Advanced Nonhematologic MalignanciesPhase 1NCT02327169

A Study MLN2480 in Combination With MLN0128 or Alisertib, or Paclitaxel, or Cetuximab, or Irinotecan in Adult Participants With Advanced Nonhematologic Malignancies

A Phase 1 study testing MLN2480, MLN0128 and Alisertib in people with Advanced Nonhematologic Malignancies, run by Millennium Pharmaceuticals, Inc. at 14 sites in 4 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

Search all trials

Trial summary

The primary purpose of this study is to determine the safety profile and the maximum tolerated doses (MTDs)/ potential recommended phase 2 doses (RP2Ds) of the combination treatments of MLN2480 + MLN0128, MLN2480 + alisertib, MLN2480 + paclitaxel, MLN2480 + cetuximab, and MLN2480 + irinotecan in participants with… Read more about this study

Who is it for?: Ages 18 years and older
Conditions the study is for: Advanced Nonhematologic Malignancies
What is being tested?: MLN2480, MLN0128 and Alisertib
Type of treatment: Pill or oral medicine, Injection or infusion
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 81 participants
Where: 14 sitesin 4 countries
Study dates: 14 Jan 2015to 2 Jul 2018
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

All Treatment Arms:
Male or female participants 18 years or older.
Participants who, in the opinion of the treating physician, have failed standard therapies and for whom a phase 1 trial is an appropriate option.
Radiographically or clinically evaluable tumor. For expansion phase: Tumors must be measurable and of the protocol specified genetic mutational status, where applicable.
Recovered (ie, less than or equal to [<=] Grade 1 toxicity) from adverse effects (except alopecia) of prior therapy.
Eastern Cooperative Oncology Group (ECOG) performance status 0-1.

Show all 17Show fewer

Expected survival time of at least 3 months in the opinion of the investigator.
Block of banked tumor tissue and/or greater than or equal to (>=) 10 unstained slides. Participants who satisfy all other eligibility criteria but do not have banked tissue/slides may be asked to consent to baseline biopsy.
Suitable vein access for the study-required blood sampling.
Thyroid function tests consistent with stable thyroid function. Note: Participants on a stable dose of thyroid replacement therapy for a suggested minimum of 12 weeks before Cycle 1, Day 1 are eligible.
Left ventricular ejection fraction (LVEF) of 50 percent (%) or greater, as measured by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA), within 28 days before the first dose of MLN2480
Female participants who are post-menopausal for at least 1 year, surgically sterile, or agree to practice 2 effective methods of contraception through 120 days (4 months) after the last dose of study drug for participants in Arms 1, 2, and 5, and through 6 months for participants in Arms 3 and 4, or agree to practice true abstinence.
Male participants who, even if surgically sterilized, agree to practice effective barrier contraception through 120 days (4 months) after the last dose of study drug for participants in Arms 1, 2, and 5, and through 6 months for participants in Arms 3, and 4, or agree to practice true abstinence.
Additional inclusion criteria for arm 3 expansion only (MLN2480 + paclitaxel):
Participants with Kirsten rat sarcoma viral oncogene homolog (KRAS) exon 2 or BRAF non-V600 mutation-positive non-small cell lung cancer (NSCLC) who have received a minimum of 1 but not more than 2 prior cytotoxic-approved regimens.
Additional inclusion criteria for arms 4 and 5 expansion only (MLN2480 + cetuximab; MLN2480 + irinotecan):
Participants with CRC who have received a minimum of 1 but not more than 2 prior cytotoxic-approved regimens.

Who cannot join

All treatment arms:
Female participants who are pregnant or currently breastfeeding.
History of any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with safe protocol completion.
History of uncontrolled brain metastasis unless: previously treated with surgery, whole-brain radiation, or stereotactic radiosurgery; stable disease for >= 60 days without steroid use (or stable steroid dose established for >= 28 days before the first dose of MLN2480).
Ongoing seizure disorder or a requirement for antiepileptics.
Recent prior therapies, including: chemotherapy and hormonal therapy <= 4 weeks or 4 half lives, whichever occurs first, before administration of study drug; immunotherapy/monoclonal antibody use <= 4 weeks before administration of MLN2480; or radiation therapy <= 3 weeks before administration of study drug.

Show all 22Show fewer

Chronic therapeutic corticosteroid use with the exception of replacement therapy for adrenal insufficiency or corticosteroid inhalers.
Known history of human immunodeficiency virus infection, hepatitis B, or hepatitis C; Prior allogeneic bone marrow or organ transplantation, or active condition of chronic immune suppression is not allowed.
Concomitant use, or administration <= 14 days before first dose of study drug(s), of clinically significant enzyme inducers.
Treatment with gemfibrozil (strong Cytochrome P4502C8 [CYP2C8] inhibitor) within 14 days before the first dose of MLN2480.
History of or current illicit drug use, drug abuse, or alcohol abuse.
Major surgery within 14 days before the first dose of study drug.
Inability to comply with study requirements.
Other unspecified reasons that, in the opinion of the investigator or Millennium, make the participant unsuitable for enrollment.
Additional exclusion criteria for arms 3, 5, and 6 expansion only (MLN2480 + paclitaxel; MLN2480 + irinotecan; MLN2480 monotherapy):
Prior treatment with rapidly accelerated fibrosarcoma (RAF), extracellular signal-regulated kinases (MEK), or other inhibitors of the mitogen-activated protein kinase (MAPK) pathway.
Additional exclusion criteria for arm 2 only (MLN2480 + alisertib):
History of uncontrolled sleep apnea syndrome and other conditions that could result in excessive daytime sleepiness, such as severe chronic obstructive pulmonary disease.
Additional exclusion criteria for arm 3 only (MLN2480 + paclitaxel):
Known hypersensitivity to paclitaxel, or its components or other drugs formulated in Cremophor® EL (polyoxyethylated castor oil).
Additional exclusion criteria for arm 5 only (MLN2480 + irinotecan):
Use of strong or moderate Cytochrome P4503A (CYP3A) inhibitors <= days of the first dose of irinotecan.

Trial locations and contacts

14 sites in 4 countries.

Country

City, postcode or hospital

14 sites in 4 countries

United States5 sites

Massachusetts General Hospital Cancer Center
Boston, Massachusetts, 2114
Beth Israel Deaconess Medical Center
Boston, Massachusetts, 2115
Dana Farber Cancer Institute
Boston, Massachusetts, 2115
The University of Texas MD Anderson Cancer Center
Houston, Texas, 77030
Fox Chase Cancer Center
Philadelphia, Pennsylvania, 19111

Other trials in United States

France3 sites

Institut Bergonie
Bordeaux, Gironde, 33076
Institut Claudius Regaud-Oncopole
Toulouse, Haute Garonne, 31059
Institut Gustave Roussy
Villejuif, Val De Marne, 94805

Other trials in France

Spain3 sites

Hospital Universitari Vall d'Hebron
Barcelona, 8035
START Madrid. Fundacion Jimenez Diaz
Madrid, 28040
Hospital Clinico Universitario Virgen de la Victoria
Málaga, 29010

Other trials in Spain

United Kingdom3 sites

Sarah Cannon Research Institure UK
London, Greater London, W1G 6AD
The Chrisie
Manchester, Greater Manchester, M20 4BX
Churchill Hospital
Oxford, Oxfordshire, OX3 7LJ

Other trials in United Kingdom

About this study

Official title: A Multiarm, Open-label, Phase 1b Study of MLN2480 (an Oral A-, B-, and CRAF Inhibitor) in Combination With MLN0128 (an Oral mTORC 1/2 Inhibitor), or Alisertib (an Oral Aurora A Kinase Inhibitor), or Paclitaxel, or Cetuximab, or Irinotecan, in Adult Patients With Advanced Nonhematologic Malignancies

Read the detailed description

The drug being tested in this study is called MLN2480 (TAK-580). MLN2480 was tested to evaluate side effects and determine the maximum tolerated dose (MTD) and recommended dose for future studies when administered in combination with five other medications. This study was to assess the safety of MLN2480 as well as how it is processed by the body in participants with solid nonhematologic malignancies who have failed standard therapies.

The study was to be conducted in two phases, the dose escalation phase and the dose expansion phase. A total of 71 participants were enrolled in the escalation phase. Participants in this phase were assigned to one of the five treatment groups:

MLN2480 + MLN0128
MLN2480 + Alisertib
MLN2480 + Paclitaxel
MLN2480 + Cetuximab
MLN2480 + Irinotecan

Once the MTD for each combination treatment arm was established in the escalation phase, one or more of the combination treatments will be selected for the expansion phase. A total of 10 participants were enrolled in the expansion phase.

This multi-centre trial was be conducted worldwide. The overall time to participate in this study is approximately 14 months. Participants made multiple visits to the clinic including an end of study visit 30 days after last dose of study drug for a follow-up assessment.

Conditions: Advanced Nonhematologic Malignancies
Being tested: MLN2480, MLN0128, Alisertib, Paclitaxel, Cetuximab
Keywords: Drug therapy

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

MLN2480Drug
Also called TAK-580
MLN2480 tablets.
MLN0128Drug
MLN0128 capsules.
AlisertibDrug
Alisertib tablets.
PaclitaxelDrug
Paclitaxel IV infusion.
CetuximabDrug
Cetuximab IV infusion.
IrinotecanDrug
Irinotecan IV infusion.

Study groups in NCT02327169
Study group	Role	What they receive
MLN2480 + MLN0128	Experimental	Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and MLN0128 2 mg, capsules, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles. Receives: Drug: MLN2480; Drug: MLN0128
MLN2480 + Alisertib	Experimental	Dose Escalation Phase: MLN2480 100-200 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30-40 mg, tablets, orally, twice daily (BID) on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle. Receives: Drug: MLN2480; Drug: Alisertib
MLN2480 + Paclitaxel	Experimental	Dose Escalation Phase: MLN2480 100-200 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 milligram per square meter (mg/m^2), intravenous (IV) infusion, once weekly (QW) for 3 weeks in each 28-day cycle for up to 12 cycles or MLN2480 400-600 mg tablets, orally, QW on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care. Receives: Drug: MLN2480; Drug: Paclitaxel
MLN2480 + Cetuximab	Experimental	Dose Escalation Phase: MLN2480 400-600 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and cetuximab administered intravenously at a loading dose of 400 mg/m^2 (cycle 1 Day 1), then at 250 mg/m^2 QW on Days 8, 15, and 22 of cycle 1 and Days 1, 8, 15, and 22 in each additional 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in cetuximab dose was based on the standard of care. Receives: Drug: MLN2480; Drug: Cetuximab
ML2480 + Irinotecan	Experimental	Dose Escalation Phase: MLN2480 400-600 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and irinotecan 180 mg/m^2, IV infusion over 90 minutes, every other week (Q2W) for 2 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in irinotecan dose was based on the standard of care. Receives: Drug: MLN2480; Drug: Irinotecan
MLN2480 600 mg + Paclitaxel 80 mg (Dose Expansion Phase)	Experimental	Dose Expansion Phase: MLN2480 600 mg, tablets, orally, once per week on Days 2, 9, 16 and 23 of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg, capsules, orally, once on 1, 8, and 15 of a 28-day cycle for up to 12 cycles. Receives: Drug: MLN2480

What is being measured

The primary outcome is the main question the study is designed to answer.

Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product; the untoward medical occurrence does not necessarily have a causal relationship with this treatment. An SAE means any untoward medical occurrence that at any dose results in death, is life-threatening, requires in patient hospitalization or prolongation of an existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly/birth defect or is a medically important event.
Measured: From Day 1, Cycle 1 through 30 days after the last dose of study drug (up to 13 months)
Number of Participants With Dose-Limiting Toxicities (DLTs)
DLT was defined using National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 and included: any drug-related hematologic toxicity ≥Grade 4 with the exception of Grade 4 neutropenia <7 days duration; Grade 3 or 4 neutropenia with fever >38.5 degrees Celsius and/or infection or neutropenia requiring colony-stimulating factor OR non-hematologic DLTs that were any Grade 3, 4, or 5 toxicity with the following exceptions: Grade 3 nausea, vomiting, diarrhea, and dehydration occurring in a setting of inadequate treatment; inadequately treated hypersensitivity reactions; Grade 3 elevated transaminases or urine electrolyte abnormality ≤1 week in duration; Grade 3 serum electrolyte abnormality ≤72 hours in duration. DLTs also included: drug-related adverse experience that lead to a dose modification; unresolved drug-related toxicity resulted in delay in initiation of Cycle 2.
Measured: From Day 1, Cycle 1 through 30 days after the last dose in Cycle 1 (up to 8 weeks)
Maximum Tolerated Dose (MTD) for MLN2480
Measured: Day 1, Cycle 1 up to 28 days
Recommended Phase 2 Dose (RP2D) of MLN2480
Measured: Day 1, Cycle 1 up to 28 days

Secondary outcomes (17)

Cmax : Maximum Observed Plasma Concentration for MLN2480
Measured: Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose
Cmax: Maximum Observed Plasma Concentration for MLN0128
Measured: Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose
Cmax: Maximum Observed Plasma Concentration for Alisertib
Measured: Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose
Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for MLN2480
Measured: Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose
Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for MLN0128
Measured: Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose
Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Alisertib
Measured: Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose
AUC(0-tau): Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for MLN2480
Measured: Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose
AUC(0-tau): Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for MLN0128
Measured: Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose
AUC(0-tau): Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for Alisertib
Measured: Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose
Cmax: Maximum Observed Plasma Concentration for Paclitaxel
Measured: Cycle 1, Day 15 pre-dose and at multiple timepoints (Up to 48 hours) post-dose
AUC(0-last): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Paclitaxel
Measured: Cycle 1, Day 15 pre-dose and at multiple timepoints (Up to 48 hours) post-dose
AUC(0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity, Calculated Using the Observed Value of the Last Quantifiable Concentration for Paclitaxel
Measured: Cycle 1, Day 15 pre-dose and at multiple timepoints (Up to 48 hours) post-dose
Terminal Elimination Half-life (T1/2) for Paclitaxel
Measured: Cycle 1, Day 15 pre-dose and at multiple timepoints (Up to 48 hours) post-dose
Objective Response Rate (ORR) Based on Response Evaluation Criteria in Solid Tumors (RECIST)
ORR was defined as the percentage of participants with complete response (CR) or partial response (PR) using Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1. CR: Disappearance of all target lesions, non-target lesions, no new lesions, and normalization of tumor marker level. PR: At least a 30% decrease in the sum of diameters of target lesions, no progression in non-target lesion, and no new lesions.
Measured: Baseline then every 2 cycles beginning at Cycle 2, Day 27, until disease progression, death or end of study (Up to 13 months)
Duration of Response
Duration of Response (DOR) was defined as the time in months from the first documented CR or PR per RECIST v. 1.1 to disease recurrence or disease progression (PD) whichever occurs first.
Measured: From first documented response until disease progression (Up to 13 months)
Time to Response
Time to response was defined as the time in months from the date of first dose of study treatment to the date of the first documentation of a PR or better response.
Measured: From date of enrollment to the date of the first documentation of a confirmed response (Up to 13 months)
Progression Free Survival (PFS)
PFS is defined as the time in months from the date of first study drug administration to the date of first documented PD or death due to any cause. PD was based on response evaluation criteria in solid tumors (RECIST V1.1), defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.
Measured: Baseline then every 2 cycles beginning at Cycle 2, Day 27, until disease progression, death or end of study (Approximately up to 13 months)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

14 Jan 20152 Jul 2018

First posted30 Dec 2014 (estimated)
Study start14 Jan 2015
Primary completion2 Jul 2018
Study completion2 Jul 2018

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 Nonhematologic 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: 81 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT02327169
Sponsor's protocol ID: C28002
Other IDs: 2014-003340-12, U1111-1159-5831, 2014
Status last verified: Feb 2020
First submitted: 23 Dec 2014
Last updated: 25 Feb 2020
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: Yes
FDA-regulated drug: Yes
FDA-regulated device: No
Individual data sharing: Yes: Takeda makes patient-level, de-identified data sets and associated documents available for all interventional studies after applicable marketing approvals and commercial availability have been received (or program is completely terminated), an opportunity for the primary publication of the research and final report development has been allowed, and other criteria have been met as set forth in Takeda's Data Sharing Policy (see www.TakedaClinicalTrials.com for details). To obtain access, researchers must submit a legitimate academic research proposal for adjudication by an independent review panel, who will review the scientific merit of the research and the requestor's qualifications and conflict of interest that can result in potential bias. Once approved, qualified researchers who sign a data sharing agreement are provided access to these data in a secure research environment.

Study at a glance

From the registry record, last updated by the sponsor on 25 Feb 2020. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: A Multiarm, Open-label, Phase 1b Study of MLN2480 (an Oral A-, B-, and CRAF Inhibitor) in Combination With MLN0128 (an Oral mTORC 1/2 Inhibitor), or Alisertib (an Oral Aurora A Kinase Inhibitor), or Paclitaxel, or Cetuximab, or Irinotecan, in Adult Patients With Advanced Nonhematologic Malignancies
ClinicalTrials.gov ID: NCT02327169
Acronym / sponsor ID: C28002
Conditions: Advanced Nonhematologic Malignancies
Keywords: Drug therapy
Phase: Phase 1
Study type: Interventional
Recruitment status: Completed
Enrolment: 81 participants (actual)
Lead sponsor: Millennium Pharmaceuticals, Inc.Industry (pharma, biotech, devices)
Study start: 14 Jan 2015 (actual)
Primary completion: 2 Jul 2018 (actual)
Study completion: 2 Jul 2018 (actual)
First posted: 30 Dec 2014 (estimated)
Results: Posted 25 Feb 2020

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Detailed description

MLN2480 + MLN0128
MLN2480 + Alisertib
MLN2480 + Paclitaxel
MLN2480 + Cetuximab
MLN2480 + Irinotecan

Study design

Primary purpose: Treatment
Allocation: Non-randomised
Intervention model: Parallel groups
Masking: None (open label)
Number of arms: 6

Arm	Type	Receives
MLN2480 + MLN0128	Experimental	Drug: MLN2480, Drug: MLN0128Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and MLN0128 2 mg, capsules, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles.
MLN2480 + Alisertib	Experimental	Drug: MLN2480, Drug: AlisertibDose Escalation Phase: MLN2480 100-200 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30-40 mg, tablets, orally, twice daily (BID) on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle.
MLN2480 + Paclitaxel	Experimental	Drug: MLN2480, Drug: PaclitaxelDose Escalation Phase: MLN2480 100-200 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 milligram per square meter (mg/m^2), intravenous (IV) infusion, once weekly (QW) for 3 weeks in each 28-day cycle for up to 12 cycles or MLN2480 400-600 mg tablets, orally, QW on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care.
MLN2480 + Cetuximab	Experimental	Drug: MLN2480, Drug: CetuximabDose Escalation Phase: MLN2480 400-600 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and cetuximab administered intravenously at a loading dose of 400 mg/m^2 (cycle 1 Day 1), then at 250 mg/m^2 QW on Days 8, 15, and 22 of cycle 1 and Days 1, 8, 15, and 22 in each additional 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in cetuximab dose was based on the standard of care.
ML2480 + Irinotecan	Experimental	Drug: MLN2480, Drug: IrinotecanDose Escalation Phase: MLN2480 400-600 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and irinotecan 180 mg/m^2, IV infusion over 90 minutes, every other week (Q2W) for 2 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in irinotecan dose was based on the standard of care.
MLN2480 600 mg + Paclitaxel 80 mg (Dose Expansion Phase)	Experimental	Drug: MLN2480Dose Expansion Phase: MLN2480 600 mg, tablets, orally, once per week on Days 2, 9, 16 and 23 of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg, capsules, orally, once on 1, 8, and 15 of a 28-day cycle for up to 12 cycles.

Who may qualify

Ages: 18 years and older
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (17 listed)

Male or female participants 18 years or older.
Participants who, in the opinion of the treating physician, have failed standard therapies and for whom a phase 1 trial is an appropriate option.
Radiographically or clinically evaluable tumor. For expansion phase: Tumors must be measurable and of the protocol specified genetic mutational status, where applicable.
Recovered (ie, less than or equal to [<=] Grade 1 toxicity) from adverse effects (except alopecia) of prior therapy.
Eastern Cooperative Oncology Group (ECOG) performance status 0-1.

Key exclusion criteria (22 listed)

Female participants who are pregnant or currently breastfeeding.
History of any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with safe protocol completion.
History of uncontrolled brain metastasis unless: previously treated with surgery, whole-brain radiation, or stereotactic radiosurgery; stable disease for >= 60 days without steroid use (or stable steroid dose established for >= 28 days before the first dose of MLN2480).
Ongoing seizure disorder or a requirement for antiepileptics.
Recent prior therapies, including: chemotherapy and hormonal therapy <= 4 weeks or 4 half lives, whichever occurs first, before administration of study drug; immunotherapy/monoclonal antibody use <= 4 weeks before administration of MLN2480; or radiation therapy <= 3 weeks before administration of study drug.

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
MLN2480Also: TAK-580MLN2480 tablets.	Drug	ML2480 + Irinotecan, MLN2480 + Alisertib, MLN2480 + Cetuximab, MLN2480 + MLN0128, MLN2480 + Paclitaxel, MLN2480 600 mg + Paclitaxel 80 mg (Dose Expansion Phase)
MLN0128MLN0128 capsules.	Drug	MLN2480 + MLN0128
AlisertibAlisertib tablets.	Drug	MLN2480 + Alisertib
PaclitaxelPaclitaxel IV infusion.	Drug	MLN2480 + Paclitaxel
CetuximabCetuximab IV infusion.	Drug	MLN2480 + Cetuximab
IrinotecanIrinotecan IV infusion.	Drug	ML2480 + Irinotecan

Primary outcome

Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
Time frame: From Day 1, Cycle 1 through 30 days after the last dose of study drug (up to 13 months)
An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product; the untoward medical occurrence does not necessarily have a causal relationship with this treatment. An SAE means any untoward medical occurrence that at any dose results in death, is life-threatening, requires in patient hospitalization or prolongation of an existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly/birth defect or is a medically important event.
Number of Participants With Dose-Limiting Toxicities (DLTs)
Time frame: From Day 1, Cycle 1 through 30 days after the last dose in Cycle 1 (up to 8 weeks)
DLT was defined using National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 and included: any drug-related hematologic toxicity ≥Grade 4 with the exception of Grade 4 neutropenia <7 days duration; Grade 3 or 4 neutropenia with fever >38.5 degrees Celsius and/or infection or neutropenia requiring colony-stimulating factor OR non-hematologic DLTs that were any Grade 3, 4, or 5 toxicity with the following exceptions: Grade 3 nausea, vomiting, diarrhea, and dehydration occurring in a setting of inadequate treatment; inadequately treated hypersensitivity reactions; Grade 3 elevated transaminases or urine electrolyte abnormality ≤1 week in duration; Grade 3 serum electrolyte abnormality ≤72 hours in duration. DLTs also included: drug-related adverse experience that lead to a dose modification; unresolved drug-related toxicity resulted in delay in initiation of Cycle 2.
Maximum Tolerated Dose (MTD) for MLN2480
Time frame: Day 1, Cycle 1 up to 28 days
Recommended Phase 2 Dose (RP2D) of MLN2480
Time frame: Day 1, Cycle 1 up to 28 days

17 secondary outcomes

Cmax : Maximum Observed Plasma Concentration for MLN2480
Time frame: Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose
Cmax: Maximum Observed Plasma Concentration for MLN0128
Time frame: Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose
Cmax: Maximum Observed Plasma Concentration for Alisertib
Time frame: Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose
Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for MLN2480
Time frame: Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose
Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for MLN0128
Time frame: Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose
Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Alisertib
Time frame: Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose
AUC(0-tau): Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for MLN2480
Time frame: Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose
AUC(0-tau): Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for MLN0128
Time frame: Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose
AUC(0-tau): Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for Alisertib
Time frame: Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose
Cmax: Maximum Observed Plasma Concentration for Paclitaxel
Time frame: Cycle 1, Day 15 pre-dose and at multiple timepoints (Up to 48 hours) post-dose
AUC(0-last): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Paclitaxel
Time frame: Cycle 1, Day 15 pre-dose and at multiple timepoints (Up to 48 hours) post-dose
AUC(0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity, Calculated Using the Observed Value of the Last Quantifiable Concentration for Paclitaxel
Time frame: Cycle 1, Day 15 pre-dose and at multiple timepoints (Up to 48 hours) post-dose
Terminal Elimination Half-life (T1/2) for Paclitaxel
Time frame: Cycle 1, Day 15 pre-dose and at multiple timepoints (Up to 48 hours) post-dose
Objective Response Rate (ORR) Based on Response Evaluation Criteria in Solid Tumors (RECIST)
Time frame: Baseline then every 2 cycles beginning at Cycle 2, Day 27, until disease progression, death or end of study (Up to 13 months)
Duration of Response
Time frame: From first documented response until disease progression (Up to 13 months)
Time to Response
Time frame: From date of enrollment to the date of the first documentation of a confirmed response (Up to 13 months)
Progression Free Survival (PFS)
Time frame: Baseline then every 2 cycles beginning at Cycle 2, Day 27, until disease progression, death or end of study (Approximately up to 13 months)

Results and safety

Results posted to the registry on 25 Feb 2020, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
MLN2480 100 mg + MLN0128 2 mg	4	0
MLN2480 100 mg + Alisertib 30 mg	3	0
MLN2480 160 mg + Alisertib 30 mg	7	0
MLN2480 200 mg + Alisertib 30 mg	3	0
MLN2480 100 mg + Alisertib 40 mg	8	0
MLN2480 100 mg + Paclitaxel 80 mg/m^2	4	0
MLN2480 160 mg + Paclitaxel 80 mg/m^2	3	0
MLN2480 200 mg + Paclitaxel 80 mg/m^2	4	0
MLN2480 400 mg + Paclitaxel 80 mg/m^2	6	0
MLN2480 600 mg + Paclitaxel 80 mg/m^2	8	0
MLN2480 400 mg + Cetuximab 250 mg/m^2	6	0
MLN2480 600 mg + Cetuximab 250 mg/m^2	7	0
ML2480 300 mg + Irinotecan 180 mg/m^2	1	0
ML2480 400 mg + Irinotecan 180 mg/m^2	7	0
Dose Expansion: MLN2480 600 mg + Paclitaxel 80 mg/m^2	10	0

Primary outcome: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)

Time frame: From Day 1, Cycle 1 through 30 days after the last dose of study drug (up to 13 months). Count of participants. Unit: Participants

Measure	MLN2480 100 mg + MLN0128 2 mg n = 4	MLN2480 100 mg + Alisertib 30 mg n = 3	MLN2480 160 mg + Alisertib 30 mg n = 7	MLN2480 200 mg + Alisertib 30 mg n = 3	MLN2480 100 mg + Alisertib 40 mg n = 8	MLN2480 100 mg + Paclitaxel 80 mg/m^2 n = 4	MLN2480 160 mg + Paclitaxel 80 mg/m^2 n = 3	MLN2480 200 mg + Paclitaxel 80 mg/m^2 n = 4	MLN2480 400 mg + Paclitaxel 80 mg/m^2 n = 6	MLN2480 600 mg + Paclitaxel 80 mg/m^2 n = 8	MLN2480 400 mg + Cetuximab 250 mg/m^2 n = 6	MLN2480 600 mg + Cetuximab 250 mg/m^2 n = 7	ML2480 300 mg + Irinotecan 180 mg/m^2 n = 1	ML2480 400 mg + Irinotecan 180 mg/m^2 n = 7	Dose Expansion: MLN2480 600 mg + Paclitaxel 80 mg/m^2 n = 10
AEs	4	3	7	3	8	4	3	4	6	8	6	7	1	7	10
SAEs	2	1	5	1	3	1	1	2	3	4	2	3	0	4	7

Population analysed: Safety population was defined as all participants who received any amount of MLN2480.

Primary outcome: Number of Participants With Dose-Limiting Toxicities (DLTs)

Time frame: From Day 1, Cycle 1 through 30 days after the last dose in Cycle 1 (up to 8 weeks). Count of participants. Unit: Participants

Measure	MLN2480 100 mg + MLN0128 2 mg n = 4	MLN2480 100 mg + Alisertib 30 mg n = 3	MLN2480 160 mg + Alisertib 30 mg n = 7	MLN2480 200 mg + Alisertib 30 mg n = 3	MLN2480 100 mg + Alisertib 40 mg n = 8	MLN2480 100 mg + Paclitaxel 80 mg/m^2 n = 8	MLN2480 160 mg + Paclitaxel 80 mg/m^2 n = 3	MLN2480 200 mg + Paclitaxel 80 mg/m^2 n = 4	MLN2480 400 mg + Paclitaxel 80 mg/m^2 n = 6	MLN2480 600 mg + Paclitaxel 80 mg/m^2 n = 8	MLN2480 400 mg + Cetuximab 250 mg/m^2 n = 6	MLN2480 600 mg + Cetuximab 250 mg/m^2 n = 7	ML2480 300 mg + Irinotecan 180 mg/m^2 n = 1	ML2480 400 mg + Irinotecan 180 mg/m^2 n = 7	Dose Expansion: MLN2480 600 mg + Paclitaxel 80 mg/m^2 n = 10
Value	1	0	0	0	1	0	0	0	1	1	0	1	0	1	1

Population analysed: The DLT-evaluable population was defined as all participants in the dose escalation phase of the study who either experienced DLT during cycle 1, or completed at least 75% of the scheduled doses in cycle 1 without DLT.

Primary outcome: Maximum Tolerated Dose (MTD) for MLN2480

Time frame: Day 1, Cycle 1 up to 28 days. Number. Unit: mg

Measure	MLN2480 100 mg + MLN0128 2 mg n = 4	MLN2480 100 mg + Alisertib 30 mg n = 3	MLN2480 160 mg + Alisertib 30 mg n = 7	MLN2480 200 mg + Alisertib 30 mg n = 3	MLN2480 100 mg + Alisertib 40 mg n = 8	MLN2480 100 mg + Paclitaxel 80 mg/m^2 n = 8	MLN2480 160 mg + Paclitaxel 80 mg/m^2 n = 3	MLN2480 200 mg + Paclitaxel 80 mg/m^2 n = 4	MLN2480 400 mg + Paclitaxel 80 mg/m^2 n = 6	MLN2480 600 mg + Paclitaxel 80 mg/m^2 n = 8	MLN2480 400 mg + Cetuximab 250 mg/m^2 n = 6	MLN2480 600 mg + Cetuximab 250 mg/m^2 n = 7	ML2480 300 mg + Irinotecan 180 mg/m^2 n = 1	ML2480 400 mg + Irinotecan 180 mg/m^2 n = 7	Dose Expansion: MLN2480 600 mg + Paclitaxel 80 mg/m^2 n = 10
Value	NA	NA	NA	NA	NA	NA	NA	NA	NA	600	NA	NA	NA	NA	NA

Primary outcome: Recommended Phase 2 Dose (RP2D) of MLN2480

Time frame: Day 1, Cycle 1 up to 28 days. Number. Unit: mg

Measure	MLN2480 100 mg + MLN0128 2 mg n = 4	MLN2480 100 mg + Alisertib 30 mg n = 3	MLN2480 160 mg + Alisertib 30 mg n = 7	MLN2480 200 mg + Alisertib 30 mg n = 3	MLN2480 100 mg + Alisertib 40 mg n = 8	MLN2480 100 mg + Paclitaxel 80 mg/m^2 n = 8	MLN2480 160 mg + Paclitaxel 80 mg/m^2 n = 3	MLN2480 200 mg + Paclitaxel 80 mg/m^2 n = 4	MLN2480 400 mg + Paclitaxel 80 mg/m^2 n = 6	MLN2480 600 mg + Paclitaxel 80 mg/m^2 n = 8	MLN2480 400 mg + Cetuximab 250 mg/m^2 n = 6	MLN2480 600 mg + Cetuximab 250 mg/m^2 n = 7	ML2480 300 mg + Irinotecan 180 mg/m^2 n = 1	ML2480 400 mg + Irinotecan 180 mg/m^2 n = 7	Dose Expansion: MLN2480 600 mg + Paclitaxel 80 mg/m^2 n = 10
Value	NA	NA	NA	NA	NA	NA	NA	NA	NA	600	NA	NA	NA	NA	NA

17 secondary outcomes are reported in the full results.

Adverse events

Time frame: AEs were recorded from the first dose of study drug through 30 days after the last dose of study drug or the start of subsequent antineoplastic therapy, whichever occurred first. SAEs were collected from the signing of Informed Consent through 30 days after the last dose of study drug (Up to 13 months). Other adverse events reported at 5% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
MLN2480 100 mg + MLN0128 2 mg	2 of 4 (50%)	4 of 4 (100%)	0 of 4
MLN2480 100 mg + Alisertib 30 mg	1 of 3 (33.3%)	3 of 3 (100%)	0 of 3
MLN2480 160 mg + Alisertib 30 mg	5 of 7 (71.4%)	7 of 7 (100%)	2 of 7
MLN2480 200 mg + Alisertib 30 mg	1 of 3 (33.3%)	3 of 3 (100%)	0 of 3
MLN2480 100 mg + Alisertib 40 mg	3 of 8 (37.5%)	8 of 8 (100%)	1 of 8
MLN2480 100 mg + Paclitaxel 80 mg/m^2	1 of 4 (25%)	4 of 4 (100%)	0 of 4
MLN2480 160 mg + Paclitaxel 80 mg/m^2	1 of 3 (33.3%)	3 of 3 (100%)	0 of 3
MLN2480 200 mg + Paclitaxel 80 mg/m^2	2 of 4 (50%)	4 of 4 (100%)	0 of 4
MLN2480 400 mg + Paclitaxel 80 mg/m^2	3 of 6 (50%)	6 of 6 (100%)	0 of 6
MLN2480 600 mg + Paclitaxel 80 mg/m^2	4 of 8 (50%)	8 of 8 (100%)	0 of 8
MLN2480 400 mg + Cetuximab 250 mg/m^2	2 of 6 (33.3%)	6 of 6 (100%)	2 of 6
MLN2480 600 mg + Cetuximab 250 mg/m^2	3 of 7 (42.9%)	7 of 7 (100%)	2 of 7
ML2480 300 mg + Irinotecan 180 mg/m^2	0 of 1 (0%)	1 of 1 (100%)	0 of 1
ML2480 400 mg + Irinotecan 180 mg/m^2	4 of 7 (57.1%)	7 of 7 (100%)	0 of 7
Dose Expansion: MLN2480 600 mg + Paclitaxel 80 mg/m^2	7 of 10 (70%)	10 of 10 (100%)	2 of 10

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 25 Feb 2020.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Individual participant dataSharing planned: Yes. Takeda makes patient-level, de-identified data sets and associated documents available for all interventional studies after applicable marketing approvals and commercial availability have been received (or program is completely terminated), an opportunity for the primary publication of the research and final report development has been allowed, and other criteria have been met as set forth in Takeda's Data Sharing Policy (see www.TakedaClinicalTrials.com for details). To obtain access, researchers must submit a legitimate academic research proposal for adjudication by an independent review panel, who will review the scientific merit of the research and the requestor's qualifications and conflict of interest that can result in potential bias. Once approved, qualified researchers who sign a data sharing agreement are provided access to these data in a secure research environment.

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

14 sites in 4 countries: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing MLN2480, MLN0128 and Alisertib in people with Advanced Nonhematologic Malignancies, run by Millennium Pharmaceuticals, Inc. at 14 sites in 4 countries.

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 17 inclusion and 22 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 25 Feb 2020. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 14 sites in United States, France, Spain, United Kingdom. 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 25 Feb 2020). 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 Adverse Events (AEs) and Serious Adverse Events (SAEs) (time frame: From Day 1, Cycle 1 through 30 days after the last dose of study drug (up to 13 months)). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02327169.

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 25 Feb 2020.