A Study of MLN8237, a Novel Aurora A Kinase Inhibitor, in Participants With Advanced Solid Tumors

NCT00500903 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: C14001U1111-1187-1087
• Study Type: interventional
• Target: 87
• Locations: 1 country
• Sites: 1

Brief Summary

To determine the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of MLN8237 when given by mouth (PO) for a minimum of 7 and a maximum of 21 consecutive days, followed by a 14-day recovery period.

Conditions

Advanced Malignancies

Keywords

Drug therapy

Outcome Measures

Primary Outcomes (3)

• 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 \>1 week due to failure of adequate hematologic or nonhematologic recovery from 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.

  Cycle 1 Day 1 up to Day 35 (alisertib daily for 7 to 21 days followed by a 14-day recovery period)

• Maximum Tolerated Dose (MTD) of Alisertib

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

  From first dose of study drug to 30 days after the last dose (up to 1011 days)

• Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)

  An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. A Serious Adverse Event (SAE) A serious is any experience that suggests a significant hazard, contraindication, side effect or precaution that: results in death, is life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or is medically significant.

  From first dose of study drug to 30 days after the last dose (up to 1011 days)

Secondary Outcomes (55)

• Cmax: Maximum Observed Concentration for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing

  Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose and Day 7 predose and at multiple time-points (up to 10 hours) postdose

• Tmax: Time of First Occurrence of Cmax for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing

  Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose and Day 7 predose and at multiple time-points (up to 10 hours) postdose

• AUCt: Area Under the Concentration-Time Curve From Time 0 to Time t for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing

  Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose and Day 7 predose and at multiple time-points (up to 10 hours) postdose

• Terminal Half-Life (t1/2) for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing

  Cycle 1 Day 7 predose and at multiple time-points (up to 10 hours) postdose

• Accumulation Ratio (Rac) for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing

  Cycle 1 Day 7 predose and at multiple time-points (up to 10 hours) postdose

Study Arms (3)

PIC Dose Escalation

EXPERIMENTAL

Alisertib 5, 10, 20, 40, 80, 110 or 150 mg, Powder-in-Capsule (PIC) formulation, orally, once daily (QD) for 7 to 21 days followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib--related toxicity (up to 51 cycles).

Drug: Alisertib

ECT Dose Escalation

EXPERIMENTAL

Alisertib 10 or 20 mg, Enteric-coated Tablet (ECT) formulation, orally, once daily (QD) for 7 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

Relative Bioavailability

EXPERIMENTAL

Alisertib 40 mg ECT or PIC formulation, orally, twice daily (BID) for 7 days followed by a 14--day recovery period in cycle 1, followed by alisertib 40 mg in the opposite formulation (PIC or ECT) orally, twice daily (BID) for 7 days followed by a 14--day recovery period in cycle 2, followed by alisertib 50 mg PIC formulation 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 9 cycles).

Drug: Alisertib

Interventions

Alisertib DRUG

Alisertib (MLN8237) will be supplied in capsules of 5 or 25 mg and will be given on an empty stomach, with patients remaining nothing by mouth except for water and prescribed medications for 2 hours before and 1 hour after each dose. Each dose will be given by mouth with 8 ounces of water for 7 to 21 consecutive days. A 14-day recovery period will follow each dosing period regardless of its duration.

Also known as: MLN8237

ECT Dose Escalation; PIC Dose Escalation; Relative Bioavailability

Eligibility Criteria

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

You may qualify if:

• Histologically or cytologically confirmed metastatic and/or advanced solid tumors (including lymphomas) for which no effective standard treatment is available
• Aged 18 years or more
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
• Expected survival longer than 3 months from enrollment in the study
• Radiographically or clinically evaluable tumor; however, measurable disease as defined by (RECIST) criteria is not required for participation in this study
• Suitable venous access for the conduct of blood sampling for MLN8237 PK
• 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®, and hormonal agents, such as Femara®) must not have received treatment with these drugs for at least 2 weeks before the first dose of MLN8237 is given.
• Male participants must use an appropriate method of barrier contraception (eg, condoms) and inform any sexual partners that they must also use a reliable method of contraception (eg, birth control pills) from the time of informed consent until 3 months after the last dose of study treatment.
• Female participants must be postmenopausal, surgically sterilized, or willing to use reliable methods of birth control (eg, a hormonal contraceptive, an intrauterine device, diaphragm with spermicide, or abstinence) and inform male sexual partners that they must also use a reliable method of contraception (eg, condoms) from the time of informed consent until 3 months after the last dose of study treatment.
• Willing and able to give written informed consent before the conduct of any study related procedure that is not part of normal medical care, and willing to comply with the protocol

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 illness or uncontrolled medical illness unrelated to cancer
• Ongoing nausea or vomiting of any severity
• \> Grade 1 diarrhea
• Known gastrointestinal (GI) disease or GI procedure 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.
• 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. There is no limit on the number of noncytotoxic therapies (eg, hormonal and immunologic) that participants may have received. Tyrosine kinase inhibitors (eg, Tarceva and Iressa®) are considered noncytotoxic compounds.
• 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
• Clinical and/or radiographic evidence of cerebral metastases. However, participants who have a history of central nervous system (CNS) 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 \<1500/mm\^3; platelet count \<100,000/mm\^3
• Serum creatinine \>1.6 mg/dl or a measured or estimated creatinine clearance \<40 mL/minute

Sponsors & Collaborators

• Millennium Pharmaceuticals, Inc.: lead

Study Sites (1)

Sarah Cannon Research Institute (SCRI)

Nashville, Tennessee, 37203, United States

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 Monitor

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

Study Record Dates

• First Submitted: July 12, 2007
• First Posted: July 13, 2007
• Study Start: May 15, 2007
• Primary Completion: August 1, 2010
• Study Completion: February 23, 2011
• Last Updated: March 14, 2019
• Results First Posted: March 14, 2019

Record last verified: 2018-11

Locations

US (1)