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Bortezomib

Proteasome Inhibitors

Patients will be treated with vandetanib and bortezomib to find the maximally tolerated dose

Patients will be treated with vandetanib alone.

Patients will be treated with vandetanib and bortezomib at the maximally tolerated dose (MTD) of the Phase I study

This study is designed to assess the safety, tolerance and activity of daily oral vandetanib and bortezomib on days 1, 4, 8 \& 11 every 28 days in adults

Vandetanib

Ravi A Madan, M.D.

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.

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)

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)

A maximum tolerated dose for vandetanib will be determined if dose limiting toxicity is observed in 2 or more patients at one of the dose levels being evaluated. The MTD will be the dose level immediately preceding the dose level at which DLT (e.g. defined as neutrophil count below 1000/ µL (grade 3) on 2 consecutive measurements drawn at least 72 hours OR a single neutrophil count below 500/µL occurred. Platelet count below 50,000 µL (grade 3) on 2 consecutive measurements drawn at least 72 hours apart OR a singe platelet count below 25,000/µL. A platelet transfusion administered when platelet count is below 50,000/µL is dose limiting thrombocytopenia, unless the transfusion is being administered for peri-operative coverage.

A maximum tolerated dose for bortezomib will be determined if dose limiting toxicity is observed in 2 or more patients at one of the dose levels being evaluated. The MTD will be the dose level immediately preceding the dose level at which DLT (e.g. defined as neutrophil count below 1000/ µL (grade 3) on 2 consecutive measurements drawn at least 72 hours OR a single neutrophil count below 500/µL occurred. Platelet count below 50,000 µL (grade 3) on 2 consecutive measurements drawn at least 72 hours apart OR a singe platelet count below 25,000/µL. A platelet transfusion administered when platelet count is below 50,000/µL is dose limiting thrombocytopenia, unless the transfusion is being administered for peri-operative coverage.

Response is assessed by the Response Evaluation Criteria in Solid Tumors (RECIST). Complete response is disappearance of all target lesions. Partial response is at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. Progressive disease is at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. Stable disease is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started.

Progression free survival is defined as the duration of time from start of treatment to time of progression. Progression is assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) and is defined as the appearance of one or more new lesions or unequivocal progression of existing non-target lesions. Although a clear progression of "non-target" lesions only is exceptional, the opinion of the treating physician should prevail in such circumstances, and the progression status should be confirmed at a later time by the review panel (or Principal Investigator).

Comparison of response between cohorts 1, 2A and 2B was to be determined by computed tomography scan reviews using the Response Evaluation Criteria in Solid Tumors (RECIST). Complete response is disappearance of all target lesions. Partial response is at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD.

Progression free survival is defined as the duration of time from start of treatment to time of progression. Comparison of PFS between cohorts 1, 2A and 2B was to be assessed by the Response Evaluation Criteria in Solid Tumors (RECIST). Progressive disease is at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions.

Here is the number of participants with adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE) v4.0. For the detailed list of adverse events see the adverse event module.

Calcitonin was measured by the biomarker response criteria. Complete response (CR) is normalization (≤ upper limit of normal) of CTN level following treatment, confirmed with a repeat CTN level at least 4 weeks apart. Partial response (PR) is a ≥50% decrease in the CTN level relative to the baseline level, confirmed with a repeat CTN level at least 4 weeks apart. Progressive disease is a ≥50% increase in the CTN relative to the baseline level, confirmed with a repeat CTN level at least 4 weeks apart. Stable disease is \<50% increase or decrease in CTN level relative to the baseline level.

Carcinoembryonic Antigen (CEA) was measured by the biomarker response criteria. Complete response (CR) is normalization (≤ upper limit of normal) of CEA level following treatment, confirmed with a repeat CEA level at least 4 weeks apart. Partial response (PR) is a ≥50% decrease in the CEA level relative to the baseline level, confirmed with a repeat CEA level at least 4 weeks apart. Progressive disease is a ≥50% increase in the CEA relative to the baseline level, confirmed with a repeat CEA level at least 4 weeks apart. Stable disease is \<50% increase or decrease in CEA level relative to the baseline level.

Complete response is an average of 0-2 formed stools per day for a period of at least 4 weeks. partial response is a ≥50% decrease in the average stool frequency relative to baseline and a change in stool consistency from watery to loose (partially formed) for a period of at least 4 weeks. No response is criteria for CR or PR not met. Only patients with a stool frequency of ≥5/day and a stool consistency of watery will be evaluable for clinical response.

Baseline stool consistency (formed, loose or partially formed, watery) will be the consistency most frequently observed during a 7-day period immediately prior to starting vandetanib. Complete response (CR) is an average of 0-2 formed stools per day for a period of at least 4 weeks. Partial response (PR) is a ≥50% decrease in the average stool frequency relative to baseline and a change in stool consistency from watery to loose (partially formed) for a period of at least 4 weeks. No response is criteria for CR or PR not met. Only patients with a stool frequency of ≥5/day and a stool consistency of watery will be evaluable for clinical response.

Geometric mean for Bortezomib pharmacokinetic (PK) parameters both before (cycle 1 day 1) and during steady-state Vandetanib (cycle 3 day 1; exposures are dose normalized). Bortezomib plasma concentrations were measured using a validated LC-MS/MS assay with a lower limit of quantification (LLOQ) of 1 ng/mL. Only measured concentrations above the LLOQ were used in the calculation of PK parameters. The maximum plasma concentration (Cmax) was recorded as observed values.

The area under the concentration-time curve (AUC) extrapolated to infinity (AUCinf) was calculated using the linear up-log down trapezoidal method via extrapolation of AUC(LAST) (AUC to the last quantifiable time point) by dividing C(LAST) (the last measurable drug concentration, typically at 24 hour post-dose) by the rate constant of the terminal phase, lambda z. This constant was determined from the slope of the terminal phase of the concentration-time curve using weighted least-squares as the estimation procedure.

The time it takes for the measured concentration of the drug to drop by half.

Total systemic clearance = dose/area under curve extrapolated to infinity (AUCinf.). This measurement represents the rate at which plasma is systematically cleared of drug.

Vss represents the volume into which the drug distributes into once given to the patient at steady-state. This volume parameter provides a measure of where in the body the drug is going, based on fluid volume.

Because vandetanib PK exposure was only measured during a single 8-hr window during daily dosing, the only comparison to assess the effect of bortezomib is to compare these values to published literature."

National Cancer Institute (NCI)

Principal Investigator

No participants were enrolled in the phase IIB cohort.

Patients will be treated with vandetanib and bortezomib to find the maximally tolerated dos

Bortezomib: This study is designed to assess the safety, tolerance and activity of daily oral vandetanib and bortezomib on days 1, 4, 8 \& 11 every 28 days in adults

Vandetanib: This study is designed to assess the safety, tolerance and activity of daily oral vandetanib and bortezomib on days 1, 4, 8 \& 11 every 28 days in adults

Phase 1

Patients will be treated with vandetanib and bortezomib at the maximally tolerated dose of the Phase I study

Bortezomib: This study is designed to assess the safety, tolerance and activity of daily oral vandetanib and bortezomib on days 1, 4, 8 \& 11 every 28 days in adults

Vandetanib: This study is designed to assess the safety, tolerance and activity of daily oral vandetanib and bortezomib on days 1, 4, 8 \& 11 every 28 days in adults

Phase 2 A

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Dr. Ravi Madan

Patients will be treated with vandetanib to find the maximally tolerated dose.

Vandetanib: This study is designed to assess the safety, tolerance and activity of daily oral vandetanib on days 1, 4, 8 \& 11 every 28 days in adults

Phase I: Maximum Tolerated Dose (MTD) of Daily Oral Vandetanib

Patients will be treated with bortezomib to find the maximally tolerated dos

Bortezomib: This study is designed to assess the safety, tolerance and activity of daily oral bortezomib on days 1, 4, 8 \& 11 every 28 days in adults

Phase I: Maximum Tolerated Dose (MTD) of Daily Oral Bortezomib

Phase 2: Tumor Response in Adults With a Diagnosis of Medullary Thyroid Cancer (MTC) Treated With Daily Oral Vandetanib and Bortezomib

Patients will be treated with vandetanib and bortezomib at the maximally tolerated dose (MTD) of the Phase I study

Bortezomib: This study is designed to assess the safety, tolerance and activity of daily oral vandetanib and bortezomib on days 1, 4, 8 \& 11 every 28 days in adults

Vandetanib: This study is designed to assess the safety, tolerance and activity of daily oral vandetanib and bortezomib on days 1, 4, 8 \& 11 every 28 days in adults

Phase 2 A - Vandetanib and Bortezomib at the MTD

No participants were enrolled in the phase IIB cohort. One participant was in cohort 2A, thus standard deviation could not be calculated.

Phase 2: Progression Free Survival in Adults With a Diagnosis of Medullary Thyroid Cancer (MTC) Treated With Daily Oral Vandetanib and Bortezomib

Complete Response

Partial Response

Phase 2A

A comparison between phase 1, 2A and 2B was not done because no participants were enrolled in the phase 2B cohort.

Response Rate (Complete Response (CR) + Partial Response (PR) of Adults With a Diagnosis of MTC Treated With Either of Two Regimens: (1) Daily Oral Vandetanib and Bortezomib or (2) Daily Oral Vandetanib

Progression Free Survival (PFS)

Number of Participants With Adverse Events

No participants were enrolled in the phase IIB cohort. Only participants with average pre-treatment CTN levels that are \>2 times the upper limit of normal are evaluable for biomarker response. There were 16 participants that met this criteria.

Number of Participants With Tumor Biomarker Calcitonin (CTN) Response

Phase 1 - Vandetanib and Bortezomib

No participants were enrolled in the phase IIB cohort. Only participants with average pre-treatment CEA levels that are \>2 times the upper limit of normal are evaluable for biomarker response. There were 14 participants that met this criteria.

Number of Participants With Tumor Biomarker Carcinoembryonic Antigen (CEA) Response

Baseline -Complete response

Baseline -Partial response

Baseline - No response

4 Weeks - Complete response

4 Weeks - Partial response

4 Weeks - No response

This outcome measure was not analyzed because no participant had a baseline diarrhea that met the criteria for analysis. They needed to have diarrhea 5 times a day for several days in a row and no one had the baseline problem.

Percentage of Participants With a Change in Frequency in Tumor-Related Diarrhea Compared to Baseline

This outcome measure was not analyzed because the number of patients eligible for this response is 0, in both the Phase I and Phase II cohorts. None of the participants met the criteria of \>=5 watery stools per day at baseline. No participants were enrolled in the phase IIB cohort.

Percentage of Participants With a Change in Consistency in Tumor-Related Diarrhea Compared to Baseline

Patients given bortezomib on cycle 1, day 1 vs. cycle 3, day 1. A paired analysis among same 14 patients on Phase 1 portion. To assess whether presence of vandetanib significantly altered bortezomib Cmax (normalized to dose).

Before Vandetanib

After Vandetanib

"7/14 patients were analyzed on day 1; 13/14 patients analyzed on day 61. Those patients that were not analyzed had insufficient PK data to calculate this parameter."

Maximum Bortezomib Plasma Concentration Normalized to Dose (Cmax/D)

Patients given bortezomib on cycle 1 day 1 vs. cycle 3 day 1. A paired analysis among same 14 patients on Phase 1 portion. To assess whether presence of vandetanib significantly altered bortezomib AUCinf (normalized to dose).

PK samples were only done during the phase I portion of the study. "7/14 patients were analyzed on day 1; 13/14 patients analyzed on day 61. Those patients that were not analyzed had insufficient PK data to calculate this parameter." Please see other outcome measure modules for details.

Area Under the Bortezomib Plasma Concentration Versus Time Curve From Time Zero to Infinity/Dose (AUCinf/D)

Patients given bortezomib on cycle 1 day 1 vs. cycle 3 day 1. A paired analysis among same 14 patients on Phase 1 portion. To assess whether presence of vandetanib significantly altered bortezomib half-life.

Terminal Half-Life (T1/2) of Bortezomib

Patients given bortezomib on cycle 1 day 1 vs. cycle 3 day 1. A paired analysis among same 14 patients on Phase 1 portion. To assess whether presence of vandetanib significantly altered bortezomib clearance.

Total Systemic Clearance (CL) of Bortezomib

Patients given bortezomib on cycle 1 day 1 vs. cycle 3 day 1. A paired analysis among same 14 patients on Phase I portion. To assess whether presence of vandetanib significantly altered bortezomib volume of distribution.

Bortezomib Volume of Distribution (Vss)

Published Literature

Study 090089 Results

Vandetanib PK samples were only obtained during the phase 1 portion of the study during cycle 3, day 1, where patients received both vandetanib (at steady-state) and bortezomib. "13/14 patients analyzed on day 61 (C3D1). Those patients that were not analyzed had insufficient PK data to calculate this parameter."

Spots Global Cancer Trial Database for medullary thyroid