Clinical Trials /

Dendritic Cell Vaccines Against Her2/Her3, Cytokine Modulation Regimen, and Pembrolizumab for the Treatment of Brain Metastasis From Triple Negative Breast Cancer or HER2+ Breast Cancer

NCT04348747

Description:

This phase IIa trial studies how well dendritic cell vaccines against Her2/Her3, cytokine modulation (CKM) regimen, and pembrolizumab work for the treatment of triple negative breast cancer or HER2+ breast cancer that has spread to the brain (brain metastasis). Dendritic cell vaccines work by boosting the immune system (a system in the body that protect against infection) to recognize and destroy the cancer cells. CKM regimen, consisting of rintatolimod, interferon alpha-2b and celecoxib, attempt to direct the immune cells to the cancer cells and maximize the effectiveness of pembrolizumab. Pembrolizumab is an "immune checkpoint inhibitor" which is designed to either "unleash" or "enhance" the cancer immune responses that already exist by either blocking inhibitory molecules" or by activating stimulatory molecules. Giving dendritic cell vaccines, CKM regimen, and pembrolizumab may shrink the cancer.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Dendritic Cell Vaccines Against Her2/Her3, Cytokine Modulation Regimen, and Pembrolizumab for the Treatment of Brain Metastasis From Triple Negative Breast Cancer or HER2+ Breast Cancer
  • Official Title: A Phase IIa Study of Dendritic Cell Vaccines Against Her2/Her3, Cytokine Modulation (CKM) Regime and Pembrolizumab in Patients With Asymptomatic Brain Metastasis From Triple Negative Breast Cancer (TNBC) or HER2+ Breast Cancer (HER2+BC)

Clinical Trial IDs

  • ORG STUDY ID: I-19-04120
  • SECONDARY ID: NCI-2020-01520
  • SECONDARY ID: I-19-04120
  • SECONDARY ID: P30CA016056
  • NCT ID: NCT04348747

Conditions

  • Anatomic Stage IV Breast Cancer AJCC v8
  • Metastatic Malignant Neoplasm in the Brain
  • Metastatic Triple-Negative Breast Carcinoma
  • Prognostic Stage IV Breast Cancer AJCC v8

Interventions

DrugSynonymsArms
Anti-HER2/HER3 Dendritic Cell VaccineAnti-HER2/3 DC Vaccine, Anti-HER2/3 Dendritic Cell VaccineTreatment (anti-HER2/3 dendritic cell vaccine)
CelecoxibBenzenesulfonamide, 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-, Celebrex, SC-58635, YM 177Treatment (anti-HER2/3 dendritic cell vaccine)
PembrolizumabKeytruda, Lambrolizumab, MK-3475, SCH 900475Treatment (anti-HER2/3 dendritic cell vaccine)
Recombinant Interferon Alfa-2bAlfatronol, Glucoferon, Heberon Alfa, IFN alpha-2B, Interferon alfa 2b, INTERFERON ALFA-2B, Interferon Alpha-2b, Intron A, Sch 30500, Urifron, ViraferonTreatment (anti-HER2/3 dendritic cell vaccine)
RintatolimodAmpligen, AtvogenTreatment (anti-HER2/3 dendritic cell vaccine)

Purpose

This phase IIa trial studies how well dendritic cell vaccines against Her2/Her3, cytokine modulation (CKM) regimen, and pembrolizumab work for the treatment of triple negative breast cancer or HER2+ breast cancer that has spread to the brain (brain metastasis). Dendritic cell vaccines work by boosting the immune system (a system in the body that protect against infection) to recognize and destroy the cancer cells. CKM regimen, consisting of rintatolimod, interferon alpha-2b and celecoxib, attempt to direct the immune cells to the cancer cells and maximize the effectiveness of pembrolizumab. Pembrolizumab is an "immune checkpoint inhibitor" which is designed to either "unleash" or "enhance" the cancer immune responses that already exist by either blocking inhibitory molecules" or by activating stimulatory molecules. Giving dendritic cell vaccines, CKM regimen, and pembrolizumab may shrink the cancer.

Detailed Description

      PRIMARY OBJECTIVE:

      I. The best overall central nervous system (CNS) response as per Response Assessment in
      Neuro-Oncology Brain Metastases (RANO-BM).

      SECONDARY OBJECTIVES:

      I. Volumetric quantification of brain metastases. II. The non-CNS (i.e. of systemic disease)
      response rate as per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.

      III. The median CNS, non-CNS and overall progression free survival (PFS). IV. The median
      overall survival (OS). V. The safety of this regimen. VI. The proportion of patients not
      requiring retreatment for their brain metastasis at 6 months since the first dose of
      anti-HER2/3 vaccine.

      VII. Rate of failure of irradiated lesions.

      EXPLORATORY OBJECTIVE:

      I. To evaluate baseline and post-treatment molecular biomarkers (including PD-L1) in
      peripheral tumor tissue and peripheral blood, and correlate with treatment response.

      OUTLINE:

      TREATMENT PHASE: Patients receive anti-HER2/HER3 dendritic cell vaccine intradermally (ID) on
      days 1, 15, and 29. Patients also receive celecoxib orally (PO) twice daily (BID),
      recombinant interferon alfa-2b IV over 20 minutes, and rintatolimod IV on days 15-17 and
      29-31.

      MAINTENANCE PHASE: Patients receive pembrolizumab IV over 30 minutes on day 1. Cycles repeat
      every 21 days for 2 years in the absence of disease progression or unacceptable toxicity.
      Patients may also receive a booster dose of anti-HER2/HER3 dendritic cell vaccine ID,
      celecoxib PO BID, recombinant interferon alfa-2b IV over 20 minutes, and rintatolimod IV
      every 3 months in the opinion of principal investigator.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (anti-HER2/3 dendritic cell vaccine)ExperimentalTREATMENT PHASE: Patients receive anti-HER2/HER3 dendritic cell vaccine ID on days 1, 15, and 29. Patients also receive celecoxib PO BID, recombinant interferon alfa-2b IV over 20 minutes, and rintatolimod IV on days 15-17 and 29-31. MAINTENANCE PHASE: Patients receive pembrolizumab IV over 30 minutes on day 1. Cycles repeat every 21 days for 2 years in the absence of disease progression or unacceptable toxicity. Patients may also receive a booster dose of anti-HER2/3 dendritic cell vaccine ID, celecoxib PO BID, recombinant interferon alfa-2b IV over 20 minutes, and rintatolimod IV every 3 months in the opinion of principal investigator.
  • Anti-HER2/HER3 Dendritic Cell Vaccine
  • Celecoxib
  • Pembrolizumab
  • Recombinant Interferon Alfa-2b
  • Rintatolimod

Eligibility Criteria

        Inclusion Criteria:

          -  Histologically or cytologically confirmed diagnosis of triple negative breast cancer
             (TNBC) (estrogen receptor [ER] =< 1%, progesterone receptor [PR] =< 1% HER2 negative)
             as per guidelines below or HER2 positive (as below). HER2 testing guidelines (as per
             the American Society of Clinical Oncology/College of American Pathologists [ASCO/CAP]
             guidelines for HER2 testing):

               -  HER2 testing should be performed on the invasive component using a validated
                  immunohistochemistry (IHC) or in situ hybridization (ISH) assay

               -  IHC staining is defined as:

                    -  IHC 3+ if there is complete and intense circumferential membrane staining
                       within > 10 percent of tumor cells. All IHC 3+ tumors are considered HER2
                       positive

                    -  IHC 2+ if there is incomplete and/or weak/moderate, circumferential membrane
                       staining within > 10 percent of tumor cells. All IHC 2+ tumors are reported
                       as HER2 equivocal

                    -  IHC 1+ if there is faint or barely perceptible, incomplete membrane staining
                       within > 10 percent of tumor cells. All IHC 1+ tumors are reported as HER2
                       negative

                    -  IHC 0 if (1) no staining is observed, or (2) there is faint or barely
                       perceptible, incomplete membrane staining within < 10 percent of tumor
                       cells. All IHC 0 tumors are reported as HER2 negative

                    -  Equivocal HER2 testing should trigger reflex HER2 testing using ISH on the
                       same specimen or a new test (using a different specimen with either IHC or
                       ISH)

               -  Results from ISH are defined as the ratio of gene amplification of HER2 and the
                  chromosome 17 enumeration probe (CEP17). Results are reported as:

                    -  ISH positive if the HER2/CEP17 ratio is >= 2.0, and the HER2 copy number
                       signals/cell is >= 4

                    -  Definitive diagnosis will be rendered pending further workup in the
                       following instances:

                         -  If the HER2/CEP17 ratio is >= 2.0 and an average HER2 copy number is <
                            4.0 signals/cell - negative if confirmed on retesting

                         -  If the HER2/CEP17 ratio is < 2.0 and the average HER2 copy number is >=
                            6.0 signals/cell positive - if confirmed on retesting

                         -  If the HER2/CEP17 ratio is < 2.0 and an average HER2 copy number is
                            between >= 4.0 and < 6.0 signals/cell negative - if confirmed on
                            retesting

                    -  ISH negative if the HER2/CEP17 ratio is < 2.0 and average HER2 copy number
                       is < 4.0 signals/cell

          -  Measurable brain disease as per RANO-BM criteria. Have at least one untreated brain
             metastasis approved by a research team that meets the following size requirements:

               -  >= 0.5 cm AND twice the magnetic resonance imaging (MRI) slice thickness; and

               -  < 3.0 cm, that is asymptomatic and does not require local therapy at the time of
                  enrollment (i.e. target lesion[s])

               -  Of note, lesions >= 0.5 cm and < 3 cm may be determined ineligible by the
                  research team because of location or symptoms. An untreated brain metastasis is
                  defined as a lesion not present at the time of whole brain radiation therapy or
                  not included in a stereotactic radiotherapy field (or within 0.2 cm of a treated
                  lesion), or any lesion that is new or unequivocally progressing since prior
                  radiation therapy or prior surgery. If >= 0.5 cm is used, then the MRI imaging
                  should have a 1.5 mm slice thickness or less must be used. If thicker slices are
                  used, then the size of the measurable lesion at baseline should be at least
                  double the size of the slice thickness

          -  Any brain metastasis >= 3.0 cm or causing symptoms must have previously been treated
             with local therapy (i.e. radiation or surgical resection, as clinically appropriate)
             prior to study enrollment. Any lesion present at the time of whole brain radiation
             therapy (WBRT) or included in the stereotactic radiotherapy field (or within 2 mm of
             the treated lesion) will NOT be considered evaluable unless it is new or documented to
             have progressed since treatment

          -  Stereotactic radiosurgery (SRS) is permitted on the day of enrollment (leaving one or
             more lesions which are not radiated and will be used as target lesions) but a follow
             up brain MRI should be obtained prior to dendritic cell (DC) vaccine to determine
             stability of the lesions. An interval of at least 4 weeks after the end of whole brain
             radiation, any surgical resection of brain lesions; or the last cytotoxic, targeted,
             immunotherapeutic or investigational agent

               -  Previous whole brain radiation is allowed if patient has been diagnosed with
                  recurrent, progressive brain metastasis. Previously irradiated lesions would be
                  considered non-target lesions

               -  Previously resected lesions or those treated with SRS would be considered
                  nontarget lesions

          -  Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

          -  Women of childbearing potential must agree to use acceptable birth control methods for
             the duration of the study and until persistence of the study drug is no longer
             detected in the peripheral blood: This may be a period of several years. Methods for
             acceptable birth control include: condoms, diaphragm or cervical cap with spermicide,
             intrauterine device, and hormonal contraception. It is recommended that a combination
             of two methods be used. NOTE: If the risk of conception exists, both males and females
             must agree to use highly effective contraception throughout the study and for at least
             30 days after last treatment administration

          -  Hemoglobin >= 9 g/dL or >= 5.6 mmol/L

          -  Leukocytes: >= 3 x 10^9/L

          -  Absolute neutrophil count: >= 1.5 x 10^9/L

          -  Platelets: >= 100 x 10^9/L

          -  Total bilirubin: =< 1.5 x upper limit of normal (ULN) OR direct bilirubin =< ULN for
             participants with total bilirubin levels > 1.5 x ULN

          -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
             [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]):
             =< 2.5 x institutional upper limit of normal (=< 5 x ULN for participants with liver
             metastases)

          -  Creatinine level =< ULN or, creatinine clearance >= 50 mL/min per Cockcroft-Gault
             Equation for patients with creatinine levels greater than ULN

          -  International normalized ratio (INR) OR prothrombin time (PT) activated partial
             thromboplastin time (APTT) =< 1.5 x ULN unless participant is receiving anticoagulant
             therapy as long as PT or aPTT is within therapeutic range of intended use of
             anticoagulants

          -  Negative serum or urine pregnancy test at screening for women of childbearing
             potential: must be repeated once-monthly during treatment

          -  No evidence of leptomeningeal disease

          -  If patient is currently on steroids, they must be on a steroid dose less than or equal
             to an equivalent prednisone dose of 10 mg daily

          -  Life expectancy of > 3 months

          -  Prior checkpoint inhibitors permitted 3 weeks prior to enrollment

          -  If the disease has progressed in the CNS, patients may continue Her 2 directed
             antibody treatment (trastuzumab and pertuzumab); aromatase inhibitor/ tamoxifen while
             on the study

          -  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

        Exclusion Criteria:

          -  Any condition which in the Investigator's opinion deems the participant an unsuitable
             candidate for the study

          -  Symptomatic brain metastases. Any neurologic symptoms present must have resolved with
             local therapy by the time of administration of study drugs

          -  Patients may not be receiving any other investigational agents and may not have
             participated in a study of an investigational agent or using an investigational device
             within 4 weeks of the first dose of treatment

          -  Has had prior chemotherapy or targeted small molecule therapy within 2 weeks prior to
             start of treatment or who has not recovered (i.e., =< grade 1 or at baseline) from
             adverse events due to a previously administered agent. Previous radiation to
             extracranial sites may be completed at any time prior to initiation of study drugs

               -  Note:

                    -  If subject received major surgery, they must have recovered adequately from
                       the toxicity and/or complications from the intervention prior to starting
                       therapy

                    -  Toxicity that has not recovered to =< grade 1 is allowed if it meets the
                       inclusion requirements for laboratory parameters

          -  Rapidly progressing systemic disease which might interfere with completion of all the
             vaccine doses

          -  Patients with active autoimmune disease that has required systemic treatment in the
             past 2 years (i.e. with use of disease modifying agents, corticosteroids or
             immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or
             physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency,
             etc.) is not considered a form of systemic treatment

          -  Patients with history of organ transplantation

          -  Has an active infection requiring systemic therapy which in the investigator's opinion
             will increase risk to the patient

          -  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 received a blood transfusion in the two weeks prior to leukapheresis

          -  Pregnant or actively nursing (females who agree to stop nursing would be eligible)
             female participants

          -  Unwilling or unable to follow protocol requirements

          -  Patients with known serious mood disorders. (Major depression diagnosis is an
             exclusionary criterion: Other stable mood disorders on stable therapy for > 6 months
             or not requiring therapy may be allowed after consultation with principal investigator
             [PI])

          -  Cardiac risk factors including: Patients experiencing cardiac event(s) (acute coronary
             syndrome, myocardial infarction, or ischemia) within 6 months of signing consent,
             Patients with a New York Heart Association classification of III or IV

          -  History of upper gastrointestinal ulceration, upper gastrointestinal bleeding,
             abdominal or tracheoesophageal fistula or gastrointestinal perforation within 6 months
             prior to cycle 1, day 1

          -  Prior allergic reaction or hypersensitivity to non-steroidal anti-inflammatory drugs
             (NSAIDs) or any drugs administered on protocol

          -  Patients are ineligible if they plan on regular use of NSAIDs at any dose more than 2
             times per week (on average) or aspirin at more than 325 mg at least three times per
             week, on average. Low-dose aspirin not exceeding 100 mg/day is permitted. Patients who
             agree to stop regular NSAIDs or higher dose aspirin are eligible and no wash out
             period is required

          -  Untreated brain lesion size >= 3 cm or with significant midline shift or obstructive
             hydrocephalus

          -  The use of corticosteroids to control cerebral edema or treat neurologic symptoms will
             not be allowed unless at a low dose, not to exceed 10 mg of prednisone (or equivalent)
             per day

          -  History of stroke or transient ischemic attack within 6 months prior to cycle 1, day 1

          -  Has a history of (non-infectious) pneumonitis that required steroids, current
             pneumonitis or evidence of interstitial lung disease

          -  Presence of leptomeningeal disease

          -  Any contraindication to MRI (i.e. patients with pacemakers or other metal implanted
             medical devices). An MRI safety questionnaire is required prior to MR imaging

          -  Has received prior radiotherapy within 2 weeks of start of study treatment with
             dendritic cell (DC) vaccine. SBRT is allowed at the time of enrollment to the study.
             Participants must have recovered from all radiation-related toxicities, not require
             corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted
             for palliative radiation (=< 2 weeks of radiotherapy) to non-CNS disease

          -  Has received a live vaccine within 30 days prior to the first dose of study drug.
             Examples of live vaccines include, but are not limited to, the following: measles,
             mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, bacillus
             Calmette-Guerin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection
             are generally killed virus vaccines and are allowed; however, intranasal influenza
             vaccines (e.g., FluMist) are live attenuated vaccines and are not allowed

          -  Receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of
             prednisone equivalent) or any other form of immunosuppressive therapy within 7 days
             prior to the first dose of study drug

          -  Has a known additional malignancy that is progressing or has required active treatment
             within the past 3 years. Note: Participants with basal cell carcinoma of the skin,
             squamous cell carcinoma of the skin, or carcinoma in situ (e.g. breast carcinoma,
             cervical cancer in situ) that have undergone potentially curative therapy are not
             excluded
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Central nervous system (CNS) objective response rate (ORR)
Time Frame:Up to 2 years
Safety Issue:
Description:Assessed per Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) working group. Will be summarized using frequencies and relative frequencies. A 90% confidence interval about the true ORR will be obtained using Jeffrey's prior method.

Secondary Outcome Measures

Measure:Volumetric quantification of brain metastases
Time Frame:Up to 2 years
Safety Issue:
Description:
Measure:Non-CNS (i.e. of systemic disease) response rate
Time Frame:Up to 2 years
Safety Issue:
Description:Assessed per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.
Measure:Median CNS progression free survival (PFS)
Time Frame:Up to 2 years
Safety Issue:
Description:Will be summarized using frequencies and relative frequencies. A 90% confidence interval about the true response rate will be obtained using Jeffrey's prior method.
Measure:Non-CNS PFS
Time Frame:Up to 2 years
Safety Issue:
Description:Will be summarized using frequencies and relative frequencies. A 90% confidence interval about the true response rate will be obtained using Jeffrey's prior method.
Measure:Overall PFS
Time Frame:Up to 2 years
Safety Issue:
Description:Will be summarized using frequencies and relative frequencies. A 90% confidence interval about the true response rate will be obtained using Jeffrey's prior method.
Measure:Proportion of patients who have a CNS PFS
Time Frame:At 6 months
Safety Issue:
Description:
Measure:Median overall survival (OS)
Time Frame:Up to 2 years
Safety Issue:
Description:
Measure:Incidence of adverse events
Time Frame:Up to 2 years
Safety Issue:
Description:Safety of the regimen characterized by type, frequency, severity (according to Common Terminology Criteria for Adverse Events [CTCAE] version 5.0), timing, seriousness and relationship to study treatment. All toxicities and adverse events will be summarized by grade using frequencies and relative frequencies.
Measure:Proportion of patients not requiring retreatment for their brain metastasis at 6 months since the first dose of anti-HER2/3 vaccine
Time Frame:At 6 months
Safety Issue:
Description:Will be summarized using standard Kaplan-Meier methods. Estimates of the median time and 6-month rates will be obtained with 90% confidence intervals.
Measure:Rate of failure of irradiated lesions
Time Frame:Up to 2 years
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Roswell Park Cancer Institute

Last Updated

April 13, 2020