MelanomaPhase 1NCT01425008

Study of MLN2480 in Participants With Relapsed or Refractory Solid Tumors Followed by a Dose Expansion in Participants With Metastatic Melanoma

A Phase 1 study testing MLN2480 in people with Melanoma and Metastatic Melanoma, run by Millennium Pharmaceuticals, Inc. at 16 sites in 2 countries.

Completed

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

Official record

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Trial summary

This is a phase 1, multicenter, nonrandomized, open-label, dose escalation study. The study will be conducted in 2 stages, Dose Escalation and Dose Expansion. The Dose Escalation phase will include participants with solid tumors (including melanoma) who have failed or are not candidates for standard therapies or for… Read more about this study

Who is it for?: Ages 18 years and older
Conditions the study is for: Melanoma, Metastatic Melanoma, Solid Tumor
What is being tested?: MLN2480
Type of treatment: Pill or oral medicine
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 149 participants
Where: 16 sitesin 2 countries
Study dates: 15 Sep 2011to 16 Oct 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

Informed consent.
Male or female participants 18 years or older.
Dose Escalation phase: Participants with solid tumors (including melanoma) who have failed or are not candidates for standard therapies of for whom no approved therapy is available.
Dose Expansion phase: Metastatic melanoma (locally advanced or metastatic melanoma).
Dose Expansion phase: At least 1 measurable lesion which has not been treated previously with radiotherapy. A newly arising lesion in a previously irradiated field is acceptable.
For participants undergoing biopsy procedures: Prothrombin time (PT) and activated partial thromboplastin time (aPTT) must be within the normal range.

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Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to (<=) 1.
Adequate tissue sample from either archival formalin-fixed paraffin-embedded (FFPE) tumor tissue or new biopsy of tumor.
Previous chemotherapy, immunotherapy, and hormone therapy must be completed at least 4 weeks prior to the administration of MLN2480 and radiation must be completed at least 3 weeks prior to the administration of MLN2480; all associated toxicity must be resolved to <=Grade 1.
Expected survival time of at least 3 months in the opinion of the investigator.
Participants who do not have hypo- or hyperthyroidism.
Ability to swallow and retain oral medication.
Female participants who are postmenopausal for at least 1 year, surgically sterile, or agree to practice 2 effective methods of contraception through 3 months after the last dose of study drug or agree to practice true abstinence.
Male participants who, even if surgically sterilized, agree to practice effective barrier contraception through 3 months after the last dose of alisertib or agree to practice true abstinence.

Who cannot join

History of any major disease that might interfere with safe protocol participation.
Dose Expansion phase: Previous treatment with RAF or MEK inhibitors.
Laboratory values as specified in study protocol.
Current enrollment in any other investigational treatment study.
Evidence of current uncontrolled cardiovascular conditions within the past 6 months.
Prior investigational agents for malignant or non-malignant disease within 4 weeks prior to Day 1.

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Active hepatitis or human immunodeficiency virus (HIV) infection.
Active bacterial or viral infection.
Female participants who are pregnant or currently breastfeeding.
Major surgery within 28 days of Day 1.
Refractory nausea and vomiting, malabsorption, or significant bowel or stomach resection.
Inability to comply with study requirements.
Other unspecified reasons that, in the opinion of the investigator or Millennium, make the participant unsuitable for enrollment.

Trial locations and contacts

16 sites in 2 countries.

Country

City, postcode or hospital

16 sites in 2 countries

United States9 sites

Study site
Augusta, Georgia
Study site
Denver, Colorado
Study site
Easton, Pennsylvania
Study site
Indianapolis, Indiana
Study site
Lakewood, Washington
Study site
New York, New York
Study site
Philadelphia, Pennsylvania
Study site
San Antonio, Texas
Study site
San Francisco, California

Other trials in United States

United Kingdom7 sites

Study site
Bristol, Avon
Study site
Cambridge, Cambridgeshire
Study site
Chelmsford, Essex
Study site
London, Greater London
Study site
Manchester, Greater Manchester
Study site
Newcastle upon Tyne, Tyne & Wear
Study site
Oxford, Oxfordshire

Other trials in United Kingdom

About this study

Official title: An Open-Label, Phase 1, Dose Escalation Study of MLN2480 in Patients With Relapsed or Refractory Solid Tumors Followed by a Dose Expansion Phase in Patients With Metastatic Melanoma

Conditions: Melanoma, Metastatic Melanoma, Solid Tumor, Neoplasm
Being tested: MLN2480
Keywords: Drug Therapy
Medical subject headings: Melanoma, Neoplasms

What participants receive

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

MLN2480Drug
Also called TAK-580
Dose Escalation Phase: participants will receive MLN2480 orally in escalating doses every other day or once weekly for three weeks of a 28-day cycle. Participants may continue treatment for additional cycles (up to 12 months) until disease progression, unacceptable toxicity, or the participant discontinues for any other reason. If it is determined that a participant would derive benefit from continued therapy beyond 12 months treatment may continue. Dose Expansion Phase: Participants will take MLN2480 at the maximum tolerated dose orally every other day or once weekly for three weeks of a 28-day cycle until disease progression, unacceptable toxicity, or the participant discontinues for any other reason. The maximum duration of treatment is 1 year unless determined that a participant would derive benefit from continued therapy beyond 12 months.

Study groups in NCT01425008
Study group	Role	What they receive
MLN2480	Experimental	Not described Receives: Drug: MLN2480

What is being measured

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

Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and Deaths
Measured: Baseline up to 30 days after last dose, or start of subsequent therapy, whichever occurred first (up to Cycle 38 Days 52 [Q2D] and 58 [QW] [Cycle=22 days (Q2D) and 28 days (QW)] in Escalation Phase; Cycle 49 Day 58 [Cycle=28 days] in Expansion Phase)
Dose Escalation Phase: Number of Participants With Dose-limiting Adverse Events (AEs)
Dose limiting AEs were evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03. Dose limiting AEs were defined as any of the following events: Grade 4 neutropenia for more than 7 days under maximum supportive therapy; febrile neutropenia; platelet counts decreased of Grade 3 requiring platelet transfusion or blood platelet decreased of Grade 4; if Course 2 was not initiated within 14 days due to AE related to the protocol treatment; Grade 3 or higher non-hematologic toxicity that was considered clinically significant, except the following cases, Grade 3 gastrointestinal symptoms that could be controlled with supportive therapy (example, appropriate use of antiemetics, antidiarrheals), and Grade 3 or higher electrolyte abnormalities that were not deemed clinically significant.
Measured: Cycle 1 (Cycle length= 22 days [Q2D] and 28 days [QW])
Number of Participants With TEAEs Related to Physical Examination Findings
Measured: Baseline up to 30 days after last dose, or start of subsequent therapy, whichever occurred first (up to Cycle 38 Days 52 [Q2D] and 58 [QW] [Cycle=22 days (Q2D) and 28 days (QW)] in Escalation Phase; Cycle 49 Day 58 [Cycle=28 days] in Expansion Phase)
Clinically Significant Change From Baseline in Body Weight at End of Study Visit (EOSV)
Measured: Baseline up to EOSV (up to Cycle 38 Days 52 [Q2D] and 58 [QW] [Cycle length =22 days (Q2D) and 28 days (QW)] in Escalation Phase; Cycle 49 Day 58 [Cycle length =28 days] in Expansion Phase)
Number of Participants With Abnormal Clinically Significant Electrocardiogram (ECG) Findings
Measured: Baseline up to 30 days after last dose, or start of subsequent therapy, whichever occurred first (up to Cycle 38 Days 52 [Q2D] and 58 [QW] [Cycle=22 days (Q2D) and 28 days (QW)] in Escalation Phase; Cycle 49 Day 58 [Cycle=28 days] in Expansion Phase)
Eastern Cooperative Oncology Group (ECOG) Performance Score
ECOG performance score was measured on 6 point scale to assess participant's performance status, where: 0 (fully active, able to carry on all pre-disease activities without restriction); 1 (restricted in physically strenuous activity, but ambulatory and able to carry out light or sedentary work); 2 (ambulatory greater than(>) 50 percent (%) of waking hours), capable of all self-care, unable to carry out any work activities); 3 (capable of only limited self-care, confined to bed or chair >50% of waking hours); 4(completely disabled, cannot carry on any self-care, totally confined to bed or chair); 5 (dead). A higher score indicated greater functional impairment.
Measured: at EOSV (up to Cycle 38 Days 52 [Q2D] and 58 [QW] [Cycle length =22 days (Q2D) and 28 days (QW)] in Escalation Phase; Cycle 49 Day 58 [Cycle length =28 days] in Expansion Phase)
Number of Participants With TEAEs Categorized Into Investigations Related to Laboratory Test of Chemistry, Hematology or Urinalysis
Measured: Baseline up to 30 days after last dose, or start of subsequent therapy, whichever occurred first (up to Cycle 38 Days 52 [Q2D] and 58 [QW] [Cycle=22 days (Q2D) and 28 days (QW)] in Escalation Phase; Cycle 49 Day 58 [Cycle=28 days] in Expansion Phase)

Secondary outcomes (12)

Overall Response Rate (ORR)
ORR was defined as the percentage of participants with complete response (CR) or partial response (PR). The ORR assessment was based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. CR: was disappearance of all target lesions. Any pathological lymph nodes (target or non-target) had to be reduced in short axis to less than (<) 10 millimeter (mm). PR: was at least a 30% decrease in sum of diameter (SOD) of target lesions, taking as reference the baseline SOD.
Measured: Baseline up to EOSV (up to Cycle 38 Days 52 [Q2D] and 58 [QW] [Cycle length =22 days (Q2D) and 28 days (QW)] in Escalation Phase; Cycle 49 Day 58 [Cycle length =28 days] in Expansion Phase)
Progression-free Survival (PFS)
PFS was the time from first dose date of study drug to date of the first documentation of confirmed progressive disease (PD) or death, whichever occurred first. The PFS assessment was based on RECIST 1.1. PD: at least 20% increase (including an absolute increase of at least 5 mm) in the SOD of target lesions. PFS was calculated using Kaplan-Meier estimate and presented with 2-sided 95% confidence interval. Participants with no response assessment were censored at the date of first dose.
Measured: Baseline up to the date of first document PD, or death due to any cause, whichever occurred first (up to Cycle 38 Days 52 [Q2D] and 58 [QW] [Cycle =22 days (Q2D) and 28 days (QW)] in Escalation Phase; Cycle 49 Day 58 [Cycle =28 days] in Expansion Phase)
Duration of Response (DOR)
DOR was assessed from the first documented response (CR or PR) to the date of first documented PD and was censored at the date of the last assessment for responders who died without documented PD and for responders who were still alive and had not progressed. DOR assessment was based on RECIST v1.1. CR: was disappearance of all target lesions. Any pathological lymph nodes (target or non-target) had to be reduced in short axis to <10 mm. PR: at least 30% decrease in SOD of target lesions, taking as reference the baseline SOD persistence of one or more non-target lesions and/or maintenance of tumor marker level above the normal limits. PD: at least 20% increase (including an absolute increase of at least 5 mm) in the SOD of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions. DOR was calculated using Kaplan-Meier estimate.
Measured: From the first documented response (CR or PR) up to the date of first documented PD (up to Cycle 38 Days 52 [Q2D] and 58 [QW] [Cycle =22 days (Q2D) and 28 days (QW)] in Escalation Phase; Cycle 49 Day 58 [Cycle =28 days] in Expansion Phase)
Dose Escalation Phase and Dose Expansion Pharmacokinetic Cohort, Cmax: Maximum Observed Plasma Concentration for TAK-580
Measured: Escalation (Esc.) and Expansion (Exp.) Q2D: C1D1 and 21 pre-dose and at multiple time points (up to 48 hours [h]) post-dose (C=22 days [Esc. Q2D] and 28 days [Exp. Q2D]); Esc. QW: C1D1 and 22 at multiple time-points (up to168 h) post-dose (C=28 days)
Dose Escalation Phase and Dose Expansion Pharmacokinetic Cohort, Ctrough: Trough Concentration for TAK-580
Measured: Escalation and Expansion Q2D Cohorts: C1D21 pre-dose (C=22 days [Escalation Q2D] and 28 days [Expansion Q2D]); Escalation QW Cohorts: C1D22 pre-dose (C= 28 days)
Dose Escalation Phase and Dose Expansion Pharmacokinetic Cohort, Tmax: Time to Reach the Cmax for TAK-580
Measured: Escalation (Esc.) and Expansion (Exp.) Q2D: C1D1 and 21 pre-dose and at multiple time points (up to 48 h) post-dose (C=22 days [Esc. Q2D] and 28 days [Exp. Q2D]); Esc. QW: C1D1 and 22 at multiple time-points (up to168 h) post-dose (C=28 days)
Dose Escalation Phase and Dose Expansion Pharmacokinetic Cohort, t1/2z: Terminal Phase Disposition Half-life for TAK-580
Measured: Escalation (Esc.) and Expansion (Exp.) Q2D: C1D21 pre-dose and at multiple time points (up to 48 h) post-dose (C=22 days [Esc. Q2D] and 28 days [Exp. Q2D]); Esc. QW: C1D22 at multiple time-points (up to168 h) post-dose (C=28 days)
Dose Escalation Phase and Dose Expansion Pharmacokinetic Cohort, CLr: Renal Clearance for TAK-580
Measured: Q2D Cohorts: Cycle1 Days 1 and 21 up to 24 hours post-dose (Cycle1 length= 22 days); QW Cohorts: Cycle2 Days 1 and 22 up to 7 hours post-dose (Cycle 2 length= 28 days)
Q2D Dose Escalation Phase and Q2D Dose Expansion Pharmacokinetic Cohort, AUC(0-48): Area Under the Plasma Concentration-time Curve From Time 0 to 48 Hours Postdose for TAK-580
Measured: Cycle 1 Days 1 and 21 pre-dose and at multiple time points (up to 48 hours) post-dose (Cycle length= 22 days)
QW Dose Escalation Phase, AUC(0-168): Area Under the Plasma Concentration-time Curve From Time 0 to 168 Hours Postdose for TAK-580
Measured: Cycle 1 Days 1 and 22 pre-dose and at multiple time points (up to 168 hours) post-dose (Cycle length= 28 days)
Dose Expansion Phase, Melanoma Cohorts: Percent Change From Baseline in RAF Inhibition Biomarkers at Specified Time Points
The extent of phosphorylated extracellular signal-regulated kinase (pERK) staining was assessed in the melanoma expansion cohorts. The level of staining was assessed by a pathologist (semi-H scores) and by quantified image analysis (quant H-scores). The H-score scale used to interpret data from the pathologist rating was as follows: 0 to 99 =low staining; 100 to 199= medium staining; 200 to 300 =high staining. The H-score scale used to interpret data from the quantified image analysis was as followed: 0 to 100 =low staining; 100 to 150= medium staining; 150 to 235= high staining.
Measured: Baseline, Cycle 1 Day 21 (Q2D), and Cycle 1 Day 22 (QW) (Cycle length= 22 days [Q2D] and 28 days [QW])
Dose Expansion Phase, Melanoma Cohorts: Percent Change From Baseline in Apoptotic Biomarkers at Specified Time Points
The extent of cleaved poly ADP-ribose polymerase (cPARP) and BIM-1 was assessed in the melanoma expansion cohorts. The level of staining was assessed by quantified image analysis (quant H-scores) and by quantified image analysis (quant H-scores). The H-score scale used to interpret data from the pathologist rating was as follows: 0 to 99= low staining; 100 to 199 =medium staining; 200 to 300 =high staining. The H-score scale used to interpret data from the quantified image analysis was as followed in cPARP: 0 to 70= low staining; 70 to 175 =medium staining; 175 to 240 =high staining; BIM-1: 0 to 128= low staining; 128 to 155 =medium staining; 155 to 229 =high staining.
Measured: Baseline, Cycle 1 Day 21 (Q2D), and Cycle 1 Day 22 (QW) (Cycle length= 22 days [Q2D] and 28 days [QW])

Timeline

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

15 Sep 201116 Oct 2018

First posted29 Aug 2011 (estimated)
Study start15 Sep 2011
Primary completion11 Apr 2017
Study completion16 Oct 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.
Publications (1)Papers the sponsor has linked to this study.
Other trials for MelanomaStudies 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: Not applicable
Intervention model: Single group
Masking: None (open label)
Enrolment: 149 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT01425008
Sponsor's protocol ID: C28001
Other IDs: 2012-003397-16, U1111-1164-7508, 13/SC/0007
Status last verified: Jul 2020
First submitted: 26 Aug 2011
Last updated: 10 Aug 2020
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: No
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."

Publications

Rasco DW, Medina T, Corrie P, Pavlick AC, Middleton MR, Lorigan P, Hebert C, Plummer R, Larkin J, Agarwala SS, Daud AI, Qiu J, Bozon V, Kneissl M, Barry E, Olszanski AJ. Phase 1 study of the pan-RAF inhibitor tovorafenib in patients with advanced solid tumors followed by dose expansion in patients with metastatic melanoma. Cancer Chemother Pharmacol. 2023 Jul;92(1):15-28. doi: 10.1007/s00280-023-04544-5. Epub 2023 May 23.
PubMed 37219686

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

See locations

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Study at a glance

From the registry record, last updated by the sponsor on 10 Aug 2020. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: An Open-Label, Phase 1, Dose Escalation Study of MLN2480 in Patients With Relapsed or Refractory Solid Tumors Followed by a Dose Expansion Phase in Patients With Metastatic Melanoma
ClinicalTrials.gov ID: NCT01425008
Acronym / sponsor ID: C28001
Conditions: Melanoma, Metastatic Melanoma, Solid Tumor, Neoplasm
Keywords: Drug Therapy
Phase: Phase 1
Study type: Interventional
Recruitment status: Completed
Enrolment: 149 participants (actual)
Lead sponsor: Millennium Pharmaceuticals, Inc.Industry (pharma, biotech, devices)
Study start: 15 Sep 2011 (actual)
Primary completion: 11 Apr 2017 (actual)
Study completion: 16 Oct 2018 (actual)
First posted: 29 Aug 2011 (estimated)
Results: Posted 10 Aug 2020

Clinical summary

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

Study design

Primary purpose: Treatment
Allocation: Not applicable
Intervention model: Single group
Masking: None (open label)
Number of arms: 1

Arm	Type	Receives
MLN2480	Experimental	Drug: MLN2480

Who may qualify

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

Key inclusion criteria (14 listed)

Informed consent.
Male or female participants 18 years or older.
Dose Escalation phase: Participants with solid tumors (including melanoma) who have failed or are not candidates for standard therapies of for whom no approved therapy is available.
Dose Expansion phase: Metastatic melanoma (locally advanced or metastatic melanoma).
Dose Expansion phase: At least 1 measurable lesion which has not been treated previously with radiotherapy. A newly arising lesion in a previously irradiated field is acceptable.

Key exclusion criteria (13 listed)

History of any major disease that might interfere with safe protocol participation.
Dose Expansion phase: Previous treatment with RAF or MEK inhibitors.
Laboratory values as specified in study protocol.
Current enrollment in any other investigational treatment study.
Evidence of current uncontrolled cardiovascular conditions within the past 6 months.

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-580Dose Escalation Phase: participants will receive MLN2480 orally in escalating doses every other day or once weekly for three weeks of a 28-day cycle. Participants may continue treatment for additional cycles (up to 12 months) until disease progression, unacceptable toxicity, or the participant discontinues for any other reason. If it is determined that a participant would derive benefit from continued therapy beyond 12 months treatment may continue. Dose Expansion Phase: Participants will take MLN2480 at the maximum tolerated dose orally every other day or once weekly for three weeks of a 28-day cycle until disease progression, unacceptable toxicity, or the participant discontinues for any other reason. The maximum duration of treatment is 1 year unless determined that a participant would derive benefit from continued therapy beyond 12 months.	Drug	MLN2480

Primary outcome

Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and Deaths
Time frame: Baseline up to 30 days after last dose, or start of subsequent therapy, whichever occurred first (up to Cycle 38 Days 52 [Q2D] and 58 [QW] [Cycle=22 days (Q2D) and 28 days (QW)] in Escalation Phase; Cycle 49 Day 58 [Cycle=28 days] in Expansion Phase)
Dose Escalation Phase: Number of Participants With Dose-limiting Adverse Events (AEs)
Time frame: Cycle 1 (Cycle length= 22 days [Q2D] and 28 days [QW])
Dose limiting AEs were evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03. Dose limiting AEs were defined as any of the following events: Grade 4 neutropenia for more than 7 days under maximum supportive therapy; febrile neutropenia; platelet counts decreased of Grade 3 requiring platelet transfusion or blood platelet decreased of Grade 4; if Course 2 was not initiated within 14 days due to AE related to the protocol treatment; Grade 3 or higher non-hematologic toxicity that was considered clinically significant, except the following cases, Grade 3 gastrointestinal symptoms that could be controlled with supportive therapy (example, appropriate use of antiemetics, antidiarrheals), and Grade 3 or higher electrolyte abnormalities that were not deemed clinically significant.
Number of Participants With TEAEs Related to Physical Examination Findings
Time frame: Baseline up to 30 days after last dose, or start of subsequent therapy, whichever occurred first (up to Cycle 38 Days 52 [Q2D] and 58 [QW] [Cycle=22 days (Q2D) and 28 days (QW)] in Escalation Phase; Cycle 49 Day 58 [Cycle=28 days] in Expansion Phase)
Clinically Significant Change From Baseline in Body Weight at End of Study Visit (EOSV)
Time frame: Baseline up to EOSV (up to Cycle 38 Days 52 [Q2D] and 58 [QW] [Cycle length =22 days (Q2D) and 28 days (QW)] in Escalation Phase; Cycle 49 Day 58 [Cycle length =28 days] in Expansion Phase)
Number of Participants With Abnormal Clinically Significant Electrocardiogram (ECG) Findings
Time frame: Baseline up to 30 days after last dose, or start of subsequent therapy, whichever occurred first (up to Cycle 38 Days 52 [Q2D] and 58 [QW] [Cycle=22 days (Q2D) and 28 days (QW)] in Escalation Phase; Cycle 49 Day 58 [Cycle=28 days] in Expansion Phase)
Eastern Cooperative Oncology Group (ECOG) Performance Score
Time frame: at EOSV (up to Cycle 38 Days 52 [Q2D] and 58 [QW] [Cycle length =22 days (Q2D) and 28 days (QW)] in Escalation Phase; Cycle 49 Day 58 [Cycle length =28 days] in Expansion Phase)
ECOG performance score was measured on 6 point scale to assess participant's performance status, where: 0 (fully active, able to carry on all pre-disease activities without restriction); 1 (restricted in physically strenuous activity, but ambulatory and able to carry out light or sedentary work); 2 (ambulatory greater than(>) 50 percent (%) of waking hours), capable of all self-care, unable to carry out any work activities); 3 (capable of only limited self-care, confined to bed or chair >50% of waking hours); 4(completely disabled, cannot carry on any self-care, totally confined to bed or chair); 5 (dead). A higher score indicated greater functional impairment.
Number of Participants With TEAEs Categorized Into Investigations Related to Laboratory Test of Chemistry, Hematology or Urinalysis
Time frame: Baseline up to 30 days after last dose, or start of subsequent therapy, whichever occurred first (up to Cycle 38 Days 52 [Q2D] and 58 [QW] [Cycle=22 days (Q2D) and 28 days (QW)] in Escalation Phase; Cycle 49 Day 58 [Cycle=28 days] in Expansion Phase)

12 secondary outcomes

Overall Response Rate (ORR)
Time frame: Baseline up to EOSV (up to Cycle 38 Days 52 [Q2D] and 58 [QW] [Cycle length =22 days (Q2D) and 28 days (QW)] in Escalation Phase; Cycle 49 Day 58 [Cycle length =28 days] in Expansion Phase)
Progression-free Survival (PFS)
Time frame: Baseline up to the date of first document PD, or death due to any cause, whichever occurred first (up to Cycle 38 Days 52 [Q2D] and 58 [QW] [Cycle =22 days (Q2D) and 28 days (QW)] in Escalation Phase; Cycle 49 Day 58 [Cycle =28 days] in Expansion Phase)
Duration of Response (DOR)
Time frame: From the first documented response (CR or PR) up to the date of first documented PD (up to Cycle 38 Days 52 [Q2D] and 58 [QW] [Cycle =22 days (Q2D) and 28 days (QW)] in Escalation Phase; Cycle 49 Day 58 [Cycle =28 days] in Expansion Phase)
Dose Escalation Phase and Dose Expansion Pharmacokinetic Cohort, Cmax: Maximum Observed Plasma Concentration for TAK-580
Time frame: Escalation (Esc.) and Expansion (Exp.) Q2D: C1D1 and 21 pre-dose and at multiple time points (up to 48 hours [h]) post-dose (C=22 days [Esc. Q2D] and 28 days [Exp. Q2D]); Esc. QW: C1D1 and 22 at multiple time-points (up to168 h) post-dose (C=28 days)
Dose Escalation Phase and Dose Expansion Pharmacokinetic Cohort, Ctrough: Trough Concentration for TAK-580
Time frame: Escalation and Expansion Q2D Cohorts: C1D21 pre-dose (C=22 days [Escalation Q2D] and 28 days [Expansion Q2D]); Escalation QW Cohorts: C1D22 pre-dose (C= 28 days)
Dose Escalation Phase and Dose Expansion Pharmacokinetic Cohort, Tmax: Time to Reach the Cmax for TAK-580
Time frame: Escalation (Esc.) and Expansion (Exp.) Q2D: C1D1 and 21 pre-dose and at multiple time points (up to 48 h) post-dose (C=22 days [Esc. Q2D] and 28 days [Exp. Q2D]); Esc. QW: C1D1 and 22 at multiple time-points (up to168 h) post-dose (C=28 days)
Dose Escalation Phase and Dose Expansion Pharmacokinetic Cohort, t1/2z: Terminal Phase Disposition Half-life for TAK-580
Time frame: Escalation (Esc.) and Expansion (Exp.) Q2D: C1D21 pre-dose and at multiple time points (up to 48 h) post-dose (C=22 days [Esc. Q2D] and 28 days [Exp. Q2D]); Esc. QW: C1D22 at multiple time-points (up to168 h) post-dose (C=28 days)
Dose Escalation Phase and Dose Expansion Pharmacokinetic Cohort, CLr: Renal Clearance for TAK-580
Time frame: Q2D Cohorts: Cycle1 Days 1 and 21 up to 24 hours post-dose (Cycle1 length= 22 days); QW Cohorts: Cycle2 Days 1 and 22 up to 7 hours post-dose (Cycle 2 length= 28 days)
Q2D Dose Escalation Phase and Q2D Dose Expansion Pharmacokinetic Cohort, AUC(0-48): Area Under the Plasma Concentration-time Curve From Time 0 to 48 Hours Postdose for TAK-580
Time frame: Cycle 1 Days 1 and 21 pre-dose and at multiple time points (up to 48 hours) post-dose (Cycle length= 22 days)
QW Dose Escalation Phase, AUC(0-168): Area Under the Plasma Concentration-time Curve From Time 0 to 168 Hours Postdose for TAK-580
Time frame: Cycle 1 Days 1 and 22 pre-dose and at multiple time points (up to 168 hours) post-dose (Cycle length= 28 days)
Dose Expansion Phase, Melanoma Cohorts: Percent Change From Baseline in RAF Inhibition Biomarkers at Specified Time Points
Time frame: Baseline, Cycle 1 Day 21 (Q2D), and Cycle 1 Day 22 (QW) (Cycle length= 22 days [Q2D] and 28 days [QW])
Dose Expansion Phase, Melanoma Cohorts: Percent Change From Baseline in Apoptotic Biomarkers at Specified Time Points
Time frame: Baseline, Cycle 1 Day 21 (Q2D), and Cycle 1 Day 22 (QW) (Cycle length= 22 days [Q2D] and 28 days [QW])

Results and safety

Results posted to the registry on 10 Aug 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
Q2D Dose Escalation Phase: TAK-580 20 mg (22 Days Cycle)	4	0
Q2D Dose Escalation Phase: TAK-580 40 mg (22 Days Cycle)	3	0
Q2D Dose Escalation Phase: TAK-580 80 mg (22 Days Cycle)	3	0
Q2D Dose Escalation Phase: TAK-580 135 mg (22 Days Cycle)	3	0
Q2D Dose Escalation Phase: TAK-580 200 mg (22 Days Cycle)	7	0
Q2D Dose Escalation Phase: TAK-580 280 mg (22 Days Cycle)	7	0
Q2D Dose Escalation Phase: TAK-580 200 mg (28 Days Cycle)	3	0
QW Dose Escalation Phase: TAK-580 400 mg (28 Days Cycle)	3	0
QW Dose Escalation Phase: TAK-580 600 mg (28 Days Cycle)	13	0
QW Dose Escalation Phase: TAK-580 800 mg (28 Days Cycle)	4	0
Q2D Dose Expansion Phase: TAK-580 (BRAF+ Naive)	0	0
Q2D Dose Expansion Phase: TAK-580 (BRAF+ Previously Treated)	0	0
Q2D Dose Expansion Phase: TAK-580 (NRAS+ Naive)	0	0
Q2D Dose Expansion Phase: TAK-580 (NRAS+ Previously Treated)	0	0
Q2D Dose Expansion Phase: TAK-580 BRAF/NRAS WT+ Naive	0	0
Q2D Dose Expansion Phase:TAK-580 BRAF/NRASWT+PreviouslyTreated	0	0
Q2D Dose Expansion Phase: Pharmacokinetic Cohort	0	0
Q2D Dose Expansion Phase: TAK-580 (BRAF+)	0	0
QW Dose Expansion Phase: TAK-580 NRAS WT+ Naive	0	0

Primary outcome: Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and Deaths

Time frame: Baseline up to 30 days after last dose, or start of subsequent therapy, whichever occurred first (up to Cycle 38 Days 52 [Q2D] and 58 [QW] [Cycle=22 days (Q2D) and 28 days (QW)] in Escalation Phase; Cycle 49 Day 58 [Cycle=28 days] in Expansion Phase). Count of participants. Unit: Participants

Measure	Q2D Dose Escalation Phase: TAK-580 20 mg (22 Days Cycle) n = 4	Q2D Dose Escalation Phase: TAK-580 40 mg (22 Days Cycle) n = 3	Q2D Dose Escalation Phase: TAK-580 80 mg (22 Days Cycle) n = 3	Q2D Dose Escalation Phase: TAK-580 135 mg (22 Days Cycle) n = 3	Q2D Dose Escalation Phase: TAK-580 200 mg (22 Days Cycle) n = 7	Q2D Dose Escalation Phase: TAK-580 280 mg (22 Days Cycle) n = 7	Q2D Dose Escalation Phase: TAK-580 200 mg (28 Days Cycle) n = 3	QW Dose Escalation Phase: TAK-580 400 mg (28 Days Cycle) n = 3	QW Dose Escalation Phase: TAK-580 600 mg (28 Days Cycle) n = 13	QW Dose Escalation Phase: TAK-580 800 mg (28 Days Cycle) n = 4	Q2D Dose Expansion Phase: TAK-580 (BRAF+ Naive) n = 16	Q2D Dose Expansion Phase: TAK-580 (BRAF+ Previously Treated) n = 8	Q2D Dose Expansion Phase: TAK-580 (NRAS+ Naive) n = 16	Q2D Dose Expansion Phase: TAK-580 (NRAS+ Previously Treated) n = 1	Q2D Dose Expansion Phase: TAK-580 BRAF/NRAS WT+ Naive n = 6	Q2D Dose Expansion Phase:TAK-580 BRAF/NRASWT+PreviouslyTreated n = 11	Q2D Dose Expansion Phase: Pharmacokinetic Cohort n = 20	QW Dose Expansion Phase: TAK-580 NRAS WT+ Naive n = 19	Q2D Dose Expansion Phase: TAK-580 (BRAF+) n = 2
TEAEs	4	3	3	3	7	7	3	3	13	4	16	8	16	1	6	11	20	19	2
SAEs	2	0	1	0	2	4	1	2	5	3	9	6

Population analysed: The safety population included all participants who received at least 1 dose of study drug (TAK-580).

Primary outcome: Dose Escalation Phase: Number of Participants With Dose-limiting Adverse Events (AEs)

Time frame: Cycle 1 (Cycle length= 22 days [Q2D] and 28 days [QW]). Count of participants. Unit: Participants

Measure	Q2D Dose Escalation Phase: TAK-580 20 mg (22 Days Cycle) n = 4	Q2D Dose Escalation Phase: TAK-580 40 mg (22 Days Cycle) n = 3	Q2D Dose Escalation Phase: TAK-580 80 mg (22 Days Cycle) n = 3	Q2D Dose Escalation Phase: TAK-580 135 mg (22 Days Cycle) n = 3	Q2D Dose Escalation Phase: TAK-580 200 mg (22 Days Cycle) n = 7	Q2D Dose Escalation Phase: TAK-580 280 mg (22 Days Cycle) n = 7	Q2D Dose Escalation Phase: TAK-580 200 mg (28 Days Cycle) n = 3	QW Dose Escalation Phase: TAK-580 400 mg (28 Days Cycle) n = 3	QW Dose Escalation Phase: TAK-580 600 mg (28 Days Cycle) n = 13	QW Dose Escalation Phase: TAK-580 800 mg (28 Days Cycle) n = 4
Value	0	0	0	0	0	2	0	0	0	2

Population analysed: The safety population included all participants who received at least 1 dose of study drug (TAK-580).

Primary outcome: Number of Participants With TEAEs Related to Physical Examination Findings

Measure	Q2D Dose Escalation Phase: TAK-580 20 mg (22 Days Cycle) n = 4	Q2D Dose Escalation Phase: TAK-580 40 mg (22 Days Cycle) n = 3	Q2D Dose Escalation Phase: TAK-580 80 mg (22 Days Cycle) n = 3	Q2D Dose Escalation Phase: TAK-580 135 mg (22 Days Cycle) n = 3	Q2D Dose Escalation Phase: TAK-580 200 mg (22 Days Cycle) n = 7	Q2D Dose Escalation Phase: TAK-580 280 mg (22 Days Cycle) n = 7	Q2D Dose Escalation Phase: TAK-580 200 mg (28 Days Cycle) n = 3	QW Dose Escalation Phase: TAK-580 400 mg (28 Days Cycle) n = 3	QW Dose Escalation Phase: TAK-580 600 mg (28 Days Cycle) n = 13	QW Dose Escalation Phase: TAK-580 800 mg (28 Days Cycle) n = 4	Q2D Dose Expansion Phase: TAK-580 (BRAF+ Naive) n = 16	Q2D Dose Expansion Phase: TAK-580 (BRAF+ Previously Treated) n = 8	Q2D Dose Expansion Phase: TAK-580 (NRAS+ Naive) n = 16	Q2D Dose Expansion Phase: TAK-580 (NRAS+ Previously Treated) n = 1	Q2D Dose Expansion Phase: TAK-580 BRAF/NRAS WT+ Naive n = 6	Q2D Dose Expansion Phase:TAK-580 BRAF/NRASWT+PreviouslyTreated n = 11	Q2D Dose Expansion Phase: Pharmacokinetic Cohort n = 20	QW Dose Expansion Phase: TAK-580 NRAS WT+ Naive n = 19	Q2D Dose Expansion Phase: TAK-580 (BRAF+) n = 2
Weight decreased	0	0	0	0	0	1

Primary outcome: Clinically Significant Change From Baseline in Body Weight at End of Study Visit (EOSV)

Time frame: Baseline up to EOSV (up to Cycle 38 Days 52 [Q2D] and 58 [QW] [Cycle length =22 days (Q2D) and 28 days (QW)] in Escalation Phase; Cycle 49 Day 58 [Cycle length =28 days] in Expansion Phase). Mean (Standard Deviation). Unit: kilogram (kg)

Measure	Q2D Dose Escalation Phase: TAK-580 20 mg (22 Days Cycle) n = 4	Q2D Dose Escalation Phase: TAK-580 40 mg (22 Days Cycle) n = 3	Q2D Dose Escalation Phase: TAK-580 80 mg (22 Days Cycle) n = 3	Q2D Dose Escalation Phase: TAK-580 135 mg (22 Days Cycle) n = 3	Q2D Dose Escalation Phase: TAK-580 200 mg (22 Days Cycle) n = 7	Q2D Dose Escalation Phase: TAK-580 280 mg (22 Days Cycle) n = 7	Q2D Dose Escalation Phase: TAK-580 200 mg (28 Days Cycle) n = 3	QW Dose Escalation Phase: TAK-580 400 mg (28 Days Cycle) n = 3	QW Dose Escalation Phase: TAK-580 600 mg (28 Days Cycle) n = 13	QW Dose Escalation Phase: TAK-580 800 mg (28 Days Cycle) n = 4	Q2D Dose Expansion Phase: TAK-580 (BRAF+ Naive) n = 16	Q2D Dose Expansion Phase: TAK-580 (BRAF+ Previously Treated) n = 8	Q2D Dose Expansion Phase: TAK-580 (NRAS+ Naive) n = 16	Q2D Dose Expansion Phase: TAK-580 (NRAS+ Previously Treated) n = 1	Q2D Dose Expansion Phase: TAK-580 BRAF/NRAS WT+ Naive n = 6	Q2D Dose Expansion Phase:TAK-580 BRAF/NRASWT+PreviouslyTreated n = 11	Q2D Dose Expansion Phase: Pharmacokinetic Cohort n = 20	QW Dose Expansion Phase: TAK-580 NRAS WT+ Naive n = 19	Q2D Dose Expansion Phase: TAK-580 (BRAF+) n = 2
Baseline	87.477 (15.7794)	72.077 (8.2162)	67.375 (17.3371)	77.717 (4.1695)	76.963 (21.9026)

12 secondary outcomes are reported in the full results.

Adverse events

Time frame: TEAEs are AEs that started after the first dose of study drug and no more than 30 days after the last dose of study drug (approximately Cycle 38 Days 52 [Q2D] and 58 [QW] in Escalation Phase; Cycle 49 Day 58 in Expansion Phase). Other adverse events reported at 0% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Q2D Dose Escalation Phase: TAK-580 20 mg (22 Days Cycle)	2 of 4 (50%)	4 of 4 (100%)	1 of 4
Q2D Dose Escalation Phase: TAK-580 40 mg (22 Days Cycle)	0 of 3 (0%)	3 of 3 (100%)	0 of 3
Q2D Dose Escalation Phase: TAK-580 80 mg (22 Days Cycle)	1 of 3 (33.3%)	3 of 3 (100%)	1 of 3
Q2D Dose Escalation Phase: TAK-580 135 mg (22 Days Cycle)	0 of 3 (0%)	3 of 3 (100%)	0 of 3
Q2D Dose Escalation Phase: TAK-580 200 mg (22 Days Cycle)	2 of 7 (28.6%)	7 of 7 (100%)	0 of 7
Q2D Dose Escalation Phase: TAK-580 280 mg (22 Days Cycle)	4 of 7 (57.1%)	7 of 7 (100%)	1 of 7
Q2D Dose Escalation Phase: TAK-580 200 mg (28 Days Cycle)	1 of 3 (33.3%)	3 of 3 (100%)	0 of 3
QW Dose Escalation Phase: TAK-580 400 mg (28 Days Cycle)	2 of 3 (66.7%)	3 of 3 (100%)	0 of 3
QW Dose Escalation Phase: TAK-580 600 mg (28 Days Cycle)	5 of 13 (38.5%)	12 of 13 (92.3%)	2 of 13
QW Dose Escalation Phase: TAK-580 800 mg (28 Days Cycle)	3 of 4 (75%)	4 of 4 (100%)	1 of 4
Q2D Dose Expansion Phase: TAK-580 (BRAF+ Naive)	9 of 16 (56.3%)	16 of 16 (100%)	0 of 16
Q2D Dose Expansion Phase: TAK-580 (BRAF+ Previously Treated)	6 of 8 (75%)	8 of 8 (100%)	2 of 8
Q2D Dose Expansion Phase: TAK-580 (NRAS+ Naive)	5 of 16 (31.3%)	16 of 16 (100%)	2 of 16
Q2D Dose Expansion Phase: TAK-580 (NRAS+ Previously Treated)	1 of 1 (100%)	1 of 1 (100%)	0 of 1
Q2D Dose Expansion Phase: TAK-580 BRAF/NRAS WT+ Naive	2 of 6 (33.3%)

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 10 Aug 2020.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Derived from this study: PubMed 37219686Rasco DW, Medina T, Corrie P, Pavlick AC, Middleton MR, Lorigan P, Hebert C, Plummer R, Larkin J, Agarwala SS, Daud AI, Qiu J, Bozon V, Kneissl M, Barry E, Olszanski AJ. Phase 1 study of the pan-RAF inhibitor tovorafenib in patients with advanced solid tumors followed by dose expansion in patients with metastatic melanoma. Cancer Chemother Pharmacol. 2023 Jul;92(1):15-28. doi: 10.1007/s00280-023-04544-5. Epub 2023 May 23.
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."

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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 Monitor study director

Millennium Pharmaceuticals, Inc.

16 sites in 2 countries: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing MLN2480 in people with Melanoma and Metastatic Melanoma, run by Millennium Pharmaceuticals, Inc. at 16 sites in 2 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 14 inclusion and 13 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 10 Aug 2020. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 16 sites in United States, 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 10 Aug 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 Reporting One or More Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and Deaths (time frame: Baseline up to 30 days after last dose, or start of subsequent therapy, whichever occurred first (up to Cycle 38 Days 52 [Q2D] and 58 [QW] [Cycle=22 days (Q2D) and 28 days (QW)] in Escalation Phase; Cycle 49 Day 58 [Cycle=28 days] in Expansion Phase)). The study lists 7 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 NCT01425008, which also lists 1 linked publication.

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 10 Aug 2020.