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A Pilot Study to Assess the Safety and Feasibility of Autologous Tumor Cell-TLR9 Agonist Vaccination Prior to Autologous Hematopoietic and Immune Cell Rescue in Metastatic Colorectal Cancer

Phase 1
18 Years
Not Enrolling
Colorectal Neoplasms, Anal, Colon, and Rectal Cancers

Thank you

Trial Information

A Pilot Study to Assess the Safety and Feasibility of Autologous Tumor Cell-TLR9 Agonist Vaccination Prior to Autologous Hematopoietic and Immune Cell Rescue in Metastatic Colorectal Cancer

As the third most common cancer in incidence and second in mortality, colorectal cancer
(CRC) significantly impacts the lives of many Americans.1 In 2008, it is estimated that
148,810 cases will be diagnosed and 49,960 patients will die from this disease.
Approximately 20% of patients present with metastatic disease at diagnosis. The
introduction of more effective chemotherapy regimens and biologically targeted agents over
the last few years has led to considerable improvement in treatment options for metastatic
CRC yet median survival approximates only 2 years. Resection of the primary tumor when
clinically indicated followed by combinations of oxaliplatin or irinotecan with intravenous
or oral 5-FU, leucovorin, and bevacizumab for first-line therapy of metastatic CRC is
standard of care.

In 2004, Goldberg and colleagues established FOLFOX4 as the standard of care chemotherapy
regimen in metastatic CRC when they demonstrated its superiority over two older regimens,
IFL (bolus 5-FU/leucovorin/irinotecan) and IROX (irinotecan/oxaliplatin), in terms of
prolonging median overall survival (OS), progression-free survival (PFS), and increased
response.2 FOLFOX4 increased median survival time to 19.5 months compared to 15 months and
17.4 months for IFL and IROX respectively (p= .0001; HR .66, 95% CI 0.54-0.82). Time to
progression was also significantly increased to 8.7 months compared to 6.9 and 6.5 months
(p=.0014). Furthermore FOLFOX-4 effected a 45% overall response rate compared to 31%
(p=.002) and 35% (p=.03) for IFL and IROX respectively. It also induced significantly less
associated grade; 3 nausea, vomiting, diarrhea, febrile neutropenia, and dehydration than
the other two regimens.

Hoping to improve this regimen further, capecitabine, an oral pro-drug of 5-FU, was
introduced. It has significant advantages over infusional 5-FU including ease of
administration with its oral formulation, lack of infusion-related toxicities, and decreased
duration of hospitalization and clinic time. Multiple trials have pitted capecitabine-based
therapies against infusional 5-FU regimens and have shown comparable efficacy.3-8 Overall
toxicity profiles are also comparable between the two regimens with the exception of less
myelosuppression and more hand-foot syndrome with capecitabine compared to the
infusional-5-FU-based regimens. Thus, in clinical practice, CAPOX
(capecitabine-oxaliplatin) is largely considered to be a comparable regimen to FOLFOX, with
significantly more convenient administration.

The addition of targeted therapies that inhibit vascular endothelial growth factor (VEGF)
and endothelial growth factor receptor (EGFR) to the 5-FU/LV regimens have further increased
survival. Bevacizumab, a monoclonal antibody against VEGF, was approved for metastatic CRC
in 2004 after the pivotal phase III trial, AVF2107g, showed a significant improvement in OS
from 15.6 months to 20.3 months (HR for death, 0.66, p <0.001) with the addition of
bevacizumab to IFL.9 PFS and response were also significantly increased from 6.2 months to
10.6 months (p<0.001) and 34.8% to 44.8% (p= 0.004) respectively. The first phase III trial
to evaluate the combination of bevacizumab with oxaliplatin-based chemotherapy (FOLFOX-4 or
CAPOX), NO16966, demonstrated that the addition of bevacizumab improved PFS by 1.4 months
(9.4 vs. 8.0 months, HR 0.83, p=.0023) but overall response rates were similar.10 Median
OS also increased from 19.9 months in the placebo group to 21.3 months in the bevacizumab
arm but was not statistically significant (HR 0.89, p=.077).

Cetuximab, a mouse/human chimeric monoclonal antibody to EGFR, has also shown promise in
metastatic CRC.11, 12 The BOND trial, a multicenter randomized phase II trial showed a
significant doubling of response rate and a 2.6 month increase in PFS with the combination
of irinotecan-cetuximab over cetuximab alone in the second line setting, but no difference
in median OS.11 These results led the FDA to approve cetuximab in February 2004 for
second-line treatment either as a monotherapy in those who cannot tolerate irinotecan or in
combination with irinotecan in those who do not have a response to irinotecan alone. The
CRYSTAL trial, a phase III multicenter randomized trial also demonstrated that cetuximab
holds promise in the first line setting.13 In this trial (n=1217), the addition of
cetuximab to FOLFIRI significantly increased response rate by 6% (46.9% vs. 38.7%, p=0.005)
and PFS by 1.9 months (p=0.036). Trials evaluating the first line use of cetuximab with
oxaliplatin-based regimens appear promising and are ongoing.14, 15 When using cetuximab, the
presence of K-RAS mutations must be considered. Activating mutations in the K-RAS gene are
present in 40-45% of colorectal cancer patients.16 The presence of these mutations
correlates with a worse outcome and a lack of response to cetuximab in patients with
advanced chemotherapy-refractory CRC.17, 18 Even with these new agents and improved
combinations, median survival for metastatic CRC patients remains less than 2 years with
less than 5%surviving to 5 years.19 Furthermore, one can expect 20% of patients to progress
within 4-6 months.10 Better regimens and treatments are greatly needed to impact this
pervasive and fatal disease.

Inclusion Criteria:

- Histologically confirmed Stage IV, TxNxM1 colon adenocarcinoma with a
surgically accessible primary or metastatic site.

- Estimated survival of 6 months or greater

- Primary may be in place

- Age 18-70

- Must have an ECOG performance status of 0 or 1

- Must have adequate organ and marrow function. Specifically:

- Absolute neutrophil count (ANC) > 1500/uL

- Platelet count >= 100 x 109/L

- Total bilirubin <= 2.0 x the upper limit of normal (ULN)

- Alkaline phosphatase, AST, and/or ALT <2.5 x the ULN for patients

- without evidence of liver metastases; <5 X ULN for patients with

- documented liver metastases

- Serum creatinine < 2.0 mg/dL

- Hemoglobin > 9 g/dL

a. Patients may be transfused or receive epoetin alfa to maintain or exceed this
level up to the hemoglobin level recommended on the current label for epoetin
alfa. There is concern that hemoglobin levels greater than the level recommended
by the current labeling have been associated with the potential increased risk
of thrombotic events and increased mortality. Also, a rapid increase in
hemoglobin may exacerbate hypertension (a concern in patients with pre-existing
hypertension and if bevacizumab is administered).

- Cardiac ejection fraction >40 % by transthoracic echo or MUGA scan within 12 wks
of transplant

- Adequate pulmonary function tests (PFTs) within 6 wks of transplant

a. DLCO >=60% predicted

- Patients must be HIV negative

- No prior therapy which would preclude the use of total body irradiation

- Pathology must be reviewed and diagnosis confirmed by Stanford University Medical

- Ability to understand and the willingness to sign a written informed consent

- Ability and capacity to comply with the study and follow-up procedures.; Exclusion
Criteria:- Disease-Specific Exclusions

- Radiotherapy within 28 days prior to the day of tumor resection (Day 1).

- No myelosuppressive chemotherapy within 28 days prior to the day of tumor

- History of brain metastases, regardless if treated.

- Co-morbid diseases or intercurrent illness

- Active infection or fever > 38.5°C within 3 days of starting treatment

- History of other malignancies within 5 years prior to Day 1 except for tumors
with a negligible risk for metastasis or death, such as adequately controlled
basal cell carcinoma, squamous-cell carcinoma of the skin, carcinoma in situ of
the cervix, early-stage bladder cancer, or low-grade endometrial cancer

- Malignancies that have undergone a putative surgical cure (i.e., localized
prostate cancer post-prostatectomy) within 5 years prior to Day 1 may be
discussed with the Medical Monitor.

- History or presence of autoimmune disorders requiring treatment

- Any other medical conditions (including mental illness or substance abuse)
deemed by the clinician to be likely to interfere with a patient's ability to
provide informed consent, cooperate, or participate in the study, or to
interfere with the interpretation of the results.

- Inadequately controlled hypertension (defined as systolic blood pressure >150
and/or diastolic blood pressure > 100 mmHg on antihypertensive medications)

- Any prior history of hypertensive crisis or hypertensive encephalopathy

- New York Heart Association (NYHA) Grade II or greater congestive heart failure
(see Appendix A)

- History of myocardial infarction or unstable angina within 6 months prior to
study enrollment

- History of stroke or transient ischemic attack within 6 months prior to study

- Significant vascular disease (e.g., aortic aneurysm, aortic dissection)

- Symptomatic peripheral vascular disease

- Evidence of bleeding diathesis or coagulopathy that is not intentionally
pharmacologically-induced Serious, non-healing wound, ulcer, or bone fracture

- Proteinuria at screening as demonstrated by either:

1. Urine protein: creatinine (UPC) ratio >= 1.0 at screening OR

2. Urine dipstick for proteinuria >= 2+ (patients discovered to have >=2+
proteinuria on dipstick urinalysis at baseline should undergo a 24 hour
urine collection and must demonstrate <= 1g of protein in 24 hours to be

- Radiation-specific exclusions

o Prior radiation to >25% of the marrow

- Pregnancy

- Women who are pregnant or breast feeding, or women/men able to conceive and
unwilling to practice an effective method of birth control.

a. Women of childbearing potential must have a negative urine or serum pregnancy
test within 7 days of study entry.

- Nursing patients will be excluded

Type of Study:


Study Design:

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

Outcome Measure:

To assess the feasibility of using an autologous tumor cell vaccine in combination with standard chemotherapy followed by investigational autologous hematopoietic and immune cell rescue in terms of acceptable clinical toxicity.

Principal Investigator

George Albert Fisher M.D. Ph.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

Stanford University


United States: Food and Drug Administration

Study ID:




Start Date:

Completion Date:

Related Keywords:

  • Colorectal Neoplasms
  • Anal, Colon, and Rectal Cancers
  • Neoplasms
  • Rectal Neoplasms
  • Colorectal Neoplasms



Stanford University School of MedicineStanford, California  94305-5317