLN8237 to irinotecan and temozolomide. This study therefore evaluates the tolerability and activity of MLN8237 in combination with irinotecan and temozolomide in children with refractory or relapsed neuroblastoma. Patients receive irinotecan (50 mg/m2/dose IV) and temozolomide (100 mg/m2/dose orally) once daily for 5 days along with MLN8237 orally once daily for 7 days. The doses of irinotecan and temozolomide will be fixed and the dose of MLN8237 will be dose-escalated. In the phase I portion of the study, the primary aims are to determine the recommended phase II doses of this combination, describe the toxicity of this combination, and characterize the pharmacokinetic profile of MLN8237 and irinotecan when used in combination. In the phase II portion of the study, the primary aim is to determine the objective response rate of this combination in patients with relapsed or refractory neuroblastoma. With Amendment 5, the tolerability and pharmacokinetics of an MLN8237 oral solution will be evaluated. Optional correlative studies will evaluate UGT1A1 polymorphisms as predictors of toxicity and archival tumor tissue Aurora A expression as a predictor of response with this combination.
Study Design
Study Type:
Interventional
Actual Enrollment
:
54 participants
Intervention Model:
Sequential Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Phase I/II Study of MLN8237 in Combination With Irinotecan and Temozolomide for Patients With Relapsed or Refractory Neuroblastoma
Study Start Date
:
May 1, 2012
Actual Primary Completion Date
:
Jul 25, 2018
Actual Study Completion Date
:
Jul 25, 2018
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Treatment Every course will be 21 days. MLN8237 will be administered orally daily starting on day 1 through day 7. Irinotecan will be administered intravenously during each course on study day 1 through day 5. Temozolomide will be administered orally during each course on study day 1 through day 5. |
Drug: MLN8237
Every course will be 21 days. MLN8237 will be administered orally daily starting on day 1 through day 7.
Drug: Irinotecan
Irinotecan will be administered intravenously during each course on study day 1 through day 5.
Other Names:
Drug: Temozolomide
Temozolomide will be administered orally during each course on study day 1 through day 5.
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Maximum Tolerated Dose (MTD) When Given Together With Fixed Doses of Irinotecan and Temozolomide in Children and Young Adults With Relapsed or Refractory Neuroblastoma [21 days, from study day 1]
The MTD was the highest dose level tested at which fewer than two of six patients had first course DLT. Hematologic DLT was defined as grade 4 neutropenia for more than 7 days, need for platelet transfusion for a platelet count of less than 20,000/mL twice within a 7-day period, or greater than 14-day delay in the start of a subsequent course because of neutropenia or thrombocytopenia. Nonhematologic DLT was defined as any nonhematologic toxicity that delayed the start of a subsequent cycle by more than 14 days or any grade ≥3 toxicity with the exception of the following grade 3 toxicities: nausea, vomiting, anorexia, or dehydration resolving to grade ≤ 2 within 72 hours; increase in hepatic transaminase or electrolyte abnormality resolving to grade ≤ 1 within 7 days; diarrhea persisting for less than 72 hours; fever; infection; or febrile neutropenia. DLT definitions included only toxicities deemed at least possibly related to therapy.
- Dose Limiting Toxicity (DLT) Data Associated With the Determination of the Recommended Phase 2 Dose [21 days, from study day 1]
The MTD was the highest dose level tested at which fewer than two of six patients had first course DLT. Hematologic DLT was defined as grade 4 neutropenia for more than 7 days, need for platelet transfusion for a platelet count of less than 20,000/mL twice within a 7-day period, or greater than 14-day delay in the start of a subsequent course because of neutropenia or thrombocytopenia. Nonhematologic DLT was defined as any nonhematologic toxicity that delayed the start of a subsequent cycle by more than 14 days or any grade ≥3 toxicity with the exception of the following grade 3 toxicities: nausea, vomiting, anorexia, or dehydration resolving to grade ≤ 2 within 72 hours; increase in hepatic transaminase or electrolyte abnormality resolving to grade ≤ 1 within 7 days; diarrhea persisting for less than 72 hours; fever; infection; or febrile neutropenia. DLT definitions included only toxicities deemed at least possibly related to therapy.
- Pharmacokinetics When Given Together With Fixed Doses of Irinotecan and Temozolomide in Children and Young Adults With Relapsed or Refractory Neuroblastoma: Alisertib Day 4 Trough, Day 5 Trough and Cmax [1st week of cycle 1]
Outcomes included Alisertib, irinotecan, APC, SN-38, and SN-38G. APC, SN-38, and SN-38G are metabolites of irinotecan.
- Pharmacokinetics When Given Together With Fixed Doses of Irinotecan and Temozolomide in Children and Young Adults With Relapsed or Refractory Neuroblastoma: Alisertib Tmax and Half-life [1st week of cycle 1]
Outcomes included Alisertib, irinotecan, APC, SN-38, and SN-38G. APC, SN-38, and SN-38G are metabolites of irinotecan.
- Pharmacokinetics When Given Together With Fixed Doses of Irinotecan and Temozolomide in Children and Young Adults With Relapsed or Refractory Neuroblastoma: Alisertib AUC [1st week of cycle 1]
Outcomes included Alisertib, irinotecan, APC, SN-38, and SN-38G. APC, SN-38, and SN-38G are metabolites of irinotecan.
- Pharmacokinetics When Given Together With Fixed Doses of Irinotecan and Temozolomide in Children and Young Adults With Relapsed or Refractory Neuroblastoma: Irinotecan Cmax, APC Cmax, SN-38 Cmax, and SN-38G Cmax [1st week of cycle 1]
Outcomes included Alisertib, irinotecan, APC, SN-38, and SN-38G. APC, SN-38, and SN-38G are metabolites of irinotecan.
- Pharmacokinetics When Given Together With Fixed Doses of Irinotecan and Temozolomide in Children and Young Adults With Relapsed or Refractory Neuroblastoma: Irinotecan AUC, APC AUC, SN-38 AUC, and SN-38G AUC [1st week of cycle 1]
Outcomes included Alisertib, irinotecan, APC, SN-38, and SN-38G. APC, SN-38, and SN-38G are metabolites of irinotecan.
- Pharmacokinetics When Given Together With Fixed Doses of Irinotecan and Temozolomide in Children and Young Adults With Relapsed or Refractory Neuroblastoma: Irinotecan Clearance [1st week of cycle 1]
Outcomes included Alisertib, irinotecan, APC, SN-38, and SN-38G. APC, SN-38, and SN-38G are metabolites of irinotecan.
- Response Rate for Patients With Relapsed or Refractory Neuroblastoma Treated With MLN8237, Irinotecan, and Temozolomide at the Identified MTD [Cycles repeated every 21 days for up to 34 cycles.]
Response was graded according to version 1.2 of the NANT response criteria that classifies patients as having one of the following overall response categories based upon underlying response at soft tissue sites, MIBG positive sites, and bone marrow disease: complete response (CR); CR with minimal residual disease (CR-MRD); partial response (PR); minor response (MR); stable disease (SD); and progressive disease (PD). These criteria utilize RECIST criteria for measurable tumors, Curie score for MIBG scan response, and bone marrow (BM) morphology. BM response was graded as CR (required two time points to confirm), CR unconfirmed (one time point only), CR-MRD (bone marrow involvement < 5% at study entry with negative follow-up biopsies), SD, or PD. Patients with at least SD or better underwent central review of MIBG scans, CT scans, and bone marrow pathology slides. Overall responses of CR, CR-MRD, or PR were considered objective responses.
Secondary Outcome Measures
- Aurora A Expression [From date of study enrollment to the date of progression or withdrawal from the study, up to 34 cycles (about 2 years).]
To explore whether MYCN status and markers of expression of Aurora A in archival tumor tissue are associated with the antitumor activity of the combination of MLN8237, irinotecan, and temozolomide
- UGT1A1 Genotype [Day 7 of cycle 1]
To explore whether UGT1A1 genotype is associated with toxicity in children with refractory neuroblastoma treated with the combination of MLN8237, irinotecan, and temozolomide
- AURKA Genotype [Day 7 of cycle 1]
To explore whether AURKA genotype is associated with antitumor activity in children with refractory neuroblastoma treated with the combination of MLN8237, irinotecan, and temozolomide.
- One Year Progression Free Survival Rate [1 Years after completion of study]
To determine the progression free survival rates for patients with relapsed or refractory neuroblastoma treated with MLN8237, irinotecan, and temozolomide at the identified MTD
Eligibility Criteria
Criteria
Ages Eligible for Study:
12 Months
to 30 Years
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Criteria that need to be met to participate in this study:
-
Patients must be > 12 months and < 30 years of age when registered on study.
-
Patients must have relapsed neuroblastoma, refractory neuroblastoma that had less than a partial response to standard treatment or persistent neuroblastoma that had at least a partial response to standard treatment. All patients must have at least ONE site of evaluable disease.
o Patients who have at least a partial response to standard treatment who still have neuroblastoma that can be seen on CT/MRI or MIBG scans must have a surgical biopsy done of the tumor to confirm that it is neuroblastoma. Patients with relapsed or refractory neuroblastoma do not need to have a biopsy done to enter on study.
-
Patients must have adequate heart, kidney, liver and bone marrow function. Patients who have bone marrow disease must still have adequate bone marrow function to enter the study.
-
MLN8237 must be swallowed as whole tablets. Therefore, patients must be able to swallow pills to be eligible for study. One tablet is the size of small breath mint, or baby aspirin. Due to the size of MLN8237 tablets, patients must have a body surface area of at least 0.38 m2 to be eligible for study. A body surface area is a combination of a patient's height and weight. An example of a child with a BSA of 0.45 is a child that is 25 inches tall and weighs 25 pounds.You can use the link below to calculate your child's body surface area and determine if they are too small for this trial.
Patients cannot participate in the study if:
-
Patients who have received prior MLN8237 are excluded from all phases of the study. Patients previously treated with irinotecan and/or temozolomide will be eligible if they have not had documented progressive disease during treatment with a regimen containing these agents.
-
They have other medical problems that could get much worse if they had this treatment.
-
They are on dialysis for bad kidney function.
-
They are pregnant or breast feeding.
-
They have active infections such as hepatitis or fungal infections.
-
They have an allergy to treatment with cefixime and cefpodixime.
-
They have brain metastasis at study entry, or have received cranial spinal radiation.
-
They have had an allogeneic stem cell transplant (received stem cell from someone else).
-
They can't cooperate with the special precautions that are needed for this trial.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Children's Hospital Los Angeles | Los Angeles | California | United States | 90027-0700 |
| 2 | Lucile Packard Children's Hospital at Stanford University Medical Center | Palo Alto | California | United States | 94304 |
| 3 | UCSF Helen Diller Family Comprehensive Cancer Center | San Francisco | California | United States | 94115 |
| 4 | Children Hospital of Colorado | Aurora | Colorado | United States | 80045 |
| 5 | Children's Healthcare of Atlanta | Atlanta | Georgia | United States | 30322 |
| 6 | University of Chicago Comer Children's Hospital | Chicago | Illinois | United States | 60637 |
| 7 | Childrens Hospital Boston, Dana-Farber Cancer Institute. | Boston | Massachusetts | United States | 02115 |
| 8 | University of Michigan Comprehensive Cancer Center | Ann Arbor | Michigan | United States | 48109 |
| 9 | Cincinnati Children's Hospital Medical Center | Cincinnati | Ohio | United States | 45229-3039 |
| 10 | Children's Hospital of Philadelphia | Philadelphia | Pennsylvania | United States | 19104-4318 |
| 11 | Cook Children's Medical Center - Fort Worth | Fort Worth | Texas | United States | 76104 |
| 12 | Children's Hospital and Regional Medical Center - Seattle | Seattle | Washington | United States | 98105 |
| 13 | Hospital for Sick Children | Toronto | Ontario | Canada | M5G 1X8 |
Sponsors and Collaborators
- New Approaches to Neuroblastoma Therapy Consortium
Investigators
- Study Chair: Steven DuBois, MD, Dana-Farber Cancer Institute
Study Documents (Full-Text)
More Information
Publications
None provided.Responsible Party:
New Approaches to Neuroblastoma Therapy Consortium
ClinicalTrials.gov Identifier:
NCT01601535
Other Study ID Numbers:
- N2009-03
First Posted:
May 18, 2012
Last Update Posted:
Jul 31, 2019
Last Verified:
Jul 1, 2019
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | DL 1 | DL 1B | DL 2B | DL 3B | Ph 2 | Oral Solution |
|---|---|---|---|---|---|---|
| Arm/Group Description | alisertib tablets (45 mg/m^2/dose x 7 days), irinotecan (50 mg/m^2/dose IV x 5 days), temozolomide (100 mg/m^2/dose orally x 5 days), myeloid growth factor support and cephalosporin diarrhea prophylaxis optional | alisertib tablets (45 mg/m^2/dose x 7 days), irinotecan (50 mg/m^2/dose IV x 5 days), temozolomide (100 mg/m^2/dose orally x 5 days), myeloid growth factor support and cephalosporin diarrhea prophylaxis required | alisertib tablets (60 mg/m^2/dose x 7 days), irinotecan (50 mg/m^2/dose IV x 5 days), temozolomide (100 mg/m^2/dose orally x 5 days), myeloid growth factor support and cephalosporin diarrhea prophylaxis required | alisertib tablets (80 mg/m^2/dose x 7 days), irinotecan (50 mg/m^2/dose IV x 5 days), temozolomide (100 mg/m^2/dose orally x 5 days), myeloid growth factor support and cephalosporin diarrhea prophylaxis required | alisertib tablets (60 mg/m^2/dose x 7 days), irinotecan (50 mg/m^2/dose IV x 5 days), temozolomide (100 mg/m^2/dose orally x 5 days), myeloid growth factor support and cephalosporin diarrhea prophylaxis required | alisertib oral solution (45 mg/m^2/dose x 7 days), irinotecan (50 mg/m^2/dose IV x 5 days), temozolomide (100 mg/m^2/dose orally x 5 days), myeloid growth factor support and cephalosporin diarrhea prophylaxis required |
| Period Title: Phase 1 | ||||||
| STARTED | 6 | 6 | 6 | 4 | 0 | 0 |
| COMPLETED | 0 | 0 | 1 | 0 | 0 | 0 |
| NOT COMPLETED | 6 | 6 | 5 | 4 | 0 | 0 |
| Period Title: Phase 1 | ||||||
| STARTED | 0 | 0 | 0 | 0 | 20 | 12 |
| COMPLETED | 0 | 0 | 0 | 0 | 1 | 0 |
| NOT COMPLETED | 0 | 0 | 0 | 0 | 19 | 12 |
Baseline Characteristics
| Arm/Group Title | DL 1 | DL 1B | DL 2B | DL 3B | Ph 2 | Oral Solution | Total |
|---|---|---|---|---|---|---|---|
| Arm/Group Description | alisertib tablets (45 mg/m^2/dose x 7 days), irinotecan (50 mg/m^2/dose IV x 5 days), temozolomide (100 mg/m^2/dose orally x 5 days), myeloid growth factor support and cephalosporin diarrhea prophylaxis optional | alisertib tablets (45 mg/m^2/dose x 7 days), irinotecan (50 mg/m^2/dose IV x 5 days), temozolomide (100 mg/m^2/dose orally x 5 days), myeloid growth factor support and cephalosporin diarrhea prophylaxis required | alisertib tablets (60 mg/m^2/dose x 7 days), irinotecan (50 mg/m^2/dose IV x 5 days), temozolomide (100 mg/m^2/dose orally x 5 days), myeloid growth factor support and cephalosporin diarrhea prophylaxis required | alisertib tablets (80 mg/m^2/dose x 7 days), irinotecan (50 mg/m^2/dose IV x 5 days), temozolomide (100 mg/m^2/dose orally x 5 days), myeloid growth factor support and cephalosporin diarrhea prophylaxis required | alisertib tablets (60 mg/m^2/dose x 7 days), irinotecan (50 mg/m^2/dose IV x 5 days), temozolomide (100 mg/m^2/dose orally x 5 days), myeloid growth factor support and cephalosporin diarrhea prophylaxis required | alisertib oral solution (45 mg/m^2/dose x 7 days), irinotecan (50 mg/m^2/dose IV x 5 days), temozolomide (100 mg/m^2/dose orally x 5 days), myeloid growth factor support and cephalosporin diarrhea prophylaxis required | Total of all reporting groups |
| Overall Participants | 6 | 6 | 6 | 4 | 20 | 12 | 54 |
| Age (years) [Median (Full Range) ] | |||||||
| Median (Full Range) [years] |
8.60
|
6.81
|
7.67
|
6.14
|
10.74
|
3.05
|
7.61
|
| Sex: Female, Male (Count of Participants) | |||||||
| Female |
0
0%
|
2
33.3%
|
1
16.7%
|
1
25%
|
6
30%
|
6
50%
|
16
29.6%
|
| Male |
6
100%
|
4
66.7%
|
5
83.3%
|
3
75%
|
14
70%
|
6
50%
|
38
70.4%
|
| Race/Ethnicity, Customized (Count of Participants) | |||||||
| Hispanic |
0
0%
|
1
16.7%
|
0
0%
|
0
0%
|
1
5%
|
0
0%
|
2
3.7%
|
| Not Hispanic Black or African American |
1
16.7%
|
0
0%
|
1
16.7%
|
0
0%
|
3
15%
|
0
0%
|
5
9.3%
|
| Not Hispanic White |
5
83.3%
|
5
83.3%
|
5
83.3%
|
4
100%
|
14
70%
|
12
100%
|
45
83.3%
|
| Not Hispanic Other |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
1
5%
|
0
0%
|
1
1.9%
|
| Not Hispanic Unknown |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
1
5%
|
0
0%
|
1
1.9%
|
| Region of Enrollment (participants) [Number] | |||||||
| United States |
6
100%
|
6
100%
|
6
100%
|
4
100%
|
20
100%
|
12
100%
|
54
100%
|
| Prior Irinotecan (Count of Participants) | |||||||
| Yes |
3
50%
|
1
16.7%
|
0
0%
|
1
25%
|
11
55%
|
2
16.7%
|
18
33.3%
|
| No |
3
50%
|
5
83.3%
|
6
100%
|
3
75%
|
9
45%
|
10
83.3%
|
36
66.7%
|
| Prior Temozolomide (Count of Participants) | |||||||
| Yes |
3
50%
|
1
16.7%
|
0
0%
|
1
25%
|
10
50%
|
2
16.7%
|
17
31.5%
|
| No |
3
50%
|
5
83.3%
|
6
100%
|
3
75%
|
10
50%
|
10
83.3%
|
37
68.5%
|
Outcome Measures
| Title | Maximum Tolerated Dose (MTD) When Given Together With Fixed Doses of Irinotecan and Temozolomide in Children and Young Adults With Relapsed or Refractory Neuroblastoma |
|---|---|
| Description | The MTD was the highest dose level tested at which fewer than two of six patients had first course DLT. Hematologic DLT was defined as grade 4 neutropenia for more than 7 days, need for platelet transfusion for a platelet count of less than 20,000/mL twice within a 7-day period, or greater than 14-day delay in the start of a subsequent course because of neutropenia or thrombocytopenia. Nonhematologic DLT was defined as any nonhematologic toxicity that delayed the start of a subsequent cycle by more than 14 days or any grade ≥3 toxicity with the exception of the following grade 3 toxicities: nausea, vomiting, anorexia, or dehydration resolving to grade ≤ 2 within 72 hours; increase in hepatic transaminase or electrolyte abnormality resolving to grade ≤ 1 within 7 days; diarrhea persisting for less than 72 hours; fever; infection; or febrile neutropenia. DLT definitions included only toxicities deemed at least possibly related to therapy. |
| Time Frame | 21 days, from study day 1 |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Phase I |
|---|---|
| Arm/Group Description | Patients received alisertib tablets at dose levels of 45, 60, and 80 mg/m^2 per day on days 1 to 7 along with irinotecan 50 mg/m^2 intravenously and temozolomide 100 mg/m^2 orally on days 1 to 5. |
| Measure Participants | 22 |
| Number [mg/m^2] |
60
|
| Title | Dose Limiting Toxicity (DLT) Data Associated With the Determination of the Recommended Phase 2 Dose |
|---|---|
| Description | The MTD was the highest dose level tested at which fewer than two of six patients had first course DLT. Hematologic DLT was defined as grade 4 neutropenia for more than 7 days, need for platelet transfusion for a platelet count of less than 20,000/mL twice within a 7-day period, or greater than 14-day delay in the start of a subsequent course because of neutropenia or thrombocytopenia. Nonhematologic DLT was defined as any nonhematologic toxicity that delayed the start of a subsequent cycle by more than 14 days or any grade ≥3 toxicity with the exception of the following grade 3 toxicities: nausea, vomiting, anorexia, or dehydration resolving to grade ≤ 2 within 72 hours; increase in hepatic transaminase or electrolyte abnormality resolving to grade ≤ 1 within 7 days; diarrhea persisting for less than 72 hours; fever; infection; or febrile neutropenia. DLT definitions included only toxicities deemed at least possibly related to therapy. |
| Time Frame | 21 days, from study day 1 |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | DL 1 | DL 1B | DL 2B | DL 3B |
|---|---|---|---|---|
| Arm/Group Description | alisertib tablets (45 mg/m^2/dose x 7 days), irinotecan (50 mg/m^2/dose IV x 5 days), temozolomide (100 mg/m^2/dose orally x 5 days), myeloid growth factor support and cephalosporin diarrhea prophylaxis optional | alisertib tablets (45 mg/m^2/dose x 7 days), irinotecan (50 mg/m^2/dose IV x 5 days), temozolomide (100 mg/m^2/dose orally x 5 days), myeloid growth factor support and cephalosporin diarrhea prophylaxis required | alisertib tablets (60 mg/m^2/dose x 7 days), irinotecan (50 mg/m^2/dose IV x 5 days), temozolomide (100 mg/m^2/dose orally x 5 days), myeloid growth factor support and cephalosporin diarrhea prophylaxis required | alisertib tablets (80 mg/m^2/dose x 7 days), irinotecan (50 mg/m^2/dose IV x 5 days), temozolomide (100 mg/m^2/dose orally x 5 days), myeloid growth factor support and cephalosporin diarrhea prophylaxis required |
| Measure Participants | 6 | 6 | 6 | 4 |
| Number [DLTs] |
2
|
0
|
1
|
2
|
| Title | Pharmacokinetics When Given Together With Fixed Doses of Irinotecan and Temozolomide in Children and Young Adults With Relapsed or Refractory Neuroblastoma: Alisertib Day 4 Trough, Day 5 Trough and Cmax |
|---|---|
| Description | Outcomes included Alisertib, irinotecan, APC, SN-38, and SN-38G. APC, SN-38, and SN-38G are metabolites of irinotecan. |
| Time Frame | 1st week of cycle 1 |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | DL 1 | DL 1B | DL 2B | DL 3B | Oral Solution |
|---|---|---|---|---|---|
| Arm/Group Description | alisertib tablets (45 mg/m^2/dose x 7 days), irinotecan (50 mg/m^2/dose IV x 5 days), temozolomide (100 mg/m^2/dose orally x 5 days), myeloid growth factor support and cephalosporin diarrhea prophylaxis optional | alisertib tablets (45 mg/m^2/dose x 7 days), irinotecan (50 mg/m^2/dose IV x 5 days), temozolomide (100 mg/m^2/dose orally x 5 days), myeloid growth factor support and cephalosporin diarrhea prophylaxis required | alisertib tablets (60 mg/m^2/dose x 7 days), irinotecan (50 mg/m^2/dose IV x 5 days), temozolomide (100 mg/m^2/dose orally x 5 days), myeloid growth factor support and cephalosporin diarrhea prophylaxis required | alisertib tablets (80 mg/m^2/dose x 7 days), irinotecan (50 mg/m^2/dose IV x 5 days), temozolomide (100 mg/m^2/dose orally x 5 days), myeloid growth factor support and cephalosporin diarrhea prophylaxis required | alisertib oral solution (45 mg/m^2/dose x 7 days), irinotecan (50 mg/m^2/dose IV x 5 days), temozolomide (100 mg/m^2/dose orally x 5 days), myeloid growth factor support and cephalosporin diarrhea prophylaxis required |
| Measure Participants | 6 | 6 | 6 | 4 | 12 |
| Alisertib Day 4 trough |
0.48
|
0.35
|
0.3
|
0.73
|
0.47
|
| Alisertib Day 5 trough |
0.37
|
0.36
|
0.2
|
0.69
|
0.58
|
| Alisertib Cmax |
2.56
|
2.39
|
3.77
|
4.94
|
8.66
|
| Title | Pharmacokinetics When Given Together With Fixed Doses of Irinotecan and Temozolomide in Children and Young Adults With Relapsed or Refractory Neuroblastoma: Alisertib Tmax and Half-life |
|---|---|
| Description | Outcomes included Alisertib, irinotecan, APC, SN-38, and SN-38G. APC, SN-38, and SN-38G are metabolites of irinotecan. |
| Time Frame | 1st week of cycle 1 |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | DL 1 | DL 1B | DL 2B | DL 3B | Oral Solution |
|---|---|---|---|---|---|
| Arm/Group Description | alisertib tablets (45 mg/m^2/dose x 7 days), irinotecan (50 mg/m^2/dose IV x 5 days), temozolomide (100 mg/m^2/dose orally x 5 days), myeloid growth factor support and cephalosporin diarrhea prophylaxis optional | alisertib tablets (45 mg/m^2/dose x 7 days), irinotecan (50 mg/m^2/dose IV x 5 days), temozolomide (100 mg/m^2/dose orally x 5 days), myeloid growth factor support and cephalosporin diarrhea prophylaxis required | alisertib tablets (60 mg/m^2/dose x 7 days), irinotecan (50 mg/m^2/dose IV x 5 days), temozolomide (100 mg/m^2/dose orally x 5 days), myeloid growth factor support and cephalosporin diarrhea prophylaxis required | alisertib tablets (80 mg/m^2/dose x 7 days), irinotecan (50 mg/m^2/dose IV x 5 days), temozolomide (100 mg/m^2/dose orally x 5 days), myeloid growth factor support and cephalosporin diarrhea prophylaxis required | alisertib oral solution (45 mg/m^2/dose x 7 days), irinotecan (50 mg/m^2/dose IV x 5 days), temozolomide (100 mg/m^2/dose orally x 5 days), myeloid growth factor support and cephalosporin diarrhea prophylaxis required |
| Measure Participants | 6 | 6 | 6 | 4 | 12 |
| Alisertib Tmax |
2.04
|
1.74
|
2.5
|
2.52
|
2
|
| Alisertib Half-life |
7.20
|
8.61
|
6.19
|
8.54
|
8.34
|
| Title | Pharmacokinetics When Given Together With Fixed Doses of Irinotecan and Temozolomide in Children and Young Adults With Relapsed or Refractory Neuroblastoma: Alisertib AUC |
|---|---|
| Description | Outcomes included Alisertib, irinotecan, APC, SN-38, and SN-38G. APC, SN-38, and SN-38G are metabolites of irinotecan. |
| Time Frame | 1st week of cycle 1 |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | DL 1 | DL 1B | DL 2B | DL 3B | Oral Solution |
|---|---|---|---|---|---|
| Arm/Group Description | alisertib tablets (45 mg/m^2/dose x 7 days), irinotecan (50 mg/m^2/dose IV x 5 days), temozolomide (100 mg/m^2/dose orally x 5 days), myeloid growth factor support and cephalosporin diarrhea prophylaxis optional | alisertib tablets (45 mg/m^2/dose x 7 days), irinotecan (50 mg/m^2/dose IV x 5 days), temozolomide (100 mg/m^2/dose orally x 5 days), myeloid growth factor support and cephalosporin diarrhea prophylaxis required | alisertib tablets (60 mg/m^2/dose x 7 days), irinotecan (50 mg/m^2/dose IV x 5 days), temozolomide (100 mg/m^2/dose orally x 5 days), myeloid growth factor support and cephalosporin diarrhea prophylaxis required | alisertib tablets (80 mg/m^2/dose x 7 days), irinotecan (50 mg/m^2/dose IV x 5 days), temozolomide (100 mg/m^2/dose orally x 5 days), myeloid growth factor support and cephalosporin diarrhea prophylaxis required | alisertib oral solution (45 mg/m^2/dose x 7 days), irinotecan (50 mg/m^2/dose IV x 5 days), temozolomide (100 mg/m^2/dose orally x 5 days), myeloid growth factor support and cephalosporin diarrhea prophylaxis required |
| Measure Participants | 6 | 6 | 6 | 4 | 12 |
| Median (Full Range) [µM•hour] |
28.15
|
21
|
30.71
|
47.73
|
58.15
|
| Title | Pharmacokinetics When Given Together With Fixed Doses of Irinotecan and Temozolomide in Children and Young Adults With Relapsed or Refractory Neuroblastoma: Irinotecan Cmax, APC Cmax, SN-38 Cmax, and SN-38G Cmax |
|---|---|
| Description | Outcomes included Alisertib, irinotecan, APC, SN-38, and SN-38G. APC, SN-38, and SN-38G are metabolites of irinotecan. |
| Time Frame | 1st week of cycle 1 |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | DL 1 | DL 1B | DL 2B | DL 3B | Ph 2 | Oral Solution |
|---|---|---|---|---|---|---|
| Arm/Group Description | alisertib tablets (45 mg/m^2/dose x 7 days), irinotecan (50 mg/m^2/dose IV x 5 days), temozolomide (100 mg/m^2/dose orally x 5 days), myeloid growth factor support and cephalosporin diarrhea prophylaxis optional | alisertib tablets (45 mg/m^2/dose x 7 days), irinotecan (50 mg/m^2/dose IV x 5 days), temozolomide (100 mg/m^2/dose orally x 5 days), myeloid growth factor support and cephalosporin diarrhea prophylaxis required | alisertib tablets (60 mg/m^2/dose x 7 days), irinotecan (50 mg/m^2/dose IV x 5 days), temozolomide (100 mg/m^2/dose orally x 5 days), myeloid growth factor support and cephalosporin diarrhea prophylaxis required | alisertib tablets (80 mg/m^2/dose x 7 days), irinotecan (50 mg/m^2/dose IV x 5 days), temozolomide (100 mg/m^2/dose orally x 5 days), myeloid growth factor support and cephalosporin diarrhea prophylaxis required | alisertib tablets (60 mg/m^2/dose x 7 days), irinotecan (50 mg/m^2/dose IV x 5 days), temozolomide (100 mg/m^2/dose orally x 5 days), myeloid growth factor support and cephalosporin diarrhea prophylaxis required | alisertib oral solution (45 mg/m^2/dose x 7 days), irinotecan (50 mg/m^2/dose IV x 5 days), temozolomide (100 mg/m^2/dose orally x 5 days), myeloid growth factor support and cephalosporin diarrhea prophylaxis required |
| Measure Participants | 6 | 6 | 6 | 4 | 12 | 8 |
| Irinotecan Cmax |
722
|
703
|
1,238
|
784
|
881
|
732
|
| APC Cmax |
61.2
|
59.8
|
55.8
|
43.4
|
57.1
|
51.4
|
| SN-38 Cmax |
9.5
|
12.6
|
12.0
|
11.7
|
10.4
|
8.26
|
| SN-38G Cmax |
18.2
|
16.9
|
13.8
|
13.0
|
12.8
|
15.2
|
| Title | Pharmacokinetics When Given Together With Fixed Doses of Irinotecan and Temozolomide in Children and Young Adults With Relapsed or Refractory Neuroblastoma: Irinotecan AUC, APC AUC, SN-38 AUC, and SN-38G AUC |
|---|---|
| Description | Outcomes included Alisertib, irinotecan, APC, SN-38, and SN-38G. APC, SN-38, and SN-38G are metabolites of irinotecan. |
| Time Frame | 1st week of cycle 1 |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | DL 1 | DL 1B | DL 2B | DL 3B | Ph 2 | Oral Solution |
|---|---|---|---|---|---|---|
| Arm/Group Description | alisertib tablets (45 mg/m^2/dose x 7 days), irinotecan (50 mg/m^2/dose IV x 5 days), temozolomide (100 mg/m^2/dose orally x 5 days), myeloid growth factor support and cephalosporin diarrhea prophylaxis optional | alisertib tablets (45 mg/m^2/dose x 7 days), irinotecan (50 mg/m^2/dose IV x 5 days), temozolomide (100 mg/m^2/dose orally x 5 days), myeloid growth factor support and cephalosporin diarrhea prophylaxis required | alisertib tablets (60 mg/m^2/dose x 7 days), irinotecan (50 mg/m^2/dose IV x 5 days), temozolomide (100 mg/m^2/dose orally x 5 days), myeloid growth factor support and cephalosporin diarrhea prophylaxis required | alisertib tablets (80 mg/m^2/dose x 7 days), irinotecan (50 mg/m^2/dose IV x 5 days), temozolomide (100 mg/m^2/dose orally x 5 days), myeloid growth factor support and cephalosporin diarrhea prophylaxis required | alisertib tablets (60 mg/m^2/dose x 7 days), irinotecan (50 mg/m^2/dose IV x 5 days), temozolomide (100 mg/m^2/dose orally x 5 days), myeloid growth factor support and cephalosporin diarrhea prophylaxis required | alisertib oral solution (45 mg/m^2/dose x 7 days), irinotecan (50 mg/m^2/dose IV x 5 days), temozolomide (100 mg/m^2/dose orally x 5 days), myeloid growth factor support and cephalosporin diarrhea prophylaxis required |
| Measure Participants | 6 | 6 | 6 | 4 | 12 | 8 |
| Irinotecan AUC |
3,702
|
2,680
|
3,957
|
2,615
|
3,533
|
3,121
|
| APC AUC |
571
|
477
|
511
|
418
|
511
|
616
|
| SN-38 AUC |
63.2
|
52.9
|
80.8
|
72.0
|
90.0
|
56.7
|
| SN-38G AUC |
206.5
|
97.6
|
141.8
|
134.4
|
132
|
136
|
| Title | Pharmacokinetics When Given Together With Fixed Doses of Irinotecan and Temozolomide in Children and Young Adults With Relapsed or Refractory Neuroblastoma: Irinotecan Clearance |
|---|---|
| Description | Outcomes included Alisertib, irinotecan, APC, SN-38, and SN-38G. APC, SN-38, and SN-38G are metabolites of irinotecan. |
| Time Frame | 1st week of cycle 1 |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | DL 1 | DL 1B | DL 2B | DL 3B | Ph 2 | Oral Solution |
|---|---|---|---|---|---|---|
| Arm/Group Description | alisertib tablets (45 mg/m^2/dose x 7 days), irinotecan (50 mg/m^2/dose IV x 5 days), temozolomide (100 mg/m^2/dose orally x 5 days), myeloid growth factor support and cephalosporin diarrhea prophylaxis optional | alisertib tablets (45 mg/m^2/dose x 7 days), irinotecan (50 mg/m^2/dose IV x 5 days), temozolomide (100 mg/m^2/dose orally x 5 days), myeloid growth factor support and cephalosporin diarrhea prophylaxis required | alisertib tablets (60 mg/m^2/dose x 7 days), irinotecan (50 mg/m^2/dose IV x 5 days), temozolomide (100 mg/m^2/dose orally x 5 days), myeloid growth factor support and cephalosporin diarrhea prophylaxis required | alisertib tablets (80 mg/m^2/dose x 7 days), irinotecan (50 mg/m^2/dose IV x 5 days), temozolomide (100 mg/m^2/dose orally x 5 days), myeloid growth factor support and cephalosporin diarrhea prophylaxis required | alisertib tablets (60 mg/m^2/dose x 7 days), irinotecan (50 mg/m^2/dose IV x 5 days), temozolomide (100 mg/m^2/dose orally x 5 days), myeloid growth factor support and cephalosporin diarrhea prophylaxis required | alisertib oral solution (45 mg/m^2/dose x 7 days), irinotecan (50 mg/m^2/dose IV x 5 days), temozolomide (100 mg/m^2/dose orally x 5 days), myeloid growth factor support and cephalosporin diarrhea prophylaxis required |
| Measure Participants | 6 | 6 | 6 | 4 | 12 | 8 |
| Median (Full Range) [L/h] |
14.0
|
15.7
|
10.4
|
16.0
|
12.6
|
10.3
|
| Title | Response Rate for Patients With Relapsed or Refractory Neuroblastoma Treated With MLN8237, Irinotecan, and Temozolomide at the Identified MTD |
|---|---|
| Description | Response was graded according to version 1.2 of the NANT response criteria that classifies patients as having one of the following overall response categories based upon underlying response at soft tissue sites, MIBG positive sites, and bone marrow disease: complete response (CR); CR with minimal residual disease (CR-MRD); partial response (PR); minor response (MR); stable disease (SD); and progressive disease (PD). These criteria utilize RECIST criteria for measurable tumors, Curie score for MIBG scan response, and bone marrow (BM) morphology. BM response was graded as CR (required two time points to confirm), CR unconfirmed (one time point only), CR-MRD (bone marrow involvement < 5% at study entry with negative follow-up biopsies), SD, or PD. Patients with at least SD or better underwent central review of MIBG scans, CT scans, and bone marrow pathology slides. Overall responses of CR, CR-MRD, or PR were considered objective responses. |
| Time Frame | Cycles repeated every 21 days for up to 34 cycles. |
Outcome Measure Data
| Analysis Population Description |
|---|
| The analysis was performed on 19 phase II patients, with 1 inevaluable patient excluded. |
| Arm/Group Title | Ph 2 |
|---|---|
| Arm/Group Description | alisertib tablets (60 mg/m^2/dose x 7 days), irinotecan (50 mg/m^2/dose IV x 5 days), temozolomide (100 mg/m^2/dose orally x 5 days), myeloid growth factor support and cephalosporin diarrhea prophylaxis required |
| Measure Participants | 19 |
| Complete Response (CR) |
0
0%
|
| CR-Minimal Residual Disease (MRD) |
0
0%
|
| Partial Response (PR) |
4
66.7%
|
| Minor Response |
2
33.3%
|
| Stable Disease |
8
133.3%
|
| Progressive Disease |
5
83.3%
|
| Response Rate (CR + CR-MRD + PR) |
4
66.7%
|
| Title | Aurora A Expression |
|---|---|
| Description | To explore whether MYCN status and markers of expression of Aurora A in archival tumor tissue are associated with the antitumor activity of the combination of MLN8237, irinotecan, and temozolomide |
| Time Frame | From date of study enrollment to the date of progression or withdrawal from the study, up to 34 cycles (about 2 years). |
Outcome Measure Data
| Analysis Population Description |
|---|
| Consisting of patients treated on the Phase 1 (n = 22), Phase 2 (n = 20), and Oral Solution (n = 12) cohorts. |
| Arm/Group Title | Objective Responders | Objective Non-Responders |
|---|---|---|
| Arm/Group Description | Consisting of complete response (CR), CR with minimal residual disease (CR-MRD), and partial response (PR). | Consisting of minor response (MR), stable disease (SD) and progressive disease (PD). |
| Measure Participants | 12 | 42 |
| MYCN Amplified |
1
16.7%
|
14
233.3%
|
| MYCN not Amplified |
9
150%
|
24
400%
|
| MYCN Missing |
2
33.3%
|
4
66.7%
|
| MYCN Amplified or Myc Positive |
2
33.3%
|
16
266.7%
|
| MYCN Non-amplified and Myc Negative |
5
83.3%
|
11
183.3%
|
| MYCN or Myc Missing |
5
83.3%
|
15
250%
|
| Aurora A protein Positive |
2
33.3%
|
10
166.7%
|
| Aurora A protein Negative |
4
66.7%
|
14
233.3%
|
| Aurora A protein Missing |
6
100%
|
18
300%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Phase I, DL 1B |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.14 |
| Comments | MYCN Amplified vs. MYCN not Amplified | |
| Method | Fisher Exact | |
| Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Phase I, DL 1B |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.21 |
| Comments | ||
| Method | Fisher Exact | |
| Comments | MYCN Amplified or Myc Positive vs. MYCN Non-amplified and Myc Negative | |
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Phase I, DL 1B |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 1.0 |
| Comments | ||
| Method | Fisher Exact | |
| Comments | Aurora A protein Positive vs. Aurora A protein Negative | |
| Title | UGT1A1 Genotype |
|---|---|
| Description | To explore whether UGT1A1 genotype is associated with toxicity in children with refractory neuroblastoma treated with the combination of MLN8237, irinotecan, and temozolomide |
| Time Frame | Day 7 of cycle 1 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Consisting of patients treated on the Phase 1 (n = 22), Phase 2 (n = 20), and Oral Solution (n = 12) cohorts. |
| Arm/Group Title | First Cycle DLT Yes | First Cycle DLT No | DLT in Any Cycle Yes | DLT in Any Cycle No |
|---|---|---|---|---|
| Arm/Group Description | Patients who had DLT in the first cycle of treatment. | Patients who did not have DLT in the first cycle of treatment. | Patients who had DLT in any cycle of treatment. | Patients who did not have DLT in any cycle of treatment. |
| Measure Participants | 11 | 43 | 27 | 27 |
| UGT1A1 6\6 |
2
33.3%
|
15
250%
|
8
133.3%
|
9
225%
|
| UGT1A1 6\7 |
3
50%
|
14
233.3%
|
6
100%
|
11
275%
|
| UGT1A1 7\7 |
3
50%
|
2
33.3%
|
4
66.7%
|
1
25%
|
| UGT1A1 Missing |
3
50%
|
12
200%
|
9
150%
|
6
150%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Phase I, DL 1B |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.094 |
| Comments | UGT1A1 6\6 vs. UGT1A1 6\7 vs. UGT1A1 7\7 | |
| Method | Fisher Exact | |
| Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | DL 2B, DL 3B |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.63 |
| Comments | UGT1A1 6\6 vs. UGT1A1 6\7 vs. UGT1A1 7\7 | |
| Method | Fisher Exact | |
| Comments | ||
| Title | AURKA Genotype |
|---|---|
| Description | To explore whether AURKA genotype is associated with antitumor activity in children with refractory neuroblastoma treated with the combination of MLN8237, irinotecan, and temozolomide. |
| Time Frame | Day 7 of cycle 1 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Consisting of patients treated on the Phase 1 (n = 22), Phase 2 (n = 20), and Oral Solution (n = 12) cohorts. |
| Arm/Group Title | Objective Responders | Objective Non-Responders |
|---|---|---|
| Arm/Group Description | Consisting of complete response (CR), CR with minimal residual disease (CR-MRD), and partial response (PR). | Consisting of minor response (MR), stable disease (SD) and progressive disease (PD). |
| Measure Participants | 12 | 42 |
| AurkA Codon 31 Summary H |
3
50%
|
9
150%
|
| AurkA Codon 31 Summary V |
0
0%
|
1
16.7%
|
| AurkA Codon 31 Summary W |
5
83.3%
|
22
366.7%
|
| AurkA Codon 31 Summary Missing |
4
66.7%
|
10
166.7%
|
| AurkA Codon 57 Summary H |
3
50%
|
10
166.7%
|
| AurkA Codon 57 Summary W |
5
83.3%
|
22
366.7%
|
| AurkA Codon 57 Summary Missing |
4
66.7%
|
10
166.7%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Phase I, DL 1B |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.90 |
| Comments | AurkA Codon 31 Summary H vs. AurkA Codon 31 Summary V vs. AurkA Codon 31 Summary W | |
| Method | Fisher Exact | |
| Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Phase I, DL 1B |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 1.0 |
| Comments | AurkA Codon 57 Summary H vs. AurkA Codon 57 Summary W | |
| Method | Fisher Exact | |
| Comments | ||
| Title | One Year Progression Free Survival Rate |
|---|---|
| Description | To determine the progression free survival rates for patients with relapsed or refractory neuroblastoma treated with MLN8237, irinotecan, and temozolomide at the identified MTD |
| Time Frame | 1 Years after completion of study |
Outcome Measure Data
| Analysis Population Description |
|---|
| The analysis was performed in phase II patients. |
| Arm/Group Title | Ph 2 |
|---|---|
| Arm/Group Description | alisertib tablets (60 mg/m^2/dose x 7 days), irinotecan (50 mg/m^2/dose IV x 5 days), temozolomide (100 mg/m^2/dose orally x 5 days), myeloid growth factor support and cephalosporin diarrhea prophylaxis required |
| Measure Participants | 20 |
| Count of Participants [Participants] |
4
66.7%
|
Adverse Events
| Time Frame | From date of study enrollment to the date of progression or withdrawal from the study, up to 34 cycles (about 2 years). | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | ||||||||||||
| Arm/Group Title | DL 1 | DL 1B | DL 2B | DL 3B | Ph 2 | Oral Solution | ||||||
| Arm/Group Description | alisertib tablets (45 mg/m^2/dose x 7 days), irinotecan (50 mg/m^2/dose IV x 5 days), temozolomide (100 mg/m^2/dose orally x 5 days), myeloid growth factor support and cephalosporin diarrhea prophylaxis optional | alisertib tablets (45 mg/m^2/dose x 7 days), irinotecan (50 mg/m^2/dose IV x 5 days), temozolomide (100 mg/m^2/dose orally x 5 days), myeloid growth factor support and cephalosporin diarrhea prophylaxis required | alisertib tablets (60 mg/m^2/dose x 7 days), irinotecan (50 mg/m^2/dose IV x 5 days), temozolomide (100 mg/m^2/dose orally x 5 days), myeloid growth factor support and cephalosporin diarrhea prophylaxis required | alisertib tablets (80 mg/m^2/dose x 7 days), irinotecan (50 mg/m^2/dose IV x 5 days), temozolomide (100 mg/m^2/dose orally x 5 days), myeloid growth factor support and cephalosporin diarrhea prophylaxis required | alisertib tablets (60 mg/m^2/dose x 7 days), irinotecan (50 mg/m^2/dose IV x 5 days), temozolomide (100 mg/m^2/dose orally x 5 days), myeloid growth factor support and cephalosporin diarrhea prophylaxis required | alisertib oral solution (45 mg/m^2/dose x 7 days), irinotecan (50 mg/m^2/dose IV x 5 days), temozolomide (100 mg/m^2/dose orally x 5 days), myeloid growth factor support and cephalosporin diarrhea prophylaxis required | ||||||
All Cause Mortality |
||||||||||||
| DL 1 | DL 1B | DL 2B | DL 3B | Ph 2 | Oral Solution | |||||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/6 (0%) | 0/6 (0%) | 0/6 (0%) | 0/4 (0%) | 0/20 (0%) | 0/12 (0%) | ||||||
Serious Adverse Events |
||||||||||||
| DL 1 | DL 1B | DL 2B | DL 3B | Ph 2 | Oral Solution | |||||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 3/6 (50%) | 3/6 (50%) | 3/6 (50%) | 2/4 (50%) | 1/20 (5%) | 2/12 (16.7%) | ||||||
| Blood and lymphatic system disorders | ||||||||||||
| Febrile neutropenia | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 3/6 (50%) | 3 | 1/4 (25%) | 1 | 0/20 (0%) | 0 | 0/12 (0%) | 0 |
| Gastrointestinal disorders | ||||||||||||
| Diarrhea | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/4 (0%) | 0 | 0/20 (0%) | 0 | 1/12 (8.3%) | 1 |
| Mucositis oral | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/4 (0%) | 0 | 0/20 (0%) | 0 | 0/12 (0%) | 0 |
| Oral pain | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/4 (0%) | 0 | 0/20 (0%) | 0 | 0/12 (0%) | 0 |
| Vomiting | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/4 (25%) | 1 | 0/20 (0%) | 0 | 0/12 (0%) | 0 |
| Infections and infestations | ||||||||||||
| Catheter related infection | 1/6 (16.7%) | 1 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/4 (0%) | 0 | 0/20 (0%) | 0 | 0/12 (0%) | 0 |
| Infections and infestations - Other, specify | 1/6 (16.7%) | 1 | 1/6 (16.7%) | 2 | 0/6 (0%) | 0 | 0/4 (0%) | 0 | 0/20 (0%) | 0 | 0/12 (0%) | 0 |
| Investigations | ||||||||||||
| Neutrophil count decreased | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/4 (0%) | 0 | 0/20 (0%) | 0 | 0/12 (0%) | 0 |
| Metabolism and nutrition disorders | ||||||||||||
| Anorexia | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/4 (0%) | 0 | 0/20 (0%) | 0 | 0/12 (0%) | 0 |
| Dehydration | 1/6 (16.7%) | 1 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 2/4 (50%) | 2 | 0/20 (0%) | 0 | 0/12 (0%) | 0 |
| Hypoalbuminemia | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/4 (0%) | 0 | 1/20 (5%) | 1 | 0/12 (0%) | 0 |
| Nervous system disorders | ||||||||||||
| Movements involuntary | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/4 (0%) | 0 | 0/20 (0%) | 0 | 0/12 (0%) | 0 |
| Respiratory, thoracic and mediastinal disorders | ||||||||||||
| Pharyngeal mucositis | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/4 (0%) | 0 | 0/20 (0%) | 0 | 0/12 (0%) | 0 |
| Pleural effusion | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/4 (0%) | 0 | 0/20 (0%) | 0 | 1/12 (8.3%) | 1 |
Other (Not Including Serious) Adverse Events |
||||||||||||
| DL 1 | DL 1B | DL 2B | DL 3B | Ph 2 | Oral Solution | |||||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 6/6 (100%) | 6/6 (100%) | 6/6 (100%) | 4/4 (100%) | 20/20 (100%) | 12/12 (100%) | ||||||
| Blood and lymphatic system disorders | ||||||||||||
| Anemia | 6/6 (100%) | 50 | 6/6 (100%) | 61 | 6/6 (100%) | 100 | 4/4 (100%) | 17 | 19/20 (95%) | 147 | 10/12 (83.3%) | 41 |
| Febrile neutropenia | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 2/6 (33.3%) | 2 | 1/4 (25%) | 1 | 3/20 (15%) | 4 | 2/12 (16.7%) | 2 |
| Hemolysis | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 2/6 (33.3%) | 2 | 0/4 (0%) | 0 | 0/20 (0%) | 0 | 0/12 (0%) | 0 |
| Cardiac disorders | ||||||||||||
| Palpitations | 1/6 (16.7%) | 2 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/4 (0%) | 0 | 1/20 (5%) | 1 | 0/12 (0%) | 0 |
| Sinus tachycardia | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 6/6 (100%) | 22 | 1/4 (25%) | 3 | 4/20 (20%) | 9 | 0/12 (0%) | 0 |
| Ear and labyrinth disorders | ||||||||||||
| Ear pain | 2/6 (33.3%) | 5 | 0/6 (0%) | 0 | 2/6 (33.3%) | 2 | 1/4 (25%) | 5 | 0/20 (0%) | 0 | 1/12 (8.3%) | 1 |
| Endocrine disorders | ||||||||||||
| Hypothyroidism | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/4 (0%) | 0 | 1/20 (5%) | 14 | 0/12 (0%) | 0 |
| Eye disorders | ||||||||||||
| Blurred vision | 0/6 (0%) | 0 | 1/6 (16.7%) | 3 | 1/6 (16.7%) | 1 | 0/4 (0%) | 0 | 2/20 (10%) | 13 | 1/12 (8.3%) | 1 |
| Conjunctivitis | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/4 (0%) | 0 | 0/20 (0%) | 0 | 0/12 (0%) | 0 |
| Dry eye | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 3 | 0/4 (0%) | 0 | 0/20 (0%) | 0 | 1/12 (8.3%) | 1 |
| Eye disorders - Other, specify | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 2/6 (33.3%) | 4 | 0/4 (0%) | 0 | 2/20 (10%) | 3 | 1/12 (8.3%) | 1 |
| Eye pain | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 1/6 (16.7%) | 1 | 0/4 (0%) | 0 | 1/20 (5%) | 1 | 1/12 (8.3%) | 1 |
| Photophobia | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/4 (0%) | 0 | 0/20 (0%) | 0 | 1/12 (8.3%) | 1 |
| Gastrointestinal disorders | ||||||||||||
| Abdominal distension | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/4 (25%) | 2 | 0/20 (0%) | 0 | 0/12 (0%) | 0 |
| Abdominal pain | 4/6 (66.7%) | 17 | 2/6 (33.3%) | 8 | 5/6 (83.3%) | 20 | 0/4 (0%) | 0 | 10/20 (50%) | 17 | 4/12 (33.3%) | 9 |
| Anal pain | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/4 (0%) | 0 | 0/20 (0%) | 0 | 0/12 (0%) | 0 |
| Colitis | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/4 (25%) | 1 | 0/20 (0%) | 0 | 0/12 (0%) | 0 |
| Constipation | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 2/6 (33.3%) | 5 | 1/4 (25%) | 2 | 0/20 (0%) | 0 | 2/12 (16.7%) | 2 |
| Dental caries | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/4 (0%) | 0 | 1/20 (5%) | 3 | 0/12 (0%) | 0 |
| Diarrhea | 6/6 (100%) | 45 | 6/6 (100%) | 27 | 6/6 (100%) | 50 | 4/4 (100%) | 14 | 18/20 (90%) | 88 | 9/12 (75%) | 27 |
| Dry mouth | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/4 (0%) | 0 | 1/20 (5%) | 2 | 0/12 (0%) | 0 |
| Dyspepsia | 1/6 (16.7%) | 2 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/4 (0%) | 0 | 0/20 (0%) | 0 | 0/12 (0%) | 0 |
| Enterocolitis | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/4 (25%) | 1 | 0/20 (0%) | 0 | 0/12 (0%) | 0 |
| Flatulence | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 1/4 (25%) | 1 | 0/20 (0%) | 0 | 0/12 (0%) | 0 |
| Gastroesophageal reflux disease | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/4 (0%) | 0 | 0/20 (0%) | 0 | 0/12 (0%) | 0 |
| Gastrointestinal disorders - Other, specify | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 2/6 (33.3%) | 5 | 0/4 (0%) | 0 | 3/20 (15%) | 5 | 2/12 (16.7%) | 2 |
| Mucositis oral | 2/6 (33.3%) | 3 | 1/6 (16.7%) | 1 | 4/6 (66.7%) | 18 | 2/4 (50%) | 2 | 5/20 (25%) | 11 | 0/12 (0%) | 0 |
| Nausea | 6/6 (100%) | 33 | 5/6 (83.3%) | 37 | 5/6 (83.3%) | 52 | 4/4 (100%) | 11 | 18/20 (90%) | 98 | 9/12 (75%) | 17 |
| Oral dysesthesia | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/4 (0%) | 0 | 0/20 (0%) | 0 | 0/12 (0%) | 0 |
| Oral hemorrhage | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/4 (0%) | 0 | 0/20 (0%) | 0 | 0/12 (0%) | 0 |
| Oral pain | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 2 | 1/4 (25%) | 1 | 2/20 (10%) | 2 | 0/12 (0%) | 0 |
| Rectal hemorrhage | 1/6 (16.7%) | 3 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/4 (0%) | 0 | 0/20 (0%) | 0 | 0/12 (0%) | 0 |
| Rectal pain | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 2 | 0/4 (0%) | 0 | 0/20 (0%) | 0 | 0/12 (0%) | 0 |
| Stomach pain | 0/6 (0%) | 0 | 1/6 (16.7%) | 5 | 1/6 (16.7%) | 1 | 1/4 (25%) | 2 | 0/20 (0%) | 0 | 0/12 (0%) | 0 |
| Toothache | 0/6 (0%) | 0 | 1/6 (16.7%) | 3 | 1/6 (16.7%) | 4 | 0/4 (0%) | 0 | 1/20 (5%) | 2 | 1/12 (8.3%) | 1 |
| Vomiting | 4/6 (66.7%) | 29 | 6/6 (100%) | 38 | 6/6 (100%) | 34 | 4/4 (100%) | 6 | 17/20 (85%) | 68 | 11/12 (91.7%) | 24 |
| General disorders | ||||||||||||
| Chills | 1/6 (16.7%) | 2 | 1/6 (16.7%) | 2 | 1/6 (16.7%) | 1 | 0/4 (0%) | 0 | 0/20 (0%) | 0 | 0/12 (0%) | 0 |
| Edema face | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/4 (0%) | 0 | 1/20 (5%) | 1 | 0/12 (0%) | 0 |
| Edema trunk | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/4 (0%) | 0 | 0/20 (0%) | 0 | 1/12 (8.3%) | 1 |
| Facial pain | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/4 (0%) | 0 | 0/20 (0%) | 0 | 0/12 (0%) | 0 |
| Fatigue | 4/6 (66.7%) | 10 | 3/6 (50%) | 6 | 5/6 (83.3%) | 24 | 3/4 (75%) | 12 | 10/20 (50%) | 23 | 4/12 (33.3%) | 7 |
| Fever | 5/6 (83.3%) | 7 | 3/6 (50%) | 10 | 5/6 (83.3%) | 9 | 2/4 (50%) | 2 | 10/20 (50%) | 15 | 4/12 (33.3%) | 4 |
| General disorders and administration site conditions - Other, specify | 1/6 (16.7%) | 1 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/4 (0%) | 0 | 0/20 (0%) | 0 | 0/12 (0%) | 0 |
| Infusion related reaction | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 2 | 0/4 (0%) | 0 | 1/20 (5%) | 1 | 0/12 (0%) | 0 |
| Infusion site extravasation | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/4 (0%) | 0 | 1/20 (5%) | 1 | 0/12 (0%) | 0 |
| Irritability | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/4 (0%) | 0 | 1/20 (5%) | 2 | 3/12 (25%) | 4 |
| Malaise | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/4 (25%) | 1 | 2/20 (10%) | 2 | 0/12 (0%) | 0 |
| Non-cardiac chest pain | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/4 (0%) | 0 | 2/20 (10%) | 3 | 0/12 (0%) | 0 |
| Pain | 2/6 (33.3%) | 3 | 1/6 (16.7%) | 1 | 1/6 (16.7%) | 5 | 1/4 (25%) | 1 | 3/20 (15%) | 6 | 2/12 (16.7%) | 3 |
| Infections and infestations | ||||||||||||
| Conjunctivitis infective | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/4 (0%) | 0 | 1/20 (5%) | 1 | 0/12 (0%) | 0 |
| Enterocolitis infectious | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/4 (0%) | 0 | 1/20 (5%) | 1 | 1/12 (8.3%) | 1 |
| Infections and infestations - Other, specify | 1/6 (16.7%) | 1 | 1/6 (16.7%) | 2 | 2/6 (33.3%) | 6 | 1/4 (25%) | 1 | 3/20 (15%) | 3 | 0/12 (0%) | 0 |
| Lung infection | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 1/4 (25%) | 1 | 1/20 (5%) | 3 | 0/12 (0%) | 0 |
| Mucosal infection | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/4 (0%) | 0 | 0/20 (0%) | 0 | 1/12 (8.3%) | 1 |
| Otitis externa | 0/6 (0%) | 0 | 1/6 (16.7%) | 2 | 0/6 (0%) | 0 | 0/4 (0%) | 0 | 0/20 (0%) | 0 | 0/12 (0%) | 0 |
| Otitis media | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/4 (0%) | 0 | 1/20 (5%) | 1 | 1/12 (8.3%) | 2 |
| Rhinitis infective | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/4 (0%) | 0 | 1/20 (5%) | 1 | 0/12 (0%) | 0 |
| Sepsis | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/4 (0%) | 0 | 1/20 (5%) | 1 | 0/12 (0%) | 0 |
| Skin infection | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/4 (0%) | 0 | 0/20 (0%) | 0 | 1/12 (8.3%) | 1 |
| Upper respiratory infection | 0/6 (0%) | 0 | 2/6 (33.3%) | 4 | 3/6 (50%) | 8 | 1/4 (25%) | 1 | 6/20 (30%) | 8 | 0/12 (0%) | 0 |
| Urinary tract infection | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 1/6 (16.7%) | 1 | 0/4 (0%) | 0 | 1/20 (5%) | 4 | 0/12 (0%) | 0 |
| Vaginal infection | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/4 (0%) | 0 | 0/20 (0%) | 0 | 0/12 (0%) | 0 |
| Injury, poisoning and procedural complications | ||||||||||||
| Bruising | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 3/6 (50%) | 7 | 1/4 (25%) | 2 | 4/20 (20%) | 9 | 1/12 (8.3%) | 3 |
| Burn | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/4 (0%) | 0 | 1/20 (5%) | 2 | 0/12 (0%) | 0 |
| Fall | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/4 (0%) | 0 | 1/20 (5%) | 2 | 0/12 (0%) | 0 |
| Vascular access complication | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/4 (0%) | 0 | 0/20 (0%) | 0 | 0/12 (0%) | 0 |
| Investigations | ||||||||||||
| Activated partial thromboplastin time prolonged | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/4 (0%) | 0 | 0/20 (0%) | 0 | 0/12 (0%) | 0 |
| Alanine aminotransferase increased | 6/6 (100%) | 36 | 4/6 (66.7%) | 32 | 5/6 (83.3%) | 51 | 3/4 (75%) | 3 | 18/20 (90%) | 112 | 8/12 (66.7%) | 23 |
| Alkaline phosphatase increased | 2/6 (33.3%) | 4 | 0/6 (0%) | 0 | 1/6 (16.7%) | 6 | 0/4 (0%) | 0 | 7/20 (35%) | 32 | 0/12 (0%) | 0 |
| Aspartate aminotransferase increased | 6/6 (100%) | 42 | 4/6 (66.7%) | 23 | 6/6 (100%) | 51 | 2/4 (50%) | 2 | 17/20 (85%) | 103 | 10/12 (83.3%) | 22 |
| Blood bilirubin increased | 2/6 (33.3%) | 17 | 2/6 (33.3%) | 11 | 1/6 (16.7%) | 7 | 1/4 (25%) | 2 | 3/20 (15%) | 4 | 0/12 (0%) | 0 |
| Creatinine increased | 0/6 (0%) | 0 | 2/6 (33.3%) | 5 | 3/6 (50%) | 27 | 1/4 (25%) | 1 | 5/20 (25%) | 9 | 3/12 (25%) | 4 |
| Electrocardiogram QT corrected interval prolonged | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/4 (0%) | 0 | 1/20 (5%) | 2 | 0/12 (0%) | 0 |
| GGT increased | 3/6 (50%) | 12 | 1/6 (16.7%) | 32 | 2/6 (33.3%) | 3 | 0/4 (0%) | 0 | 0/20 (0%) | 0 | 0/12 (0%) | 0 |
| Hemoglobin increased | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/4 (0%) | 0 | 0/20 (0%) | 0 | 0/12 (0%) | 0 |
| Investigations - Other, specify | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 5 | 1/4 (25%) | 2 | 0/20 (0%) | 0 | 0/12 (0%) | 0 |
| Lymphocyte count decreased | 3/6 (50%) | 32 | 4/6 (66.7%) | 21 | 5/6 (83.3%) | 43 | 3/4 (75%) | 14 | 17/20 (85%) | 111 | 10/12 (83.3%) | 26 |
| Lymphocyte count increased | 1/6 (16.7%) | 2 | 0/6 (0%) | 0 | 2/6 (33.3%) | 8 | 0/4 (0%) | 0 | 1/20 (5%) | 2 | 0/12 (0%) | 0 |
| Neutrophil count decreased | 6/6 (100%) | 43 | 6/6 (100%) | 46 | 6/6 (100%) | 66 | 4/4 (100%) | 15 | 20/20 (100%) | 132 | 12/12 (100%) | 41 |
| Platelet count decreased | 5/6 (83.3%) | 43 | 5/6 (83.3%) | 55 | 6/6 (100%) | 93 | 4/4 (100%) | 16 | 20/20 (100%) | 154 | 10/12 (83.3%) | 43 |
| Weight gain | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 2/6 (33.3%) | 25 | 0/4 (0%) | 0 | 1/20 (5%) | 3 | 0/12 (0%) | 0 |
| Weight loss | 2/6 (33.3%) | 22 | 1/6 (16.7%) | 1 | 2/6 (33.3%) | 13 | 3/4 (75%) | 4 | 3/20 (15%) | 9 | 5/12 (41.7%) | 6 |
| White blood cell decreased | 6/6 (100%) | 55 | 6/6 (100%) | 57 | 6/6 (100%) | 89 | 3/4 (75%) | 15 | 20/20 (100%) | 150 | 11/12 (91.7%) | 45 |
| Metabolism and nutrition disorders | ||||||||||||
| Acidosis | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/4 (25%) | 2 | 1/20 (5%) | 2 | 1/12 (8.3%) | 1 |
| Anorexia | 3/6 (50%) | 7 | 2/6 (33.3%) | 3 | 4/6 (66.7%) | 40 | 4/4 (100%) | 9 | 10/20 (50%) | 25 | 5/12 (41.7%) | 17 |
| Dehydration | 2/6 (33.3%) | 3 | 1/6 (16.7%) | 4 | 4/6 (66.7%) | 6 | 1/4 (25%) | 1 | 6/20 (30%) | 10 | 2/12 (16.7%) | 4 |
| Hypercalcemia | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 2 | 1/4 (25%) | 1 | 1/20 (5%) | 1 | 0/12 (0%) | 0 |
| Hyperglycemia | 4/6 (66.7%) | 11 | 2/6 (33.3%) | 5 | 4/6 (66.7%) | 22 | 2/4 (50%) | 3 | 9/20 (45%) | 27 | 5/12 (41.7%) | 9 |
| Hyperkalemia | 1/6 (16.7%) | 4 | 1/6 (16.7%) | 2 | 2/6 (33.3%) | 2 | 0/4 (0%) | 0 | 1/20 (5%) | 1 | 0/12 (0%) | 0 |
| Hypermagnesemia | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 2/6 (33.3%) | 17 | 0/4 (0%) | 0 | 0/20 (0%) | 0 | 3/12 (25%) | 11 |
| Hypernatremia | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 3/6 (50%) | 10 | 0/4 (0%) | 0 | 3/20 (15%) | 6 | 3/12 (25%) | 4 |
| Hypertriglyceridemia | 0/6 (0%) | 0 | 1/6 (16.7%) | 3 | 0/6 (0%) | 0 | 0/4 (0%) | 0 | 1/20 (5%) | 1 | 0/12 (0%) | 0 |
| Hypoalbuminemia | 4/6 (66.7%) | 18 | 3/6 (50%) | 5 | 5/6 (83.3%) | 18 | 2/4 (50%) | 2 | 11/20 (55%) | 19 | 8/12 (66.7%) | 14 |
| Hypocalcemia | 3/6 (50%) | 27 | 1/6 (16.7%) | 2 | 5/6 (83.3%) | 29 | 1/4 (25%) | 1 | 11/20 (55%) | 22 | 5/12 (41.7%) | 9 |
| Hypoglycemia | 2/6 (33.3%) | 3 | 3/6 (50%) | 13 | 2/6 (33.3%) | 2 | 0/4 (0%) | 0 | 1/20 (5%) | 4 | 1/12 (8.3%) | 1 |
| Hypokalemia | 4/6 (66.7%) | 29 | 3/6 (50%) | 6 | 4/6 (66.7%) | 14 | 3/4 (75%) | 4 | 10/20 (50%) | 26 | 6/12 (50%) | 7 |
| Hypomagnesemia | 1/6 (16.7%) | 2 | 2/6 (33.3%) | 9 | 2/6 (33.3%) | 10 | 2/4 (50%) | 2 | 5/20 (25%) | 10 | 4/12 (33.3%) | 4 |
| Hyponatremia | 4/6 (66.7%) | 11 | 2/6 (33.3%) | 10 | 5/6 (83.3%) | 9 | 2/4 (50%) | 3 | 8/20 (40%) | 12 | 6/12 (50%) | 6 |
| Hypophosphatemia | 3/6 (50%) | 7 | 1/6 (16.7%) | 2 | 2/6 (33.3%) | 5 | 1/4 (25%) | 1 | 8/20 (40%) | 11 | 6/12 (50%) | 15 |
| Metabolism and nutrition disorders - Other, specify | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 3 | 0/4 (0%) | 0 | 0/20 (0%) | 0 | 0/12 (0%) | 0 |
| Musculoskeletal and connective tissue disorders | ||||||||||||
| Back pain | 2/6 (33.3%) | 2 | 2/6 (33.3%) | 9 | 0/6 (0%) | 0 | 0/4 (0%) | 0 | 0/20 (0%) | 0 | 0/12 (0%) | 0 |
| Bone pain | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/4 (0%) | 0 | 1/20 (5%) | 1 | 1/12 (8.3%) | 1 |
| Chest wall pain | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/4 (0%) | 0 | 1/20 (5%) | 2 | 0/12 (0%) | 0 |
| Generalized muscle weakness | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/4 (0%) | 0 | 0/20 (0%) | 0 | 1/12 (8.3%) | 1 |
| Muscle weakness lower limb | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/4 (0%) | 0 | 0/20 (0%) | 0 | 0/12 (0%) | 0 |
| Musculoskeletal and connective tissue disorder - Other, specify | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 2/6 (33.3%) | 6 | 0/4 (0%) | 0 | 1/20 (5%) | 2 | 0/12 (0%) | 0 |
| Neck pain | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/4 (0%) | 0 | 1/20 (5%) | 2 | 0/12 (0%) | 0 |
| Pain in extremity | 1/6 (16.7%) | 2 | 1/6 (16.7%) | 3 | 4/6 (66.7%) | 25 | 1/4 (25%) | 2 | 4/20 (20%) | 5 | 3/12 (25%) | 4 |
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||||||||||
| Tumor pain | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/4 (0%) | 0 | 1/20 (5%) | 9 | 0/12 (0%) | 0 |
| Nervous system disorders | ||||||||||||
| Depressed level of consciousness | 1/6 (16.7%) | 2 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/4 (0%) | 0 | 0/20 (0%) | 0 | 0/12 (0%) | 0 |
| Dizziness | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 2 | 0/4 (0%) | 0 | 4/20 (20%) | 4 | 2/12 (16.7%) | 2 |
| Dysgeusia | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 1/6 (16.7%) | 2 | 0/4 (0%) | 0 | 1/20 (5%) | 1 | 0/12 (0%) | 0 |
| Headache | 2/6 (33.3%) | 3 | 3/6 (50%) | 9 | 3/6 (50%) | 11 | 3/4 (75%) | 6 | 9/20 (45%) | 18 | 1/12 (8.3%) | 1 |
| Nervous system disorders - Other, specify | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/4 (0%) | 0 | 0/20 (0%) | 0 | 0/12 (0%) | 0 |
| Paresthesia | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 2 | 0/4 (0%) | 0 | 0/20 (0%) | 0 | 0/12 (0%) | 0 |
| Peripheral motor neuropathy | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/4 (0%) | 0 | 1/20 (5%) | 1 | 1/12 (8.3%) | 2 |
| Peripheral sensory neuropathy | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/4 (0%) | 0 | 2/20 (10%) | 3 | 0/12 (0%) | 0 |
| Presyncope | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/4 (0%) | 0 | 0/20 (0%) | 0 | 0/12 (0%) | 0 |
| Somnolence | 1/6 (16.7%) | 7 | 2/6 (33.3%) | 3 | 0/6 (0%) | 0 | 2/4 (50%) | 2 | 4/20 (20%) | 4 | 3/12 (25%) | 4 |
| Syncope | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/4 (0%) | 0 | 1/20 (5%) | 1 | 0/12 (0%) | 0 |
| Tremor | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/4 (25%) | 1 | 0/20 (0%) | 0 | 0/12 (0%) | 0 |
| Psychiatric disorders | ||||||||||||
| Agitation | 1/6 (16.7%) | 3 | 1/6 (16.7%) | 8 | 0/6 (0%) | 0 | 2/4 (50%) | 3 | 2/20 (10%) | 2 | 2/12 (16.7%) | 3 |
| Anxiety | 0/6 (0%) | 0 | 2/6 (33.3%) | 9 | 2/6 (33.3%) | 5 | 1/4 (25%) | 2 | 3/20 (15%) | 9 | 0/12 (0%) | 0 |
| Depression | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/4 (25%) | 1 | 0/20 (0%) | 0 | 1/12 (8.3%) | 1 |
| Hallucinations | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/4 (0%) | 0 | 0/20 (0%) | 0 | 0/12 (0%) | 0 |
| Insomnia | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/4 (25%) | 1 | 0/20 (0%) | 0 | 0/12 (0%) | 0 |
| Psychiatric disorders - Other, specify | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/4 (0%) | 0 | 2/20 (10%) | 2 | 0/12 (0%) | 0 |
| Restlessness | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/4 (0%) | 0 | 0/20 (0%) | 0 | 0/12 (0%) | 0 |
| Renal and urinary disorders | ||||||||||||
| Acute kidney injury | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/4 (0%) | 0 | 2/20 (10%) | 2 | 0/12 (0%) | 0 |
| Hematuria | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 2/6 (33.3%) | 4 | 0/4 (0%) | 0 | 3/20 (15%) | 24 | 0/12 (0%) | 0 |
| Proteinuria | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 1/6 (16.7%) | 23 | 0/4 (0%) | 0 | 0/20 (0%) | 0 | 0/12 (0%) | 0 |
| Urinary retention | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/4 (0%) | 0 | 1/20 (5%) | 2 | 0/12 (0%) | 0 |
| Urinary tract pain | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/4 (0%) | 0 | 1/20 (5%) | 2 | 0/12 (0%) | 0 |
| Urine discoloration | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/4 (0%) | 0 | 0/20 (0%) | 0 | 0/12 (0%) | 0 |
| Reproductive system and breast disorders | ||||||||||||
| Penile pain | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 2 | 0/4 (0%) | 0 | 0/20 (0%) | 0 | 0/12 (0%) | 0 |
| Respiratory, thoracic and mediastinal disorders | ||||||||||||
| Allergic rhinitis | 1/6 (16.7%) | 8 | 0/6 (0%) | 0 | 2/6 (33.3%) | 6 | 1/4 (25%) | 8 | 3/20 (15%) | 13 | 1/12 (8.3%) | 14 |
| Apnea | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/4 (0%) | 0 | 1/20 (5%) | 1 | 0/12 (0%) | 0 |
| Atelectasis | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/4 (0%) | 0 | 1/20 (5%) | 2 | 0/12 (0%) | 0 |
| Bronchospasm | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/4 (0%) | 0 | 1/20 (5%) | 1 | 0/12 (0%) | 0 |
| Cough | 5/6 (83.3%) | 10 | 5/6 (83.3%) | 13 | 5/6 (83.3%) | 29 | 3/4 (75%) | 9 | 7/20 (35%) | 14 | 5/12 (41.7%) | 9 |
| Dyspnea | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/4 (0%) | 0 | 2/20 (10%) | 2 | 0/12 (0%) | 0 |
| Epistaxis | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 2/4 (50%) | 6 | 5/20 (25%) | 16 | 0/12 (0%) | 0 |
| Nasal congestion | 3/6 (50%) | 5 | 3/6 (50%) | 5 | 3/6 (50%) | 10 | 1/4 (25%) | 2 | 6/20 (30%) | 7 | 1/12 (8.3%) | 3 |
| Pharyngeal mucositis | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/4 (0%) | 0 | 1/20 (5%) | 1 | 0/12 (0%) | 0 |
| Pharyngolaryngeal pain | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/4 (0%) | 0 | 1/20 (5%) | 1 | 0/12 (0%) | 0 |
| Postnasal drip | 1/6 (16.7%) | 2 | 0/6 (0%) | 0 | 1/6 (16.7%) | 2 | 0/4 (0%) | 0 | 0/20 (0%) | 0 | 0/12 (0%) | 0 |
| Respiratory, thoracic and mediastinal disorders - Other, specify | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 3/6 (50%) | 22 | 1/4 (25%) | 2 | 2/20 (10%) | 2 | 0/12 (0%) | 0 |
| Sore throat | 2/6 (33.3%) | 3 | 1/6 (16.7%) | 1 | 2/6 (33.3%) | 5 | 1/4 (25%) | 2 | 4/20 (20%) | 7 | 1/12 (8.3%) | 2 |
| Skin and subcutaneous tissue disorders | ||||||||||||
| Alopecia | 3/6 (50%) | 38 | 1/6 (16.7%) | 2 | 3/6 (50%) | 52 | 2/4 (50%) | 12 | 8/20 (40%) | 86 | 4/12 (33.3%) | 32 |
| Bullous dermatitis | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/4 (0%) | 0 | 0/20 (0%) | 0 | 1/12 (8.3%) | 1 |
| Dry skin | 1/6 (16.7%) | 5 | 0/6 (0%) | 0 | 3/6 (50%) | 9 | 0/4 (0%) | 0 | 2/20 (10%) | 8 | 1/12 (8.3%) | 18 |
| Palmar-plantar erythrodysesthesia syndrome | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/4 (25%) | 2 | 1/20 (5%) | 2 | 0/12 (0%) | 0 |
| Pruritus | 2/6 (33.3%) | 6 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/4 (0%) | 0 | 3/20 (15%) | 3 | 4/12 (33.3%) | 4 |
| Rash acneiform | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/4 (0%) | 0 | 1/20 (5%) | 2 | 0/12 (0%) | 0 |
| Rash maculo-papular | 2/6 (33.3%) | 2 | 2/6 (33.3%) | 3 | 2/6 (33.3%) | 7 | 1/4 (25%) | 1 | 3/20 (15%) | 3 | 2/12 (16.7%) | 3 |
| Skin and subcutaneous tissue disorders - Other, specify | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 2/6 (33.3%) | 11 | 0/4 (0%) | 0 | 1/20 (5%) | 2 | 2/12 (16.7%) | 2 |
| Skin hyperpigmentation | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/4 (0%) | 0 | 0/20 (0%) | 0 | 0/12 (0%) | 0 |
| Skin ulceration | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 2 | 0/4 (0%) | 0 | 0/20 (0%) | 0 | 0/12 (0%) | 0 |
| Urticaria | 1/6 (16.7%) | 1 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/4 (0%) | 0 | 1/20 (5%) | 1 | 0/12 (0%) | 0 |
| Surgical and medical procedures | ||||||||||||
| Surgical and medical procedures - Other, specify | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 1/6 (16.7%) | 1 | 0/4 (0%) | 0 | 0/20 (0%) | 0 | 0/12 (0%) | 0 |
| Vascular disorders | ||||||||||||
| Flushing | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/4 (0%) | 0 | 2/20 (10%) | 2 | 0/12 (0%) | 0 |
| Hematoma | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/4 (0%) | 0 | 1/20 (5%) | 12 | 0/12 (0%) | 0 |
| Hypertension | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 2/4 (50%) | 3 | 1/20 (5%) | 4 | 0/12 (0%) | 0 |
| Hypotension | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 1/6 (16.7%) | 7 | 1/4 (25%) | 2 | 2/20 (10%) | 7 | 1/12 (8.3%) | 1 |
Limitations/Caveats
[Not Specified]
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
| Name/Title | NANT Medical Director |
|---|---|
| Organization | New Approaches to Neuroblastoma Therapy |
| Phone | 323-361-5687 |
| nantops@chla.usc.edu |
Responsible Party:
New Approaches to Neuroblastoma Therapy Consortium
ClinicalTrials.gov Identifier:
NCT01601535
Other Study ID Numbers:
- N2009-03
First Posted:
May 18, 2012
Last Update Posted:
Jul 31, 2019
Last Verified:
Jul 1, 2019