Study of MLN8237 in Participants With Advanced Hematological Malignancies

NCT00697346 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: C14003U1111-1187-1184
• Study Type: interventional
• Target: 58
• Locations: 1 country
• Sites: 10

Brief Summary

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.

Conditions

B-cell Follicular Lymphoma; B-cell Marginal Zone Lymphoma; Diffuse Large B-cell Lymphoma; B-cell Mantle Cell Lymphoma; B-cell Small Lymphocytic Lymphoma; B-Cell Chronic Lymphocytic Leukemia; Multiple Myeloma; Waldenstrom's Macroglobulinemia; Noncutaneous Peripheral T-cell Lymphoma Not Otherwise Specified; Angioimmunoblastic T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Enteropathy Associated T-cell Lymphoma; NK Lymphoma

Keywords

Drug therapy

Outcome Measures

Primary Outcomes (37)

• Number of Participants With Dose-Limiting Toxicity (DLT)

  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.

  From first dose of study drug to 30 days after the last dose (up to 422 days)

• Maximum Tolerated Dose (MTD) of Alisertib

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

  From first dose of study drug to 30 days after the last dose (up to 422 days)

• Cmax: Maximum Observed Concentration for Alisertib as Pill in Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing at Day 1

  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

  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

  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

  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

  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

  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

  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

  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

  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

  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

  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

  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

  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

  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

  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

  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

  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

  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

  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

  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

  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

  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

  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

  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

  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

  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

  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

  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

  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

  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

  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

  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

  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

  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

  Cycle 1 Day 7 predose and at multiple timepoints (up to 12 hours) postdose

Secondary Outcomes (4)

• Best Overall Response Rate Based on Investigator's Assessment

  Baseline and every 2 cycles up to Month 12 until disease progression, 30 days after end of treatment (up to 422 days)

• Duration of Response (DOR)

  Baseline and every 2 cycles up to Month 12 until disease progression, 30 days after end of treatment (up to 422 days)

• Number of Participants With Polymorphisms in Gene Encoding Enzyme UGT1A1

  Cycle 1 Day 1 predose

• Number of Participants With Polymorphisms in Aurora A Kinase

  Cycle 1 Day 1 predose

Study Arms (3)

Part 1: PIC Dose Escalation

EXPERIMENTAL

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

Part 1: ECT Dose Escalation

EXPERIMENTAL

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

Part 2: PTCL

EXPERIMENTAL

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

Interventions

Alisertib DRUG

Alisertib (MLN8237) PIC or ECT

Also known as: MLN8237

Part 1: ECT Dose Escalation; Part 1: PIC Dose Escalation; Part 2: PTCL

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Millennium Pharmaceuticals, Inc.: lead

Study Sites (10)

Unknown Facility

Scottsdale, Arizona, United States

Location

Unknown Facility

Lexington, Kentucky, United States

Location

Unknown Facility

Baltimore, Maryland, United States

Location

Unknown Facility

Omaha, Nebraska, United States

Location

Unknown Facility

Hackensack, New Jersey, United States

Location

Unknown Facility

Buffalo, New York, United States

Location

Unknown Facility

Chapel Hill, North Carolina, United States

Location

Unknown Facility

Nashville, Tennessee, United States

Location

Unknown Facility

Houston, Texas, United States

Location

Unknown Facility

San Antonio, Texas, United States

Location

Related Publications (1)

• 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.

  PMID: 24352795 DERIVED

MeSH Terms

Conditions

Lymphoma, B-Cell, Marginal Zone; Lymphoma, Large B-Cell, Diffuse; Leukemia, B-Cell; Leukemia, Lymphocytic, Chronic, B-Cell; Multiple Myeloma; Waldenstrom Macroglobulinemia; Immunoblastic Lymphadenopathy; Lymphoma, Large-Cell, Anaplastic; Enteropathy-Associated T-Cell Lymphoma

Interventions

MLN 8237

Condition Hierarchy (Ancestors)

Lymphoma, B-Cell; Lymphoma, Non-Hodgkin; Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Leukemia, Lymphoid; Leukemia; Hematologic Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Neoplasms, Plasma Cell; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hemorrhagic Disorders; Lymphadenopathy; Lymphoma, T-Cell

Results Point of Contact

• Title: Medical Director
• Organization: Takeda

trialdisclosures@takeda.com

+1-877-825-3327

Study Officials

• Medical Director Clinical Science

  Millennium Pharmaceuticals, Inc.

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 11, 2008
• First Posted: June 13, 2008
• Study Start: July 11, 2008
• Primary Completion: October 1, 2016
• Study Completion: October 19, 2016
• Last Updated: May 31, 2019
• Results First Posted: May 31, 2019

Record last verified: 2019-02

Locations

US (10)