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NCT00697346

Study of MLN8237 in Participants With Advanced Hematological Malignancies

Completed Phase 1 Results posted Last updated 31 May 2019
What this trial tests

Phase 1 trial testing Alisertib in B-cell Follicular Lymphoma in 58 participants. Completed in 19 October 2016.

Timeline
11 July 2008
Primary endpoint
1 October 2016
19 October 2016

Quick facts

Lead sponsorMillennium Pharmaceuticals, Inc.
PhasePhase 1
StatusCompleted
Study typeINTERVENTIONAL
Allocationnon randomized
Designparallel
Maskingquadruple
Primary purposetreatment
Enrollment58
Start date11 July 2008
Primary completion1 October 2016
Estimated completion19 October 2016
Sites10 locations across United States

Drugs / interventions tested

Conditions studied

Sponsor

Millennium Pharmaceuticals, Inc. — full company profile →

Who can join

18 and older, any sex, with B-cell Follicular Lymphoma or B-cell Marginal Zone Lymphoma. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Number of Participants With Dose-Limiting Toxicity (DLT) Primary · From first dose of study drug to 30 days after the last dose (up to 422 days)

DLT was evaluated according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0 and was defined as any of the following events related to therapy with alisertib:1. Grade 4 neutropenia lasting ≥7 consecutive days, 2. Grade 4 neutropenia with fever and/or infection 3. Platelet count \<25,000/mm\^3 4. Grade 3 or greater nausea and/or emesis despite use of optimal antiemetic prophylaxis 5. Grade 3 or greater diarrhea despite maximal supportive therapy with loperamide 6. Any other Grade 3 or greater nonhematologic toxicity, with the following ex

GroupValue95% CI
Alisertib 25mg PIC QD 21D1
Alisertib 35 mg PIC QD 21D2
Alisertib 35 mg PIC QD 14D0
Alisertib 45 mg PIC QD 14D1
Alisertib 65 mg PIC QD 14D2
Alisertib 90 mg PIC QD 14D2
Alisertib 40 mg ECT QD 14D2
Alisertib 30 mg ECT BID 7D0
Alisertib 40 mg ECT BID 7D0
Alisertib 50 mg ECT BID 7D1
Maximum Tolerated Dose (MTD) of Alisertib Primary · From first dose of study drug to 30 days after the last dose (up to 422 days)

MTD was defined as the highest dose at which DLT occurred in 0/3 or 1/6 participants.

GroupValue95% CI
Alisertib50
Cmax: Maximum Observed Concentration for Alisertib as Pill in Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing at Day 1 Primary · Cycle 1 Day 1 predose and at multiple timepoints (up to 24 hours) postdose
GroupValue95% CI
Alisertib 25mg PIC QD 21D833.2± 49.5
Alisertib 35 mg PIC QD 21D1078.3± 26.4
Cmax: Maximum Observed Concentration for Alisertib as Pill in Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing at Day 21 Primary · Cycle 1 Day 21 predose and at multiple timepoints (up to 6 hours) postdose
GroupValue95% CI
Alisertib 25mg PIC QD 21D1337.6± 57.8
Alisertib 35 mg PIC QD 21D1451.9± 26.2
Tmax: Time of First Occurrence of Cmax for Alisertib as Pill in Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing at Day 1 Primary · Cycle 1 Day 1 predose and at multiple timepoints (up to 24 hours) postdose
GroupValue95% CI
Alisertib 25mg PIC QD 21D2.02.0 – 3.3
Alisertib 35 mg PIC QD 21D2.01.1 – 5.2
Tmax: Time of First Occurrence of Cmax for Alisertib as Pill in Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing at Day 21 Primary · Cycle 1 Day 21 predose and at multiple timepoints (up to 6 hours) postdose
GroupValue95% CI
Alisertib 25mg PIC QD 21D2.01.0 – 5.0
Alisertib 35 mg PIC QD 21D2.02.0 – 2.0
AUCt: Area Under the Concentration Time Curve From Time 0 to Time t for Alisertib as Pill in Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing at Day 21 Primary · Cycle 1 Day 21 predose and at multiple time points (up to 6 hours) postdose
GroupValue95% CI
Alisertib 25mg PIC QD 21D14846± 69.7
Alisertib 35 mg PIC QD 21D16528± 35.6
Terminal Half-Life (t1/2) for Alisertib as Pill in Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing at Day 21 Primary · Cycle 1 Day 21 predose and at multiple time points (up to 6 hours) postdose
GroupValue95% CI
Alisertib 25mg PIC QD 21D20.5± 7.3
Alisertib 35 mg PIC QD 21D19.5± 6.0
Accumulation Ratio (Rac) for Alisertib as Pill in Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing at Day 21 Primary · Cycle 1 Day 21 predose and at multiple time points (up to 6 hours) postdose
GroupValue95% CI
Alisertib 25mg PIC QD 21D1.9± 1.1
Alisertib 35 mg PIC QD 21D1.5± 0.5
Peak/Trough Ratio for Alisertib as Pill in Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing at Day 21 Primary · Cycle 1 Day 21 predose and at multiple timepoints (up to 6 hours) postdose
GroupValue95% CI
Alisertib 25mg PIC QD 21D6.0± 4.4
Alisertib 35 mg PIC QD 21D4.3± 1.5
CLss/F: Apparent Oral Clearance at Steady State for Alisertib as Pill in Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing at Day 21 Primary · Cycle 1 Day 21 predose and at multiple timepoints (up to 6 hours) postdose
GroupValue95% CI
Alisertib 25mg PIC QD 21D3.2± 113
Alisertib 35 mg PIC QD 21D4.1± 45
Cmax: Maximum Observed Concentration for Alisertib as Pill in Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing at Day 1 Primary · Cycle 1 Day 1 predose and at multiple timepoints (up to 24 hours) postdose
GroupValue95% CI
Alisertib 35 mg PIC QD 14D726.5± 34.8
Alisertib 45 mg PIC QD 14D1637.0± 58.0
Alisertib 65 mg PIC QD 14D1773.4± 44.3
Alisertib 90 mg PIC QD 14D2497.4± 24.3

Adverse events — posted to ClinicalTrials.gov

Time frame: From first dose of study drug to 30 days after the last dose (up to 422 days). Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Part 1 PIC Dose Escalation
Serious: 12/28 (43%)
Deaths:
Part 1 ECT Dose Escalation
Serious: 15/28 (54%)
Deaths:
Part 2 PTCL
Serious: 2/2 (100%)
Deaths:

Serious adverse events (43 terms)

ReactionSystemPart 1 PIC Dose EscalationPart 1 ECT Dose EscalationPart 2 PTCL
Febrile neutropeniaBlood and lymphatic system disorders
Musculoskeletal painMusculoskeletal and connective tissue disorders
Small intestinal obstructionGastrointestinal disorders
PneumoniaInfections and infestations
HypercalcaemiaMetabolism and nutrition disorders
Plasma cell myelomaNeoplasms benign, malignant and unspecified (incl cysts and polyps)
Back painMusculoskeletal and connective tissue disorders
Flank painMusculoskeletal and connective tissue disorders
Pathological fractureMusculoskeletal and connective tissue disorders
ThrombocytopeniaBlood and lymphatic system disorders
Septic shockInfections and infestations
Staphylococcal infectionInfections and infestations
Urinary tract infectionInfections and infestations
DyspnoeaRespiratory, thoracic and mediastinal disorders
Obstructive airways disorderRespiratory, thoracic and mediastinal disorders
ConstipationGastrointestinal disorders
Systemic inflammatory response syndromeGeneral disorders
DehydrationMetabolism and nutrition disorders
LymphomaNeoplasms benign, malignant and unspecified (incl cysts and polyps)
Renal failureRenal and urinary disorders
DiarrhoeaGastrointestinal disorders
StomatitisGastrointestinal disorders
CellulitisInfections and infestations
AstheniaGeneral disorders
PyrexiaGeneral disorders
Other adverse events (78 terms — click to expand)

ReactionSystemPart 1 PIC Dose EscalationPart 1 ECT Dose EscalationPart 2 PTCL
NeutropeniaBlood and lymphatic system disorders
DiarrhoeaGastrointestinal disorders
ThrombocytopeniaBlood and lymphatic system disorders
AnaemiaBlood and lymphatic system disorders
LeukopeniaBlood and lymphatic system disorders
NauseaGastrointestinal disorders
AlopeciaSkin and subcutaneous tissue disorders
FatigueGeneral disorders
HypokalaemiaMetabolism and nutrition disorders
CoughRespiratory, thoracic and mediastinal disorders
LymphopeniaBlood and lymphatic system disorders
VomitingGastrointestinal disorders
Decreased appetiteMetabolism and nutrition disorders
SomnolenceNervous system disorders
DyspnoeaRespiratory, thoracic and mediastinal disorders
ConstipationGastrointestinal disorders
Blood bilirubin increasedInvestigations
Dry mouthGastrointestinal disorders
ChillsGeneral disorders
White blood cell count decreasedInvestigations
PruritusSkin and subcutaneous tissue disorders
DizzinessNervous system disorders
Upper respiratory tract infectionInfections and infestations
Eye disordersEye disorders
StomatitisGastrointestinal disorders
PyrexiaGeneral disorders
AstheniaGeneral disorders
HypophosphataemiaMetabolism and nutrition disorders
Blood alkaline phosphatase increasedInvestigations
Alanine aminotransferase increasedInvestigations
Aspartate aminotransferase increasedInvestigations
Urinary tract infectionInfections and infestations
ArthralgiaMusculoskeletal and connective tissue disorders
Back painMusculoskeletal and connective tissue disorders
InsomniaPsychiatric disorders
DepressionPsychiatric disorders
HypotensionVascular disorders
Abdominal painGastrointestinal disorders
DyspepsiaGastrointestinal disorders
OdynophagiaGastrointestinal disorders

Most-reported serious reactions: Febrile neutropenia, Musculoskeletal pain, Small intestinal obstruction, Pneumonia, Hypercalcaemia, Plasma cell myeloma, Back pain, Flank pain.

Data from ClinicalTrials.gov NCT00697346 adverse events section.

Sponsor's own description

This is an open-label, multicenter, phase 1 study of MLN8237 in participants with advanced hematological malignancies for whom there are limited standard treatment options.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

  1. Aurora A kinase (AURKA) in normal and pathological cell division.
    Nikonova AS, Astsaturov I, Serebriiskii IG, Dunbrack RL, et al · · 2013 · cited 368× · PMID 22864622 · DOI 10.1007/s00018-012-1073-7
  2. The two sides of chromosomal instability: drivers and brakes in cancer.
    Hosea R, Hillary S, Naqvi S, Wu S, et al · · 2024 · cited 102× · PMID 38553459 · DOI 10.1038/s41392-024-01767-7
  3. Aurora kinase A in gastrointestinal cancers: time to target.
    Katsha A, Belkhiri A, Goff L, El-Rifai W. · · 2015 · cited 74× · PMID 25987188 · DOI 10.1186/s12943-015-0375-4
  4. Phase I study of MLN8237--investigational Aurora A kinase inhibitor--in relapsed/refractory multiple myeloma, non-Hodgkin lymphoma and chronic lymphocytic leukemia.
    Kelly KR, Shea TC, Goy A, Berdeja JG, et al · · 2014 · cited 64× · PMID 24352795 · DOI 10.1007/s10637-013-0050-9
  5. Second-Generation Antimitotics in Cancer Clinical Trials.
    Novais P, Silva PMA, Amorim I, Bousbaa H. · · 2021 · cited 37× · PMID 34371703 · DOI 10.3390/pharmaceutics13071011
  6. Global population pharmacokinetics of the investigational Aurora A kinase inhibitor alisertib in cancer patients: rationale for lower dosage in Asia.
    Zhou X, Mould DR, Takubo T, Sheldon-Waniga E, et al · · 2018 · cited 17× · PMID 28891222 · DOI 10.1111/bcp.13430
  7. The Dual Cell Cycle Kinase Inhibitor JNJ-7706621 Reverses Resistance to CD37-Targeted Radioimmunotherapy in Activated B Cell Like Diffuse Large B Cell Lymphoma Cell Lines.
    Rødland GE, Melhus K, Generalov R, Gilani S, et al · · 2019 · cited 13× · PMID 31850205 · DOI 10.3389/fonc.2019.01301
  8. Knowledge mapping of AURKA in Oncology:An advanced Bibliometric analysis (1998-2023).
    Zhou Q, Tao C, Yuan J, Pan F, et al · · 2024 · cited 1× · PMID 38912486 · DOI 10.1016/j.heliyon.2024.e31945

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