Conditions: Stage IV Melanoma Metastatic Melanoma
Keywords: Stage IV metastatic melanoma
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 47
Healthy volunteers: no

Brief summary:
The purpose of this study is to examine the effectiveness of immune checkpoint inhibitors (drugs called ipilimumab, nivolumab, or pembrolizumab), either given alone, or in combination with the experimental immunotherapy drug, dorgenmeltucel-L, for melanoma. We hypothesize that this form of combinatorial immunotherapy will result in tumor stabilization or shrinkage, significant prolongation of progression-free, disease-free or overall survival compared to the use of immune checkpoint inhibitors alone.

Detailed description:
According to statistics of the American Cancer Society, an estimated 73,800 individuals will be diagnosed with melanoma and 9,900 will die of the disease in 2015 in the Unites States despite current therapy. This protocol attempts to exploit an approach to melanoma immunotherapy using a naturally occurring barrier to xenotransplantation in humans to increase the effectiveness of immunizing patients against their melanoma. The expression of the murine (1,3)galactosyltransferase \[alpha(1,3)GT\] gene results in the cell surface expression of (1,3)galactosyl-epitopes (alpha-gal) on membrane glycoproteins and glycolipids. These epitopes are the major target of the hyperacute rejection response that occurs when organs are transplanted from non-primate donor species into man. Human hosts often have pre-existing anti-alpha-gal antibodies that bind alpha-gal epitopes and lead to rapid activation of complement and cell lysis. The pre-existing anti-alpha-gal antibodies found in most individuals are thought to be due to exposure to alpha-gal epitopes that are naturally expressed on normal gut flora leading to chronic immunological stimulation.

These antibodies may comprise up to 1% of serum IgG. In this phase 2b study, patients with advanced stage melanoma will receive immune checkpoint inhibition consisting of ipilimumab, nivolumab, or pembrolizumab per the treating physician's standard of care. In addition to the immune checkpoint therapy, half of the patients will also receive dorgenmeltucel-L. Dorgenmeltucel-L is composed of irradiated allogeneic melanoma cell lines (HAM-1, HAM-2 and HAM-3). These cell lines have been transduced with a recombinant Moloney murine leukemia virus (MoMLV)-based retroviral vector expressing the murine (1,3)GT gene. Endpoints of the study include safety assessments, efficacy, and immunological responses.

Arms:
arm 1: Arm 1A will receive ipilimumab at 3 mg/kg given every 3 weeks for 4 weeks and 300 Million HyperAcute®-Melanoma (HAM) Immunotherapy cells per each immunization, given every week for 4 weeks, every 2 weeks for 5 months, every month for 6 months, and every 3 months for one year. arm 2: Arm 2A will receive ipilimumab alone at 3 mg/kg every 3 weeks for a total of four doses. arm 3: Arm 1B will receive nivolumab alone at 3 mg/kg given every 2 weeks and 300 Million HyperAcute®-Melanoma (HAM) Immunotherapy cells per each immunization, given every week for 4 weeks, every 2 weeks for 5 months, every month for 6 months, and every 3 months for one year. arm 4: Arm 2B will receive nivolumab alone at 3 mg/kg given every 2 weeks arm 5: Arm 1C will receive pembrolizumab at 2 mg/kg given every 3 weeks and 300 Million HyperAcute®-Melanoma (HAM) Immunotherapy cells per each immunization, given every week for 4 weeks, every 2 weeks for 5 months, every month for 6 months, and every 3 months for one year. arm 6: Arm 2C will receive pembrolizumab at 2 mg/kg given every 3 weeks

Interventions: intervention 1: HyperAcute®-Melanoma (HAM) Immunotherapy intervention 2: Ipilimumab intervention 3: Pembrolizumab intervention 4: Nivolumab
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None

Protocol document:
Prot_SAP_000.pdf: 
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7
8
9
10
11
12
15
18
21
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DAY
1
8
15
22
29
36
43
50
57
64
71
78
85
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Ͳ
Ͳ
Ͳ
Ͳ
Ͳ
Ͳ
Ͳ
Ͳ
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HAMInjections
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
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X
X
X
X
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X
Demographics
X
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X
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X
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X
X
X
X
X
X
X
X
X
Vitalsigns
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Height
X
Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
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X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
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CBCw/diff,plts
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serumchemistry
(withLDH)
B
B
B
B
B
B
B
B
B
B
B
B
B
B
B
B
B
B
B
bͲHCG
C
TSHandFreeT4
X
X
X
X
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E
E
E
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E
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F
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Assays(Tcells)
H
H
H
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H
H
H
H
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Ab
I
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I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
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J
J
J
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(RECIST/iRRC)
evaluation
X
X
X
X
X
X
X
X
X
X
AE/SAEEvaluation
ͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲCompleteperSOCͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲ
ͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲEvaluatethroughoutStudyandFollowUpPerProtocolͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲ
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PreͲ Wk Wk Wk Wk Wk Wk Wk Wk Wk Wk Wk Wk Wk Wk Wk Wk Wk Wk Wk Mo Mo Mo Mo Mo Mo Mo Mo Mo Mo
Study
1
2
3
4
5
6
7
8
9
10
11
12
13
14
16
18
20
22
24
7
8
9
10
11
12
15
18
21
24
DAY
1
8
15
22
29
36
43
50
57
64
71
78
85
92 106 120 134 148 162
Ͳ
Ͳ
Ͳ
Ͳ
Ͳ
Ͳ
Ͳ
Ͳ
Ͳ
Ͳ
HAMInjections
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
Nivolumab
X
X
X
X
X
X
X
X
X
X
X
Informedconsent
X
Demographics
X
Medicalhistory
X
Concurrentmeds
X
Physicalexam
X
X
X
X
X
X
X
X
Vitalsigns
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Height
X
Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Performancestatus
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CBCw/diff,plts
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serumchemistry
(withLDH)
B
B
B
B
B
B
B
B
B
B
B
B
B
B
B
B
B
B
B
B
B
B
B
bͲHCG
C
TSHandFreeT4
X
X
X
X
X
X
X
IgG,IgM,IgE
E
E
E
E
E
E
RCR
F
BloodforImmune
Assays(Tcells)
H
H
H
H
H
H
H
H
H
BloodforantiͲtumor
Ab
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
OptionalTumor
Biopsy
J
J
J
RadiologicTumor
(RECIST/iRRC)
evaluation
X
X
X
X
X
X
X
X
X
X
AE/SAEEvaluation
EVALUATIONS
ͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲCompleteperSOCͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲ
ͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲEvaluatethroughoutStudyandFollowUpPerProtocolͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲ
ͲͲͲContinueevery2weekswithNivolumabͲͲͲ
ͲͲͲContinueevery2weekswithNivolumabͲͲͲ
ͲͲͲContinueevery2weekswithNivolumabͲͲͲ
ͲͲͲContinueevery2weekswithNivolumabͲͲͲ
ͲͲͲObtainatleastmonthlywithNivolumabͲͲͲ
XͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲX
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PreͲ
Wk Wk Wk Wk Wk Wk Wk Wk Wk Wk Wk Wk Wk Wk Wk Wk Wk Wk Wk Mo Mo Mo Mo Mo Mo Mo Mo Mo Mo
Study
1
2
3
4
5
6
7
8
9
10
11
12
13
14
16
18
20
22
24
7
8
9
10
11
12
15
18
21
24
DAY
1
8
15
22
29
36
43
50
57
64
71
78
85
92 106 120 134 148 162
Ͳ
Ͳ
Ͳ
Ͳ
Ͳ
Ͳ
Ͳ
Ͳ
Ͳ
Ͳ
HAMInjections
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
Pembrolizamub
X
X
X
X
Informedconsent
X
Demographics
X
Medicalhistory
X
Concurrentmeds
X
Physicalexam
X
X
X
X
X
X
X
X
X
Vitalsigns
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Height
X
Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Performancestatus
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CBCw/diff,plts
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serumchemistry
(withLDH)
B
B
B
B
B
B
B
B
B
B
B
B
B
B
B
B
B
B
B
bͲHCG
C
TSHandFreeT4
X
X
X
X
X
X
X
IgG,IgM,IgE
E
E
E
E
E
RCR
F
BloodforImmune
Assays(Tcells)
H
H
H
H
H
H
H
H
H
BloodforantiͲtumor
Ab
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
OptionalTumor
Biopsy
J
J
J
RadiologicTumor
(RECIST/iRRC)
evaluation
X
X
X
X
X
X
X
X
X
X
AE/SAEEvaluation
EVALUATIONS
ͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲCompleteperSOCͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲ
ͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲEvaluatethroughoutStudyandFollowUpPerProtocolͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲ
ͲͲͲͲͲͲͲͲͲͲContinuePembrolizamubevery3weeksͲͲͲͲͲͲͲͲͲͲͲ
ͲͲͲͲObtainatleastmonthlyduringPembrolizamub
XͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲͲX
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