Medullary Thyroid Carcinoma Clinical Trial
Official title:
A Targeted Ph I/II Trial of ZD6474 (Vandetanib; CAPRELSA) Plus the Proteasome Inhibitor, Bortezomib (Velcade ), in Adults With Solid Tumors With a Focus on Hereditary or Sporadic, Locally Advanced or Metastatic Medullary Thyroid Ca (MTC)
Background:
- The combination of anti-cancer drugs vandetanib (given orally) and bortezomib (given
intravenously) has not been used in humans. However, both drugs have been studied
separately. Bortezomib has been approved by the U.S. Food and Drug Administration (FDA)
for treating multiple myeloma and mantle cell lymphoma, while vandetanib is still under
investigation pending FDA approval.
- Both bortezomib and vandetanib are under investigation for use in treating certain kinds
of cancer. Researchers hope that the combination of these two drugs will be more
effective than either of them alone.
Objectives:
- To determine if the combination of vandetanib and bortezomib will decrease the amount of
the cancer and, if it does, to determine how long the response will last.
- To determine any side effects that may occur with this combination of treatments.
- To determine what doses of each drug are well tolerated and safe when given together.
- To study genetic mutations in tumors to better understand how tumors grow and how these
drugs interact with the tumor.
Eligibility:
- Patients 18 years of age and older with solid tumors that cannot be surgically removed
and have either recurred or shown further growth. The tumor(s) must be able to be
evaluated by X-ray, MRI (magnetic resonance imaging), and CT (computerized tomography)
scanning.
- Patients who have been diagnosed with medullary thyroid cancer will participate in Phase
II of the study.
Design:
- Tumor samples may be taken at the start of the study for research purposes.
- Phase I: Patient groups will be treated on an outpatient basis with vandetanib and
bortezomib, given at increasing doses over four different levels to determine the
maximum tolerated dose calculated by height and weight:
- Doses will be given on Days 1, 4, 8, and 11 for each 28-day cycle.
- Two additional levels (Level 1A and Level 1B) may be included in the study, depending on
side effects at various levels.
- Phase II: Patients with medullary thyroid cancer will be divided into two groups, with
two patients in Group A for every one patient in Group B. No placebo will be involved in
this study.
- Group A: Patients will be treated with vandetanib and bortezomib at the maximally
tolerated dose of the Phase I study.
- Group B: Patients will be treated with bortezomib alone.
- A second tumor sample may be taken. In patients with thyroid cancer, the second biopsy
will be done at the 6-week evaluation (approximately 42 days after beginning). In
patients with cancer other than thyroid cancer, the second biopsy will be obtained on
Day 4 of either the first or second cycle, after the bortezomib infusion.
- The effects of the drugs will be studied through blood samples and CT scans taken during
and after various drug cycles.
Background:
- Vandetanib (CAPRELSA; ZD6474) potently inhibits vascular endothelial growth factor
receptor-2 (VEGFR-2), and shows additional inhibitory activity at sub-micromolar
concentrations against the Rearranged during Transfection (RET) receptor, Flt-4 and EGF
receptor tyrosine kinases.
- Clinical trials have shown that vandetanib is active against medullary thyroid
carcinomas (MTCs), but the activity is characterized by partial responses of variable
duration, underscoring the need to develop active combinatorial regimens.
- Bortezomib (PS-341, Velcade ), a proteasome inhibitor, has been reported to have several
putative mechanisms of action and it is likely that its toxicity is mediated by
affecting more than one pathway or target. Bortezomib is reported to inhibit the nuclear
factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) pathway and regulate
NF-kappaB-dependent expression of several other inhibitors of apoptosis.
- In vitro studies have shown bortezomib to be active against a broad range of thyroid
cancer cell lines. Given this activity of bortezomib and the role of the proteasome in
regulating diverse cellular pathways, this study proposes to combine bortezomib with
vandetanib to treat patients with advanced solid tumors with a focus on patients with
MTC.
Objectives:
- To assess the activity of vandetanib plus bortezomib in adults with MTC, using Response
Evaluation Criteria in Solid Tumors (RECIST) and tumor biomarkers including
carcinoembryonic antigen (CEA) and calcitonin as endpoints.
- To assess the safety and tolerance of vandetanib plus bortezomib in dose-seeking
cohorts.
- To compare the combination bortezomib plus vandetanib versus vandetanib alone in adults
with MTC by assessing the response rate and progression-free survival
- In exploratory analyses: (a) examine the correlation between genotype and response to
therapy in patients with MTC, (b) examine the extent, if any, of rearranged during
transfection (RET) inhibition in patients with MTC following the administration of
vandetanib; and (c) examine the effect, if any, of bortezomib on microtubules.
Eligibility:
- Adults age 18 and older with unresectable, recurrent or metastatic solid tumors,
including MTC.
- Disease must be evaluable by RECIST.
Design:
- Phase I dose-escalation study followed by randomized phase II trial.
- Maximum total number for planned enrollment: 117 - Dose-seeking cohorts of three to 6
patients until maximum tolerated dose (MTD)/dose limiting toxicity (DLT) reached (up to
24 patients) followed by a randomized phase II trial comparing the activity of the
combination of bortezomib plus vandetanib with vandetanib alone (2:1 randomization 62
plus 31 equals 93 patients).
- The MTD and DLT will be determined based on toxicities during the first eight weeks of
combined therapy.
- Cycle length will be four weeks. Response will be determined by RECIST every 12 weeks.
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