Clinical trial NCT02723006: 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
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Melanoma
Keywords: Drug Therapy
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2016-03-30
Enrollment: 22
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: OTHER

Brief 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Number of Dose Limiting Toxicities (DLTs) During the Dose-escalation Safety Lead-in Phase
timeFrame: TAK-580 + Nivolumab and TAK-202 + Nivolumab: Baseline up to Week 9; Vedolizumab + Nivolumab + Ipilimumab: Baseline up to Week 7
Secondary outcomes:
measure: Overall Response Rate (ORR) During the Dose-escalation Safety Lead-in Phase
timeFrame: Baseline up to Week 50
measure: Duration of Response (DOR) During the Dose-escalation Safety Lead-in Phase
timeFrame: From date of first documented confirmed CR/PR until date of first documentation of PD or death (up to Week 50)
measure: Progression-free Survival (PFS) During the Dose-escalation Safety Lead-in Phase
timeFrame: From first dose date to the date of the first documentation of confirmed PD or death (up to Week 50)
measure: Overall Survival (OS) During the Dose-escalation Safety Lead-in Phase
timeFrame: From first dose of study drug until date of death from any cause (up to Week 50)
measure: Number of Participants Reporting Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
timeFrame: From the first dose of study drug up to 30 days after the last dose of study drug (up to Week 50)
Other outcomes:
Locations:
city: Tucson
country: United States
facility: University of Arizona Cancer Center
state: Arizona
city: Los Angeles
country: United States
facility: University of California Los Angeles - Jonsson Comprehensive Cancer Center
state: California
city: San Francisco
country: United States
facility: University of California San Francisco Medical Center
state: California
city: Aurora
country: United States
facility: University of Colorado Cancer Center
state: Colorado
city: Atlanta
country: United States
facility: Emory University Hospital
state: Georgia
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Boston
country: United States
facility: Massachusetts General Hospital Cancer Center
state: Massachusetts
city: Minneapolis
country: United States
facility: Virginia Piper Cancer Institute
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: New York
country: United States
facility: New York University Langone Medical Center
state: New York
city: Easton
country: United States
facility: Saint Luke's Cancer Center - Bethlehem
state: Pennsylvania
city: Philadelphia
country: United States
facility: Fox Chase Cancer Center
state: Pennsylvania
city: Dallas
country: United States
facility: Texas Oncology-Baylor Charles A. Sammons Cancer Center
state: Texas
city: Fairfax
country: United States
facility: Inova Fairfax Hospital
state: Virginia
Study officials:
affiliation: Millennium Pharmaceuticals, Inc.
name: Medical Monitor
role: STUDY_DIRECTOR
References: