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)

NCT00923247 | Terminated Phase 1 Results FDA Drug

• 2 other identifiers: 09008909-C-0089
• Study Type: interventional
• Target: 22
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Medullary Thyroid Carcinoma

Keywords

Vandetanib; Bortezomib; Medullary Thyroid; Proteasome Inhibitor; Cancer; Solid Tumor; Thyroid Cancer; Medullary Thyroid Cancer

Outcome Measures

Primary Outcomes (4)

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

  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.

  80 days

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

  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.

  80 days

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

  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.

  4 months

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

  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).

  4 months

Secondary Outcomes (13)

• 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

  2-3 years

• Progression Free Survival (PFS)

  2-3 years

• Number of Participants With Adverse Events

  Date treatment consent signed to date off study, approximately 7 years and 9 days

• Number of Participants With Tumor Biomarker Calcitonin (CTN) Response

  4 weeks

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

  4 weeks

Study Arms (3)

Phase 1 - vandetanib and bortezomib

EXPERIMENTAL

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

Drug: Bortezomib; Drug: Vandetanib

Phase 2 B - vandetanib alone

ACTIVE COMPARATOR

Patients will be treated with vandetanib alone.

Drug: Vandetanib

Phase 2 A - vandetanib and bortezomib at the MTD

ACTIVE COMPARATOR

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

Drug: Bortezomib; Drug: Vandetanib

Interventions

Bortezomib DRUG

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

Also known as: Velcade

Phase 1 - vandetanib and bortezomib; Phase 2 A - vandetanib and bortezomib at the MTD

Vandetanib DRUG

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

Also known as: Caprelsa

Phase 1 - vandetanib and bortezomib; Phase 2 A - vandetanib and bortezomib at the MTD; Phase 2 B - vandetanib alone

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Pathologic confirmation of cancer by the Laboratory of Pathology, National Cancer Institute (NCI)
• 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).
• 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.
• A life expectancy of at least 3 months and Eastern Cooperative Oncology Group (ECOG) performance status 0 1.
• Age greater than or equal to 18 years
• 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.
• 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.
• 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.

You may not qualify if:

• Patients with cancer potentially curable by surgical excision alone or patients who have not received therapy that might be considered standard and potentially curable.
• 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.
• 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.
• During Phase II enrollment: Prior therapy with vandetanib.
• Women who are currently pregnant or breast-feeding, due to the possible adverse effects on the developing fetus and infants.
• 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.
• Patients with evidence of a bleeding diathesis that cannot be corrected with standard therapy or factor replacement.
• 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.
• Major surgery within 4 weeks, or incompletely healed surgical incision before starting study therapy.
• 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.
• 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.
• History (within the last 6 months) or presence of stroke/cerebrovascular accident.
• 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.
• Congenital long Q wave, T wave (QT) syndrome, or 1st degree relative with unexplained sudden death under 40 years of age.
• Presence of left bundle branch block (LBBB).

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (5)

• Davies L, Welch HG. Increasing incidence of thyroid cancer in the United States, 1973-2002. JAMA. 2006 May 10;295(18):2164-7. doi: 10.1001/jama.295.18.2164.

  PMID: 16684987 BACKGROUND

• Truong T, Rougier Y, Dubourdieu D, Guihenneuc-Jouyaux C, Orsi L, Hemon D, Guenel P. Time trends and geographic variations for thyroid cancer in New Caledonia, a very high incidence area (1985-1999). Eur J Cancer Prev. 2007 Feb;16(1):62-70. doi: 10.1097/01.cej.0000236244.32995.e1.

  PMID: 17220706 BACKGROUND

• Burgess JR, Tucker P. Incidence trends for papillary thyroid carcinoma and their correlation with thyroid surgery and thyroid fine-needle aspirate cytology. Thyroid. 2006 Jan;16(1):47-53. doi: 10.1089/thy.2006.16.47.

  PMID: 16487013 BACKGROUND

• Abstract: Phase I/II trial of vandetanib and bortezomib in adults with locally advanced or metastatic medullary thyroid cancer: Phase I results. A. W. Gramza, S. A. Wells, S. Balasubramaniam, and A. T. Fojo Journal of Clinical Oncology 2011 29:15_suppl, 5565-5565

  RESULT

• Del Rivero J, Edgerly M, Ward J, Madan RA, Balasubramaniam S, Fojo T, Gramza AW. Phase I/II Trial of Vandetanib and Bortezomib in Adults with Locally Advanced or Metastatic Medullary Thyroid Cancer. Oncologist. 2019 Jan;24(1):16-e14. doi: 10.1634/theoncologist.2018-0452. Epub 2018 Oct 8.

  PMID: 30297385 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Carcinoma, Medullary; Neoplasms; Thyroid Neoplasms

Interventions

Bortezomib; vandetanib

Condition Hierarchy (Ancestors)

Carcinoma, Neuroendocrine; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms, Ductal, Lobular, and Medullary; Neoplasms, Nerve Tissue; Endocrine Gland Neoplasms; Neoplasms by Site; Head and Neck Neoplasms; Endocrine System Diseases; Thyroid Diseases

Intervention Hierarchy (Ancestors)

Boronic Acids; Acids, Noncarboxylic; Acids; Inorganic Chemicals; Boron Compounds; Organic Chemicals; Pyrazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Dr. Ravi Madan
• Organization: National Cancer Institute

madanr@mail.nih.gov

301-480-7168

Study Officials

• Ravi A Madan, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: June 17, 2009
• First Posted: June 18, 2009
• Study Start: February 19, 2009
• Primary Completion: April 1, 2016
• Study Completion: December 9, 2016
• Last Updated: November 29, 2018
• Results First Posted: May 17, 2017

Record last verified: 2018-11

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)