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TerminatedNCT02723006Updated Mar 5, 2024Results posted

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

A Phase 1 interventional study of TAK-580 and TAK-202 in Melanoma, sponsored by Millennium Pharmaceuticals, Inc.. Terminated at 14 sites in United States. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2024-03-05.

Sponsored by Millennium Pharmaceuticals, Inc. · Phase 1, Interventional, and Other

Why this study was terminated
Business decision: Protocol efficacy futility met
Phase
Phase 1
Study type
Interventional
Enrollment
22
Allocation
Non-randomized
Ages
18 Years and older
Sex
All
01

Study summary

The purpose of this study is to determine the initial safety profile and initial antitumor activity of the combination treatments (immune checkpoint inhibitors [nivolumab, ipilimumab] with investigational drugs [TAK-580, TAK-202 (plozalizumab), vedolizumab]) in the 3 arms when administered to participants with advanced melanoma.

Read the detailed description

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.

02

Conditions studied

  • Melanoma

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Keywords

  • Drug Therapy
03

Who can participate

Ages eligible
18 Years and older
Sexes eligible
All
Accepts healthy volunteers
No

Inclusion criteria

  1. Is a male or female participant of 18 years or older.
  2. Has histologically confirmed, unresectable Stage III or Stage IV melanoma per the American Joint Committee on Cancer (AJCC) staging system.
  3. Has an eastern cooperative oncology group (ECOG) performance status of 0-1.
  4. 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.
  5. 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.

  6. 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.

  7. 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

Exclusion Criteria:

  1. 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.
  2. 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.
  3. Has active, known or suspected autoimmune disease.
  4. Has a condition requiring systemic treatment with either corticosteroids or other immunosuppressive medications within 14 days of study drug administration.
  5. 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.
  6. Is previously diagnosed human immunodeficiency virus (HIV) infection or active hepatitis B or C.

  7. Additional Exclusion Requirements for arm 1 only (nivolumab Plus TAK-580)

    1. Concomitant use or administration of clinically significant enzyme inducers less than or equal to (\<=) 14 days before the first dose of TAK-580.
    2. Treatment with gemfibrozil (or other strong CYP2C8 inhibitor) within 14 days before the first dose of TAK-580.
    3. 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.
    4. Known gastrointestinal (GI) disease or prior GI procedure that could interfere with the oral absorption or tolerance of the TAK-580.

  8. Additional Exclusion Requirements for arm 3 only (vedolizumab Plus nivolumab Plus ipilimumab)

    1. Had prior exposure to rituximab, natalizumab, vedolizumab, or alemtuzumab.
    2. Has a history of any major neurological disorders, including stroke, multiple sclerosis, or neurodegenerative disease.
    3. Has taken any live vaccinations within 30 days before study drug administration except for the influenza vaccine.
04

Study design

Phase
Phase 1
Primary purpose
Other
Allocation
Non-randomized
Intervention model
Parallel assignment
Masking
None (open label)
Enrollment
22 participants (actual)

Study arms

  • Experimental
    TAK-580 + nivolumab

    TAK-580 orally, once weekly along with nivolumab, intravenous, every 2 weeks.

    Drug: TAK-580 · Drug: nivolumab

  • 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.

    Drug: TAK-202 · Drug: nivolumab

  • 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.

    Drug: vedolizumab · Drug: nivolumab · Drug: ipilimumab

Interventions

  • DrugTAK-580

    TAK-580 tablets

    Also known as: MLN2480

  • DrugTAK-202

    TAK-202 infusion

    Also known as: MLN1202, plozalizumab

  • Drugvedolizumab

    vedolizumab infusion

    Also known as: Entyvio

  • Drugnivolumab

    nivolumab infusion

    Also known as: Opdivo

  • Drugipilimumab

    ipilimumab infusion

    Also known as: Yervoy

05

What researchers measure

Primary outcomes

  1. Number of Dose Limiting Toxicities (DLTs) During the Dose-escalation Safety Lead-in Phase

    DLTs was evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03.

    Time frame: TAK-580 + Nivolumab and TAK-202 + Nivolumab: Baseline up to Week 9; Vedolizumab + Nivolumab + Ipilimumab: Baseline up to Week 7

Secondary outcomes

  1. Overall Response Rate (ORR) During the Dose-escalation Safety Lead-in Phase

    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.

    Time frame: Baseline up to Week 50

  2. Duration of Response (DOR) During the Dose-escalation Safety Lead-in Phase

    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.

    Time frame: From date of first documented confirmed CR/PR until date of first documentation of PD or death (up to Week 50)

  3. Progression-free Survival (PFS) During the Dose-escalation Safety Lead-in Phase

    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.

    Time frame: From first dose date to the date of the first documentation of confirmed PD or death (up to Week 50)

  4. Overall Survival (OS) During the Dose-escalation Safety Lead-in Phase

    OS was the time from date of first dose of study drug until date of death from any cause.

    Time frame: From first dose of study drug until date of death from any cause (up to Week 50)

  5. 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)

06

Results

Posted Apr 1, 2021

Participant flow

Participants took part in the study at 10 investigative sites in the United States from 22 June 2016 to 11 May 2018.

Participant flow — Overall Study
MilestoneArm 1: TAK-580 + NivolumabArm 2: TAK-202 + NivolumabArm 3: Vedolizumab + Ipilimumab + Nivolumab
Started1912
Completed025
Not completed177
Withdrew: Withdrawal by subject011
Withdrew: Study terminated by sponsor166

Outcome measures

PrimaryNumber of Dose Limiting Toxicities (DLTs) During the Dose-escalation Safety Lead-in Phase

DLTs was evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03.

Time frame:
TAK-580 + Nivolumab and TAK-202 + Nivolumab: Baseline up to Week 9; Vedolizumab + Nivolumab + Ipilimumab: Baseline up to Week 7
Reported as:
Number · DLTs
Number of Dose Limiting Toxicities (DLTs) During the Dose-escalation Safety Lead-in Phase
DLTsArm 1: TAK-580 + NivolumabArm 2: TAK-202 + NivolumabArm 3: Vedolizumab + Ipilimumab + Nivolumab
Number of Dose Limiting Toxicities (DLTs) During the Dose-escalation Safety Lead-in Phase030
SecondaryOverall Response Rate (ORR) During the Dose-escalation Safety Lead-in Phase

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.

Time frame:
Baseline up to Week 50

No measurements were reported for this outcome.

SecondaryDuration of Response (DOR) During the Dose-escalation Safety Lead-in Phase

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.

Time frame:
From date of first documented confirmed CR/PR until date of first documentation of PD or death (up to Week 50)

No measurements were reported for this outcome.

SecondaryProgression-free Survival (PFS) During the Dose-escalation Safety Lead-in Phase

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.

Time frame:
From first dose date to the date of the first documentation of confirmed PD or death (up to Week 50)

No measurements were reported for this outcome.

SecondaryOverall Survival (OS) During the Dose-escalation Safety Lead-in Phase

OS was the time from date of first dose of study drug until date of death from any cause.

Time frame:
From first dose of study drug until date of death from any cause (up to Week 50)

No measurements were reported for this outcome.

SecondaryNumber 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)
Reported as:
Number · participants
Number of Participants Reporting Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
participantsArm 1: TAK-580 + NivolumabArm 2: TAK-202 + NivolumabArm 3: Vedolizumab + Ipilimumab + Nivolumab
TEAEs1912
SAEs127

Adverse events

Collected over Treatment-emergent adverse events are adverse events that started after the first dose of study drug and no more than 30 days (up to Week 50) after the last dose of study drug. Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Arm 1: TAK-580 + Nivolumab0/1 (0%)1/1 (100%)1/1 (100%)
Arm 2: TAK-202 + Nivolumab0/9 (0%)2/9 (22.2%)9/9 (100%)
Arm 3: Vedolizumab + Ipilimumab + Nivolumab2/12 (16.7%)7/12 (58.3%)12/12 (100%)
Most frequent serious events
Showing 10 of 15
Most frequent serious events
EventArm 1: TAK-580 + NivolumabArm 2: TAK-202 + NivolumabArm 3: Vedolizumab + Ipilimumab + Nivolumab
NauseaGastrointestinal disorders1/11/90/12
Adrenal insufficiencyEndocrine disorders1/10/90/12
Rectal haemorrhageGastrointestinal disorders0/11/90/12
Autoimmune colitisGastrointestinal disorders0/10/91/12
ColitisGastrointestinal disorders0/10/91/12
DiarrhoeaGastrointestinal disorders0/10/91/12
HypophysitisEndocrine disorders0/10/91/12
EosinophiliaBlood and lymphatic system disorders0/10/91/12
LeukocytosisBlood and lymphatic system disorders0/10/91/12
Acute coronary syndromeCardiac disorders0/10/91/12
Most frequent other events
Showing 10 of 131
Most frequent other events
EventArm 1: TAK-580 + NivolumabArm 2: TAK-202 + NivolumabArm 3: Vedolizumab + Ipilimumab + Nivolumab
NauseaGastrointestinal disorders1/16/98/12
FatigueGeneral disorders1/14/99/12
HeadacheNervous system disorders1/13/95/12
PyrexiaGeneral disorders1/13/95/12
ArthralgiaMusculoskeletal and connective tissue disorders1/12/92/12
DehydrationMetabolism and nutrition disorders1/10/93/12
Dry mouthGastrointestinal disorders1/11/92/12
VomitingGastrointestinal disorders1/12/91/12
Acute kidney injuryRenal and urinary disorders1/10/91/12
Amylase increasedInvestigations1/10/91/12

Baseline characteristics

The safety analysis set included all participants who received at least 1 dose, even if incomplete, of study treatment (TAK-580, TAK-202, or vedolizumab).

Age, Continuous
Age, Continuous(years)Arm 1: TAK-580 + NivolumabArm 2: TAK-202 + NivolumabArm 3: Vedolizumab + Ipilimumab + NivolumabTotal
Mean4163.9 ± 11.5455.8 ± 16.3658.5 ± 14.90
Sex: Female, Male
Sex: Female, Male(Participants)Arm 1: TAK-580 + NivolumabArm 2: TAK-202 + NivolumabArm 3: Vedolizumab + Ipilimumab + NivolumabTotal
Female13711
Male06511
Ethnicity (NIH/OMB)
Ethnicity (NIH/OMB)(Participants)Arm 1: TAK-580 + NivolumabArm 2: TAK-202 + NivolumabArm 3: Vedolizumab + Ipilimumab + NivolumabTotal
Hispanic or Latino0000
Not Hispanic or Latino19919
Unknown or Not Reported0033
Race (NIH/OMB)
Race (NIH/OMB)(Participants)Arm 1: TAK-580 + NivolumabArm 2: TAK-202 + NivolumabArm 3: Vedolizumab + Ipilimumab + NivolumabTotal
American Indian or Alaska Native0000
Asian0000
Native Hawaiian or Other Pacific Islander0000
Black or African American0101
White181120
More than one race0000
Unknown or Not Reported0011
Region of Enrollment
Region of Enrollment(Participants)Arm 1: TAK-580 + NivolumabArm 2: TAK-202 + NivolumabArm 3: Vedolizumab + Ipilimumab + NivolumabTotal
United States191222
Height
Height(centimeter (cm))Arm 1: TAK-580 + NivolumabArm 2: TAK-202 + NivolumabArm 3: Vedolizumab + Ipilimumab + NivolumabTotal
Mean171.00168.49 ± 10.479170.00 ± 10.846169.40 ± 10.170
Weight
Weight(kilogram (kg))Arm 1: TAK-580 + NivolumabArm 2: TAK-202 + NivolumabArm 3: Vedolizumab + Ipilimumab + NivolumabTotal
Mean77.8077.42 ± 9.24888.20 ± 26.78683.32 ± 20.937
07

Study locations

14 sites
  • University of Arizona Cancer Center
    Tucson, Arizona, United States
  • 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
  • University of Colorado Cancer Center
    Aurora, Colorado, United States
  • Emory University Hospital
    Atlanta, Georgia, United States
  • Dana-Farber Cancer Institute
    Boston, Massachusetts, United States
  • Massachusetts General Hospital Cancer Center
    Boston, Massachusetts, United States
  • Virginia Piper Cancer Institute
    Minneapolis, Minnesota, United States
  • Washington University School of Medicine
    Saint Louis, Missouri, United States
  • New York University Langone Medical Center
    New York, New York, United States
  • Saint Luke's Cancer Center - Bethlehem
    Easton, Pennsylvania, United States
  • Fox Chase Cancer Center
    Philadelphia, Pennsylvania, United States
  • Texas Oncology-Baylor Charles A. Sammons Cancer Center
    Dallas, Texas, United States
  • Inova Fairfax Hospital
    Fairfax, Virginia, United States
08

References and documents

Study documents

  • Protocol and statistical analysis plan · Oct 18, 2016

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: Yes — Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.

Supporting information: Study protocol, Sap, Icf, Csr

09

Registry details

Key details

Study ID
NCT02723006
Lead sponsor
Millennium Pharmaceuticals, Inc.
Responsible party
Sponsor
First posted
Mar 30, 2016
Start date
Jun 22, 2016
Primary completion
May 11, 2018
Completion
May 11, 2018
Results posted
Apr 1, 2021
Last update
Mar 5, 2024

Study contacts

Medical Monitor
study director · Millennium Pharmaceuticals, Inc.

Oversight

Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

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