Melanoma
Conditions
Keywords
Drug Therapy
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.
Interventions
DRUGTAK-580
TAK-580 tablets
DRUGTAK-202
TAK-202 infusion
DRUGvedolizumab
vedolizumab infusion
DRUGnivolumab
nivolumab infusion
DRUGipilimumab
ipilimumab infusion
Sponsors
Millennium Pharmaceuticals, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Dose Limiting Toxicities (DLTs) During the Dose-escalation Safety Lead-in Phase | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) During the Dose-escalation Safety Lead-in Phase | 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 | 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 | 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 | 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) | From the first dose of study drug up to 30 days after the last dose of study drug (up to Week 50) | — |
Countries
United States
Participant flow
Recruitment details
Participants took part in the study at 10 investigative sites in the United States from 22 June 2016 to 11 May 2018.
Pre-assignment details
Participants with advanced/metastatic melanoma were enrolled to receive:TAK-580+nivolumab,TAK-202+nivolumab,or vedolizumab+nivolumab+ipilumab. Study was terminated early after the dose escalation safety-lead in phase due to lack of enrollment(Arm 1), lack of clinical benefit(Arm 2), and after pre-specified stopping rule for diarrhea was met(Arm 3).
Participants by arm
| Arm | Count |
|---|---|
| Arm 1: TAK-580 + Nivolumab Participants in this group received TAK-580 400 mg, tablets, orally, once weekly along with nivolumab 3 mg/kg, infusion, intravenous, once every 2 weeks (up to Week 48). | 1 |
| Arm 2: TAK-202 + Nivolumab Participants in this group received TAK-202 (plozalizumab) 4 mg/kg titrated up to 8 mg/kg (stable dose), infusion, intravenous, once in Weeks 1, 3, 5, and every 4 weeks thereafter along with nivolumab 3 mg/kg, infusion, intravenously, once every 2 weeks (up to Week 50). | 9 |
| Arm 3: Vedolizumab + Ipilimumab + Nivolumab Participants in this group received vedolizumab 200 mg titrated up to 450 mg (stable dose), infusion, intravenously, once in Weeks 1, 3, 5, and 13 along with ipilimumab 3 mg/kg, infusion, intravenously, once every 3 weeks for 4 doses and nivolumab 1 mg/kg, infusion, intravenously, once every 3 weeks for 4 doses, followed by nivolumab 3 mg/kg, infusion, intravenously, once every 2 weeks until disease progression or unacceptable toxicity (up to Week 48). | 12 |
| Total | 22 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Study Terminated by Sponsor | 1 | 6 | 6 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 1 |
Baseline characteristics
| Characteristic | Arm 1: TAK-580 + Nivolumab | Total | Arm 3: Vedolizumab + Ipilimumab + Nivolumab | Arm 2: TAK-202 + Nivolumab |
|---|---|---|---|---|
| Age, Continuous | 41 years | 58.5 years STANDARD_DEVIATION 14.9 | 55.8 years STANDARD_DEVIATION 16.36 | 63.9 years STANDARD_DEVIATION 11.54 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1 Participants | 19 Participants | 9 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 3 Participants | 3 Participants | 0 Participants |
| Height | 171.00 centimeter (cm) | 169.40 centimeter (cm) STANDARD_DEVIATION 10.17 | 170.00 centimeter (cm) STANDARD_DEVIATION 10.846 | 168.49 centimeter (cm) STANDARD_DEVIATION 10.479 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 1 Participants | 20 Participants | 11 Participants | 8 Participants |
| Region of Enrollment United States | 1 Participants | 22 Participants | 12 Participants | 9 Participants |
| Sex: Female, Male Female | 1 Participants | 11 Participants | 7 Participants | 3 Participants |
| Sex: Female, Male Male | 0 Participants | 11 Participants | 5 Participants | 6 Participants |
| Weight | 77.80 kilogram (kg) | 83.32 kilogram (kg) STANDARD_DEVIATION 20.937 | 88.20 kilogram (kg) STANDARD_DEVIATION 26.786 | 77.42 kilogram (kg) STANDARD_DEVIATION 9.248 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 1 | 0 / 9 | 2 / 12 |
| other Total, other adverse events | 1 / 1 | 9 / 9 | 12 / 12 |
| serious Total, serious adverse events | 1 / 1 | 2 / 9 | 7 / 12 |
Outcome results
Primary
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
Population: 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).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1: TAK-580 + Nivolumab | Number of Dose Limiting Toxicities (DLTs) During the Dose-escalation Safety Lead-in Phase | 0 DLTs |
| Arm 2: TAK-202 + Nivolumab | Number of Dose Limiting Toxicities (DLTs) During the Dose-escalation Safety Lead-in Phase | 3 DLTs |
| Arm 3: Vedolizumab + Ipilimumab + Nivolumab | Number of Dose Limiting Toxicities (DLTs) During the Dose-escalation Safety Lead-in Phase | 0 DLTs |
Secondary
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)
Population: Planned efficacy analyses was not performed as the study was terminated due to lack of enrollment, lack of clinical benefit and after the pre-specified stopping rule was met for diarrhea.
Secondary
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)
Population: 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).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm 1: TAK-580 + Nivolumab | Number of Participants Reporting Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAEs | 1 participants |
| Arm 1: TAK-580 + Nivolumab | Number of Participants Reporting Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 1 participants |
| Arm 2: TAK-202 + Nivolumab | Number of Participants Reporting Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAEs | 9 participants |
| Arm 2: TAK-202 + Nivolumab | Number of Participants Reporting Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 2 participants |
| Arm 3: Vedolizumab + Ipilimumab + Nivolumab | Number of Participants Reporting Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAEs | 12 participants |
| Arm 3: Vedolizumab + Ipilimumab + Nivolumab | Number of Participants Reporting Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 7 participants |
Secondary
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
Population: Planned efficacy analyses was not performed as the study was terminated due to lack of enrollment, lack of clinical benefit and after the pre-specified stopping rule was met for diarrhea.
Secondary
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)
Population: Planned efficacy analyses was not performed as the study was terminated due to lack of enrollment, lack of clinical benefit and after the pre-specified stopping rule was met for diarrhea.
Secondary
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)
Population: Planned efficacy analyses was not performed as the study was terminated due to lack of enrollment, lack of clinical benefit and after the pre-specified stopping rule was met for diarrhea.