PANVAC-V and PANVAC-F Vaccines Plus Sargramostim to Treat Advanced Cancer

Background:

• Many cancers produce two proteins, carcinoembryonic antigen (CEA) and mucin-1 (MUC-1).
• The PANVAC-V priming vaccine and PANVAC-F boosting vaccine contain human genes that cause production of CEA and MUC-1, which can be used as a target for the immune system to attack the cancer. The vaccines also contain genes that cause production of other proteins that enhance immune activity.
• Sargramostim is a protein that boosts the immune system.

Objectives:

• To evaluate the safety and effectiveness of PANVAC-V and PANVAC-F in patients with advanced cancer.
• To document the immune response to the vaccines and any anti-tumor responses that may occur.

Eligibility: Patients 18 years of age and older with advanced cancer whose tumors produce CEA or MUC-1 protein

Design:

• This trial has four arms: the first arm includes 10 patients with advanced colorectal cancer; the second arm includes 10 to 15 patients with any advanced non-colorectal cancer that produces either EA or MCU-1; the third arm includes about 12 patients with advanced breast cancer; the fourth arm includes about 12 patients with advanced ovarian cancer.
• All patients receive PANVAC-V on study day 1, followed by PANVAC-F on days 15, 29 and 43. The vaccines are given by injection under the skin. Sargramostim is injected at the vaccination site on the day of each vaccination and for the next 3 days following vaccination.
• Patients whose disease has not worsened after the last boosting vaccination may receive up to 12 additional monthly boosting vaccinations. Following the 12 vaccinations, patients may receive vaccine every 3 months. Patients whose scans show that their disease has progressed, but who are otherwise clinically stable may revert back to monthly injections.
• Patients undergo apheresis to collect white blood cells (lymphocytes) on day 1 and day 71 of the study to measure the immune response to the treatment. Blood is collected through a needle placed in one arm and directed through a cell separator machine where the lymphocytes are extracted. The rest of the blood components are returned to the patient through the same needle.
• Patients are monitored with frequent blood tests and periodic imaging tests (scans) to monitor for safety and the response to treatment.

Background:

• CEA and MUC-1 are overexpressed in multiple adenocarcinomas.
• Pox viral vectors can induce a strong immune response to CEA and MUC-1.
• The use of agonist epitopes within the TAA can induce a better immune response than native peptides and have been associated with clinical responses
• Heterologous prime and boost regimens are superior in terms of generalizing immune responses; and this may translate into improved clinical responses
• The use of GM-CSF does not add significant toxicity and in pre-clinical models is essential for induction for optimal immune responses.
• It is possible by using vectors directed against TAA that there may be additive or synergistic immune responses and this may be important in overcoming antigenic escape variance
• Evidence of clinical benefit has been noted in some patients treated with this vaccine

Objectives:

• For the first two arms (colorectal cancer and non-colorectal cancer): 1 To evaluate the safety and tolerability of the vaccine. 2 To document any objective anti-tumor responses that may occur
• For the Ovarian Cancer and Breast Cancer arms: 1 To evaluate clinical response to the vaccine. 2 To evaluate the safety and tolerability of the vaccine
• 2 (all arms) To evaluate immune response generated by this combination therapy as measured by ELISPOT assay

Eligibility:

• In the first two arms (colorectal and non-colorectal cancer), histologically confirmed adenocarcinoma that is CEA or MUC-1 positive described as metastatic disease (measurable or evaluable) or metastatic disease documented by biopsy but not evaluable by imaging (e.g. small volume peritoneal disease)
• For the ovarian and breast cancer arms, patients must have evaluable disease
• Normal organ function, ECOG 0-1

Design:

• This is a non-randomized four arm, pilot trial of pox viral vaccines that contain the transgenes for CEA and MUC-1 (both with modified HLA-A2 agonist epitopes) as well as 3 human T-cell costimulatory molecules, B7-1, ICAM-1, and LFA-3 [PANVAC(TM)-V (vaccinia) and PANVAC(TM)-F (fowlpox)] in patients with metastatic carcinoma that express CEA or MUC-1 antigen.
• The first arm will enroll 10 patients with metastatic colorectal adenocarcinoma.
• The second arm will consist of 10-15 patients with any metastatic non-colorectal carcinoma that expresses either CEA or MUC-1.
• The third arm will consist of about 12 patients with metastatic breast carcinoma. The fourth arm will consist of about 12 patients with metastatic ovarian carcinoma.
• All patients will receive PANVAC(TM)-V (vaccinia) subcutaneously (s.c.) scheduled on day 1, followed by PANVAC(TM)-F (fowlpox) s.c. scheduled on days 15, 29, and 43 (Core Phase).
• Sargramostim (100 micro g) will be given at the site of the vaccination on each vaccination day and for three consecutive days thereafter.
• Up to 12 additional monthly boosting vaccinations (Extension Phase) will be offered to patients who have completed the Core Phase of the study and who have not experienced disease progression.
• Following the 12 monthly vaccinations, patients without disease progression will be allowed to receive vaccine every 3 months.
• Patients who have radiographic evidence of progressive disease, but who are otherwise clinically stable may revert back to monthly vaccinations.

• Drug: PANVAC-V [Recombinant-Vaccinia-CEA (D609)/MUC-1(L93)/TRICOM]
  N/A
• Drug: PANVAC-F [Recombinant-Fowlpox-CEA (D609)/MUC-1(L93)/TRICOM]
  N/A
• Drug: Leukine (Sargramostim)
  N/A

• Madan RA, Bilusic M, Heery C, Schlom J, Gulley JL. Clinical Evaluation of TRICOM Vector Therapeutic Cancer Vaccines. Semin Oncol. 2012 Jun;39(3):296-304.
• Mohebtash M, Tsang KY, Madan RA, Huen NY, Poole DJ, Jochems C, Jones J, Ferrara T, Heery CR, Arlen PM, Steinberg SM, Pazdur M, Rauckhorst M, Jones EC, Dahut WL, Schlom J, Gulley JL. A pilot study of MUC-1/CEA/TRICOM poxviral-based vaccine in patients with metastatic breast and ovarian cancer. Clin Cancer Res. 2011 Nov 15;17(22):7164-73. Epub 2011 Nov 8.
• Gulley JL, Arlen PM, Tsang KY, Yokokawa J, Palena C, Poole DJ, Remondo C, Cereda V, Jones JL, Pazdur MP, Higgins JP, Hodge JW, Steinberg SM, Kotz H, Dahut WL, Schlom J. Pilot study of vaccination with recombinant CEA-MUC-1-TRICOM poxviral-based vaccines in patients with metastatic carcinoma. Clin Cancer Res. 2008 May 15;14(10):3060-9.
• Madan RA, Arlen PM, Gulley JL. PANVAC-VF: poxviral-based vaccine therapy targeting CEA and MUC1 in carcinoma. Expert Opin Biol Ther. 2007 Apr;7(4):543-54. Review.

• INCLUSION CRITERIA:

A. Histologically confirmed carcinoma that for patients in the first two arms (colorectal and non-colorectal cancer) is CEA or MUC-1 positive. Tumor that has been shown to express CEA or MUC-1 (greater than or equal to 20 % of cells) by immunohistochemical techniques or patients that have had an elevated serum CEA (greater than 5 microgram/L) at any point during their disease course. For patients in the ovarian and breast cancer arms, as greater than 95% of these express MUC-1 or CEA, we will not require staining prior to coming onto trial.

B. Patients must have completed at least one 5-FU containing chemotherapy regimen (e.g. 5-FU/LV with or without either irinotecan or oxaliplatin) for the colorectal cancer arm, or either failed or not be a candidate for therapy of proven efficacy for their disease in the non-colorectal, breast, and ovarian cancer arms.

C. 18 years of age or greater.

D. All patients on the colorectal adenocarcinoma cohort must be HLA-A2 positive.

E. At least 10 patients on the non-colorectal adenocarcinoma cohort must be HLA-A2 positive.

F. Patients on the breast and ovarian arms are not required to be HLA-A2 positive.

G. For the colorectal and non-colorectal cancer arms (the initial two arms), patients will be required to have: metastatic disease (measurable or evaluable), metastatic disease documented by biopsy but not evaluable by imaging (e.g. small volume peritoneal disease), and patients with surgically resected metastatic disease at high risk of relapse. For the ovarian and breast cancer arms, patients will be required to have evaluable disease.

H. Able to understand and give informed consent.

I. Able to avoid close household contact (close household contacts are those who share housing or have close physical contact) for at least three 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 HIV infection.

J. ECOG performance status of 0 - 1.

K. Serum creatinine not above the institution limits of normal, and AST less than or equal to twice the upper limits of normal OR creatinine clearance on a 24 hour urine collection of greater than or equal to 60 mL/min.

L. Total bilirubin within the institution limits of normal OR patients with Gilbert's syndrome, a total bilirubin less than or equal to 3.0

M. Recovered completely from any reversible toxicity associated with recent therapy. Typically this is 3-4 weeks for patients who most recently received cytotoxic therapy except for the nitrosoureas and mitomycin C for which 6 weeks is needed for recovery.

N. Hematological eligibility parameters (within 16 days of starting therapy):

• Granulocyte count greater than or equal to 1,500/mm3
• Platelet count greater than or equal to 100,000/mm3
• Hgb greater than or equal to 10 Gm/dL

O. Prior immune therapy with related vaccinia and fowlpox vaccines or antigen-specific peptides is allowed.

P. Men and women must agree to use effective birth control or abstinence during and for a period of 4 months after the last vaccination therapy.

Q. Patients with prostate cancer must continue to receive GnRH agonist therapy (unless orchiectomy has been done).

R. Patients should appear clinically stable (in the opinion of the prinicipal investigator) to complete the full 3 month course of vaccination with an anticipated survival of 6 months or longer.

INCLUSION CRITERIA FOR EXTENSION OR MAINTENANCE PHASE:

A. Completion of Core phase of the protocol.

B. Stable or responding disease (PR, CR).

C. No dose limiting toxicity (see below) in Core phase possibly, probably or definitely related to the vaccine.

Dose limiting toxicities include:

• Any Grade 2 generalized urticaria or Grade 3 or greater allergic reaction.
• Any Grade 2 or greater autoimmune response.
• Any Grade 3 or greater hematologic or non-hematologic reaction, including injection-site reaction.

EXCLUSION CRITERIA:

A. Patients should have no evidence of being immunocompromised as listed below.

• Human immunodeficiency virus positivity due to the potential for decreased tolerance and risk for severe side effects
• 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.

B. Concurrent use of systemic steroids, except for physiologic doses for systemic steroid replacement or local (topical, nasal, or inhaled) steroid use. Limited doses systemic steroids to prevent IV contrast, allergic reaction, or anaphylaxis (in patients who have known contrast allergies) are allowed.

C. History of allergy or untoward reaction to prior vaccination with vaccinia virus.

D. Pregnant or breast-feeding women.

E. 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).

F. 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

G. Patients with a history of cardiomyopathy or symptomatic congestive heart failure (unless stable on treatment), symptomatic arrhythmia not controlled by medication. Unstable atherosclerotic heart disease (e.g. unstable angina) who require active intervention and history of myocardial infarction or embolic stroke within the past 6 months.

H. Clinically active brain metastasis, or a history of encephalitis, multiple sclerosis, or seizures within the last year (from seizure disorder or brain metastasis).

I. Medical conditions, which, in the opinion of the investigators would jeopardize the patient or the integrity of the data obtained.

J. Concurrent chemotherapy; an exception to this is to allow for patients with breast cancer who are receiving trastuzumab, to continue therapy with trastuzumab while receiving the vaccine treatment.

K. Serious hypersensitivity reaction to egg products.

L. Clinically significant cardiomyopathy requiring treatment.

M. Chronic hepatitis infection, including B and C, because of potential immune impairment.

N. Although topical steroids are allowed, steroid eye drop are contraindicated.

O. Cardiac complications, including recent myocardial infarction or cerebrovascular accident within one year, and/or unstable or uncontrolled angina.