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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
  Purpose
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.

Condition Intervention Phase
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 Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: Participant, Care Provider, Investigator, Outcomes Assessor
Primary Purpose: Treatment
Official Title: An Open-label, Phase 1 Study of MLN8237, a Novel Aurora A Kinase Inhibitor, in Patients With Advanced Hematological Malignancies

Resource links provided by NLM:


Further study details as provided by Takeda ( Millennium Pharmaceuticals, Inc. ):

Primary Outcome Measures:
  • 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 ]

Secondary Outcome Measures:
  • 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 ]

Enrollment: 58
Actual Study Start Date: October 7, 2008
Study Completion Date: November 27, 2016
Primary Completion Date: October 1, 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.
Drug: Alisertib
Alisertib (MLN8237) PIC or ECT
Other Name: MLN8237
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).
Drug: Alisertib
Alisertib (MLN8237) PIC or ECT
Other Name: MLN8237
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).
Drug: Alisertib
Alisertib (MLN8237) PIC or ECT
Other Name: MLN8237

Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00697346

Locations
United States, Arizona
Scottsdale, Arizona, United States
United States, Kentucky
Lexington, Kentucky, United States
United States, Maryland
Baltimore, Maryland, United States
United States, Nebraska
Omaha, Nebraska, United States
United States, New Jersey
Hackensack, New Jersey, United States
United States, New York
Buffalo, New York, United States
United States, North Carolina
Chapel Hill, North Carolina, United States
United States, Tennessee
Nashville, Tennessee, United States
United States, Texas
Houston, Texas, United States
San Antonio, Texas, United States
Sponsors and Collaborators
Millennium Pharmaceuticals, Inc.
Investigators
Study Director: Medical Director Clinical Science Millennium Pharmaceuticals, Inc.
  More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Millennium Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT00697346     History of Changes
Other Study ID Numbers: C14003
U1111-1187-1184 ( Registry Identifier: WHO )
Study First Received: June 11, 2008
Last Updated: March 29, 2017

Keywords provided by Takeda ( Millennium Pharmaceuticals, Inc. ):
Drug therapy

Additional relevant MeSH terms:
Lymphoma
Multiple Myeloma
Lymphoma, Follicular
Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Lymphoma, B-Cell
Lymphoma, Mantle-Cell
Lymphoma, B-Cell, Marginal Zone
Lymphoma, T-Cell
Lymphoma, Large B-Cell, Diffuse
Waldenstrom Macroglobulinemia
Lymphoma, Large-Cell, Anaplastic
Lymphoma, T-Cell, Peripheral
Immunoblastic Lymphadenopathy
Intestinal Diseases
Enteropathy-Associated T-Cell Lymphoma
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Neoplasms, Plasma Cell
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders

ClinicalTrials.gov processed this record on June 23, 2017