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A Phase 1/2 Study of Ad.p53 DC Vaccine in Combination With 1-methyl-D-tryptophan in Metastatic Solid Tumors and Invasive Breast Cancer

Phase 1/Phase 2
18 Years
Open (Enrolling)
Recurrent Breast Cancer, Stage IV Breast Cancer, Unspecified Adult Solid Tumor, Protocol Specific

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Trial Information

A Phase 1/2 Study of Ad.p53 DC Vaccine in Combination With 1-methyl-D-tryptophan in Metastatic Solid Tumors and Invasive Breast Cancer


I. To determine the maximum tolerated dose (MTD) and safety (using Common Terminology
Criteria for Adverse Events, [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 immunohistochemistry
(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)


I. To collect preliminary data on and study the p53 specific interferon-gamma (IFN-gamma)
enzyme-linked immunosorbent spot (ELISPOT) measurement at baseline, week 7 and week 16.
(Phase I) II. To collect preliminary data on and study the percentage of p53 specific
IFN-gamma 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.

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 computed tomography
(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

- Eastern Cooperative Oncology Group (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

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase [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

- Thyroid-stimulating hormone (TSH), luteinizing hormone (LH), follicle-stimulating
hormone (FSH), adrenocorticotropic hormone (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

- 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

- 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

- 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

- Human immunodeficiency virus (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

- Human epidermal growth factor receptor 2 positive (HER2+) patients (IHC 3+ and/or
fluorescent in situ hybridization [FISH] HER2/CEP17 ratio > 2) who require treatment
with trastuzumab or lapatinib are not eligible for this study

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum tolerated dose (MTD) of the combination using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.0 (Phase I)

Outcome Time Frame:

Up to 4 weeks

Safety Issue:


Principal Investigator

Hatem Soliman

Investigator Role:

Principal Investigator

Investigator Affiliation:

H. Lee Moffitt Cancer Center and Research Institute


United States: Food and Drug Administration

Study ID:




Start Date:

December 2009

Completion Date:

Related Keywords:

  • Recurrent Breast Cancer
  • Stage IV Breast Cancer
  • Unspecified Adult Solid Tumor, Protocol Specific
  • Breast Neoplasms



H. Lee Moffitt Cancer Center and Research Institute Tampa, Florida  33612