A Targeted Phase I/II Trial of ZD6474 (Vandetanib; ZACTIMA) Plus the Proteasome Inhibitor, Bortezomib (Velcade ), in Adults With Solid Tumors With a Focus on Hereditary or Sporadic, Locally Advanced or Metastatic Medullary Thyroid Cancer (MTC)
| Status: | Terminated |
|---|---|
| Conditions: | Breast Cancer, Lung Cancer, Prostate Cancer, Colorectal Cancer, Ovarian Cancer, Cervical Cancer, Cancer, Cancer, Women's Studies, Endocrine, Thyroid Cancer |
| Therapuetic Areas: | Endocrinology, Oncology, Reproductive |
| Healthy: | No |
| Age Range: | 18 - 80 |
| Updated: | 12/1/2018 |
| Start Date: | February 19, 2009 |
| End Date: | December 9, 2016 |
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.
- 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.
- 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.
-INCLUSION CRITERIA:
1. Pathologic confirmation of cancer by the Laboratory of Pathology, National Cancer
Institute (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 Response Evaluation Criteria in Solid
Tumors (RECIST) or by measurement of serum markers (calcitonin, carcinoembryonic
antigen (CEA), prostate specific antigen (PSA) or cancer antigen 125 or carbohydrate
antigen 125 (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 Eastern Cooperative Oncology Group (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 Common Terminology Criteria in Adverse Events (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 upper limit of the reference
range (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 lower limit of normal (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)
- Prothrombin time (PT) less than or equal to 4 seconds above ULN and partial
thromboplastin time (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 National Cancer Institute (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 four months 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
Investigators 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.
- There is one other exception to the exclusion of secondary malignancies: multiple
endocrine neoplasia type 2 (MEN2) patients with concurrent medullary thyroid cancer
and pheochromocytoma may be enrolled at the discretion of the Principal Investigator.
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. Corrected QT interval (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 Q wave, T wave (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 electrocardiogram (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 cytochrome P450 3A4 (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.
We found this trial at
1
site
9000 Rockville Pike
Bethesda, Maryland 20892
Bethesda, Maryland 20892
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