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Polarized Dendritic Cell (aDC1) Vaccine, Interferon Alpha-2, Rintalolimid, and Celecoxib for the Treatment of HLA-A2+ Refractory Melanoma

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ClinicalTrials.gov Identifier: NCT04093323
Recruitment Status : Not yet recruiting
First Posted : September 18, 2019
Last Update Posted : October 24, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Roswell Park Cancer Institute

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
HLA-A2 Positive Cells Present Refractory Melanoma Biological: Alpha-type-1 Polarized Dendritic Cells Drug: Celecoxib Drug: PD-1 Ligand Inhibitor Drug: PD1 Inhibitor Biological: Recombinant Interferon Alfa-2b Drug: Rintatolimod Phase 2

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 24 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Estimated Study Start Date : December 1, 2019
Estimated Primary Completion Date : May 2, 2022
Estimated Study Completion Date : May 2, 2023


Arm Intervention/treatment
Experimental: Treatment (IFNA2, rintatolimod, celecoxib, alphaDC1 vaccine)
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.
Biological: Alpha-type-1 Polarized Dendritic Cells
Given ID
Other Name: alphaDC1

Drug: Celecoxib
Given PO
Other Names:
  • Benzenesulfonamide, 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-
  • Celebrex
  • SC-58635
  • YM 177

Drug: PD-1 Ligand Inhibitor
Given IV
Other Name: PD-1 Ligands Inhibitor

Drug: PD1 Inhibitor
Given IV
Other Names:
  • PD-1 Inhibitor
  • Programmed Cell Death Protein 1 Inhibitor
  • Protein PD-1 Inhibitor

Biological: Recombinant Interferon Alfa-2b
Given IV
Other Names:
  • Alfatronol
  • Glucoferon
  • Heberon Alfa
  • IFN alpha-2B
  • Interferon alfa 2b
  • Interferon Alfa-2B
  • Interferon Alpha-2b
  • Intron A
  • Sch 30500
  • Urifron
  • Viraferon

Drug: Rintatolimod
Given IV
Other Names:
  • Ampligen
  • Atvogen




Primary Outcome Measures :
  1. Objective response rate (ORR) [ Time Frame: At 12 weeks ]
    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 :
  1. ORR [ Time Frame: At 6 months ]
    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.

  2. Durable objective response rate (>= 6 months) [ Time Frame: From time of first confirmed response assessed up to 2 years ]
    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.


Other Outcome Measures:
  1. Immune-related progressive free survival [ Time Frame: Up to 2 years ]
    Will be evaluated using iRECIST criteria. Will be compared to the historical control of the best supportive care and to identify the intratumoral and systemic immune correlates of the response to treatment. Will be analyzed by a Cox regression model as a function of various biomarker combinations.

  2. Overall survival [ Time Frame: Up to 2 years ]
    Will be compared to the historical control of the best supportive care and to identify the intratumoral and systemic immune correlates of the response to treatment. Will be analyzed by a Cox regression model as a function of various biomarker combinations.

  3. Change in density of CD8 positive cytotoxic T cells [ Time Frame: Baseline up to week 11 ]
    Will be evaluated using the OmniSeq immune report card (IRC). Will be analyzed by a Cox regression model as a function of various biomarker combinations.

  4. Change in density of molecular biomarkers [ Time Frame: Baseline up to week 11 ]
    Will be evaluated using the OmniSeq IRC. Will be analyzed by a Cox regression model as a function of various biomarker combinations.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04093323


Locations
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United States, New York
Roswell Park Cancer Institute Not yet recruiting
Buffalo, New York, United States, 14263
Contact: Igor Puzanov    716-845-2300 ext 7505    Igor.Puzanov@roswellpark.org   
Principal Investigator: Igor Puzanov         
Sponsors and Collaborators
Roswell Park Cancer Institute
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Igor Puzanov Roswell Park Cancer Institute

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Responsible Party: Roswell Park Cancer Institute
ClinicalTrials.gov Identifier: NCT04093323     History of Changes
Other Study ID Numbers: I 82419
NCI-2019-05911 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
I 82419 ( Other Identifier: Roswell Park Cancer Institute )
P30CA016056 ( U.S. NIH Grant/Contract )
First Posted: September 18, 2019    Key Record Dates
Last Update Posted: October 24, 2019
Last Verified: October 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Additional relevant MeSH terms:
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Melanoma
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas
Interferons
Interferon-alpha
Interferon alpha-2
poly(I).poly(c12,U)
Poly I-C
Celecoxib
Vaccines
Benzenesulfonamide
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Anti-Inflammatory Agents
Antirheumatic Agents
Cyclooxygenase 2 Inhibitors
Cyclooxygenase Inhibitors