Study to Evaluate the Safety, Tolerability, and Pharmacodynamics of Investigational Treatments in Combination With Standard of Care Immune Checkpoint Inhibitors in Participants With Advanced Melanoma
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ClinicalTrials.gov Identifier: NCT02723006 |
Recruitment Status :
Terminated
(Business decision: Protocol efficacy futility met)
First Posted : March 30, 2016
Results First Posted : April 1, 2021
Last Update Posted : April 1, 2021
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Condition or disease | Intervention/treatment | Phase |
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Melanoma | Drug: TAK-580 Drug: TAK-202 Drug: vedolizumab Drug: nivolumab Drug: ipilimumab | Phase 1 |
The drugs being tested in this study are called TAK-580, TAK-202 (plozalizumab), and vedolizumab. These investigational drugs were given along with standard of care checkpoint inhibitors ([nivolumab in Arms 1 and 2] or nivolumab + ipilimumab in Arm 3). This study looked at the safety profile of the combination treatments in each arm when administered to participants with metastatic melanoma.
The study planned to enroll approximately 156 participants. Participants were assigned to one of the 3 treatment groups:
- TAK-580 + nivolumab
- TAK-202 (plozalizumab) + nivolumab
- vedolizumab + nivolumab + ipilimumab
This study consists of 3 parts. A dose-escalation safety lead-in phase, confirmatory safety phase and a cohort expansion phase. This multi-center trial will be conducted in the United States. The overall time to participate in this study is 50 weeks. Participants may make multiple visits to the clinic and 30, 60, and 90 days after last dose of study drug for follow-up assessments.
Study Type : | Interventional (Clinical Trial) |
Actual Enrollment : | 22 participants |
Allocation: | Non-Randomized |
Intervention Model: | Parallel Assignment |
Masking: | None (Open Label) |
Primary Purpose: | Other |
Official Title: | An Open-Label, Phase 1b, Multi-Arm Study to Evaluate the Safety, Tolerability, and Pharmacodynamics of Investigational Treatments in Combination With Standard of Care Immune Checkpoint Inhibitors in Patients With Advanced Melanoma |
Actual Study Start Date : | June 22, 2016 |
Actual Primary Completion Date : | May 11, 2018 |
Actual Study Completion Date : | May 11, 2018 |

Arm | Intervention/treatment |
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Experimental: TAK-580 + nivolumab
TAK-580 orally, once weekly along with nivolumab, intravenous, every 2 weeks.
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Drug: TAK-580
TAK-580 tablets
Other Name: MLN2480 Drug: nivolumab nivolumab infusion
Other Name: Opdivo |
Experimental: TAK-202 (plozalizumab) + nivolumab
TAK-202 (plozalizumab) 2 milligram (mg), intravenous, once in Week 1, 3, 5, 9, and every 4 weeks thereafter with nivolumab infusion, intravenous, every 2 weeks.
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Drug: TAK-202
TAK-202 infusion
Other Names:
Drug: nivolumab nivolumab infusion
Other Name: Opdivo |
Experimental: vedolizumab + nivolumab + ipilimumab
Vedolizumab intravenous, once in Week 1, 3, 5, and 13 along with nivolumab infusion, intravenous, once in Week 1, 4, 7, 10, and 13 and every 2 weeks thereafter, along with ipilimumab intravenous, once in Week 1, 4, 7, and 10.
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Drug: vedolizumab
vedolizumab infusion
Other Name: Entyvio Drug: nivolumab nivolumab infusion
Other Name: Opdivo Drug: ipilimumab ipilimumab infusion
Other Name: Yervoy |
- Number of Dose Limiting Toxicities (DLTs) During the Dose-escalation Safety Lead-in Phase [ Time Frame: TAK-580 + Nivolumab and TAK-202 + Nivolumab: Baseline up to Week 9; Vedolizumab + Nivolumab + Ipilimumab: Baseline up to Week 7 ]DLTs was evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03.
- Overall Response Rate (ORR) During the Dose-escalation Safety Lead-in Phase [ Time Frame: Baseline up to Week 50 ]ORR based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. was the percentage of participants with complete response (CR) or partial response (PR). 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 percent (%) decrease in sum of diameter (SOD) of target lesions, taking as reference the baseline SOD.
- Duration of Response (DOR) During the Dose-escalation Safety Lead-in Phase [ Time Frame: From date of first documented confirmed CR/PR until date of first documentation of PD or death (up to Week 50) ]DOR based on RECIST version 1.1 was the time from the date of first documented confirmed CR/PR until the first documentation of confirmed progressive disease (PD) or death, whichever occurred first. 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.
- Progression-free Survival (PFS) During the Dose-escalation Safety Lead-in Phase [ Time Frame: From first dose date to the date of the first documentation of confirmed PD or death (up to Week 50) ]PFS was the time from first dose date to date of the first documentation of confirmed PD or death, whichever occurred first. PD: at least 20% increase (including an absolute increase of at least 5 mm) in the SOD of target lesions.
- Overall Survival (OS) During the Dose-escalation Safety Lead-in Phase [ Time Frame: From first dose of study drug until date of death from any cause (up to Week 50) ]OS was the time from date of first dose of study drug until date of death from any cause.
- Number of Participants Reporting Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [ Time Frame: From the first dose of study drug up to 30 days after the last dose of study drug (up to Week 50) ]

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- Is a male or female participant of 18 years or older.
- Has histologically confirmed, unresectable Stage III or Stage IV melanoma per the American Joint Committee on Cancer (AJCC) staging system.
- Has an eastern cooperative oncology group (ECOG) performance status of 0-1.
- Adequate bone marrow reserve and renal and hepatic function within 28 days before the first dose of study drug on the basis of the defined laboratory parameters.
- For TAK-580 + nivolumab and TAK-202 (plozalizumab) + nivolumab only: Had disease accessible for repeat nonsignificant risk biopsy (those occurring outside the brain, lung/mediastinum, and pancreas, or obtained with endoscopic procedures extending beyond the esophagus, stomach, or bowel) and willingness to undergo serial tumor biopsies.
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Additional Inclusion Requirements for TAK-580 + nivolumab
a) BRAF V600 mutation-positive or NRAS mutation-positive disease previously untreated with RAF, MEK, or other inhibitors of the mitogen-activated protein kinase (MAPK) pathway. Participants who have progressed on these agents can still be enrolled in TAK-202 (plozalizumab) + nivolumab or vedolizumab + nivolumab + ipilimumab.
- Additional Inclusion Requirements for expansion cohorts only a) Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) guidelines (Version 1.1) and at least 1 nonsignificant risk, non-target lesion accessible for biopsy per the guidelines above (for TAK-580 + nivolumab and TAK-202 (plozalizumab) + nivolumab only).
Exclusion Criteria:
- Has active brain metastases or leptomeningeal metastases. Participants with brain metastases are eligible if these have been treated and there is no magnetic resonance imaging (MRI) evidence of progression for at least 4 weeks after treatment is complete and within 28 days prior to first dose of study drug administration. There must also be no requirement for high doses of systemic corticosteroids that could result in immunosuppression (greater than [>] 10 milligram per day [mg/day] prednisone equivalents) for at least 2 weeks prior to study drug administration.
- Completed a prior therapy less than (<) 2 weeks prior to first dose and for whom adverse events (AEs) related to prior therapy had not returned to baseline or improved to Grade 1.
- Has active, known or suspected autoimmune disease.
- Has a condition requiring systemic treatment with either corticosteroids or other immunosuppressive medications within 14 days of study drug administration.
- Has a history of pneumonitis requiring treatment with steroids; history of idiopathic pulmonary fibrosis (including pneumonitis), interstitial lung disease, drug-induced pneumonitis, organizing pneumonia, or evidence of active pneumonitis on screening chest computed tomography (CT) scan; history of radiation pneumonitis in the radiation field (fibrosis) is permitted.
- Is previously diagnosed human immunodeficiency virus (HIV) infection or active hepatitis B or C.
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Additional Exclusion Requirements for arm 1 only (nivolumab Plus TAK-580)
- Concomitant use or administration of clinically significant enzyme inducers less than or equal to (<=) 14 days before the first dose of TAK-580.
- Treatment with gemfibrozil (or other strong CYP2C8 inhibitor) within 14 days before the first dose of TAK-580.
- Left ventricular ejection fraction (LVEF) <50 percent (%) as measured by echocardiogram (ECHO) or multiple gated acquisition scan (MUGA) within 4 weeks before receiving the first dose of study drug.
- Known gastrointestinal (GI) disease or prior GI procedure that could interfere with the oral absorption or tolerance of the TAK-580.
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Additional Exclusion Requirements for arm 3 only (vedolizumab Plus nivolumab Plus ipilimumab)
- Had prior exposure to rituximab, natalizumab, vedolizumab, or alemtuzumab.
- Has a history of any major neurological disorders, including stroke, multiple sclerosis, or neurodegenerative disease.
- Has taken any live vaccinations within 30 days before study drug administration except for the influenza vaccine.

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02723006
United States, Arizona | |
University of Arizona Cancer Center | |
Tucson, Arizona, United States | |
United States, California | |
University of California Los Angeles - Jonsson Comprehensive Cancer Center | |
Los Angeles, California, United States | |
University of California San Francisco Medical Center | |
San Francisco, California, United States | |
United States, Colorado | |
University of Colorado Cancer Center | |
Aurora, Colorado, United States | |
United States, Georgia | |
Emory University Hospital | |
Atlanta, Georgia, United States | |
United States, Massachusetts | |
Dana-Farber Cancer Institute | |
Boston, Massachusetts, United States | |
Massachusetts General Hospital Cancer Center | |
Boston, Massachusetts, United States | |
United States, Minnesota | |
Virginia Piper Cancer Institute | |
Minneapolis, Minnesota, United States | |
United States, Missouri | |
Washington University School of Medicine | |
Saint Louis, Missouri, United States | |
United States, New York | |
New York University Langone Medical Center | |
New York, New York, United States | |
United States, Pennsylvania | |
Saint Luke's Cancer Center - Bethlehem | |
Easton, Pennsylvania, United States | |
Fox Chase Cancer Center | |
Philadelphia, Pennsylvania, United States | |
United States, Texas | |
Texas Oncology-Baylor Charles A. Sammons Cancer Center | |
Dallas, Texas, United States | |
United States, Virginia | |
Inova Fairfax Hospital | |
Fairfax, Virginia, United States |
Study Director: | Medical Monitor | Millennium Pharmaceuticals, Inc. |
Documents provided by Takeda ( Millennium Pharmaceuticals, Inc. ):
Responsible Party: | Millennium Pharmaceuticals, Inc. |
ClinicalTrials.gov Identifier: | NCT02723006 |
Other Study ID Numbers: |
C28003 U1111-1177-4142 ( Other Identifier: WHO ) 2015-005554-35 ( EudraCT Number ) |
First Posted: | March 30, 2016 Key Record Dates |
Results First Posted: | April 1, 2021 |
Last Update Posted: | April 1, 2021 |
Last Verified: | March 2021 |
Individual Participant Data (IPD) Sharing Statement: | |
Plan to Share IPD: | Yes |
Plan Description: | Takeda makes patient-level, de-identified data sets and associated documents available after applicable marketing approvals and commercial availability have been received, an opportunity for the primary publication of the research has been allowed, and other criteria have been met as set forth in Takeda's Data Sharing Policy (see www.TakedaClinicalTrials.com/Approach 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. |
Studies a U.S. FDA-regulated Drug Product: | Yes |
Studies a U.S. FDA-regulated Device Product: | No |
Drug Therapy |
Melanoma Neuroendocrine Tumors Neuroectodermal Tumors Neoplasms, Germ Cell and Embryonal Neoplasms by Histologic Type Neoplasms Neoplasms, Nerve Tissue |
Nevi and Melanomas Nivolumab Ipilimumab Vedolizumab Antineoplastic Agents, Immunological Antineoplastic Agents Gastrointestinal Agents |