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Study of MLN8237 in Participants With Advanced Hematological Malignancies

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Takeda ( Millennium Pharmaceuticals, Inc. )
ClinicalTrials.gov Identifier:
NCT00697346
First received: June 11, 2008
Last updated: March 29, 2017
Last verified: March 2017
June 11, 2008
March 29, 2017
October 7, 2008
October 1, 2016   (Final data collection date for primary outcome measure)
  • Number of Participants With Dose-Limiting Toxicity (DLT) [ Time Frame: 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 exceptions: Grade 3 arthralgia/myalgias, Any grade of alopecia, Brief (<1 week) Grade 3 fatigue 7. Treatment delay of >21 days due to failure of adequate hematologic or non-hematologic recovery from previous cycle of treatment 8. Other alisertib related non-hematologic toxicities ≥Grade 2 that, in the opinion of the investigator required a dose reduction or discontinuation of therapy with alisertib.
  • Maximum Tolerated Dose (MTD) of Alisertib [ Time Frame: 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.
  • Cmax: Maximum Observed Concentration for Alisertib as Pill in Capsule (PIC) with Once Daily for 21 Days (QD21D) Dosing at Day 1 [ Time Frame: Cycle 1 Day 1 predose and at multiple timepoints (up to 24 hours) postdose ]
  • Cmax: Maximum Observed Concentration for Alisertib as Pill in Capsule (PIC) with Once Daily for 21 Days (QD21D) Dosing at Day 21 [ Time Frame: Cycle 1 Day 21 predose and at multiple timepoints (up to 6 hours) postdose ]
  • 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 [ Time Frame: Cycle 1 Day 1 predose and at multiple timepoints (up to 24 hours) postdose ]
  • 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 [ Time Frame: Cycle 1 Day 21 predose and at multiple timepoints (up to 6 hours) postdose ]
  • 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 [ Time Frame: Cycle 1 Day 21 predose and at multiple time points (up to 6 hours) postdose ]
  • Terminal Half-Life (t1/2) for Alisertib as Pill in Capsule (PIC) with Once Daily for 21 Days (QD21D) Dosing at Day 21 [ Time Frame: Cycle 1 Day 21 predose and at multiple time points (up to 6 hours) postdose ]
  • Accumulation Ratio (Rac) for Alisertib as Pill in Capsule (PIC) with Once Daily for 21 Days (QD21D) Dosing at Day 21 [ Time Frame: Cycle 1 Day 21 predose and at multiple time points (up to 6 hours) postdose ]
  • Peak/Trough Ratio for Alisertib as Pill in Capsule (PIC) with Once Daily for 21 Days (QD21D) Dosing at Day 21 [ Time Frame: Cycle 1 Day 21 predose and at multiple timepoints (up to 6 hours) postdose ]
  • 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 [ Time Frame: Cycle 1 Day 21 predose and at multiple timepoints (up to 6 hours) postdose ]
  • Cmax: Maximum Observed Concentration for Alisertib as Pill in Capsule (PIC) with Once Daily for 14 Days (QD14D) Dosing at Day 1 [ Time Frame: Cycle 1 Day 1 predose and at multiple timepoints (up to 24 hours) postdose ]
  • Cmax: Maximum Observed Concentration for Alisertib as Pill in Capsule (PIC) with Once Daily for 14 Days (QD14D) Dosing at Day 14 [ Time Frame: Cycle 1 Day 14 predose and at multiple timepoints (up to 8 hours) postdose ]
  • Tmax: Time of First Occurrence of Cmax for Alisertib as Pill in Capsule (PIC) with Once Daily for 14 Days (QD14D) Dosing at Day 1 [ Time Frame: Cycle 1 Day 1 predose and at multiple timepoints (up to 24 hours) postdose ]
  • Tmax: Time of First Occurrence of Cmax for Alisertib as Pill in Capsule (PIC) with Once Daily for 14 Days (QD14D) Dosing at Day 14 [ Time Frame: Cycle 1 Day 14 predose and at multiple timepoints (up to 8 hours) postdose ]
  • AUCt: Area Under the Concentration time Curve from Time 0 to Time t for Alisertib as Pill in Capsule (PIC) with Once Daily for 14 Days (QD14D) Dosing at Day 14 [ Time Frame: Cycle 1 Day 14 predose and at multiple timepoints (up to 8 hours) postdose ]
  • Accumulation Ratio (Rac) for Alisertib as Pill in Capsule (PIC) with Once Daily for 14 Days (QD14D) Dosing at Day 14 [ Time Frame: Cycle 1 Day 14 predose and at multiple timepoints (up to 8 hours) postdose ]
  • Peak/Trough Ratio for Alisertib as Pill in Capsule (PIC) with Once Daily for 14 Days (QD14D) Dosing at Day 14 [ Time Frame: Cycle 1 Day 14 predose and at multiple timepoints (up to 8 hours) postdose ]
  • CLss/F: Apparent Oral Clearance at Steady State for Alisertib as Pill in Capsule (PIC) with Once Daily for 14 Days (QD14D) Dosing at Day 14 [ Time Frame: Cycle 1 Day 14 predose and at multiple timepoints (up to 8 hours) postdose ]
  • Cmax: Maximum Observed Concentration for Alisertib as Enteric Coated Tablet (ECT) with Once Daily for 14 Days (QD14D) Dosing at Day 1 [ Time Frame: Cycle 1 Day 1 predose and at multiple timepoints (up to 24 hours) postdose ]
  • Cmax: Maximum Observed Concentration for Alisertib as Enteric Coated Tablet (ECT) with Once Daily for 14 Days (QD14D) Dosing at Day 14 [ Time Frame: Cycle 1 Day 14 predose and at multiple timepoints (up to 8 hours) postdose ]
  • Tmax: Time of First Occurrence of Cmax for Alisertib as Enteric Coated Tablet (ECT) with Once Daily for 14 Days (QD14D) Dosing at Day 1 [ Time Frame: Cycle 1 Day 1 predose and at multiple timepoints (up to 24 hours) postdose ]
  • Tmax: Time of First Occurrence of Cmax for Alisertib as Enteric Coated Tablet (ECT) with Once Daily for 14 Days (QD14D) Dosing at Day 14 [ Time Frame: Cycle 1 Day 14 predose and at multiple timepoints (up to 8 hours) postdose ]
  • AUCt: Area Under the Concentration time Curve from Time 0 to Time t for Alisertib as Enteric Coated Tablet (ECT) with Once Daily for 14 Days (QD14D) Dosing at Day 14 [ Time Frame: Cycle 1 Day 14 predose and at multiple timepoints (up to 8 hours) postdose ]
  • Terminal Half Life for Alisertib as Enteric Coated Tablet (ECT) with Once Daily for 14 Days (QD14D) Dosing at Day 14 [ Time Frame: Cycle 1 Day 14 predose and at multiple timepoints (up to 8 hours) postdose ]
  • Peak/Trough Ratio for Alisertib as Enteric Coated Tablet (ECT) with Once Daily for 14 Days (QD14D) Dosing at Day 14 [ Time Frame: Cycle 1 Day 14 predose and at multiple timepoints (up to 8 hours) postdose ]
  • CLss/F: Apparent Oral Clearance at Steady State for Alisertib as Enteric Coated Tablet (ECT) with Once Daily for 14 Days (QD14D) Dosing at Day 14 [ Time Frame: Cycle 1 Day 14 predose and at multiple timepoints (up to 8 hours) postdose ]
  • Cmax: Maximum Observed Concentration for Alisertib as Enteric Coated Tablet (ECT) with Twice Daily for 7 Days (BID7D) Dosing at Day 1 [ Time Frame: Cycle 1 Day 1 predose and at multiple timepoints (up to 12 hours) postdose ]
  • Cmax: Maximum Observed Concentration for Alisertib as Enteric Coated Tablet (ECT) with Twice Daily for 7 Days (BID7D) Dosing at Day 7 [ Time Frame: Cycle 1 Day 7 predose and at multiple timepoints (up to 12 hours) postdose ]
  • Tmax: Time of First Occurrence of Cmax for Alisertib as Enteric Coated Tablet (ECT) with Twice Daily for 7 Days (BID7D) Dosing at Day 1 [ Time Frame: Cycle 1 Day 1 predose and at multiple timepoints (up to 12 hours) postdose ]
  • Tmax: Time of First Occurrence of Cmax for Alisertib as Enteric Coated Tablet (ECT) with Twice Daily for 7 Days (BID7D) Dosing at day 7 [ Time Frame: Cycle 1 Day 7 predose and at multiple timepoints (up to 12 hours) postdose ]
  • AUCt: Area Under the Concentration time Curve from Time 0 to Time t for Alisertib as Enteric Coated Tablet (ECT) with Twice Daily for 7 Days (BID7D) Dosing at Day 1 [ Time Frame: Cycle 1 Days 1 predose and at multiple timepoints (up to 12 hours) postdose ]
  • AUCt: Area Under the Concentration time Curve from Time 0 to Time t for Alisertib as Enteric Coated Tablet (ECT) with Twice Daily for 7 Days (BID7D) Dosing at Day 7 [ Time Frame: Cycle 1 Day 7 predose and at multiple timepoints (up to 12 hours) postdose ]
  • Terminal Half-Life (t1/2) for Alisertib as Enteric Coated Tablet (ECT) with Twice Daily for 7 Days (BID7D) Dosing at Day 7 [ Time Frame: Cycle 1 Day 7 predose and at multiple timepoints (up to 12 hours) postdose ]
  • Accumulation Ratio (Rac) for Alisertib as Enteric Coated Tablet (ECT) with Twice Daily for 7 Days (BID7D) Dosing at Day 7 [ Time Frame: Cycle 1 Day 7 predose and at multiple timepoints (up to 12 hours) postdose ]
  • Peak/Trough Ratio for Alisertib as Enteric Coated Tablet (ECT) with Twice Daily for 7 Days (BID7D) Dosing at Day 7 [ Time Frame: Cycle 1 Day 7 predose and at multiple timepoints (up to 12 hours) postdose ]
  • CLss/F: Apparent Oral Clearance at Steady State for Alisertib as Enteric Coated Tablet (ECT) with Twice Daily for 7 Days (BID7D) Dosing at Day 7 [ Time Frame: Cycle 1 Day 7 predose and at multiple timepoints (up to 12 hours) postdose ]
Determine dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of orally administered MLN8237, evaluate pharmacokinetics and potential effect of MLN8237 exposure on Aurora A kinase inhibition in blood leukocytes. [ Time Frame: Duration of therapy ]
Complete list of historical versions of study NCT00697346 on ClinicalTrials.gov Archive Site
  • Best Overall Response Rate Based on Investigator's Assessment [ Time Frame: Baseline and every 2 cycles up to Month 12 until disease progression, 30 days after end of treatment (up to 422 days) ]
    Best overall response rate is defined as the percentage of participants with complete response (CR) or partial response (PR) as assessed by the Investigator using International Working Group (IWG) Criteria. CR is defined as the disappearance of all evidence of disease and PR is defined as regression of measurable disease and no new sites.
  • Duration of Response (DOR) [ Time Frame: Baseline and every 2 cycles up to Month 12 until disease progression, 30 days after end of treatment (up to 422 days) ]
    DOR is defined as the time from the date of first documentation of a CR response to the date of first documentation of PD according to IWG criteria. CR is defined as the disappearance of all evidence of disease and PD is defined as any new lesion or increase by >50% of previously involved sites from nadir.
  • Number of Participants with Polymorphisms in Gene Encoding Enzyme UGT1A1 [ Time Frame: Cycle 1 Day 1 predose ]

    One peripheral blood sample (approximately 4 mL) was to be obtained on Day 1 of Cycle 1 prior to the first dose of alisertib to genotype participants for polymorphisms in UGT1A1 because UGT1A1 is one of the enzymes responsible for glucuronidation of alisertib, which is expected to contribute to the clearance of alisertib.

    wt=wild type

    *28=polymorphism in the promoter region of a UGT1A1 allele resulting in reduced UGT1A1 expression. Not determined = blood sample was not evaluable.

  • Number of participants with Polymorphisms in Aurora A Kinase [ Time Frame: Cycle 1 Day 1 predose ]
To determine if MLN8237 has antitumor activity as measured by tumor response. [ Time Frame: Evaluations will be repeated after every 2 cycles of MLN8237 have been completed for up to 12 months ]
Not Provided
Not Provided
 
Study of MLN8237 in Participants With Advanced Hematological Malignancies
An Open-label, Phase 1 Study of MLN8237, a Novel Aurora A Kinase Inhibitor, in Patients With Advanced Hematological Malignancies
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.

The drug being tested in this study is called alisertib. Alisertib is being tested to treat people who have advanced hematological malignancies. This study determined the dose-limiting toxicity, maximum tolerated dose, safety and pharmacokinetics (how the drug moves through the body) for alisertib when given once or twice a day for 7 to 21 days.

This open label study enrolled 58 patients. Participants were enrolled in one of 3 treatment groups:

  • Part 1: Powder-in-Capsule (PIC) Dose Escalation (alisertib 25 mg PIC, orally twice daily [BID] on Day 1 [loading dose] and then alisertib 25 or 35 mg PIC once daily [QD] for 21 days (D), or alisertib 35, 45, 65 or 90 mg PIC, orally, QD for 14D)
  • Part 1: Enteric-coated Tablet (ECT) Dose Escalation (alisertib 40 mg, ECT, orally, QD for 14D or alisertib 30, 40 or 50 mg, orally, BID for 7D)
  • Part 2: Participants with Peripheral T-cell Lymphoma (PTCL) (alisertib 50 mg ECT, orally, BID for 7D)

All participants received treatment for 12 months or until their disease progressed or they experienced unacceptable alisertib-related toxicity. This multi-center trial was conducted in the United States. The overall time to participate in this study was 422 days. Participants made multiple visits to the clinic, including a final visit 30 days after receiving their last dose of alisertib for a follow-up assessment.

Interventional
Phase 1
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: Participant, Care Provider, Investigator, Outcomes Assessor
Primary Purpose: Treatment
  • B-cell Follicular Lymphoma
  • B-cell Marginal Zone Lymphoma
  • Diffuse Large B-cell Lymphoma
  • B-cell Mantle Cell Lymphoma
  • B-cell Small Lymphocytic Lymphoma (SLL)
  • B-Cell Chronic Lymphocytic Leukemia (B-CLL)
  • Multiple Myeloma
  • Waldenstrom's Macroglobulinemia
  • Noncutaneous Peripheral T-cell Lymphoma Not Otherwise Specified (PTCL-NOS)
  • Angioimmunoblastic T-cell Lymphoma (AITL)
  • Anaplastic Large Cell Lymphoma
  • Enteropathy Associated T-cell Lymphoma (EATCL)
  • NK Lymphoma (NKL)
Drug: Alisertib
Alisertib (MLN8237) PIC or ECT
Other Name: MLN8237
  • Experimental: Part 1: PIC Dose Escalation
    Alisertib 25 or 35 mg, Powder-in-Capsule (PIC) formulation, orally, once daily (QD) for 21 days followed by a 7-day recovery period in 28-day cycles or alisertib 35, 45, 65 or 90 mg PIC, orally, (QD for 14 days followed by a 14-day recovery period in 28-day cycles, until disease progression or unacceptable alisertib-related toxicity (up to 14 cycles). All participants received an initial starting dosage of alisertib PIC 25 mg, orally, twice daily (BID) on Day 1 (loading dose), followed by their respective dosage assignment.
    Intervention: Drug: Alisertib
  • Experimental: Part 1: ECT Dose Escalation
    Alisertib 40 mg, Enteric-coated Tablet (ECT) formulation, orally, QD for 14 days followed by a 14-day recovery period in 28-day cycles, or alisertib 30, 40 or 50 mg ECT, orally BID for 7 days followed by a 14-day recovery period in 21-day cycles, until disease progression or unacceptable alisertib-related toxicity (up to 15 cycles).
    Intervention: Drug: Alisertib
  • Experimental: Part 2: PTCL
    Participants with peripheral T-cell lymphoma (PTCL) received alisertib 50 mg ECT, orally, BID for 7 days followed by a 14-day recovery period in 21-day cycles, until disease progression or unacceptable alisertib-related toxicity (up to 2 cycles).
    Intervention: Drug: Alisertib
Kelly KR, Shea TC, Goy A, Berdeja JG, Reeder CB, McDonagh KT, Zhou X, Danaee H, Liu H, Ecsedy JA, Niu H, Benaim E, Iyer SP. Phase I study of MLN8237--investigational Aurora A kinase inhibitor--in relapsed/refractory multiple myeloma, non-Hodgkin lymphoma and chronic lymphocytic leukemia. Invest New Drugs. 2014 Jun;32(3):489-99. doi: 10.1007/s10637-013-0050-9. Epub 2013 Dec 20.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
58
November 27, 2016
October 1, 2016   (Final data collection date for primary outcome measure)

Inclusion Criteria:

  • Relapsed or refractory disease and a histologically or cytologically confirmed hematological malignancy of the following type for which standard curative treatment does not exist or is no longer effective:

    • B-cell Follicular lymphoma
    • B-cell Marginal zone lymphoma
    • Diffuse large B-cell lymphoma
    • B-cell Mantle cell lymphoma
    • B-cell Small lymphocytic lymphoma (SLL)
    • B-Cell Chronic lymphocytic leukemia (B-CLL)
    • Multiple myeloma
    • Waldenstrom's macroglobulinemia
    • Noncutaneous peripheral T-cell lymphoma not otherwise specified (PTCL-NOS)
    • Angioimmunoblastic T-cell lymphoma (AITL), anaplastic large cell lymphoma, enteropathy associated T-cell lymphoma (EATCL), NK lymphoma (NKL)
  • Participants with diffuse large B-cell lymphoma must have failed, be ineligible for, or have refused an autologous stem cell transplant. There is no restriction regarding the maximum number of prior regimens.
  • Aged 18 years or older
  • Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2
  • Radiographically or clinically evaluable disease for Part 1 of this study and measurable disease for Part 2 of this study
  • Suitable venous access for the conduct of blood sampling for MLN8237 pharmacokinetics (PK)
  • Recovered from the reversible effects of prior antineoplastic treatment (with the exception of alopecia and Grade 1 neuropathy)

Exclusion Criteria:

  • Pregnant or lactating
  • Treatment with clinically significant enzyme inducers within 14 days prior to the first dose of MLN8237 as specified in the protocol
  • Prior allogeneic bone marrow (or other organ) transplantation
  • Newly diagnosed or uncontrolled cancer-related central nervous system (CNS) disease
  • Systemic antineoplastic treatment within 21 days preceding the first dose of study treatment. Exceptions requiring a 42-day recovery period from last treatment include: Nitrosoureas, mitomycin C or Rituximab, alemtuzumab (Campath®), or other unconjugated therapeutic antibody (21 days if clear evidence of progressive disease)
  • Treatment with radioimmunoconjugates or toxin immunoconjugates such as ibritumomab tiuxetan (Zevalin™), or tositumomab (Bexxar®) within 56 days preceding the first dose of study treatment
  • Antineoplastic treatment with glucocorticoids within 21 days preceding the first dose of study treatment
  • Radiotherapy involving <25% of the hematopoietically active bone marrow within 21 days preceding first dose of study treatment
  • Radiotherapy involving ≥25% of the hematopoietically active bone marrow within 42 days preceding first dose of study treatment
  • Inability to swallow capsules or known gastrointestinal (GI) disease or GI procedures that could interfere with the oral absorption or tolerance of MLN8237. Examples include, but are not limited to, partial gastrectomy, history of small intestine surgery, and celiac disease.
  • History of uncontrolled sleep apnea syndrome and other conditions that could result in excessive daytime sleepiness such as severe chronic obstructive pulmonary disease
  • Known or suspected human immunodeficiency virus (HIV) positive or hepatitis B surface antigen-positive status, or known or suspected active hepatitis C infection. Testing is not required in the absence of clinical findings or suspicion.
  • Participants who fail to meet laboratory values as specified in the protocol during the screening period
Sexes Eligible for Study: All
18 Years and older   (Adult, Senior)
No
Contact information is only displayed when the study is recruiting subjects
United States
 
 
NCT00697346
C14003
U1111-1187-1184 ( Registry Identifier: WHO )
No
Not Provided
Not Provided
Takeda ( Millennium Pharmaceuticals, Inc. )
Millennium Pharmaceuticals, Inc.
Not Provided
Study Director: Medical Director Clinical Science Millennium Pharmaceuticals, Inc.
Takeda
March 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP