Malignant Melanoma
Conditions
Brief summary
This is a randomized, open label study to investigate efficacy and safety of UV1 vaccination in combination with nivolumab and ipilimumab as first line treatment of adult patients with histologically confirmed unresectable metastatic melanoma.
Detailed description
This is a randomized, open label study to investigate efficacy and safety of UV1 vaccination in combination with nivolumab and ipilimumab as first line treatment of adult patients with histologically confirmed unresectable metastatic melanoma. Patients in the experimental arm will receive 8 UV1 vaccinations over 4 cycles of nivolumab and ipilimumab. Patients in the control arm will receive 4 cycles of nivolumab and ipilimumab. Patients in both arms will start maintenance therapy 6 weeks after the last dose of induction therapy, nivolumab at a dose of 480 mg every 4 weeks. All patients will be followed up until death or until the end of the study. To support the Extended Exploratory Cohort of the study, an additional 20 patients at selected sites will be enrolled in a single arm UV1 cohort for collection of additional biological material. These patients are in addition to the 156 randomized patients in the main part of the study and will not be included in the main analysis of the study.
Interventions
BIOLOGICALUV1
UV1 vaccine (300 μg) will be injected intradermally.
BIOLOGICALSargramostim
Sargramostim (75 μg) is used as a vaccine adjuvant.
BIOLOGICALIpilimumab
Ipilimumab is dosed according to label.
BIOLOGICALNivolumab
Nivolumab is dosed according to label.
Sponsors
Ultimovacs ASA
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Male or female patients at least 18 years of age at the time of signing the ICF. 2. Histologically confirmed diagnosis of unresectable stage IIIB D, or unresectable stage IV malignant melanoma. 3. Eligible for combination treatment with nivolumab and ipilimumab. 4. An ECOG performance status of 0 or 1. 5. Adequate organ function as indicated by the following laboratory values: Hematological 1. Absolute neutrophil count ≥1,500/µL 2. Platelet count ≥100 x 103/µL 3. Hemoglobin ≥9 g/dL or ≥5.6 mmol/L Renal 4. Creatinine ≤1.5 x upper limit of normal (ULN) Hepatic 5. Total bilirubin ≤1.5 x ULN or direct bilirubin ≤ ULN for patients with total bilirubin levels \>1.5 ULN 6. Aspartate aminotransferase/serum glutamic oxaloacetic transaminase and alanine aminotransferase/serum glutamic pyruvic transaminase ≤2.5 x ULN for patients without liver metastasis or ≤5 x ULN for patients with liver metastasis. 6. Male patients who are sexually active with a female of childbearing potential must agree to use an adequate method of contraception. 7. Women of childbearing potential (WOCBP) must have a negative urine or serum/plasma pregnancy test. 8. WOCBP must use adequate contraception.
Exclusion criteria
1. Previous non melanoma malignancies unless curatively treated and complete remission was achieved at least 2 years prior to randomization. Patients with prior curatively treated basal or squamous cell carcinoma of the skin, carcinoma in situ of the cervix, or carcinoma in situ of the breast, or other in situ cancers are allowed irrespective of time passed since curative treatment. Patients with prior completely resected malignant melanoma are also allowed. 2. Known brain metastases or leptomeningeal metastases. If a patient experiences neurological symptoms indicative of brain metastases, a brain MRI should be performed. 3. Diagnosis of uveal or ocular melanoma. 4. Known history or any evidence of active, non-infectious pneumonitis. 5. History of New York Heart Association class 3-4 congestive heart failure or history of myocardial infarction within 6 months of starting induction therapy. 6. Active infection requiring systemic treatment. 7. Diagnosis of immunodeficiency. 8. Known history of severe hypersensitivity reactions to nivolumab, ipilimumab, sargramostim, or their excipients. 9. Known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies). 10. History of or active hepatitis B (hepatitis B surface antigen reactive) or active hepatitis C (hepatitis C virus antibody). 11. Women who are breastfeeding. 12. Prior systemic treatment for unresectable stage IIIB D or unresectable stage IV malignant melanoma. 13. Systemic corticosteroid treatment (doses exceeding 10 mg daily of prednisone or equivalent) or any other form of immunosuppressive treatment within 7 days prior to the first dose of induction therapy. 14. Receipt of a live vaccine within 30 days prior to start of induction therapy. 15. Receipt of any other investigational treatment within 4 weeks of the first dose of induction therapy. 16. Any medical, psychological, or social condition that would make it difficult for the patient to participate in the study and comply with the study procedures, restrictions and requirements.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| PFS Per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 (by Blinded Independent Central Review (BICR) | Time from randomization to progressive disease (PD) or death from any cause (approximately 44 months) | Compare progression free survival (PFS) of UV1 vaccination in combination with nivolumab and ipilimumab to that of nivolumab and ipilimumab |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | Time from randomization to death from any cause /follow-up until 70 PFS events/18 months post rand, approximately 44 months. | Compare Overall Survival of UV1 vaccination in combination with nivolumab and ipilimumab to that of nivolumab and ipilimumab . |
| ORR Per RECIST 1.1 | Number of complete and partial responses during the study, approximately 44 months. | Compare the objective response rate (ORR) of UV1 vaccination in combination with nivolumab and ipilimumab to that of nivolumab and ipilimumab. |
| DOR Per RECIST 1.1 | Time from first CR or PR to PD or death from any cause, approximately 44 months. | Compare duration of response (DOR) of UV1 vaccination in combination with nivolumab and ipilimumab to that of nivolumab and ipilimumab. |
| Evaluation of Adverse Events, Vital Signs, Laboratory Assessments and ECOG Performance Status | Time from randomization to end of study, approximately 47 months. | Compare the safety of UV1 vaccination in combination with nivolumab and ipilimumab to that of nivolumab and ipilimumab. Safety will be listed and summarized descriptively by treatment arm comparing number of participants with observation and changes from baseline and at each visit related to AEs, deaths, vital signs (weight (kg), systolic and diastolic blood pressure (mmHg), pulse rate (bpm), body temperature (°C)), laboratory assessments and ECOG performance status (Grade 0 - Grade 5). |
Other
| Measure | Time frame | Description |
|---|---|---|
| Immunological Mechanisms | Time from randomization to end of study to readout of primary objectives, approximately 44 months. | To elucidate the immunological mechanisms underlying the interplay between immune activation provoked by UV1 vaccination and inhibition of tumor resistance mechanisms and peripheral immune tolerance induced by checkpoint blockade and how biological factors affect the efficacy of the combination therapy. This will be evaluated by change in immune- and tumor-related gene, cell, and protein profiles in blood over time in both treatment arms (analysis of plasma proteins, cell-free plasma DNA, and cellular genomic DNA). |
Countries
Belgium, Norway, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| UV1 Vaccination + Nivolumab and Ipilimumab UV1 vaccination + nivolumab and ipilimumab
UV1 vaccination includes sargramostim (75 μg), used as a vaccine adjuvant, and the UV1 vaccine (300 μg). Both injected intradermally.
Ipilimumab: Ipilimumab is dosed according to label.
Nivolumab: Nivolumab is dosed according to label. | 78 |
| Nivolumab and Ipilimumab nivolumab and ipilimumab
Ipilimumab: Ipilimumab is dosed according to label.
Nivolumab: Nivolumab is dosed according to label. | 78 |
| Total | 156 |
Baseline characteristics
| Characteristic | Total | UV1 Vaccination + Nivolumab and Ipilimumab | Nivolumab and Ipilimumab |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 61 Participants | 38 Participants | 23 Participants |
| Age, Categorical Between 18 and 65 years | 95 Participants | 40 Participants | 55 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) White | 151 Participants | 75 Participants | 76 Participants |
| Region of Enrollment Belgium | 28 participants | 17 participants | 11 participants |
| Region of Enrollment Norway | 27 participants | 11 participants | 16 participants |
| Region of Enrollment United Kingdom | 38 participants | 21 participants | 17 participants |
| Region of Enrollment United States | 63 participants | 29 participants | 34 participants |
| Sex: Female, Male Female | 54 Participants | 25 Participants | 29 Participants |
| Sex: Female, Male Male | 102 Participants | 53 Participants | 49 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 22 / 76 | 17 / 78 |
| other Total, other adverse events | 76 / 76 | 78 / 78 |
| serious Total, serious adverse events | 40 / 76 | 43 / 78 |
Outcome results
Primary
PFS Per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 (by Blinded Independent Central Review (BICR)
Compare progression free survival (PFS) of UV1 vaccination in combination with nivolumab and ipilimumab to that of nivolumab and ipilimumab
Time frame: Time from randomization to progressive disease (PD) or death from any cause (approximately 44 months)
Population: Intention To Treat population (IIT)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| UV1 Vaccination + Nivolumab and Ipilimumab | PFS Per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 (by Blinded Independent Central Review (BICR) | 35 Participants |
| Nivolumab and Ipilimumab | PFS Per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 (by Blinded Independent Central Review (BICR) | 34 Participants |
p-value: 0.84580% CI: [0.694, 1.309]Regression, Cox
Secondary
DOR Per RECIST 1.1
Compare duration of response (DOR) of UV1 vaccination in combination with nivolumab and ipilimumab to that of nivolumab and ipilimumab.
Time frame: Time from first CR or PR to PD or death from any cause, approximately 44 months.
Secondary
Evaluation of Adverse Events, Vital Signs, Laboratory Assessments and ECOG Performance Status
Compare the safety of UV1 vaccination in combination with nivolumab and ipilimumab to that of nivolumab and ipilimumab. Safety will be listed and summarized descriptively by treatment arm comparing number of participants with observation and changes from baseline and at each visit related to AEs, deaths, vital signs (weight (kg), systolic and diastolic blood pressure (mmHg), pulse rate (bpm), body temperature (°C)), laboratory assessments and ECOG performance status (Grade 0 - Grade 5).
Time frame: Time from randomization to end of study, approximately 47 months.
Secondary
ORR Per RECIST 1.1
Compare the objective response rate (ORR) of UV1 vaccination in combination with nivolumab and ipilimumab to that of nivolumab and ipilimumab.
Time frame: Number of complete and partial responses during the study, approximately 44 months.
Secondary
Overall Survival
Compare Overall Survival of UV1 vaccination in combination with nivolumab and ipilimumab to that of nivolumab and ipilimumab .
Time frame: Time from randomization to death from any cause /follow-up until 70 PFS events/18 months post rand, approximately 44 months.
Other Pre-specified
Immunological Mechanisms
To elucidate the immunological mechanisms underlying the interplay between immune activation provoked by UV1 vaccination and inhibition of tumor resistance mechanisms and peripheral immune tolerance induced by checkpoint blockade and how biological factors affect the efficacy of the combination therapy. This will be evaluated by change in immune- and tumor-related gene, cell, and protein profiles in blood over time in both treatment arms (analysis of plasma proteins, cell-free plasma DNA, and cellular genomic DNA).
Time frame: Time from randomization to end of study to readout of primary objectives, approximately 44 months.