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A Phase I Study of an Adenoviral Transduced Autologous Dendritic Cell Vaccine Expressing Human HER2/Neu ECTM in Adults With Tumors With 1-3+ HER2/Neu Expression


Phase 1
18 Years
N/A
Open (Enrolling)
Both
Breast Neoplasms, Breast Cancer, Adenocarcinomas, Metastatic Solid Tumors Characterized by HER2/Neu Expression

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Trial Information

A Phase I Study of an Adenoviral Transduced Autologous Dendritic Cell Vaccine Expressing Human HER2/Neu ECTM in Adults With Tumors With 1-3+ HER2/Neu Expression


Background:

- Human epidermal growth factor receptor 2 (HER2, also known as c-erbB2 or neu) is a
proto-oncogene that encodes a 185-kd transmembrane (TM) tyrosine kinase receptor that
participates in receptor-receptor interactions that regulate cell growth,
differentiation and proliferation. Its over-expression- either HER2 oncogene
amplification and/or overexpression of the HER2 protein, contributes to neoplastic
transformation.

- HER2 is over-expressed in up to 25-30% of node-positive or node-negative primary breast
cancers and is associated with clinically aggressive breast cancer, a high recurrence
rate and reduced survival.

- Trastuzumab (Herceptin ) is a recombinant humanized mouse monoclonal antibody (MAb)
that binds to the extracellular (EC) domain of the HER2 receptor. Its clinical efficacy
is limited to patients with 3+ HER2 tumor expression documented by immunohistochemistry
(IHC) or a Vysis fluorescent in situ hybridization (FISH) ratio of greater than 2.2.
IHC is a subjective measurement of HER2/neu protein while FISH is an objective
measurement of amplification of the HER2 oncogene.

- Although the use of trastuzumab has been associated with improved clinical outcomes, a
significant number of patients are unresponsive to therapy and most eventually
experience clinical progression. At present no vaccine is available that induces
patients to make their own anti-HER2 antibodies.

- We propose to investigate the use of an adenoviral vector (Ad5f35) expressing human
HER2ECTM (Ad5f35HER2ECTM- AdHER2) to transduce autologous dendritic cells for
therapeutic vaccination in patients with HER2 expressing solid tumors.

Objectives:

Primary:

- To determine the safety and toxicity of autologous AdHER2 dendritic cell vaccination.

- Specifically, to determine if the fraction of patients with cardiac toxicity (if it
occurs) is sufficiently low to warrant further development in subsequent trials.
Cardiac toxicity is defined as a decrease in LVEF greater than or equal to 10% from
baseline or a decrease in absolute LVEF to less than or equal to 50% (equivalent to a
Grade II decrease in LVEF per CTCAE v4.0).

- To determine the immunogenicity of autologous AdHER2 dendritic cell vaccination as
measured by a 3-fold increase in anti-HER2/neu antibody concentration (measured as
mcg/ml) or a 4-fold increase in antibody dilution titers over baseline.

Secondary:

- To determine the preliminary activity of autologous AdHER2 dendritic cell vaccination
as measured by the fraction of subjects who have stable disease, a partial response or
better by immune-related response criteria.

- To determine the impact of autologous AdHER2 dendritic cell vaccination on tumor growth
rate and regression rate constants.

- To characterize vaccine-induced antibody profiles using HER2 peptide microarrays,
examining reactivity to HER2 extracellular (EC), transmembrane (TM) and intracellular
(IC) domains.

- To characterize and measure function-associated mRNAs in whole blood, circulating tumor
cells, other potential biologic/immunologic correlates of clinical response.

Study Design:

Open label, non-randomized, two part, phase I and pilot study of 52 weeks duration for
evaluation of primary endpoints with extended follow-up out to 30 months (124 weeks) to
monitor LVEF cardiac function for 2 years following the last dose of vaccine (delivered at
Week 24) as mandated by the FDA.

Part I involves vaccine dose escalation in a population with no prior exposure to
trastuzumab or other HER2-targeted therapies to determine if there is a significant, adverse
safety signal

regarding cardiac toxicity, in addition to preliminary assessment of the vaccine s
immunogenicity and clinical activity. Four doses of 5, 10 or 20 times 10 exponent 6 viable
cells/AdHER2 DC vaccine will be given intradermally at Weeks 4, 8, 12 and 24 in patients
with metastatic solid tumors and high risk bladder cancer in the adjuvant setting (adjuvant
bladder cancer patients) characterized by some HER2/neu expression. Re-staging for clinical
evidence of stable disease, partial response or better by immune-related response criteria
will be assessed in observations at Weeks 8, 16, 24, 36 and 48 with confirmatory scans (if
indicated to confirm irCR, irPR or irPD) at Weeks 12, 20, 28, 40 and 52. Adjuvant bladder
cancer patients will undergo re-staging for evidence of disease recurrence (with
confirmatory scans 4 weeks later if recurrence is documented) at Weeks 8, 16, 24, 36 and 48.

Part II repeats the vaccine dose escalation (as required by the FDA) in a population with
significant prior exposure to trastuzumab and other HER2-targeted therapies to determine
whether there is an adverse safety signal regarding cardiac toxicity, in addition to
assessment of the vaccine s immunogenicity and clinical activity. Vaccine dose escalation,
administration and re-staging assessment is identical to that conducted in Part I.

Eligibility:

Part I:

- Adults greater than or equal to 18 with recurrent, metastatic solid tumors
characterized by some HER2/neu expression but for whom trastuzumab is not clinically
indicated:

- Patients with ovarian, colon, non-small cell lung, renal cell, bladder and prostate
cancer that is known to be HER2 1+, 2+ or 3+ by IHC OR have a Vysis FISH result greater
than 1.8.

- Patients with breast cancer that is known to be HER2 1+ or 2+ by IHC or with a Vysis
FISH result of 1.8 - less than 2.2.

- Presence of measurable disease defined by at least one lesion that can be accurately
measured by CT scan and/or measurable, clinically visible skin lesions, with the
exception of metastatic bladder cancer patients that have completed first line
chemotherapy and may not have measurable disease.

- Adults greater than or equal to 18 with HER2+ bladder cancer in the adjuvant setting
(adjuvant bladder cancer patients)

- Tumor stage T3a, T3b, T4a and T4b and any node positive disease regardless of tumor
stage.

- Tumors that are HER2 1+, 2+ or 3+ by IHC or have a Vysis FISH result greater than 1.8.

- Status-post primary cystectomy with curative intent.

- May or may not have received neodjuvant cisplatin-based combination chemotherapy per
NCCN guidelines.

- May or may not have received adjuvant radiotherapy or chemotherapy based on pathologic
risk per NCCN guidelines.

- Greater than or equal to 6 weeks s/p primary surgery with curative intent.

- Life expectancy of greater than or equal to 6 months, ECOG 0-1.

- Na ve to trastuzumab, pertuzumab, lapatnib, ado-trastuzumab emtansine (TDM1) or other
investigational HER2- directed therapies.

Part II:

- Adults greater than or equal to 18 with breast cancer with 3+ HER2/neu expression by
IHC or a Vysis FISH result greater than 2.2.

- Recurrent metastatic disease with a life expectancy of greater than or equal to 6
months, ECOG 0-1.

- Disease progression following 1 - 2 courses of therapies with known clinical benefit
i.e. trastuzumab, lapatinib or other investigational HER2 agents e.g. pertuzumab, T-DM1
but NONE in the last 2 weeks.

- Some documented response to HER2-directed therapy for metastatic disease.

- Presence of measurable disease defined by at least one lesion that can be accurately
measured by CT scan and/or measurable, clinically visible skin lesions.

Inclusion Criteria


- INCLUSION PART I

- Adults greater than or equal to 18 with recurrent or progressive, metastatic solid
tumors characterized by some HER2/neu expression that have failed standard therapies
with known benefit but for whom trastuzumab is not clinically indicated:

- Patients with ovarian, colon, non-small cell lung, renal cell, bladder and prostate
cancer that are known to be HER2 1+, 2+ or 3+ by IHC OR have a Vysis FISH result
greater than 1.8.

- Patients with breast cancer that is known to be HER2 1+ or 2+ by IHC or with a Vysis
FISH result of 1.8 - less than 2.2.

- Adults greater than or equal to 18 with HER2+ bladder cancer in the adjuvant setting
(adjuvant bladder cancer patients):

- Tumor stage T3a, T3b, T4a, T4b and any node positive disease regardless of tumor
stage.

- Tumors that are HER2 1+, 2+ or 3+ by IHC or have a Vysis FISH result greater than
1.8.

- Status-post primary cystectomy with curative intent.

- May or may not have received neoadjuvant cisplatin-based combination chemotherapy per
NCCN guidelines.

- May or may not have received adjuvant radiotherapy or chemotherapy based on
pathologic risk per NCCN guidelines.

- Greater than or equal to 6 weeks s/p primary surgery with curative intent.

2.1.1.3 Life expectancy of greater than or equal to 6 months,

- Performance Status: ECOG 0-1.

- Naive to trastuzumab, pertuzumab and lapatnib or other investigational HER2-directed
therapies (e.g. T-DM1).

- Recurrent or progressive disease on prior standard therapies with known clinical
benefit (except adjuvant bladder cancer population).

- For adults with recurrent, metastatic solid tumors: presence of measurable disease,
defined as at least one lesion that can be accurately measured by CT scan in at least
one dimension (longest diameter to be recorded for non-nodal lesions and short axis
for nodal lesions) as greater than or equal to 20 mm with conventional techniques
and/or measurable, clinically visible skin lesions, with the exception of metastatic
bladder cancer patients that have completed first line chemotherapy and may not have
measurable disease.

- Baseline LVEF by 2D Echocardiogram greater than or equal to 55%.

- Greater than or equal to 2 weeks since standard or investigational treatment for
metastatic disease.

- Stable, concurrent use of tamoxifen or aromatase inhibitors for ER+ status allowed.

- Hematologic parameters: ANC greater than or equal to 1000 cells/mm(3), ALC greater
than or equal to 500 cells/mm(3), Hemoglobin greater than or equal to 9.0 gm/dL, WBC
greater than or equal to 2,500 cells/mm(3), platelet count greater than or equal to
75,000/mm3, PT/PTT less than or equal to 1.5 times the upper limits of normal.

- Chemistry parameters: SGOT and SGPT less than or equal to 3 times the upper limits of
normal and total bilirubin less than or equal to1.5 mg/dl, Alk PO4 less than or equal
to 2 times the upper limits of normal (except for patients with documented metastatic
disease to bone).

- Negative serum HCG if female and of childbearing potential.

- Negative serology for HIV-1.

- Negative serology for hepatitis B and C unless the result is consistent with prior
vaccination or prior infection with full recovery.

- Willingness of female and male subjects to use effective contraception e.g. oral
contraceptives, barrier device, intrauterine device, or condoms, during the study and
for three months following the last dose of study vaccine. We suggest that subjects
do not become pregnant or father a child during the study, and for 3 months following
receipt of the investigational AdHER2 DC vaccine. (FDA requested language)

- Able to understand and provide Informed Consent.

INCLUSION PART II:

- Age greater than or equal to 18 years

- Breast cancer patients with 3+ HER2/neu expression by IHC or a Vysis FISH result
greater than 2.2.

- Recurrent or progressive metastatic disease after at least 1-2 courses of standard
therapies with known clinical benefit i.e. trastuzumab or lapatinib, ado-trastuzumab
emtansine (TDM1) or other investigational HER2-directed therapies (e.g. MGAH22).

- Life expectancy of greater than or equal to 6 months.

- Performance Status: ECOG 0-1.

- Presence of measurable disease, defined as at least one lesion that can be accurately
measured by CT scan in at least one dimension (longest diameter to be recorded for
non-nodal lesions and short axis for nodal lesions) as greater than or equal to 20 mm
with conventional techniques and/or measurable clinical visible skin lesions.

- Baseline LVEF by 2D Echocardiogram greater than or equal to 55%.

- Greater than or equal to 2 weeks since receipt of standard or investigational HER2-
directed therapy for metastatic or recurrent disease.

- Stable, concurrent use of tamoxifen or aromatase inhibitors for ER+ status allowed.

- Hematologic parameters: ANC greater than or equal to 1000 cells/mm(3), ALC greater
than or equal to 500 cells/mm(3), absolute Hemoglobin greater than or equal to 9.0
gm/dL, WBC greater than or equal to 2,500 cells/mm(3), platelet count greater than or
equal to 75,000/mm(3), PT/PTT less than or equal to 1.5 times the upper limits of
normal.

- Chemistry parameters: SGOT and SGPT less than or equal to 3 times ULN, total
bilirubin less than or equal to 1.5 times ULN and Alk PO4 less than or equal to 2
times ULN (except for patients with documented metastatic disease to bone).

- Negative serum HCG if of childbearing potential.

- Negative serology for HIV-1.

- Negative serology for hepatitis B and C unless the result is consistent with prior
vaccination or prior infection with full recovery.

- Willingness of female subjects to use effective contraception e.g. oral
contraceptives, barrier device, intrauterine device, or condoms, during the study and
for three months following the last dose of study vaccine. We suggest that subjects
do not become pregnant during the study, and for 3 months following receipt of the
investigational AdHER2 DC vaccine. (FDA requested language)

- Able to understand and provide Informed Consent.

EXCLUSION CRITERIA:

- Females who are pregnant or breastfeeding.

- Patients with active or previously treated CNS metastases or leptomeningeal
involvement by tumor.

- Patients with rapidly progressing disease in the opinion of the Principal
Investigator.

- Patients with inadequate bilateral peripheral venous access for the required
apheresis to allow generation of the autologous AdHER2 DC vaccine product.

- Clinically significant cardiac dysfunction defined as a history of greater than or
equal to NYHA Class II symptoms, angina, myocardial infarction or cardiac arrhythmias
requiring treatment or discontinuation of chemotherapy.

- History of changes in baseline LVEF that occurred during prior treatment with
trastuzumab.

- Cumulative doxorubicin dose greater than or equal to 400mg/m(2) or cumulative
epirubicin dose greater than or equal to 800mg/m(2).

- Use of any standard chemotherapy or other investigational agent(s) within 2 weeks of
study enrollment.

- Use of systemic corticosteroid therapy within 2 weeks of study enrollment, including
patients receiving replacement corticosteroid therapy. Note: only topical, inhaled
and intranasal steroid therapy is permitted.

- Active systemic viral, bacterial or fungal infection requiring treatment.

Type of Study:

Interventional

Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Determine the safety and toxicity of autologous Ad HER2/neu dendritic cell vaccination r/t cardiac toxicity/output.

Principal Investigator

Lauren V Wood, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute (NCI)

Authority:

United States: Federal Government

Study ID:

130016

NCT ID:

NCT01730118

Start Date:

November 2012

Completion Date:

June 2015

Related Keywords:

  • Breast Neoplasms
  • Breast Cancer
  • Adenocarcinomas
  • Metastatic Solid Tumors Characterized by HER2/Neu Expression
  • Metastatic Solid Tumors
  • Human Epidermal Growth Factor Receptor 2 Expression (HER2/neu)
  • Trastuzumab Exposure
  • Dendritic Cell Vaccine
  • Breast Cancer
  • Adenocarcinoma
  • Adenocarcinoma, Mucinous
  • Breast Neoplasms
  • Neoplasms

Name

Location

National Institutes of Health Clinical Center, 9000 Rockville PikeBethesda, Maryland  20892