Description:
This phase II trial studies how well polarized dendritic cell (aDC1) vaccine, interferon
alpha-2, rintatolimod, and celecoxib work together in treating patients with HLA-A2 positive
(+) melanoma that has not responded to previous treatment (refractory). The aDC1 vaccine
contains white blood cells (dendritic cells or DCs) that stimulates the immune system.
Interferon alpha-2 can improve the body?s natural response to infections and other diseases.
It can also interfere with the division of cancer cells and slow tumor growth. Rintalolimid
may stimulate the immune system. Celecoxib is a drug that reduces pain. This study is being
done to find out if aDC1 vaccine, interferon alpha-2, rintatolimod, and celecoxib can prevent
the growth and/or progression of melanoma.
Title
- Brief Title: Polarized Dendritic Cell (aDC1) Vaccine, Interferon Alpha-2, Rintatolimod, and Celecoxib for the Treatment of HLA-A2+ Refractory Melanoma
- Official Title: A Phase II Study of Type-1 Polarized Dendritic Cell (aDC1) Vaccine in Combination With Tumor-Selective Chemokine Modulation (CKM: Interferon Alpha 2b, Rintatolimod and Celecoxib) in Melanoma Patients With Primary PD-1/PD-L1 Resistance
Clinical Trial IDs
- ORG STUDY ID:
I 82419
- SECONDARY ID:
NCI-2019-05911
- SECONDARY ID:
I 82419
- SECONDARY ID:
P01CA234212
- NCT ID:
NCT04093323
Conditions
- HLA-A2 Positive Cells Present
- Refractory Melanoma
Interventions
Drug | Synonyms | Arms |
---|
Alpha-type-1 Polarized Dendritic Cells | alphaDC1 | Treatment (IFNA2, rintatolimod, celecoxib, alphaDC1 vaccine) |
Celecoxib | Benzenesulfonamide, 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-, Celebrex, SC-58635, YM 177 | Treatment (IFNA2, rintatolimod, celecoxib, alphaDC1 vaccine) |
PD-1 Ligand Inhibitor | PD-1 Ligands Inhibitor | Treatment (IFNA2, rintatolimod, celecoxib, alphaDC1 vaccine) |
PD1 Inhibitor | PD-1 Inhibitor, Programmed Cell Death Protein 1 Inhibitor, Protein PD-1 Inhibitor | Treatment (IFNA2, rintatolimod, celecoxib, alphaDC1 vaccine) |
Recombinant Interferon Alfa-2b | Alfatronol, Glucoferon, Heberon Alfa, IFN alpha-2B, Interferon alfa 2b, Interferon Alfa-2B, Interferon Alpha-2b, Intron A, Sch 30500, Urifron, Viraferon | Treatment (IFNA2, rintatolimod, celecoxib, alphaDC1 vaccine) |
Rintatolimod | Ampligen, Atvogen | Treatment (IFNA2, rintatolimod, celecoxib, alphaDC1 vaccine) |
Purpose
This phase II trial studies how well polarized dendritic cell (aDC1) vaccine, interferon
alpha-2, rintatolimod, and celecoxib work together in treating patients with HLA-A2 positive
(+) melanoma that has not responded to previous treatment (refractory). The aDC1 vaccine
contains white blood cells (dendritic cells or DCs) that stimulates the immune system.
Interferon alpha-2 can improve the body?s natural response to infections and other diseases.
It can also interfere with the division of cancer cells and slow tumor growth. Rintalolimid
may stimulate the immune system. Celecoxib is a drug that reduces pain. This study is being
done to find out if aDC1 vaccine, interferon alpha-2, rintatolimod, and celecoxib can prevent
the growth and/or progression of melanoma.
Detailed Description
PRIMARY OBJECTIVE:
I. To evaluate the objective response rate to treatment with an autologous alpha-type-1
polarized dendritic cells (alphaDC1)/TBVA vaccine (alpha-type-1-polarized dendritic cells
loaded with tumor blood vessel-targeting antigenic peptides) plus cytokine modulating (CKM)
regimen (rintatolimod, recombinant interferon alpha-2 [IFN-alpha2b] and, celecoxib) in human
leukocyte antigen (HLA)-A2+ subjects with primary PD-1 resistant immuno-oncology
(IO)-refractory melanoma.
SECONDARY OBJECTIVES:
I. To evaluate the immune-related objective response rate (objective response rate [ORR]; per
immune-related Response Evaluation Criteria in Solid Tumors [iRECIST];) in the above patient
population treated with autologous alphaDC1/TBVA vaccine plus cytokine CKM regimen followed
by re-treatment with PD1 blockade (+/- CTLA4 blockade).
II. Evaluate rate of durable responses (> 6 months) on the combination treatment in the above
patient population treated with autologous alphaDC1/TBVA vaccine plus cytokine CKM regimen
followed by re-treatment with PD1 blockade (+/- CTLA4 blockade).
EXPLORATORY OBJECTIVES:
I. Examine whether the combination of peptide-loaded autologous alphaDC1 vaccines and
tumor-selective chemokine modulation (CKM: IFN-a2b, rintatolimod, and celecoxib) improves the
overall survival (OS) and immune-related progression-free survival (iPFS) in HLA-A2+ subjects
PD-1/PD-L1-refractory melanoma compared to the historical control of the best supportive
care.
II. Identify the intratumoral and systemic immune correlates of the response to treatment.
OUTLINE:
Patients receive recombinant interferon alpha-2 intravenously (IV) over 30 minutes,
rintatolimod IV over 2.5 hours, and celecoxib orally (PO) twice daily (BID) on days 1-3.
Beginning cycle 2, patients also receive alpha-type-1 polarized dendritic cells intradermally
(ID) on day 1. Treatment repeats every 3 weeks up to 4 cycles in the absence of disease
progression or unacceptable toxicity. At 12 weeks, patients with progressive disease may
switch to ipilimumab with or without a PD-1/PD-L1 inhibitor and patients with a complete
response (CR), partial response (PR), or stable disease (SD) may switch to a PD-1/PD-L1
inhibitor or best alternative care.
After completion of study treatment, patients are followed up every 3 months for up to 2
years.
Trial Arms
Name | Type | Description | Interventions |
---|
Treatment (IFNA2, rintatolimod, celecoxib, alphaDC1 vaccine) | Experimental | Patients receive recombinant interferon alpha-2 IV over 30 minutes, rintatolimod IV over 2.5 hours, and celecoxib PO BID on days 1-3. Beginning cycle 2, patients also receive alpha-type-1 polarized dendritic cells ID on day 1. Treatment repeats every 3 weeks up to 4 cycles in the absence of disease progression or unacceptable toxicity. At 12 weeks, patients with progressive disease may switch to ipilimumab with or without a PD-1/PD-L1 inhibitor and patients with a complete response CR, PR, or stable disease SD may switch to a PD-1/PD-L1 inhibitor or best alternative care. | - Alpha-type-1 Polarized Dendritic Cells
- Celecoxib
- PD-1 Ligand Inhibitor
- PD1 Inhibitor
- Recombinant Interferon Alfa-2b
- Rintatolimod
|
Eligibility Criteria
Inclusion Criteria:
- Participant must be HLA-A2+. Retesting is not required for patients who have previous
documented positivity
- Have IO-refractory melanoma with primary PD1-resistance. Note: Any lines of prior
therapies are allowed, but the last line needs to include an anti PD-1 or anti PD-L1
agent. The prior treatments may include any standard and/or experimental therapies
- Have >= 1 tumor site amenable to core needle biopsy that is not the site of disease
used to measure antitumor response
- Have measurable disease based on RECIST 1.1 criteria present
- Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
- Platelets >= 75,000/microliter
- Hemoglobin >= 9 g/deciliter
- Absolute neutrophil count (ANC) >= 1500/microliter
- Creatinine < 1.5 x institutional upper limit of normal (ULN) OR creatinine clearance
>= 50 mL/min by Cockcroft-Gault formula for subjects with creatinine levels >= 1.5 x
ULN
- Total bilirubin not greater than 1.5 x institutional ULN, except for patients with
known Gilbert's Syndrome, who are eligible to no more than 2 x institutional ULN
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and
alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) no
greater than 3 x institutional ULN OR, no greater than 5 x ULN for subjects with liver
metastases
- Participants of child-bearing potential must agree to use adequate contraceptive
methods (e.g., hormonal or barrier method of birth control; abstinence) prior to study
entry. Should a woman become pregnant or suspect she is pregnant while she or her
partner is participating in this study, she should inform her treating physician
immediately
- Participant or legal representative must understand the investigational nature of this
study and sign an Independent Ethics Committee/Institutional Review Board approved
written informed consent form prior to receiving any study related procedure
- Candidate for resumption of anti-PD1/PD-L1 or anti-CTLA4 therapy
Exclusion Criteria:
- Is currently being treated with systemic immunosuppressive agents, including steroids:
Subjects will be ineligible until 3 weeks after removal from immunosuppressive
treatments, except when they are administered as replacement therapy for endocrine
dysfunction (and receive no more than 10 mg prednisone or equivalent: inhaled steroids
are allowed)
- Has had prior anti-cancer therapy within 2 weeks prior to study day 1 or who has not
recovered (i.e., no more than grade 1 or at baseline) from adverse events due to a
previously administered agent, except for neuropathy (no more than grade 2) or
alopecia or vitiligo (any grade)
- Has a known additional malignancy that is progressing or requires active treatment
- Has known active central nervous system (CNS) metastases and/or carcinomatous
meningitis. Treated brain metastases are allowed, if stable for more than 4 weeks
- Has a history of cardiac event(s) (acute coronary syndrome, myocardial infarction, or
ischemia (within 3 months of signing consent) or, subject has a New York Heart
Association classification of III or IV
- Has an active infection requiring systemic therapy
- Has known active hepatitis B or hepatitis C infection
- Has known immunosuppressive disease (e.g. human immunodeficiency virus [HIV], acquired
immunodeficiency syndrome [AIDS] or other immune depressing disease). Testing is not
mandatory
- Has known serious hypersensitivity reactions to pegylated (peg)-interferon alpha-2b or
interferon alpha-2b
- Prior allergic reaction or hypersensitivity to sulfonamides, celecoxib, or
nonsteroidal anti-inflammatory drugs (NSAIDs)
- Has received a blood transfusion in the two weeks prior to leukapheresis
- Women of child bearing potential who are pregnant or nursing
- Unwilling or unable to follow protocol requirements
- Any condition which in the Investigator?s opinion deems the participant an unsuitable
candidate or unacceptable risk to receive study drug regimen
- Patients who showed initial response to PD1 blockade and developed secondary
resistance
Maximum Eligible Age: | N/A |
Minimum Eligible Age: | 18 Years |
Eligible Gender: | All |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | Objective response rate (ORR) |
Time Frame: | At 12 weeks |
Safety Issue: | |
Description: | Will be evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Will be carried out by an exact binomial test of a proportion within a Simon two-stage design. |
Secondary Outcome Measures
Measure: | ORR |
Time Frame: | At 6 months |
Safety Issue: | |
Description: | Will be evaluated using immune-related RECIST (iRECIST) criteria in patients that continue on with either PD1 and/or CTLA4 blockade after meeting the 12-week primary objective treated with autologous alpha-type-1 polarized dendritic cells (alphaDC1)/tumor blood vessel-targeting antigenic peptides (TBVA) vaccine plus cytokine modulating (CKM) regimen followed by re-treatment with PD1 blockade (+/- CTLA4 blockade). The analysis will be primarily descriptive and consist of sample proportions and the corresponding 95% confidence intervals. |
Measure: | Durable objective response rate (>= 6 months) |
Time Frame: | From time of first confirmed response assessed up to 2 years |
Safety Issue: | |
Description: | Will be evaluated on patients treated autologous alphaDC1/TBVA vaccine plus cytokine CKM regimen followed by retreatment with PD1 blockade (+/- CTLA4 blockade). The analysis will be primarily descriptive and consist of sample proportions and the corresponding 95% confidence intervals. |
Details
Phase: | Phase 2 |
Primary Purpose: | Interventional |
Overall Status: | Not yet recruiting |
Lead Sponsor: | Roswell Park Cancer Institute |
Last Updated
September 1, 2021