Study of MLN8237 in Combination With Irinotecan and Temozolomide

Phase I/II Study of MLN8237 in Combination With Irinotecan and Temozolomide for Patients With Relapsed or Refractory Neuroblastoma

Status

Completed

Phases

Phase 1Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01601535

Enrollment

Registered

2012-05-18

Start date

2012-05-31

Completion date

2018-07-25

Last updated

2019-07-31

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Neuroblastoma

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.

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.

Interventions

DRUGMLN8237

Every course will be 21 days. MLN8237 will be administered orally daily starting on day 1 through day 7.

DRUGIrinotecan

Irinotecan will be administered intravenously during each course on study day 1 through day 5.

DRUGTemozolomide

Temozolomide will be administered orally during each course on study day 1 through day 5.

Study design

Intervention model

SEQUENTIAL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

12 Months to 30 Years

Healthy volunteers

Inclusion criteria

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.

Design outcomes

Primary

Measure	Time frame	Description
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.
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.
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.

Secondary

Measure	Time frame	Description
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
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

Countries

Canada, United States

Participant flow

Participants by arm

Arm	Count
DL 1 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	6
DL 1B 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	6
DL 2B 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	6
DL 3B 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	4
Ph 2 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	20
Oral Solution 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	12
Total	54

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003	FG004	FG005
Phase 1	Adverse Event	1	0	2	1	0	0
Phase 1	Progressive Disease	2	3	2	1	0	0
Phase 1	Started Another Treatment	1	2	0	0	0	0
Phase 1	Withdrawal by Subject	2	1	1	2	0	0
Phase 2	Adverse Event	0	0	0	0	5	1
Phase 2	Progressive Disease	0	0	0	0	5	7
Phase 2	Started Another Treatment	0	0	0	0	1	2
Phase 2	Withdrawal by Subject	0	0	0	0	8	2

Baseline characteristics

Characteristic	DL 1	Oral Solution	Total	Ph 2	DL 3B	DL 2B	DL 1B
Age, Continuous	8.60 years	3.05 years	7.61 years	10.74 years	6.14 years	7.67 years	6.81 years
Prior Irinotecan No	3 Participants	10 Participants	36 Participants	9 Participants	3 Participants	6 Participants	5 Participants
Prior Irinotecan Yes	3 Participants	2 Participants	18 Participants	11 Participants	1 Participants	0 Participants	1 Participants
Prior Temozolomide No	3 Participants	10 Participants	37 Participants	10 Participants	3 Participants	6 Participants	5 Participants
Prior Temozolomide Yes	3 Participants	2 Participants	17 Participants	10 Participants	1 Participants	0 Participants	1 Participants
Race/Ethnicity, Customized Hispanic	0 Participants	0 Participants	2 Participants	1 Participants	0 Participants	0 Participants	1 Participants
Race/Ethnicity, Customized Not Hispanic Black or African American	1 Participants	0 Participants	5 Participants	3 Participants	0 Participants	1 Participants	0 Participants
Race/Ethnicity, Customized Not Hispanic Other	0 Participants	0 Participants	1 Participants	1 Participants	0 Participants	0 Participants	0 Participants
Race/Ethnicity, Customized Not Hispanic Unknown	0 Participants	0 Participants	1 Participants	1 Participants	0 Participants	0 Participants	0 Participants
Race/Ethnicity, Customized Not Hispanic White	5 Participants	12 Participants	45 Participants	14 Participants	4 Participants	5 Participants	5 Participants
Region of Enrollment United States	6 participants	12 participants	54 participants	20 participants	4 participants	6 participants	6 participants
Sex: Female, Male Female	0 Participants	6 Participants	16 Participants	6 Participants	1 Participants	1 Participants	2 Participants
Sex: Female, Male Male	6 Participants	6 Participants	38 Participants	14 Participants	3 Participants	5 Participants	4 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk	EG005 affected / at risk
deaths Total, all-cause mortality	0 / 6	0 / 6	0 / 6	0 / 4	0 / 20	0 / 12
other Total, other adverse events	6 / 6	6 / 6	6 / 6	4 / 4	20 / 20	12 / 12
serious Total, serious adverse events	3 / 6	3 / 6	3 / 6	2 / 4	1 / 20	2 / 12

Outcome results

Primary

Dose Limiting Toxicity (DLT) Data Associated With the Determination of the Recommended Phase 2 Dose

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

Arm	Measure	Value (NUMBER)
Phase I	Dose Limiting Toxicity (DLT) Data Associated With the Determination of the Recommended Phase 2 Dose	2 DLTs
DL 1B	Dose Limiting Toxicity (DLT) Data Associated With the Determination of the Recommended Phase 2 Dose	0 DLTs
DL 2B	Dose Limiting Toxicity (DLT) Data Associated With the Determination of the Recommended Phase 2 Dose	1 DLTs
DL 3B	Dose Limiting Toxicity (DLT) Data Associated With the Determination of the Recommended Phase 2 Dose	2 DLTs

Primary

Maximum Tolerated Dose (MTD) When Given Together With Fixed Doses of Irinotecan and Temozolomide in Children and Young Adults With Relapsed or Refractory Neuroblastoma

Time frame: 21 days, from study day 1

Arm	Measure	Value (NUMBER)
Phase I	Maximum Tolerated Dose (MTD) When Given Together With Fixed Doses of Irinotecan and Temozolomide in Children and Young Adults With Relapsed or Refractory Neuroblastoma	60 mg/m^2

Primary

Pharmacokinetics When Given Together With Fixed Doses of Irinotecan and Temozolomide in Children and Young Adults With Relapsed or Refractory Neuroblastoma: Alisertib AUC

Outcomes included Alisertib, irinotecan, APC, SN-38, and SN-38G. APC, SN-38, and SN-38G are metabolites of irinotecan.