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A Phase I Study To Evaluate The Antitumor Activity And Safety Of DUKE-002-VRP(HUHER2-ECD+TM), An Alphaviral Vector Encoding The HER2 Extracellular Domain And Transmembrane Region, In Patient With Locally Advanced Or Metastatic Human Epidermal Growth Factor Receptor 2-Positive (HER2+) Cancers Including Breast Cancer


Phase 1
18 Years
N/A
Open (Enrolling)
Both
HER2+ Cancer

Thank you

Trial Information

A Phase I Study To Evaluate The Antitumor Activity And Safety Of DUKE-002-VRP(HUHER2-ECD+TM), An Alphaviral Vector Encoding The HER2 Extracellular Domain And Transmembrane Region, In Patient With Locally Advanced Or Metastatic Human Epidermal Growth Factor Receptor 2-Positive (HER2+) Cancers Including Breast Cancer


Metastatic breast cancer continues to account for more than 400,000 deaths yearly with HER2
positive breast cancers representing approximately one third of cases. Despite the efficacy
of trastuzumab in HER2 overexpressing breast cancer, progression of metastatic disease is
inevitable. Lapatinib, when combined with capecitabine, improves time to progression in
those with trastuzumab resistant disease, but lapatinib resistance also develops in the
majority of these patients. HER2 overexpression is also reported in lung, gastric, ovarian,
and pancreatic cancers, all of which are also in need of improved treatment options. Because
HER2 continues to be expressed in patients with refractory disease, using an
immune-targeting approach against HER2 remains a promising strategy. A number of clinical
trials have confirmed the ability of vaccines to activate T cell and antibody responses
against HER2. We propose using a propagation-defective, single-cycle, RNA replicon vector
system that expresses HER2 as an antigen-specific cancer vaccine in a Phase I clinical trial
in patients with advanced or metastatic malignancies expressing HER2. The vaccine was
prepared from an attenuated strain of an alphavirus in which 3 of the 7 viral genes were
removed and replaced with a HER2 gene to create a self-amplifying RNA (replicon) that
expresses large amounts of HER2. The HER2 gene used includes the extracellular domain (ECD)
and transmembrane (TM) regions of HER2 but not the ICD region. The HER2 ECDTM replicon is
packaged into virus-like replicon particles (VRP) by providing the alphavirus structural
proteins from separate RNA molecules. When VRP are used for immunization, the VRP infect
individual cells and the replicon expresses HER2 which then induces an immune response.

The primary objective of the study is to evaluate the safety of immunization with HER2 ECDTM
VRP in patients with advanced or metastatic HER2-expressing malignancies. The study will
also monitor immune responses to HER2. Preliminary data on tumor response rate will also be
collected.


Inclusion Criteria:



- One of the following subgroups of patients with HER2 overexpression as follows:

(i) Histologically-confirmed breast cancer that is metastatic or locally
recurrent (7th Edition of the AJCC TNM System) and measurable and/or evaluable or
non-measurable by RECIST 1.1 criteria with HER2/neu overexpression by
immunohistochemistry (2+,3+) or FISH+ and progressive disease despite having
received at least 1 prior FDA approved HER2 targeted therapy (e.g. trastuzumab or
lapatinib) (determined by their physician).*

*Prior therapy has at least one of the following stipulations:

1. Patients may have received neoadjuvant or adjuvant treatment with prior
trastuzumab or lapatinib treatment

2. Patients have received a trastuzumab-based therapy for locally advanced or
metastatic disease for a minimum of 9 weeks duration. Patients may have
received more than 1 trastuzumab-based combination therapy.

3. Patients have received a lapatinib-based therapy for locally advanced or
metastatic disease for a minimum of 9 weeks duration. Patients may have received
more than 1 lapatinib-based combination therapy.

(ii) Histologically-confirmed gastric or gastroesophageal adenocarcinoma that is
metastatic or locally recurrent (7th Edition of the AJCC TNM System) and
measurable or non-measurable by RECIST 1.1 criteria with HER2/neu overexpression
by immunohistochemistry (2+,3+) or FISH+ and progressive disease despite having
received at least 1 prior trastuzumab-containing regimen for a minimum of 9
weeks duration) (determined by their physician).

(iii) Other histologically confirmed metastatic (stage IV) or locally recurrent
(stage III) (7th Edition of the AJCC TNM System) malignancy with HER2/neu
overexpression by immunohistochemistry (2+,3+) or FISH+. Because there are no
other malignancies with FDA approved HER2 targeting therapies, no prior HER2
directed therapy will be required for this subgroup. However, patients will have
been required to have at least 1 line of therapy with a known survival benefit
for their malignancy.

- Adults at least 18 years of age at the time of signing the Informed Consent Form;

- Written informed consent and HIPAA authorization (applies to covered entities in the
USA only) obtained from the patient prior to performing any study-related procedures,
including screening visits;

- Resolution of all toxic side effects of prior chemotherapy, radiotherapy or surgical
procedures to NCI CTCAE (version 4.03) Grade ≤ 1 (with the exception of grade 2
alopecia, grade 2 neuropathy and grade 2 fatigue);

- Karnofsky performance status greater than or equal to 80% or ECOG status of 0 or 1 ;

- Adequate hematologic function: (WBC = 2500 mm3, hemoglobin > 10 mg/dl, platelets >
100,000/mm3);

- Adequate renal and hepatic function (Cr < 2.0 mg/dl; bilirubin < 2 X ULN; AST < 2.5 x
ULN, ALT < 2.5 X ULN);

- Normal cardiac function defined as either a MUGA or ECHO with LVEF in normal
institutional range (MUGA 50%; ECHO 55%) and an EKG with no heart block;

- Female patients must be of non child-bearing potential or use effective
contraception, e.g., use of oral contraceptives with an additional barrier method
(since the study drug may impair the effectiveness of oral contraceptives), double
barrier methods (diaphragm with spermicidal gel or condoms with contraceptive foam),
Depo-Provera, partner vasectomy, total abstinence, and willing to continue the
effective contraception method for 30 days after the last dose of AVX901;

- Ability to return to Duke University Medical Center for adequate follow-up as
required by this protocol;

- Current therapy with endocrine agents (tamoxifen, raloxifene, torimifene and all
aromatase inhibitors) and/or bisphosphonates and/or RANK-ligand inhibitors is
permitted.

Exclusion Criteria:

- Except for patients on the concurrent trastuzumab cohort, patients may not receive
chemotherapy, monoclonal antibody, targeted therapy such as lapatinib, or radiation
therapy in the 3 weeks before the first injection, during the injection period or for
at least 2 weeks after the last injection. Patients may have received prior
radiation including for brain metastases.

- History of auto-immune disease such as, but not restricted to, inflammatory bowel
disease, systemic lupus erythematosus, ankylosing spondylitis, scleroderma, or
multiple sclerosis. Prior history of autoimmune thyroiditis or vitiligo is permitted.

- Serious intercurrent chronic or acute illness such as pulmonary (asthma or COPD) or
cardiac (NYHA class III or IV) or hepatic disease or other illness considered by the
P.I. to constitute an unwarranted high risk for investigational drug treatment.

- Medical or psychological impediment to probable compliance with the protocol.

- Concurrent or prior second malignancy (within the past 5 years) other than
non-melanoma skin cancer, controlled superficial bladder cancer or controlled
cervical cancer.

- Presence of active infection or systemic use of antimicrobials within 72 hours prior
to the first injection

- Patients on steroid therapy (or other immunosuppressives such as azathioprine or
cyclosporine A) are excluded on the basis of potential immune suppression. Patients
must have had 6 weeks of discontinuation of any steroid therapy prior to enrollment
(except steroids used as anti-emetics for systemic chemotherapy which are permitted).

- Presence of an active acute or chronic infection including HIV (as determined by
ELISA and confirmed by Western Blot) or viral hepatitis (as determined by HBsAg and
Hepatitis C serology). Patients with HIV are excluded based on immuno-suppression,
which may render them unable to respond to the vaccine; patients with chronic
hepatitis are excluded because of concern that hepatitis could be exacerbated by the
injections. .

- Pregnant or nursing women

Type of Study:

Interventional

Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label

Outcome Measure:

Safety

Outcome Description:

The primary objective of the study is to evaluate the safety of immunization with HER2 ECDTM VRP in patients with advanced or metastatic HER2-expressing malignancies

Outcome Time Frame:

3 months

Safety Issue:

Yes

Principal Investigator

Michael Morse, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Duke University

Authority:

United States: Food and Drug Administration

Study ID:

Pro00034612

NCT ID:

NCT01526473

Start Date:

September 2012

Completion Date:

September 2015

Related Keywords:

  • HER2+ Cancer
  • Alphavirus
  • Vaccine
  • Immunotherapy
  • HER2

Name

Location

Duke University Medical CenterDurham, North Carolina  27710