Advanced MalignanciesPhase 1NCT00651664
A Phase I Clinical and Pharmacodynamic Study of MLN8237, A Novel Aurora A Kinase Inhibitor, in Participants With Advanced Malignancies
A Phase 1 study testing alisertib in people with Advanced Malignancies, run by Millennium Pharmaceuticals, Inc. at 2 sites in Spain.
Trial 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). Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Advanced Malignancies
- What is being tested?
- alisertib
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 59 participants
- Where
- 2 sitesSpain
- Study dates
- 22 Oct 2007to 5 Apr 2011
- Phase
- Phase 1
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
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- 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.
Who cannot join
- 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.
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- 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
- Bilirubin >1.5 times the upper limit of the normal range (ULN); aspartate aminotransferase(AST)/alanine aminotransferase(ALT) >2.5 times the ULN, and alkaline phosphatase(ALP) >2.5 times the ULN. Both the AST and ALP could be elevated up to 5 times the ULN if their elevation could be reasonably ascribed to the presence of metastatic disease to liver and/or to bone; however, the ALT in all circumstances must have been <2.5 times the ULN.
- Abnormalities on 12-lead electrocardiogram considered by the investigator to be clinically significant or baseline prolongation of the rate-corrected QT interval (eg, repeated demonstration of QTc interval >450 milliseconds).
- Known history of human immunodeficiency virus (HIV) infection, hepatitis B or hepatitis C.
- Less than 4 weeks between the last dose of an investigational agent and the first dose of MLN8237.
- Admission or evidence of benzodiazepine dependence or abuse and/or alcohol abuse or an inability to restrict consumption of alcohol to no more than 1 standard unit of alcohol per day during the study and for 30 days from the last dose of study treatment.
- Activated partial thromboplastin time (aPTT) and/or prothrombin time (PT) exceeding the upper limit of the normal range.
- Known bleeding diathesis or history of abnormal bleeding.
- Ongoing therapy with an anticoagulant (e.g., aspirin, plavix, coumadin).
Trial locations and contacts
2 sites in 1 country.
Spain2 sites
Ciutat Sanitaria Vall d'Hebron - Servicio de Oncologia
Barcelona, 08035
H. Clínico Universitario de Valencia
Valencia
About this study
Official title: A Phase I Clinical and Pharmacodynamic Study of MLN8237, A Novel Aurora A Kinase Inhibitor, in Patients With Advanced Malignancies
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).
Read the detailed description
The drug tested in this study is called alisertib. Alisertib is being tested to treat people who have advanced 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 59 patients. Participants were enrolled in one of 10 dose escalation arms:
- Alisertib 5 mg once daily (QD) for 7 Days (D)
- Alisertib 80 mg QD 7D
- Alisertib 150 mg QD 7D
- Alisertib 50 mg twice daily (BID) 7D
- Alisertib 60 mg BID 7D
- Alisertib 75 mg BID 7D
- Alisertib 100 mg BID 7D
- Alisertib 50 mg QD 14D
- Alisertib 50 mg QD 21D
- Alisertib 70 mg QD 21D
All participants received treatment until their disease progressed or they experienced unacceptable alisertib-related toxicity.
This multi-center trial was conducted in Spain. The overall time to participate in this study was 730 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.
- Conditions
- Advanced Malignancies
- Being tested
- alisertib
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
alisertibDrug
Also called MLN8237
Alisertib (MLN8237) capsules
| Study group | Role | What they receive |
|---|---|---|
| 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). Receives: 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). Receives: 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). Receives: 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). Receives: 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). Receives: 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). Receives: 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). Receives: 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). Receives: 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). Receives: 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). Receives: Drug: alisertib |
What is being measured
The primary outcome is the main question the study is designed to answer.
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:
- Grade 4 neutropenia lasting for ≥7 consecutive days during recovery
- Grade 4 neutropenia with fever and/or infection
- Confirmed platelet count <25,000/mm^3
- ≥Grade 3 nausea and/or emesis despite the use of an antiemetic prophylaxis
- ≥Grade 3 diarrhea that occurred despite therapy with loperamide
- 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
- Treatment delay of >1 week because of a failure of adequate hematologic or nonhematologic recovery from the previous cycle of treatment.
- Other alisertib-related nonhematologic toxicities ≥ Grade 2 that, in the opinion of the investigator, required a dose reduction or discontinuation of therapy with alisertib.
Measured: 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.
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Rac for Day 7=AUCt Day 7/AUCt Day 1.
Measured: Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Day 7
Peak/Trough Ratio for Aliserib 7 Day Dosing
Measured: Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Day 7
CLss/F: Apparent Oral Clearance at Steady State 7 Day Dosing
Measured: Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Day 7
Cmax: Maximum Observed Concentration for Alisertib 14 Day Dosing
Measured: 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 Days 7 and 14
Tmax: Time of First Occurrence of Cmax for Alisertib 14 Day Dosing
Measured: 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 Days 7 and 14
AUCt: Area Under the Concentration-time Curve From Time 0 to Time t for Alisertib 14 Day Dosing
Measured: 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 Days 7 and 14
Terminal Half-Life (t1/2) for Alisertib 14 Day Dosing
Measured: Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Days 7 and 14
Accumulation Ratio (Rac) for Alisertib 14 Day Dosing
Rac for Day 7=AUCt Day 7/AUCt Day 1. Rac for Day 14=AUCt Day 7/AUCt Day 1.
Measured: Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Days 7 and 14
Peak/Trough Ratio for Aliserib 14 Day Dosing
Measured: Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Days 7 and 14
CLss/F: Apparent Oral Clearance at Steady State 14 Day Dosing
Measured: Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Days 7 and 14
Cmax: Maximum Observed Concentration for Alisertib 21 Day Dosing
Measured: 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 Days 14 and 21
Tmax: Time of First Occurrence of Cmax for Alisertib 21 Day Dosing
Measured: 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 Days 14 and 21
AUCt: Area Under the Concentration-time Curve From Time 0 to Time t for Alisertib 21 Day Dosing
Measured: 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 Days 14 and 21
Terminal Half-Life (t1/2) for Alisertib 21 Day Dosing
Measured: Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Day 21
Accumulation Ratio (Rac) for Alisertib 21 Day Dosing
Rac for Day 7=AUCt Day 7/AUCt Day 1. Rac for Day 14=AUCt Day 7/AUCt Day 1. Rac for Day 21=AUCt Day 21/AUCt Day 1.
Measured: Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Days 14 and 21
Peak/Trough Ratio for Aliserib 21 Day Dosing
Measured: Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Days 14 and 21
CLss/F: Apparent Oral Clearance at Steady State 21 Day Dosing
Measured: Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Days 14 and 21
Change From Baseline in Alisertib Skin Punch Biopsy Mitotic Index 7 Day Dosing
Mitotic index was defined as the mean number of mitotic cells per millimeter (mm) length of the basoepithelial layer (BEL). Mitotic cells were counted manually within the BEL of 4, 5 micrometer (µm) skin sections stained with fluorescent-tagged antibodies specific to 2 mitotic markers; histone H3 phosphorylated on serine 10 (pHistH3) and MPM2. Deoxyribonucleic acid (DNA) was stained with a fluorescent marker as well. A positive change from Baseline indicates improvement.
Measured: Cycle 1: Pre-dose (Baseline) and Day 1, 6 hours post-dose; Day 7, 6 and 24 hours post-dose.
Change From Baseline in Alisertib Skin Punch Biopsy Mitotic Index 14 Day Dosing
Mitotic index was defined as the mean number of mitotic cells per millimeter (mm) length of the basoepithelial layer (BEL). Mitotic cells were counted manually within the BEL of 4, 5 micrometer (µm) skin sections stained with fluorescent-tagged antibodies specific to 2 mitotic markers; histone H3 phosphorylated on serine 10 (pHistH3) and MPM2. Deoxyribonucleic acid (DNA) was stained with a fluorescent marker as well. A positive change from Baseline indicates improvement.
Measured: Cycle 1: Pre-dose (Baseline) and Day 1 and 7, 6 hours post-dose; Day 14, 6 and 24 hours post-dose
Change From Baseline in Alisertib Skin Punch Biopsy Mitotic Index 21 Day Dosing
Mitotic index was defined as the mean number of mitotic cells per millimeter (mm) length of the basoepithelial layer (BEL). Mitotic cells were counted manually within the BEL of 4, 5 micrometer (µm) skin sections stained with fluorescent-tagged antibodies specific to 2 mitotic markers; histone H3 phosphorylated on serine 10 (pHistH3) and MPM2. Deoxyribonucleic acid (DNA) was stained with a fluorescent marker as well. A positive change from Baseline indicates improvement.
Measured: Cycle 1: Pre-dose (Baseline) and Day 7, 14 and 21, 6 hours post-dose
Change From Baseline in Alisertib Skin Punch Biopsy Apoptotic Index 7 Day Dosing
Apoptotic index was defined as the mean number of apoptotic cells per mm length of the basoepithelial layer (BEL). Apoptotic cells were counted manually within the BEL of 4, 5 µm skin sections stained with hematoxylin and eosin. A positive change from Baseline indicates improvement.
Measured: Cycle 1: Day 1, 6 hours post-dose; Days 7 6 and 24 hours post-dose; Day 21: 6 hours post-dose
Change From Baseline in Alisertib Skin Punch Biopsy Apoptotic Index 14 Day Dosing
Apoptotic index was defined as the mean number of apoptotic cells per mm length of the basoepithelial layer (BEL). Apoptotic cells were counted manually within the BEL of 4, 5 µm skin sections stained with hematoxylin and eosin. A positive change from Baseline indicates improvement.
Measured: Cycle 1: Pre-dose (Baseline) and Day 1, 6 hours post-dose; Days 7 and 14, 6 and 24 hours post-dose
Change From Baseline in Alisertib Skin Punch Biopsy Apoptotic Index 21 Day Dosing
Apoptotic index was defined as the mean number of apoptotic cells per mm length of the basoepithelial layer (BEL). Apoptotic cells were counted manually within the BEL of 4, 5 µm skin sections stained with hematoxylin and eosin. A positive change from Baseline indicates improvement.
Measured: Cycle 1: Pre-dose (Baseline) and Day 1, 6 hours post-dose; Days 7 and 14, 6 and 24 hours post-dose; Day 21: 6 hours post-dose
Change From Baseline in Alisertib Tumor Biopsy Mitotic Index 7 Day Dosing
Tumor biopsy sections were immunoflourescently labeled with proliferative marker Ki67 and mitotic marker pHistH3. DNA was stained with a fluorescent marker as well. The Mitotic index was determined from the percentage of pHistH3 immunopositive cells within the Ki67 positive area. A positive change from Baseline indicates improvement.
Measured: Cycle 1: Pre-dose (Baseline) and Days 1 and 7, 6 hours post-dose
Change From Baseline in Alisertib Tumor Biopsy Mitotic Index 14 Day Dosing
Tumor biopsy sections were immunoflourescently labeled with proliferative marker Ki67 and mitotic marker pHistH3. DNA was stained with a fluorescent marker as well. The Mitotic index was determined from the percentage of pHistH3 immunopositive cells within the Ki67 positive area. A positive change from Baseline indicates improvement.
Measured: Cycle 1: Pre-dose (Baseline) and Day 7, 6 hours post-dose
Change From Baseline in Alisertib Tumor Biopsy Mitotic Index 21 Day Dosing
Tumor biopsy sections were immunoflourescently labeled with proliferative marker Ki67 and mitotic marker pHistH3. DNA was stained with a fluorescent marker as well. The Mitotic index was determined from the percentage of pHistH3 immunopositive cells within the Ki67 positive area. A positive change from Baseline indicates improvement.
Measured: Cycle 1: Pre-dose (Baseline) and Days 7 and 21, 6 hours post-dose
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted3 Apr 2008 (estimated)
- Study start22 Oct 2007
- Primary completion1 Sep 2010
- Study completion5 Apr 2011
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Advanced MalignanciesStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 59 participants (actual)
Sponsor and investigators
- Lead sponsor
- Millennium Pharmaceuticals, Inc.
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Medical Director Clinical Science, Study director, Takeda
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00651664
- Sponsor's protocol ID
- C14002
- Other IDs
- 2006-006048-68, U1111-1187-1151
- Status last verified
- Nov 2018
- First submitted
- 31 Mar 2008
- Last updated
- 15 Mar 2019
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 15 Mar 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase I Clinical and Pharmacodynamic Study of MLN8237, A Novel Aurora A Kinase Inhibitor, in Patients With Advanced Malignancies
- ClinicalTrials.gov ID
- NCT00651664
- Acronym / sponsor ID
- C14002
- Conditions
- Advanced Malignancies
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 59 participants (actual)
- Lead sponsor
- Millennium Pharmaceuticals, Inc.Industry (pharma, biotech, devices)
- Study start
- 22 Oct 2007 (actual)
- Primary completion
- 1 Sep 2010 (actual)
- Study completion
- 5 Apr 2011 (actual)
- First posted
- 3 Apr 2008 (estimated)
- Results
- Posted 15 Mar 2019
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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).
Detailed description
The drug tested in this study is called alisertib. Alisertib is being tested to treat people who have advanced 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 59 patients. Participants were enrolled in one of 10 dose escalation arms:
- Alisertib 5 mg once daily (QD) for 7 Days (D)
- Alisertib 80 mg QD 7D
- Alisertib 150 mg QD 7D
- Alisertib 50 mg twice daily (BID) 7D
- Alisertib 60 mg BID 7D
- Alisertib 75 mg BID 7D
- Alisertib 100 mg BID 7D
- Alisertib 50 mg QD 14D
- Alisertib 50 mg QD 21D
- Alisertib 70 mg QD 21D
All participants received treatment until their disease progressed or they experienced unacceptable alisertib-related toxicity.
This multi-center trial was conducted in Spain. The overall time to participate in this study was 730 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.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 10
| Arm | Type | Receives |
|---|---|---|
| Alisertib 5 mg QD 7D | Experimental | Drug: alisertibAlisertib 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). |
| Alisertib 80 mg QD 7D | Experimental | Drug: alisertibAlisertib 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). |
| Alisertib 150 mg QD 7D | Experimental | Drug: alisertibAlisertib 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). |
| Alisertib 50 mg BID 7D | Experimental | Drug: alisertibAlisertib 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). |
| Alisertib 60 mg BID 7D | Experimental | Drug: alisertibAlisertib 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). |
| Alisertib 75 mg BID 7D | Experimental | Drug: alisertibAlisertib 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). |
| Alisertib 100 mg BID 7D | Experimental | Drug: alisertibAlisertib 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). |
| Alisertib 50 mg QD 14D | Experimental | Drug: alisertibAlisertib 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). |
| Alisertib 50 mg QD 21D | Experimental | Drug: alisertibAlisertib 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). |
| Alisertib 70 mg QD 21D | Experimental | Drug: alisertibAlisertib 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). |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (10 listed)
- 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.
Key exclusion criteria (23 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| alisertibAlso: MLN8237Alisertib (MLN8237) capsules | Drug | 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 |
Primary outcome
Number of Participants With Dose-Limiting Toxicity (DLT)
Time frame: First dose through 30 days following the last dose of study drug (up to 730 days)
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.
Maximum Tolerated Dose (MTD) of Alisertib
Time frame: Signing of the Informed Consent through 30 days following the last dose of study drug (up to 730 days)
The MTD was defined as the highest dose at which DLT occurred in 0/3 or 1/6 participants.
30 secondary outcomes
Cmax: Maximum Observed Concentration for Alisertib 7 Day Dosing
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Day 7
Peak/Trough Ratio for Aliserib 7 Day Dosing
Time frame: Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Day 7
CLss/F: Apparent Oral Clearance at Steady State 7 Day Dosing
Time frame: Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Day 7
Cmax: Maximum Observed Concentration for Alisertib 14 Day Dosing
Time frame: 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 Days 7 and 14
Tmax: Time of First Occurrence of Cmax for Alisertib 14 Day Dosing
Time frame: 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 Days 7 and 14
AUCt: Area Under the Concentration-time Curve From Time 0 to Time t for Alisertib 14 Day Dosing
Time frame: 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 Days 7 and 14
Terminal Half-Life (t1/2) for Alisertib 14 Day Dosing
Time frame: Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Days 7 and 14
Accumulation Ratio (Rac) for Alisertib 14 Day Dosing
Time frame: Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Days 7 and 14
Peak/Trough Ratio for Aliserib 14 Day Dosing
Time frame: Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Days 7 and 14
CLss/F: Apparent Oral Clearance at Steady State 14 Day Dosing
Time frame: Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Days 7 and 14
Cmax: Maximum Observed Concentration for Alisertib 21 Day Dosing
Time frame: 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 Days 14 and 21
Tmax: Time of First Occurrence of Cmax for Alisertib 21 Day Dosing
Time frame: 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 Days 14 and 21
AUCt: Area Under the Concentration-time Curve From Time 0 to Time t for Alisertib 21 Day Dosing
Time frame: 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 Days 14 and 21
Terminal Half-Life (t1/2) for Alisertib 21 Day Dosing
Time frame: Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Day 21
Accumulation Ratio (Rac) for Alisertib 21 Day Dosing
Time frame: Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Days 14 and 21
Peak/Trough Ratio for Aliserib 21 Day Dosing
Time frame: Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Days 14 and 21
CLss/F: Apparent Oral Clearance at Steady State 21 Day Dosing
Time frame: Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Days 14 and 21
Change From Baseline in Alisertib Skin Punch Biopsy Mitotic Index 7 Day Dosing
Time frame: Cycle 1: Pre-dose (Baseline) and Day 1, 6 hours post-dose; Day 7, 6 and 24 hours post-dose.
Change From Baseline in Alisertib Skin Punch Biopsy Mitotic Index 14 Day Dosing
Time frame: Cycle 1: Pre-dose (Baseline) and Day 1 and 7, 6 hours post-dose; Day 14, 6 and 24 hours post-dose
Change From Baseline in Alisertib Skin Punch Biopsy Mitotic Index 21 Day Dosing
Time frame: Cycle 1: Pre-dose (Baseline) and Day 7, 14 and 21, 6 hours post-dose
Change From Baseline in Alisertib Skin Punch Biopsy Apoptotic Index 7 Day Dosing
Time frame: Cycle 1: Day 1, 6 hours post-dose; Days 7 6 and 24 hours post-dose; Day 21: 6 hours post-dose
Change From Baseline in Alisertib Skin Punch Biopsy Apoptotic Index 14 Day Dosing
Time frame: Cycle 1: Pre-dose (Baseline) and Day 1, 6 hours post-dose; Days 7 and 14, 6 and 24 hours post-dose
Change From Baseline in Alisertib Skin Punch Biopsy Apoptotic Index 21 Day Dosing
Time frame: Cycle 1: Pre-dose (Baseline) and Day 1, 6 hours post-dose; Days 7 and 14, 6 and 24 hours post-dose; Day 21: 6 hours post-dose
Change From Baseline in Alisertib Tumor Biopsy Mitotic Index 7 Day Dosing
Time frame: Cycle 1: Pre-dose (Baseline) and Days 1 and 7, 6 hours post-dose
Change From Baseline in Alisertib Tumor Biopsy Mitotic Index 14 Day Dosing
Time frame: Cycle 1: Pre-dose (Baseline) and Day 7, 6 hours post-dose
Change From Baseline in Alisertib Tumor Biopsy Mitotic Index 21 Day Dosing
Time frame: Cycle 1: Pre-dose (Baseline) and Days 7 and 21, 6 hours post-dose
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 15 Mar 2019.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Medical Director Clinical Science study director
Takeda
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing alisertib in people with Advanced Malignancies, run by Millennium Pharmaceuticals, Inc. at 2 sites in Spain.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 10 inclusion and 23 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 15 Mar 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in Spain. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 15 Mar 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of Participants With Dose-Limiting Toxicity (DLT) (time frame: First dose through 30 days following the last dose of study drug (up to 730 days)). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 15 Mar 2019.