Clinical Trial: Study of MLN8237 in Participants With Advanced Hematological Malignancies

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

Official Title: An Open-label, Phase 1 Study of MLN8237, a Novel Aurora A Kinase Inhibitor, in Patients With Advanced Hematological Malignancies

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.

Detailed Summary:

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.

Current Primary Outcome:

• 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 Aliser
  
  

  Original Primary Outcome: 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 ]
  
  

  Current Secondary Outcome:

  • 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 ]
  
  
  

  Original Secondary Outcome: 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 ]
  
  Information By: Takeda
  

  Dates:
  Date Received: June 11, 2008
  Date Started: October 7, 2008
  Date Completion:
  Last Updated: March 29, 2017
  Last Verified: March 2017