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An Open Label Phase I Study of Gemcitabine/Oxaliplatin (GEMOX) and Vandetanib (ZACTIMA; ZD6474) Combination in Patients With Advanced Solid Malignancy (IRUSZACT0070) (UPCI 07-025)

Phase 1
18 Years
Open (Enrolling)
Advanced Incurable Solid Malignancy

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Trial Information

An Open Label Phase I Study of Gemcitabine/Oxaliplatin (GEMOX) and Vandetanib (ZACTIMA; ZD6474) Combination in Patients With Advanced Solid Malignancy (IRUSZACT0070) (UPCI 07-025)

This is a Phase I, open-label, dose-escalating, non-randomized study of the safety and
tolerability of vandetanib in combination with a fixed dose of gemcitabine and oxaliplatin
(GemOx) in the treatment of patients with advanced solid malignancy. EGFR is an important
target for therapeutic drug development. It is widely expressed in most cancers and has a
vital role in the regulation of proliferation signals. EGFR is expressed in a high degree
(>80%) of pancreatic tumors and is a rational target for therapy. Vandetanib selectively
inhibits EGFR tyrosine kinase activity and VEGF-2 receptor. It has good oral bioavailability
and has growth inhibitory activity in a wide variety of human cell lines including cells
with acquired resistance to other EGFR inhibitors. The growth inhibitory property of
vandetanib in vivo correlates more with its anti VEGF property, especially in cell lines
with acquired resistance to EGFR inhibition. The combination of gemcitabine and oxaliplatin
(GEMOX) is a well-established regimen that has demonstrated encouraging antitumor activity
in pancreaticobiliary cancers in phase II studies. Recent clinical trials have also shown
activity in hepatobiliary and germ cell tumors. The combination of vandetanib and
gemcitabine has potential advantages and may result in an additive or synergistic effect.
The GEMOX regimen is well tolerated, and toxicity does not overlap with the most common
toxicity of rash or diarrhea observed with vandetanib. Thus, the combination of vandetanib
and GEMOX is expected to be a well tolerated, and an easily administered regimen with
improved efficacy and no overlapping toxicities.

Inclusion Criteria:

- Patients with advanced incurable solid malignancy who are likely to benefit from
GEMOX therapy.

- Provision of informed consent prior to any study procedures.

- Females and males age ≥18 years

- Histological/cytological confirmation of malignancy

- Negative pregnancy test for women of childbearing potential

- ECOG performance status of 0 or 1

- Ability to take oral medications without difficulty

- Adequate bone marrow function: ANC >1500/L and platelet count >100,000/dL

- Adequate hepatic function: Total Bilirubin ≤ 1.5 x ULN, ALT/AST ≤ 2.5 x ULN (≤ 5 x
ULN in case of liver metastasis), ALP ≤ 2.5 x ULN (≤ 5 x ULN in case of liver

- Serum calcium in normal range (ionized or adjusted for albumin), Serum magnesium in
normal range, Serum Potassium ≥ 4.0 mmol/L. Supplementation allowed.

- Serum Cr < 1.5 x UNL or Creatinine Clearance ≥ 50 mL/min calculated by
Cockcroft-Gault formula

- Men and women of childbearing potential must be willing to practice acceptable
methods of birth control.

- Patients with brain metastasis should have received appropriate therapy and have
stable disease at least 4 weeks after radiotherapy/surgery.

- Subjects should have recovered from side effects of prior therapy to grade 1 or less

Exclusion Criteria:

- Evidence of severe or uncontrolled systemic disease or any concurrent condition which
in the Investigator's opinion makes it undesirable for the patient to participate in
the trial or which would jeopardize compliance with the protocol.

- Clinically significant cardiovascular event (e.g. myocardial infarction, superior
vena cava syndrome (SVC), New York Heart Association (NYHA) classification of heart
disease ≥2 within 3 months before entry; or presence of cardiac disease that, in the
opinion of the Investigator, increases the risk of ventricular arrhythmia.

- History of arrhythmia (multifocal premature ventricular contractions PVCs), bigeminy,
trigeminy, ventricular tachycardia, or uncontrolled atrial fibrillation) which is
symptomatic or requires treatment (CTCAE grade 3) or asymptomatic sustained
ventricular tachycardia. Atrial fibrillation, controlled on medication is not

- Previous history of QTc prolongation with other medications that required
discontinuation of that medication.

- Congenital long QT syndrome or 1st degree relative with unexplained sudden death
under 40 years of age.

- Presence of left bundle branch block (LBBB.)

- QTc with Bazett's correction that is unmeasurable, or ≥480 msec on screening ECG.
(Note: If a subject has a QTc interval ≥480 msec on screening ECG, the screen ECG
may be repeated twice (at least 24 hours apart). The average QTc from the three
screening ECGs must be <480 msec in order for the subject to be eligible for the
study.) Patients who are receiving a drug that has a risk of QTc prolongation are
excluded if QTc is ≥ 460 msec.

- Any concurrent medication that may cause QTc prolongation or induce Torsades de

- Hypertension not controlled by medical therapy (systolic blood pressure greater than
160 mm Hg or diastolic blood pressure greater than 100 mm Hg)

- Currently active diarrhea that may affect the ability of the patient to absorb the
vandetanib or tolerate diarrhea.

- Women who are currently pregnant or breast feeding.

- Receipt of any investigational agents within 30 days or commercially available agents
within 21 days prior to commencing study treatment

- Last dose of prior chemotherapy discontinued less than 4 weeks before the start of
study therapy

- Last radiation therapy within the last 4 weeks before the start of study therapy,
except palliative radiotherapy for less than 12 fractions

- Any unresolved toxicity greater than CTCAE grade 1 from previous anti-cancer therapy

- Previous enrollment or randomization of treatment in the present study

- Major surgery within 4 weeks, or incompletely healed surgical incision before
starting study therapy

- Peripheral neuropathy grade 2 or of greater severity of any cause

- More than 2 prior systemic chemotherapy regimens for advanced stage disease. Prior
adjuvant chemotherapy will not count as a prior regimen.

- Known severe hypersensitivity to vandetanib or any of the excipients of these

- Previous or current malignancies of other histologies within the last 5 years, with
the exception of cervical carcinoma in situ and adequately treated basal cell or
squamous cell carcinoma of the skin.

- Concomitant medications that are potent inducers (rifampicin, rifabutin, phenytoin,
carbamazepine, phenobarbital and St. John's Wort) of CYP3A4 function.

Type of Study:


Study Design:

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

Outcome Measure:

To establish the Maximum Tolerated Dose (MTD) and toxicities of vandetanib (Zactima; ZD6474) in combination with fixed dose of GEMOX (gemcitabine/oxaliplatin) and to establish the recommended phase II dose of the GEMOX and vandetanib regimen

Outcome Time Frame:

The MTD (and recommended phase II dose) is defined as the highest dose at which <2 of 6 patients experience DLT. The observation period for DLT is the first cycle of therapy.

Safety Issue:


Principal Investigator

Leonard J. Appleman, M.D., Ph.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of Pittsburgh


United States: Food and Drug Administration

Study ID:




Start Date:

February 2009

Completion Date:

October 2013

Related Keywords:

  • Advanced Incurable Solid Malignancy
  • Gemcitabine
  • Oxaliplatin
  • Vandetanib
  • Phase I
  • Neoplasms



University of Pittsburgh Cancer Institute / Hillman Cancer Center Pittsburgh, Pennsylvania  15232