A Phase I Clinical and Pharmacodynamic Study of MLN8237, A Novel Aurora A Kinase Inhibitor, in Participants With Advanced Malignancies

NCT00651664 | Completed Phase 1 Results

• 3 other identifiers: C140022006-006048-68U1111-1187-1151
• Study Type: interventional
• Target: 59
• Locations: 1 country
• Sites: 2

Brief Summary

This is a multicenter, dose escalation, phase 1 study of MLN8237 in adult participants with advanced malignancies (excluding those with primary bone marrow involvement, such as leukemias and multiple myeloma).

Conditions

Advanced Malignancies

Outcome Measures

Primary Outcomes (2)

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

  DLT was evaluated using the National Cancer Institutes Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0; defined as any of the following events related to alisertib therapy: 1. Grade 4 neutropenia lasting for ≥7 consecutive days during recovery 2. Grade 4 neutropenia with fever and/or infection 3. Confirmed platelet count \<25,000/mm\^3 4. ≥Grade 3 nausea and/or emesis despite the use of an antiemetic prophylaxis 5. ≥Grade 3 diarrhea that occurred despite 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 \>1 week because of a failure of adequate hematologic or nonhematologic recovery from the previous cycle of treatment. 8. Other alisertib-related nonhematologic toxicities ≥ Grade 2 that, in the opinion of the investigator, required a dose reduction or discontinuation of therapy with alisertib.

  First dose through 30 days following the last dose of study drug (up to 730 days)

• Maximum Tolerated Dose (MTD) of Alisertib

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

  Signing of the Informed Consent through 30 days following the last dose of study drug (up to 730 days)

Secondary Outcomes (30)

• Cmax: Maximum Observed Concentration for Alisertib 7 Day Dosing

  Cycle 1: Pre-dose and multiple time-points (up to 24 hour) post-dose on Day 1 and Pre-dose and multiple time-points (up to 10 hours) on Day 7

• Tmax: Time of First Occurrence of Cmax for Alisertib 7 Day Dosing

  Cycle 1: Pre-dose and multiple time-points (up to 24 hour) post-dose on Day 1 and Pre-dose and multiple time-points (up to 10 hours) on Day 7

• AUCt: Area Under the Concentration-time Curve From Time 0 to Time t for Alisertib 7 Day Dosing

  Cycle1: Pre-dose and multiple time-points (up to 24 hour) post-dose on Day 1 and Pre-dose and multiple time-points (up to 10 hours) on Day 7

• Terminal Half-Life (t1/2) for Alisertib 7 Day Dosing

  Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Day 7 or 8 (BID arms)

• Accumulation Ratio (Rac) for Alisertib 7 Day Dosing

  Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Day 7

Other Outcomes (1)

• Percentage of Participants With Polymorphisms in Gene Encoding Enzyme UGT1A1

  Cycle 1: Pre-dose

Study Arms (10)

Alisertib 5 mg QD 7D

EXPERIMENTAL

Alisertib 5 mg, capsules, orally, once daily (QD) for 7 days (D) followed by a 14-day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 3 cycles).

Drug: alisertib

Alisertib 80 mg QD 7D

EXPERIMENTAL

Alisertib 80 mg, capsules, orally, QD for 7 days followed by a 14-day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 4 cycles).

Drug: alisertib

Alisertib 150 mg QD 7D

EXPERIMENTAL

Alisertib 150 mg, capsules, orally, QD for 7 days followed by a 14-day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles).

Drug: alisertib

Alisertib 50 mg BID 7D

EXPERIMENTAL

Alisertib 50 mg, capsules, orally, twice daily (BID) for 7 days followed by a 14-day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 29 cycles).

Drug: alisertib

Alisertib 60 mg BID 7D

EXPERIMENTAL

Alisertib 60 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles).

Drug: alisertib

Alisertib 75 mg BID 7D

EXPERIMENTAL

Alisertib 75 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 8 cycles).

Drug: alisertib

Alisertib 100 mg BID 7D

EXPERIMENTAL

Alisertib 100 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 21 cycles).

Drug: alisertib

Alisertib 50 mg QD 14D

EXPERIMENTAL

Alisertib 50 mg, capsules, orally, QD for 14 days followed by a 14-day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 25 cycles).

Drug: alisertib

Alisertib 50 mg QD 21D

EXPERIMENTAL

Alisertib 50 mg, capsules, orally, QD for 21 days followed by a 14-day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 10 cycles).

Drug: alisertib

Alisertib 70 mg QD 21D

EXPERIMENTAL

Alisertib 70 mg, capsules, orally, QD for 21 days followed by a 14-day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 2 cycles).

Drug: alisertib

Interventions

alisertib DRUG

Alisertib (MLN8237) capsules

Also known as: MLN8237

Alisertib 100 mg BID 7D; Alisertib 150 mg QD 7D; Alisertib 5 mg QD 7D; Alisertib 50 mg BID 7D; Alisertib 50 mg QD 14D; Alisertib 50 mg QD 21D; Alisertib 60 mg BID 7D; Alisertib 70 mg QD 21D; Alisertib 75 mg BID 7D; Alisertib 80 mg QD 7D

Eligibility Criteria

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

You may qualify if:

• Have a histologically or cytologically confirmed metastatic and/or advanced malignancy (including lymphomas but excluding malignancies with extensive bone marrow involvement such as leukemias and multiple myeloma) for which standard treatment does not offer curative or life-prolonging potential.
• Aged 18 years or more.
• Eastern Cooperative Oncology Group performance status 0 or 1.
• Have an expected survival longer than 3 months from enrollment in the study.
• Radiographically or clinically evaluable tumor.
• Suitable venous access for the conduct of blood sampling.
• Recovered from the reversible effects of prior antineoplastic therapy (with the exception of alopecia and grade 1 neuropathy) with at least 4 weeks elapsed since the last exposure to cytotoxic chemotherapy or to radiotherapy and at least 6 weeks elapsed since exposure to nitrosoureas or mitomycin C. Participants treated with fully human monoclonal antibodies must not have received treatment with such antibodies for at least 6 weeks, and those treated with chimeric monoclonal antibodies must not have received treatment with such antibodies for at least 4 weeks. Participants treated with noncytotoxic small molecule drugs (eg, tyrosine kinase inhibitors, such as Tarceva® \[erlotinib\], and hormonal agents, such as Femara® \[letrozole\]) must not have received treatment with these drugs for at least 2 weeks before the first dose of alisertib was given.
• Male participants must use an appropriate method of barrier contraception and inform any sexual partners that they must also use a reliable method of contraception from the time of informed consent until 3 months after the last dose of study treatment.
• Female participants must be postmenopausal at least 1 year, OR surgically sterile, OR if of childbearing potential, agree to 2 effective methods of nonhormonal contraception, or agree to completely abstain from heterosexual intercourse.
• Able to give written consent.

You may not qualify if:

• Pregnant or lactating.
• Major surgery or serious infection within the 28 days preceding the first dose of study treatment.
• Life-threatening or uncontrolled medical illness unrelated to cancer.
• Ongoing nausea or vomiting of any severity.
• \>Grade 1 diarrhea. Participants who require ongoing therapy with an antimotility agent to control diarrhea to a Grade 1 or lower level are not allowed to participate in this trial.
• Known gastrointestinal disease or gastrointestinal procedures that could interfere with the oral absorption or tolerance of MLN8237.
• History of uncontrolled sleep apnea syndrome and other conditions that could result in excessive daytime sleepiness such as severe chronic obstructive pulmonary disease.
• Difficulty swallowing capsules.
• Inability to take nothing by mouth except for water and prescribed medications for 2 hours before and 1 hour after each dose of MLN8237.
• Received more than 4 previous cytotoxic chemotherapeutic regimens, including regimens used as adjuvant or neo-adjuvant therapies (in participants with metastatic breast cancer, a total of 5 previous cytotoxic chemotherapeutic regimens is permitted).
• Prior treatment with high-dose chemotherapy, defined as chemotherapy requiring the use of peripheral blood or bone marrow stem cell support for hematopoietic reconstitution.
• Prior treatment with radiation therapy involving ≥25% of the hematopoietically active bone marrow for the distribution of active bone marrow in adults).
• Clinical and/or radiographic evidence of cerebral metastases. However, participants who have a history of central nervous system metastasis but who have no radiographic or clinical evidence of residual tumor (eg, following complete surgical resection or stereotactic radiosurgery) are not excluded from participation in this study.
• Absolute neutrophil count(ANC) \< 1500/mm\^3; platelet count\< 100,000/mm\^3.
• Serum creatinine \>1.6 mg/dL or a measured or estimated (Cockcroft-Gault formula) creatinine clearance \<40 mL/min

Sponsors & Collaborators

• Millennium Pharmaceuticals, Inc.: lead

Study Sites (2)

Ciutat Sanitaria Vall d'Hebron - Servicio de Oncologia

Barcelona, 08035, Spain

Location

H. Clínico Universitario de Valencia

Valencia, Spain

Location

MeSH Terms

Interventions

MLN 8237

Results Point of Contact

• Title: Medical Director
• Organization: Takeda

trialdisclosures@takeda.com

+1-877-825-3327

Study Officials

• Medical Director Clinical Science

  Takeda

  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: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 31, 2008
• First Posted: April 3, 2008
• Study Start: October 22, 2007
• Primary Completion: September 1, 2010
• Study Completion: April 5, 2011
• Last Updated: March 15, 2019
• Results First Posted: March 15, 2019

Record last verified: 2018-11

Locations

ES (2)