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Phase I/II Study of the Combination of Oxaliplatin / Docetaxel and ZACTIMA for the Treatment of Advanced Cancers of the Esophagus and Gastroesophageal Junction


Phase 1
18 Years
N/A
Not Enrolling
Both
Adenocarcinoma of the Gastroesophageal Junction, Esophageal Cancer

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Trial Information

Phase I/II Study of the Combination of Oxaliplatin / Docetaxel and ZACTIMA for the Treatment of Advanced Cancers of the Esophagus and Gastroesophageal Junction


OBJECTIVES:

Primary

- To determine the maximum tolerated dose of vandetanib when administered with
oxaliplatin and docetaxel in patients with advanced cancer of the esophagus or
gastroesophageal junction. (Phase I)

- To evaluate the toxicity of this regimen in these patients. (Phase I)

- To determine the progression-free survival of these patients. (Phase II)

Secondary

- To determine the response rate in patients treated with oxaliplatin and docetaxel with
or without vandetanib. (Phase II)

- To determine the overall survival of patients treated with these regimens. (Phase II)

- To determine the toxicity of these regimens in these patients. (Phase II)

- To determine whether tumor characteristics (e.g., EGFR/ErbB2 expression, activation and
mutational status of the EGFR and ErbB2 pathway [total and phosphorylated EGFR and
ErbB2, mutational and FISH analysis] and tumoral expression of HIF1-alpha) may have an
association with response and outcome. (Phase II)

OUTLINE: This is a multicenter, phase I, dose-escalation study of vandetanib followed by a
randomized phase II study.

Patients are stratified according to histology (adenosarcoma vs squamous cell carcinoma) and
prior neoadjuvant/adjuvant chemotherapy/chemoradiotherapy (yes vs no). Patients are
randomized to 1 of 2 treatment arms. Patients in phase I receive treatment as in phase II
arm I.

- Phase II arm I: Patients receive docetaxel IV over 1 hour on days 1 and 8, oxaliplatin
IV over 2 hours on day 1, and oral vandetanib (at the maximum tolerated dose determined
in phase I) once daily on days 1-21. Treatment repeats every 21 days for up to 8
courses in the absence of disease progression or unacceptable toxicity. Patients with
responding or stable disease may continue to receive vandetanib beyond 8 courses in the
absence of disease progression or unacceptable toxicity.

- Phase II arm II: Patients receive docetaxel and oxaliplatin as in arm I. Patients also
receive an oral placebo once daily on days 1-21. Treatment repeats every 21 days for up
to 8 courses in the absence of disease progression or unacceptable toxicity. Patients
with responding or stable disease may continue to receive vandetanib beyond 8 courses
in the absence of disease progression or unacceptable toxicity.

Patients enrolled in phase II submit baseline tumor tissue samples for correlative
laboratory studies, including analysis of EGFR and ErbB2 by mutational, FISH, and IHC
analysis and HIF1-alpha expression by IHC analysis.

Inclusion Criteria


DISEASE CHARACTERISTICS:

- Histologically confirmed advanced adenocarcinoma or squamous cell carcinoma of the
esophagus or gastroesophageal junction

- Patients with locally advanced, unresectable disease are eligible provided they
failed prior radiation-based therapy

- At least one measurable lesion

- No active CNS metastases as indicated by clinical symptoms, cerebral edema, or
progressive growth

- Patients with a clinical history of CNS metastases or cord compression are
eligible provided they have been definitively treated and are clinically stable
for ≥ 4 weeks (if treated with whole brain irradiation) or for ≥ 2 weeks (if
treated with gamma knife therapy)

PATIENT CHARACTERISTICS:

- ECOG performance status 0-1

- Life expectancy > 12 weeks

- Hemoglobin > 9.5 g/dL

- ANC > 1,500/μL

- Platelets > 100,000/μL

- Total bilirubin normal

- Creatinine < 1.5 times upper limit of normal (ULN)

- Creatinine clearance ≥ 30 mL/min

- AST, ALT, and alkaline phosphatase (AP) must meet one of the following criteria:

- AST or ALT ≤ 5 times ULN AND AP normal

- AST or ALT ≤ 1.5 times ULN AND AP ≤ 2.5 times ULN

- AST or ALT normal AND AP ≤ 5 times ULN

- Potassium between 4 mmol/L and the upper limit of CTCAE grade 1 (supplementation
allowed)

- Calcium (ionized or adjusted for albumin) and magnesium normal (supplementation
allowed)

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception during and for ≥ 3 months after
completion of study treatment

- No significant cardiovascular events within the past 3 months, including the
following:

- Myocardial infarction

- Superior vena cava syndrome

- NYHA class II-IV congestive heart failure

- No cardiac disease that, in the opinion of the investigator, may increase the risk of
ventricular arrhythmia

- No prior arrhythmia (e.g., multifocal premature ventricular contractions, bigeminy,
trigeminy, ventricular tachycardia, or uncontrolled atrial fibrillation) that is
symptomatic or requires treatment (CTCAE grade 3)

- Atrial fibrillation allowed provided it is controlled with medication

- No asymptomatic sustained ventricular tachycardia

- No hypertension not controlled by medical therapy (i.e., systolic blood pressure [BP]
> 160 mm Hg or diastolic BP > 100 mm Hg)

- No QTc prolongation with other medication that required discontinuation of that
medication

- No congenital long QT syndrome or 1st degree relative with unexplained sudden death
under 40 years of age

- QTc is < 480 with Bazett's correction on screening ECG at baseline

- No presence of left bundle branch block

- No active diarrhea > CTC grade 1

- No prior severe hypersensitivity reaction to docetaxel or other drugs formulated with
polysorbate 80

- No prior allergic reactions to compounds of similar chemical or biologic composition
to study drugs

- No other severe acute or chronic medical or psychiatric condition or laboratory
abnormality that, in the opinion of the investigator, would preclude study
participation

- No other malignancy within the past 5 years, except for curatively treated basal cell
carcinoma of the skin, cervical intra-epithelial neoplasia, or localized prostate
cancer with a current PSA of < 1.0 mg/dL on 2 successive evaluations ≥ 3 months
apart, with the most recent evaluation performed within the past 4 weeks

- No peripheral neuropathy > grade 1

- No blood donation during and for 3 months after completion of study treatment

- No severe or uncontrolled systemic disease or other medical condition, including
mental illness or substance abuse, that would preclude study participation

PRIOR CONCURRENT THERAPY:

- See Disease Characteristics

- Recovered from prior therapy

- No prior systemic therapy for metastatic disease

- Prior chemotherapy given as part of a definitive treatment plan (e.g.,
neoadjuvant or adjuvant chemotherapy or concurrent chemoradiotherapy) allowed

- More than 6 months since prior oxaliplatin and docetaxel as neoadjuvant or adjuvant
therapy

- More than 4 weeks since prior major surgery, chemotherapy, radiotherapy,
investigational agents, or other cancer therapy

- No prior anti-VEGF or EGFR therapy, including bevacizumab

- More than 2 weeks since prior and no concurrent potent CYP3A4 inducers
(e.g.,rifampin, rifabutin, phenytoin, carbamazepine, phenobarbital, and Hypericum
perforatum [St. John's wort])

- More than 2 weeks since prior and no concurrent medications known to cause QTc
prolongation or to induce torsades de pointes

- No other concurrent chemotherapy, systemic antineoplastic therapy, or investigational
therapy

- No concurrent radiotherapy, unless for local control of bone pain

- No concurrent cold cap or iced mouth rinses for prevention of alopecia or stomatitis

- No concurrent routine prophylactic use of granulocyte colony-stimulating factor
(G-CSF) or pegfilgrastim

- No concurrent vitamin B6 supplementation, except as part of a standard multivitamin

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum tolerated dose of vandetanib when administered with oxaliplatin and docetaxel (Phase I)

Outcome Time Frame:

Each cycle of treatment consists of 21 days. Dose-limiting toxicities will be defined during cycle 1 of therapy. Patients will need to be observed for at least 2 cycles. A maximum of eight cycles of chemotherapy will be allowed.

Safety Issue:

Yes

Principal Investigator

Afshin Dowlati, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Case Medical Center, University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center

Authority:

United States: Institutional Review Board

Study ID:

CASE6507

NCT ID:

NCT00732745

Start Date:

October 2008

Completion Date:

Related Keywords:

  • Adenocarcinoma of the Gastroesophageal Junction
  • Esophageal Cancer
  • adenocarcinoma of the esophagus
  • adenocarcinoma of the gastroesophageal junction
  • squamous cell carcinoma of the esophagus
  • stage III esophageal cancer
  • stage IV esophageal cancer
  • recurrent esophageal cancer
  • Adenocarcinoma
  • Adenocarcinoma, Mucinous
  • Esophageal Diseases
  • Esophageal Neoplasms

Name

Location

Case Medical Center, University Hospitals Seidman Cancer Center, Case Comprehensive Cancer CenterCleveland, Ohio  44106-5065