Docetaxel Alone or in Combination With Vaccine to Treat Breast Cancer
Condition: Breast Cancer
MeSH terms: Breast Neoplasms
Intervention: Docetaxel; PANVAC-V; PANVAC-F; Sargramostim
Intervention description: 35 mg/m^2 intravenous 30-60 minutes once a week for 3 consecutive weeks with 1 week off drug.; 2 x 10^8 PFU; 1 x 10^9 PFU; Given subcutaneously under the skin, usually in the thigh on the day of vaccination and daily for the next 3 days.
Intervention MeSH terms: Docetaxel; Sargramostim
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Enrollment: 48.0
Sex: All
Minimum age: 18 Years
Maximum age: 85 Years
Healthy volunteers: No
Keywords: CEA; MUC-1; Immunotherapy; GM-CSF; Vaccine; Breast Cancer; Metastatic Breast Cancer

Summary:

      This study will test whether giving a combination of a vaccine together with docetaxel is
      more effective against breast cancer than docetaxel alone. The Food and Drug Administration
      has approved docetaxel to treat many cancers, including breast cancer. The vaccine consists
      of three parts: 1) a "priming vaccine" called PANVAC (PAN (all) VAC (vaccine)) trademark
      [TM]-V, which is made from vaccinia virus; 2) a "boosting vaccine" called PANVAC[TM]-F, made
      from fowlpox virus; and 3) sargramostim, or granulocyte macrophage colony stimulating factor
      (GM-CSF), a protein that may help boost the immune system. Human genes are inserted into the
      vaccinia and fowlpox viruses to cause production of carcinoembryonic antigen (CEA) and mucin
      1 (MUC-1)-two proteins that are often produced by cancer cells and can be used as a target
      for the immune system to attack the cancer. Another type of deoxyribonucleic acid (DNA) is
      inserted to cause production of other proteins that enhance immune activity.

      Patients 18 years of age or older with metastatic breast cancer (disease that has spread
      beyond the original site) and whose cancer produces CEA or mucin 1 (MUC-1) protein may be
      eligible for this study. Patients must have antigen type human leukocyte antigen A2 (HLA-A2).
      They may have received adjuvant docetaxel treatment at least 3 months before entering this
      study, prior hormonal therapy and up to three chemotherapy regimens. Candidates are screened
      with a medical history and physical examination, blood and urine tests, electrocardiogram,
      and computerized tomography (CT) or magnetic resonance imaging scans.

      Participants are randomly assigned to one of two treatment groups - docetaxel alone or
      docetaxel plus vaccine - as follows:

      Docetaxel Alone

      All patients receive docetaxel. The drug is infused through a vein over 30 to 60 minutes once
      a week for 3 consecutive weeks with 1 week off drug. Patients also take dexamethasone 12
      hours and 1 hour before and 12 hours after the docetaxel to help prevent fluid retention
      (edema) that docetaxel may cause.

      Docetaxel Plus Vaccine

      Participants receive the priming vaccination followed by monthly boosting vaccinations, along
      with the weekly docetaxel therapy. With every vaccination, patients also receive an injection
      of sargramostim to increase the number of immune cells at the vaccination site. Sargramostim
      injections are given the day of vaccination and daily for the next 3 days. All vaccine and
      sargramostim doses are given as injections under the skin, usually in the thigh. Patients are
      observed in the clinic for 1 hour after each injection.

      Patients have blood tests every four weeks to monitor drug side effects and before every
      vaccination to check blood counts. A bone scan or CT scan (or both) is done every 2 to 3
      months to check the response to treatment.

      Patients may continue receiving treatment as long as their disease does not worsen and they
      can tolerate the treatment without significant side effects. Patients assigned to receive
      docetaxel alone whose disease progresses after 3 months on the drug may choose to receive the
      vaccine or come off the study to receive other treatment options. Patients are monitored with
      yearly telephone calls for up to 15 years.
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

          -  Metastatic Breast Cancer (either male or female) with evidence of metastatic disease
             (must have radiographic evidence of measurable disease) on computed tomography (CT)
             scan or X-ray, or evidence of evaluable disease on bone scan that is consistent with
             metastasis and a life expectancy of at least 4 months. Patients may have received
             unlimited prior hormonal therapy and chemotherapy.

          -  Histologically confirmed adenocarcinoma of the breast cancer confirmed in the
             Pathology Clinical Center at National Cancer Institute (NCI), (or National Naval
             Medical Center (NNMC)) or MD Anderson Pathology Department prior to starting this
             study. Note: However, if no pathologic specimen is available, patients may enroll with
             a clinical course consistent with breast cancer and a pathological documentation of
             the disease.

          -  18 years of age or greater.

          -  May have received docetaxel in the adjuvant setting at least 12 months prior to study
             entry.

          -  Able to understand and give informed consent.

          -  Able to avoid close household contact (close household contacts are those who share
             housing or have close physical contact) for at least two weeks after recombinant
             vaccinia vaccination with persons with active or a history of eczema or other
             eczematoid skin disorders; those with other acute, chronic or exfoliative skin
             conditions (e.g., atopic dermatitis, burns, impetigo, varicella zoster, severe acne,
             or other open rashes or wounds) until condition resolves; pregnant or nursing women;
             children 3 years of age and under; and immunodeficient or immunosuppressed persons (by
             disease or therapy), including human immunodeficiency virus (HIV) infection. We have
             vaccinated over 700 cancer patients and have reported no cases of either self
             inoculation or person to person transmission of the virus.

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 1.

          -  Serum creatinine less than 1.5 times upper limits of normal (ULN) OR creatinine
             clearance on a 24 hour urine collection of greater than or equal to 60 mL/min,
             standard liver function tests (LFT) limitations for patients receiving docetaxel
             therapy include bilirubin within ULN and serum glutamic oxaloacetic transaminase
             (SGOT)/serum glutamic pyruvic transaminase (SGPT) less than 1.5 times the ULN. If
             transaminases are greater than 1.5 times the ULN up to 2 times the ULN (as currently
             indicated), then alk phos should be less than 2.5 times the ULN. (Patients with renal
             abnormalities should be evaluated for creatinine clearance (CrCl) and interstitial
             abnormalities. A Cr Cl of greater than or equal to 60ml/min measured or calculated and
             proteinuria less than 1000mg per 24 hours are eligible unless explained by non-renal
             causes.)

          -  Recovered completely from any grade 3 or 4 reversible hematologic and non hematologic
             toxicity associated with recent therapy. Typically this is 3-4 weeks for patients who
             most recently received cytotoxic therapy. Patients previously treated with mitomycin c
             or carboplatin will require a minimum of 6 weeks.

          -  Hematological eligibility parameters (within 16 days of starting therapy):

               1. Granulocyte count greater than or equal to1,500/mm^3

               2. Platelet count greater than or equal to 100,000/mm^3

               3. Hemoglobin (Hgb) greater than or equal to 8 Gm/dL

          -  Must agree to use effective birth control or abstinence during and for a period of 4
             months after the last vaccination therapy.

          -  Patients whose tumors are estrogen receptor (ER) positive should have failed primary
             hormone therapy unless clinically indicated, i.e. in patients with visceral disease or
             symptomatic bone disease where up front chemotherapy is warranted. Patients who
             progressed or recurred following Trastuzumab (Herceptin) therapy if a patient is
             fluorescence in situ hybridization (FISH) positive or immunohistochemistry (IHC) 3+
             positive for human epidermal growth factor receptor 2 (Her-2 neu). Those patients who
             have progressed on trastuzumab may continue to receive the drug by their referring
             physician. However, if trastuzumab has been discontinued at the time of enrolling on
             study, it cannot be resumed while a patient remains on study.

          -  Patients randomized to docetaxel alone (arm B) may at time of progression go on to
             receive vaccine alone if their ECOG performance status remains 0-1, and they do not
             have any uncontrolled pain or organ dysfunction that would require another
             intervention such as radiation or chemotherapy.

        Furthermore, patients initially randomized to arm B that would like to cross over and
        continue vaccine therapy must meet on-study eligibility and exclusion criteria with the
        exception of liver transaminase requirement. Patients with liver transaminase levels within
        Grade 1 by Common Terminology Criteria for Adverse Events (CTCAE) v4.0 (up to 3 x ULN) will
        be allowed to crossover to vaccine.

          -  Patients should appear clinically stable (in the opinion of the principle
             investigator) to complete the full 3 month course of vaccination with an anticipated
             survival of 6 months or longer.

          -  No other active malignancies within the past 12 months (with the exception of
             non-melanoma skin cancers or carcinoma in situ of the bladder) or life threatening
             illnesses.

          -  Patients with cardiovascular symptoms should be fully evaluated for signs and symptoms
             of cardiovascular disease and other standard evaluations including electrocardiogram
             (EKG), chest X-ray, cardiac enzymes, and echocardiogram as clinically indicated.

        EXCLUSION CRITERIA:

          -  Patients should have no evidence of being immunocompromised as listed below.

               1. Human immunodeficiency virus positivity due to the potential for decreased
                  tolerance and risk for severe side effects

               2. Active autoimmune diseases requiring treatment or a history of autoimmune disease
                  that might be stimulated by vaccine treatment. This requirement is due to the
                  potential risks of exacerbating autoimmunity Patients with endocrine disease that
                  is controlled by replacement therapy including thyroid disease and adrenal
                  disease and vitiligo may be enrolled

               3. Concurrent use of systemic steroids, except for local (topical, nasal, or
                  inhaled) steroid use

          -  History of allergy or untoward reaction to prior vaccination with vaccinia virus.

          -  Pregnant or breast-feeding women

          -  Altered immune function, including immunodeficiency or history of immunodeficiency;
             eczema; history of eczema, or other eczematoid skin disorders; or those with acute,
             chronic or exfoliative skin conditions (e.g. atopic dermatitis, burns, impetigo,
             varicella zoster, severe acne, or other open rashes or wounds)

          -  Serious intercurrent medical illness which would interfere with the ability of the
             patient to carry out the treatment program, including, but not limited to,
             inflammatory bowel disease, Crohn's disease, ulcerative colitis, or active
             diverticulitis

          -  Clinically active brain metastasis, or a history of seizures that have been active
             within one year

          -  Medical conditions, which, in the opinion of the investigators would jeopardize the
             patient or the integrity of the data obtained

          -  Prior docetaxel chemotherapy for metastatic disease

          -  Serious hypersensitivity reaction to egg products

          -  Clinically significant cardiomyopathy requiring treatment

          -  Chronic hepatitis infection, including B and C, because of potential immune impairment

          -  Although topical steroids are allowed, steroid eye-drops are contraindicated

          -  Patients who have received prior PANVAC vaccine therapy

          -  Patients with a prior history of allergy to eggs or egg products should not receive
             the vaccine

          -  Patients with cardiac disease that have fatigue, palpitation, dyspnea or angina with
             ordinary physical activity (New York Heart Association class 2 or greater) are not
             eligible.

          -  Prior splenectomy.

          -  Cardiac complications, including recent myocardial infarction or cerebrovascular
             accident within one year, and/or unstable or uncontrolled angina.