| City: |
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Bethesda |
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State:
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MD |
| Zip Code: |
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20892 |
| Conditions: |
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Breast Cancer - Colon Cancer - Prostate Cancer - Lung Cancer - Adrenal Cancer - Renal Cancer - Gastric Cancer - Ovarian Cancer - Cervical Cancer - Thyroid Cancer - Sarcoma |
| Purpose: |
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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...
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| Study summary: |
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Background:
- Vandetanib (ZACTIMA; 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(Registered Trademark)), a proteasome inhibitor, has been
reported to have several putative mechanisms of action and it is likely that its
toxcitiy is mediated by affecting more than one pathway or target. Bortezomib is
reported to inhibit the 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 RECIST
and tumor biomarkers including 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 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 MTD/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. |
| Criteria: |
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-INCLUSION CRITERIA:
1. Pathologic confirmation of cancer by the Laboratory of Pathology, NCI
2. Phase I: Diagnosis of recurrent, metastatic or primary unresectable solid tumor that
does not have curative standard treatment.
Phase II: Diagnosis of recurrent, metastatic or primary unresectable medullary
thyroid cancer (MTC).
3. Measurable disease at presentation: Either by RECIST or by measurement of serum
markers (calcitonin, CEA, PSA or CA-125) in the dose-finding portion of the study;
with disease measurable by RECIST required only in the phase II cohort.
4. A life expectancy of at least 3 months and ECOG performance status 0 - 1.
5. Age greater than or equal to 18 years
6. Last dose of chemotherapy or experimental therapy more than 4 weeks (6 weeks in the
case of nitrosourea) prior to enrollment date; unless the last therapy consisted of
an oral agent whose average half life is known to be less than 48 hours in which case
only 2 weeks need to have elapsed. Regardless of the therapy, any toxicity greater
than CTCAE grade 1 from previous anti-cancer therapy must have been resolved.
7. Last radiotherapy treatment 4 weeks prior to starting treatment with this protocol -
with the exception of palliative radiotherapy - and there must be sites of measurable
disease that did not receive radiation.
8. Organ and marrow function as defined:
- total bilirubin less than 1.5 times the upper limit of reference range (ULRR),
unless the patient meets the criteria for Gilbert's Syndrome
- alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline
phosphatase (ALP) all three less than 2.5 times the ULRR, or less than 5 times
the ULRR if judged by the investigator to be related to liver metastases
- serum creatinine less than 1.5 times the ULRR or creatinine clearance greater
than or equal to 30 mL/minute (calculated by Cockcroft-Gault formula or measured
in a timed urine collection)
- serum calcium below the CTCAE grade 1 upper limit (11.5mg/dL or 2.9 mmol/L). In
cases where the serum calcium is below the normal range, the calcium adjusted
for albumin is calculated and substituted for the measured value.
- serum potassium greater than the LLN and less than 5.5 mmol/L.
- serum magnesium greater than the LLN and less than 3.0 mg/dL or 1.23 mmol/L.
- absolute neutrophil count greater than or equal to 1000/mm(3)
- platelet count greater than or equal to 100,000/mm(3)
- PT less than or equal to 4 seconds above ULN and PTT less than or equal to 10
seconds above ULN.
9. Ability to understand and sign an informed consent document.
10. Provision of informed consent prior to any study-related procedures
11. Negative pregnancy test for women of childbearing potential
12. Ability and willingness to follow the guidelines of the clinical protocol including
visits to NCI, Bethesda, Maryland for treatment and follow up visits.
13. Because the effects of chemotherapy on the developing human fetus are potentially
harmful, female patients must be one year post-menopausal, surgically sterile, or
using an acceptable method of contraception during and continued after the last dose
of study medications (oral contraceptives, barrier methods, approved contraceptive
implant, long-term injectable contraception, intrauterine device or tubal ligation).
Male patients must be surgically sterile or using an acceptable method of
contraception during their participation in this study. Contraceptive use will
continue for at least two months, five half-lives, after the last dose of study
medication.
EXCLUSION CRITERIA:
1. Patients with cancer potentially curable by surgical excision alone or patients who
have not received therapy that might be considered standard and potentially curable.
2. Evidence of severe or uncontrolled systemic disease or any concurrent condition -
including, but not limited to symptomatic congestive heart failure, unstable angina
pectoris, unstable hypertension, seizure disorder, or psychiatric illness - 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.
3. Untreated brain metastases (or local treatment of brain metastases within the last 6
months) due to the poor prognosis of these patients and difficulty ascertaining the
cause of neurologic toxicities.
4. During Phase II enrollment: Prior therapy with vandetanib.
5. Women who are currently pregnant or breast-feeding, due to the possible adverse
effects on the developing fetus and infants.
6. The presence of a second malignancy within the last 2 years, other than squamous cell
carcinoma of the skin or in situ cervical cancer because it will complicate the
primary objective of the study. Cancer survivors who have been free of disease for at
least two years can be enrolled in this study.
7. Patients with evidence of a bleeding diathesis that cannot be corrected with standard
therapy or factor replacement.
8. Any unresolved toxicity greater than CTCAE grade 1 (except alopecia) from previous
anticancer therapy. Patients with grade 1 neuropathy will be evaluated on a case by
case basis for entry into study. Baseline conditions will be taken into
consideration.
9. Major surgery within 4 weeks, or incompletely healed surgical incision before
starting study therapy.
10. Clinically significant cardiovascular event (e.g. myocardial infarction, superior
vena cava syndrome (SVC), New York Heart Association (NYHA) classification of heart
disease greater than or equal to 2 within 3 months before entry; or presence of
cardiac disease that, in the opinion of the Investigator, increases the risk of
ventricular arrhythmia.
11. 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
excluded.
12. History (within the last 6 months) or presence of stroke/cerebrovascular accident.
13. QTc prolongation with other medications. If the medication can be discontinued and an
alternative medication started that does not cause QTc prolongation, the patient
would be eligible. If no alternative medication is available and the medication
cannot be discontinued for medical reasons, then the patient would not be eligible.
14. Congenital long QT syndrome, or 1st degree relative with unexplained sudden death
under 40 years of age.
15. Presence of left bundle branch block (LBBB).
16. QTc with Bazett's correction that is not measurable, or greater than or equal to 480
msec on screening ECG. (Note: If a patient has a QTc interval greater than or equal
to 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 less than 480 msec in
order for the patient to be eligible for the study). Patients who are receiving a
drug that has a risk of QTc prolongation are excluded if QTc is greater than or equal
to 460 msec.
17. Concurrent medication that may cause QTc prolongation or induce Torsades de Pointes:
Those medications in Group One will not be allowed. Those medications in Group Two
will be allowed.
18. Hypertension not controlled by medical therapy (systolic blood pressure greater than
160 mm Hg or diastolic blood pressure greater than 100 mm Hg)
19. Currently active (uncontrolled) diarrhea greater than or equal to CTCAE Grade 2 that
may affect the ability of the patient to absorb the vandetanib or tolerate diarrhea.
Antidiarrhea medications are allowed in patients with chronic diarrhea.
20. Concomitant medications that are potent inducers (rifampicin, rifabutin, phenytoin,
carbamazepine, phenobarbital and St. John's Wort) of CYP3A4 function.
21. Major surgery within 4-weeks, or incompletely healed surgical incision before
starting study medications. Biopsies, port placements, and dental work are examples
of acceptable (nonmajor) surgery within the 4 week time frame.
22. Inability to take oral medications for whatever reason. |
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| Study is available at: |
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National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, MD 20892
United States
Primary Contact:
NCI Referral Office
Email: ncicssc@mail.nih.gov
Phone: 1-888-NCI-1937 |
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If you are interested in this clinical trial please use the contact information above. If you would like to get additional information about this clinical trial please visit ClinicalTrials.gov.
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| Data Source: |
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ClinicalTrials.gov |
| Date Processed: |
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March 23, 2011 |
Modifications to
this listing: |
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Only selected fields are shown, please use the link
above to view all information about this clinical trial. |
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