Basic Trial Information
Trial Description
     Summary
     Further Trial Information
     Eligibility Criteria
Trial Contact Information

Basic Trial Information

Trial Description

Summary

This randomized phase I/II trial studies the side effects and best dose of giving vaccine therapy and to see how well it works in treating patients with metastatic breast cancer. Vaccines made from a person's tumor cells and white blood cells may help the body build an effective immune response to kill tumor cells

Further Study Information

PRIMARY OBJECTIVES:

I. To determine the MTD and safety (using CTCAE version 4.0) of the combination Ad.p53 DC vaccine plus 1-MT in patients with any solid malignancy that has mutated p53 by IHC. (Phase I) II. To determine efficacy (objective response rate) of the combination Ad.p53 DC vaccine plus 1-MT in metastatic breast cancer patients whose tumor expresses mutated p53 by IHC. (Phase II)

SECONDARY OBJECTIVES:

I. To collect preliminary data on and study the p53 specific IFNγ ELISPOT measurement at baseline, week 7 and week 16. (Phase I) II. To collect preliminary data on and study the percentage of p53 specific IFNγ ELISPOT responders at week 7 and 16. (Phase II) III. To collect preliminary data on and study progression-free survival on the study treatment. (Phase II) IV. To collect preliminary data on and study response and progression-free survival on the subsequent chemotherapy if administered. (Phase II) V. To collect preliminary data on and study the effects of 1-methyl-D-tryptophan (1-MT) on serum kynurenine, serum tryptophan, C reactive protein, and circulating T-regulatory cells (CD4+ 25+ CD127low FoxP3+) by flow cytometry at each vaccination point on study when compared their corresponding baseline. (Phase II)

OUTLINE: This is a phase I, dose escalation study followed by a phase II study.

Patients receive adenovirus-p53 transduced dendritic cell vaccine intradermally (ID) in weeks 1, 3, 5, and 10, and then every 3 weeks for 6 total doses. Patients also receive 1-methyl-d-tryptophan orally (PO) once daily (QD) on days 1-21. Treatment for 1-methyl-d-tryptophan repeats every 28 days (patients with stable disease) for up to 12 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 4 weeks.

Eligibility Criteria

Inclusion Criteria:

• In the phase I patients with any solid tumor positive for p53 by IHC (≥ 5% of cells with any degree of nuclear staining) staining; for the phase II, patients must have histologically or cytologically confirmed metastatic invasive breast cancer that is positive for p53 staining by IHC (≥ 5% of cells with any degree of nuclear staining); patients will sign a separate consent for the p53 testing, and those that meet the above requirements will then be allowed to sign the vaccine trial consent

• Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as >= 20 mm with conventional techniques or as >= 10 mm with spiral CT scan

• There are no restrictions on prior therapies for the phase I part of the trial; for the phase II, patients may have received up to 2 prior lines of chemotherapy (not counting endocrine therapy lines) with the last dose of chemotherapy given 3 weeks (6 weeks for nitrosoureas and mitomycin C) prior to initiation on this study

• Life expectancy of greater than 4 months

• ECOG performance status =< 1 (Karnofsky >= 70%)

• Leukocytes >= 3,000/μL

• Absolute neutrophil count >= 1,500/μL

• Platelets >= 100,000/μL

• Total bilirubin within normal institutional limits unless patient has Gilbert's disease

• AST(SGOT)/ALT(SGPT) =< 2.5 X institutional upper limit of normal

• Creatinine within normal institutional limits OR creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal

• TSH, LH, FSH, ACTH showing normal pituitary function; these values may deviate if in the opinion of the investigator these are normal pituitary responses to another endocrine condition such as suboptimally treated hypothyroidism

• Patients with known brain metastases will only be eligible after their tumors have been treated with definitive resection and/or radiotherapy and they are neurologically stable for at least 1 month off steroids

• No history of gastrointestinal disease causing malabsorption or obstruction such as but not limited to Crohn's disease, celiac sprue, tropical sprue, bacterial overgrowth/blind loop syndrome, gastric bypass surgery, strictures, adhesions, achalasia, bowel obstruction, or extensive small bowel resection

• The effects of 1-methyl-D-tryptophan on the developing human fetus are unknown; for this reason and because 1-MT may affect maternal immune tolerance of the fetus, sexually active women of child-bearing potential must agree to use two forms of contraception (hormonal and barrier method of birth control or abstinence) prior to study entry and for the duration of study participation; males should use barrier contraception or abstinence during the study; use of contraception or abstinence should continue for a minimum of 1 month after completion of the study; should a woman become pregnant or suspect she is pregnant while participating in this study, she should discontinue the study drug and inform her treating physician immediately; a pregnancy test is required prior to study enrollment and monthly while on treatment with 1-MT for all women of child-bearing potential; also men should be discouraged from fathering children while on treatment

• Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

• Patients who have had chemotherapy or radiotherapy within 3 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 3 weeks earlier

• Patients may not receive any other investigational agents or chemotherapy to treat their underlying malignancy while on study; patients who are stable on prior endocrine therapies (i.e. aromatase inhibitors, tamoxifen, and fulvestrant) may stay on these treatments

• Patients with known untreated brain metastases are excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events; patients with stable previously treated lesions in a patient off steroids and radiation for 1 month are not excluded

• History of allergic reactions (significant urticaria, angioedema, anaphylaxis) attributed to compounds of similar chemical or biologic composition to 1-methyl-D-tryptophan; this would include L-tryptophan or 5-hyrdoxy-tryptophan supplements

• Patients with any active autoimmune disease (i.e. psoriasis, extensive atopic dermatitis, asthma, IBD, M.S., uveitis, vasculitis), chronic inflammatory condition, or any condition requiring concurrent use of any systemic immunosuppressants or steroids for any reason would be excluded from the study; any patient with an allo-transplant of any kind would be excluded as well; this would include those with a xenograft heart valve to avoid the potential risk of any immune reaction causing valvular degeneration; mild-intermittent asthma requiring only occasional beta-agonist inhaler use or mild localized eczema will not be excluded

• Uncontrolled concurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, myocardial infarction or percutaneous coronary interventions within the last 6 months, cardiac arrhythmia, active autoimmune diseases, or major psychiatric illness/social situations that would limit compliance with study requirements as judged by the primary investigator at each site; those with well controlled, chronic medical conditions under the supervision of the patient's primary physician (i.e. hypertension, hyperlipidemia, coronary heart disease, diabetes mellitus) would not be excluded

• Pregnant women are excluded from this study because 1-methyl-D-tryptophan is an immunoregulatory agent with the potential for abortifacient effects due to fetal rejection by the maternal immune system; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with 1-methyl-D-tryptophan, breastfeeding should be discontinued if the mother is treated with 1-methyl-D-tryptophan

• HIV-positive patients and those with other acquired/inherited immunodeficiencies are ineligible due the possibility of affecting the response to 1-MT and the higher risk of active opportunistic infections

• Patients with more than one active malignancy at the time of enrollment

• Patients who have received any prior experimental active immunotherapy consisting of targeted monoclonal antibodies or pharmaceutical compounds are excluded; prior experimental vaccine patients may be enrolled if approved by the PI; patients who have received commercially available active immunotherapies such as adjuvant interferon must have completed therapy over 1 year prior to enrollment and have no evidence of autoimmune sequelae; prior therapy with approved monoclonal antibodies such as bevacizumab, cetuximab, panitumumab, or trastuzumab is allowed; concurrent treatment with these agents and the study treatment is not allowed

• HER2+ patients (IHC 3+ and/or FISH HER2/CEP17 ratio > 2) who require treatment with trastuzumab or lapatinib are not eligible for this study

Trial Contact Information

Trial Lead Organizations/Sponsors

National Cancer Institute

Hatem Soliman

Principal Investigator

U.S.A.
Florida
	Tampa
	H. Lee Moffitt Cancer Center and Research Institute at University of South Florida
		Hatem H. Soliman	Ph: 813-745-4933
			Email: hatem.soliman@moffitt.org
		Hatem H. Soliman	Principal Investigator

Link to the current ClinicalTrials.gov record.
NLM Identifer NCT01042535
Information obtained from ClinicalTrials.gov on March 15, 2013

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