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

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

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.

Study Overview

• Status: Terminated
• Conditions: Melanoma
• Intervention / Treatment: Drug: TAK-580; Drug: nivolumab; Drug: TAK-202; Drug: vedolizumab; Drug: ipilimumab

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.

• Study Type: Interventional
• Enrollment (Actual): 22
• Phase: Phase 1

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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:

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: TAK-580 + nivolumab; TAK-580 orally, once weekly along with nivolumab, intravenous, every 2 weeks.	Drug: TAK-580; TAK-580 tablets; Other Names: MLN2480; Drug: nivolumab; nivolumab infusion; Other Names: 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.	Drug: nivolumab; nivolumab infusion; Other Names: Opdivo; Drug: TAK-202; TAK-202 infusion; Other Names: MLN1202; plozalizumab
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: nivolumab; nivolumab infusion; Other Names: Opdivo; Drug: vedolizumab; vedolizumab infusion; Other Names: Entyvio; Drug: ipilimumab; ipilimumab infusion; Other Names: Yervoy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	TAK-580 + Nivolumab and TAK-202 + Nivolumab: Baseline up to Week 9; Vedolizumab + Nivolumab + Ipilimumab: Baseline up to Week 7

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Baseline up to Week 50
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.	From date of first documented confirmed CR/PR until date of first documentation of PD or death (up to Week 50)
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.	From first dose date to the date of the first documentation of confirmed PD or death (up to Week 50)
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.	From first dose of study drug until date of death from any cause (up to Week 50)
Number of Participants Reporting Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)		From the first dose of study drug up to 30 days after the last dose of study drug (up to Week 50)

Collaborators and Investigators

• Sponsor: Millennium Pharmaceuticals, Inc.
• Investigators: Study Director: Medical Monitor, Millennium Pharmaceuticals, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): June 22, 2016
• Primary Completion (Actual): May 11, 2018
• Study Completion (Actual): May 11, 2018

Study Registration Dates

• First Submitted: March 25, 2016
• First Submitted That Met QC Criteria: March 25, 2016
• First Posted (Estimated): March 30, 2016

Study Record Updates

• Last Update Posted (Estimated): March 5, 2024
• Last Update Submitted That Met QC Criteria: February 12, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Drug Therapy
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Skin Neoplasms; Melanoma; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Gastrointestinal Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Nivolumab; Vedolizumab; Ipilimumab
• Other Study ID Numbers: C28003; U1111-1177-4142 (Other Identifier: WHO); 2015-005554-35 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: 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.
• IPD Sharing Access Criteria: IPD from eligible studies will be shared with qualified researchers according to the criteria and process described on https://vivli.org/ourmember/takeda/. For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No