Clinical trial NCT01621568: Sunitinib for Advanced Thymus Cancer Following Earlier Treatment
Official title: A Phase II Study of Sunitinib in Patients With Advanced Relapsed or Refractory Thymoma or Thymic Carcinoma With at Least One Prior Line of Platinum-Based Systemic Chemotherapy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Thymoma
Thymus Neoplasms
Keywords: VEGF
Anti-Angiogenesis
Targeted Agent
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
Collaborators: name: Indiana University School of Medicine
First posted: 2012-06-18
Enrollment: 56
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Background:

- Sunitinib is drug that is approved for treating various types of cancers, including kidney cancers. However, it has not been approved to treat cancers of the thymus. Sunitinib works by blocking proteins that are responsible for cell division and growth. Some of these proteins can be found on thymus cancer cells. Researchers want to see if sunitinib can be used to treat advanced thymus cancer. It will be given to people who have had at least one earlier chemotherapy treatment containing platinum.

Objectives:

- To see if sunitinib is a safe and effective treatment for advanced thymus cancer that has not responded to earlier treatments.

Eligibility:

* Individuals at least 18 years of age who have advanced thymus cancer that has not responded to earlier treatments.
* At least one previous cancer treatment must have been chemotherapy treatment containing platinum.

Design:

* Participants will be screened with a physical exam and medical history. Blood and urine samples will be collected. Imaging studies and tumor biopsies will be used to check the severity of the cancer.
* Participants will take sunitinib tablets once a day, in the morning. They will take the tablets daily for 4 weeks, followed by 2 weeks of rest with no sunitinib. This 6-week period is called a cycle.
* Treatment will be monitored with frequent blood tests and imaging studies.
* Treatment cycles may be repeated as long as the tumor does not continue to grow and there are no severe side effects....

Detailed description: BACKGROUND:

Platinum-based chemotherapy is the standard of care for advanced unresectable thymoma and thymic carcinoma. However over 50% of these patients may fail initial therapy and therefore require second-line therapy. New therapeutic options are needed for patients who have disease progression on or after platinum-containing therapy. Results obtained from protocol 12-C-0118 so far have shown impressive clinical activity of sunitinib in patients with recurrent thymic carcinoma with an objective response rate of 23% and disease control rate of 91% which is unprecedented for this histology. Treatment at a dose of 50 mg once daily for four weeks followed by 2 weeks off was poorly tolerated. Twenty five out of 41 patients needed dose reductions due to development of intolerable adverse events.

OBJECTIVES:

Primary objective:

- To evaluate the objective response rate (Partial Response (PR)+Complete Response (CR) for sunitinib in patients with relapsed or refractory thymoma or thymic carcinoma

MAIN ELIGIBILITY:

* Patients with histologically confirmed thymoma (Group 1 only) or thymic carcinoma who have previously been treated with at least one platinum-containing chemotherapy regimen with progressive disease prior to study entry
* Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria
* Adequate renal, hepatic and hematopoietic function
* No major surgery, radiotherapy, chemotherapy or biologic therapy within 28 days of sunitinib

DESIGN:

* In the first group (Group 1), sunitinib will be administered orally using a continuous schedule at 50 mg per day for 4 weeks with 2 weeks off to constitute a 6-week cycle (Schedule 4/2) until disease progression or development of intolerable side-effects.
* In the second group (Group 2), sunitinib will be administered orally using a continuous schedule at 50 mg per day for 2 weeks with 1 week off to constitute a 3-week cycle (Schedule 2/1) until disease progression or development of intolerable side-effects.
* Toxicity will be assessed every cycle by Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0
* Tumor response assessments by RECIST 1.1 criteria will be performed every cycle for Group 1 and every other cycle for Group 2 (every 6 weeks) for patients receiving treatment for less than one year, and every two cycles for Group 1 and every four cycles for Group 2 (every 12 weeks) for patients who have been receiving treatment one year or longer.
* Exploratory studies include evaluation of serum vascular endothelial growth factor (VEGF), placental growth factor (PlGF), interleukin 4 (IL-4), interleukin 12 (IL-12), hepatocyte growth factor (HGF), and basic fibroblast growth factor (bFGF) (Group 1 only); and circulating tumor cells, endothelial progenitors, and mature apoptotic endothelial cells (both groups). In Group 2, regulatory T cells (Tregs), exhausted cluster of differentiation 8 (CD8) T cells, myeloid-derived suppressor cells (MDSCs), and Type 1 T helper (Th1)/Type 2 T helper (Th1) T cell populations will also be evaluated. Where tumor samples are available, intra-tumoral immune infiltrate will be assessed (both groups). Exploratory studies apply to National Cancer Institute (NCI) only.

Eligibility criteria: * INCLUSION CRITERIA:

3.1.1 Histological confirmation of thymoma (Group 1 only) or thymic carcinoma by the pathology department/Center for Cancer Research (CCR)/national Cancer Institute (NCI) or the pathology department of participating institutions.

3.1.2 At least one prior line of platinum-based chemotherapy or patient must have refused cytotoxic chemotherapy. Progressive disease must be documented prior to study entry.

3.1.3 Patients must not have received chemotherapy, radiation therapy, or undergone major surgery within 4 weeks prior to enrollment.

3.1.4 Patients must have measurable disease, per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1

3.1.5 Age greater than or equal to 18 years.

3.1.6 Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2 (Karnofsky \> 50 percent)

3.1.7 Life expectancy of greater than 3 months.

3.1.8 Patients must have normal organ and marrow function as defined below:

* hemoglobin greater than or equal to 9 g/dL
* leukocytes greater than or equal to 3,000/mcL
* absolute neutrophil count greater than or equal to 1,200/mcL
* platelets greater than or equal to 100,000/mcL
* total bilirubin within normal institutional limits
* serum calcium less than or equal to 12.0 mg/dL
* Aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase (SGOT)/alanine transaminase (ALT)/serum glutamic-pyruvic transaminase (SGPT) less than or equal to 2.5 times institutional upper limit of normal
* creatinine within normal institutional limits

OR

* creatinine clearance greater than or equal to 60 mL/min/1.73 m(2) for patients with creatinine levels above institutional normal.
* If subjects have liver metastases, both ALT and AST must be less than or equal to 5 times upper limit of normal (ULN).
* Patients must have corrected QT Interval (QTc) \< 500 msec

3.1.9 Prothrombin time (PT) or international normalized ratio (INR), and partial thromboplastin time test (APTT) less than or equal to 1.5 times upper limit of normal (ULN), unless the abnormality can be explained by the presence of lupus anticoagulant or if these values are in the therapeutic range for a patient on low molecular weight heparin.

3.1.10 The following groups of patients are eligible provided they have New York Heart Association Class II (NYHA) cardiac function on baseline echocardiogram (ECHO)/multi-gated acquisition scan (MUGA):

* those with a history of Class II heart failure who are asymptomatic on treatment
* those with prior anthracycline exposure
* those who have received central thoracic radiation that included the heart in the radiotherapy port.

3.1.11 Patients must have blood pressure (BP) no greater than 140 mmHg (systolic) and 90 mmHg (diastolic) for eligibility. Initiation or adjustment of BP medication is permitted prior to study entry provided that the average of three BP readings at a visit prior to enrollment is less than 140/90 mmHg.

3.1.12 Absence of brain metastases as confirmed by imaging of the brain by magnetic resonance imaging (MRI) or computed tomography (CT) brain with contrast performed at baseline screening

3.1.13 The effects of sunitinib on the developing human fetus at the recommended therapeutic dose are unknown. For this reason and because anti-angiogenic agents are known to be teratogenic, women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. All women of childbearing potential must have a negative pregnancy test prior to receiving sunitinib. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of sunitinib administration.

3.1.14 Ability to understand and willingness to sign a written informed consent document.

EXCLUSION CRITERIA:

3.2.1 Patients with tumor amenable to potentially curative therapy.

3.2.2 Prior treatment within the past 6 months with sunitinib, sorafenib, bevacizumab or other multikinase inhibitors targeting any of the following: vascular endothelial growth factors 1 3 (VEGF1 3), FMS-like tyrosine kinase 3 (FLT3), stem cell growth factor (c-KIT), platelet-derived growth factors-alpha and -beta (PDGF-alpha,-beta), colony-stimulating factor 1 (CSF1), and the RET receptor for glial-derived neurotrophic factors.

3.2.3 Patients with symptomatic brain metastases will be excluded from trial secondary to poor prognosis. However, patients who have had treatment for their brain metastasis and whose brain disease has remained stable for 3 months without steroid therapy may be enrolled.

3.2.4 Patients with evidence of severe or uncontrolled systemic disease, or any concurrent condition, which could compromise participation in the study, including, but not limited to, active or uncontrolled infection, immune deficiencies, uncontrolled hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infection unless sustained virologic response to HCV therapy, uncontrolled diabetes, serious non-healing ulcer, wound or bone fracture, history of intra-abdominal abscess, abdominal fistula or gastrointestinal perforation within 28 days of treatment, history of pulmonary embolism in the past 12 months, uncontrolled hypertension, myocardial infarction, cardiac arrhythmia, stable/unstable angina, symptomatic congestive heart failure, or coronary/peripheral artery bypass graft or stenting within 12 months prior to study entry, Class III or IV heart failure as defined by the NYHA functional classification system, stroke/cerebrovascular accident or transient ischemic attack within the past 12 months or psychiatric illness/social situations which would jeopardize compliance with the protocol.

3.2.5 History of a previous invasive malignancy within the last 5 years, except adequately treated non-melanoma skin cancer, papillary carcinoma of the thyroid or carcinoma in situ of the uterine cervix.

3.2.6 Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier.

3.2.7 Patients who are receiving any other investigational agents.

3.2.8 History of allergic reactions attributed to compounds of similar chemical or biologic composition to sunitinib. Patients receiving any medications or substances that are strong inhibitors or inducers of cytochrome P450 3A4 (CYP3A4) are ineligible. (A list of potent CYP3A4 inducers or inhibitors can be found in Section 5.2.) An exception will be made for patients who are on ritonavir-based highly active antiretroviral therapy, in which case the starting dose of sunitinib will be modified as indicated in Sections 5.1.1 and 5.2.12. Every effort should be made to switch patients taking such agents or substances to other medications. A comprehensive list of medications and substances known or with the potential to alter the pharmacokinetics of sunitinib through CYP3A4 is provided.

3.2.9 Pregnant women are excluded from this study because sunitinib angiogenesis inhibitor with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with sunitinib breastfeeding should be discontinued if the mother is treated with sunitinib.

3.2.10 Patients who require therapeutic doses of Coumadin derivative anticoagulants such as warfarin are excluded. Low molecular weight heparin is permitted, provided the patient's prothrombin time (PT)/INR is less than or equal to 1.5. Coumadin doses of up to 2 mg daily are permitted for prophylaxis of thrombosis.

3.2.11 Patients with a pre-existing thyroid abnormality who are unable to maintain thyroid function in the normal range with medication are ineligible.

3.2.12 Patients with any condition (e.g., gastrointestinal tract disease resulting in an inability to take oral medication or a requirement for intravenous (IV) alimentation, prior surgical procedures affecting absorption, or active peptic ulcer disease) that impairs their ability to swallow and retain sunitinib tablets are excluded.

3.2.13 Patients with QTc prolongation (defined as a QTc interval equal to or greater than 500 msec) or other significant electrocardiogram (ECG) abnormalities are excluded.

3.2.14 Patients with poorly controlled hypertension (systolic blood pressure of 140 mmHg or higher or diastolic blood pressure of 91 mmHg or higher) are ineligible.

3.2.15 Patients who require use of therapeutic doses of coumarin derivative anticoagulants such as warfarin are excluded, although doses of up to 2 mg daily are permitted for prophylaxis of thrombosis. Note: Low molecular weight heparin is permitted provided the patient's PT INR is less than or equal to 1.5.

3.2.16 Patients with human immunodeficiency virus (HIV) infection are eligible provided their cluster of differentiation 4 (CD4) count is greater than or equal to the institutional lower limit of normal (LLN) ( greater than or equal to 334 cells/uL).

Primary outcomes:
measure: Percentage of Participants With an Objective Response (Partial Response (PR) + Complete Response (CR) for Sunitinib in Participants With Relapsed or Refractory Thymoma or Thymic Carcinoma
timeFrame: A median duration of 6 months
Secondary outcomes:
measure: Progression-free Survival for Sunitinib in Participants With Relapsed or Refractory Thymoma or Thymic Carcinoma
timeFrame: An average of 10 months
measure: Number of Participants Alive at 1 Year After Treatment With Sunitinib
timeFrame: 12 months after initiation of treatment
measure: Number of Grades ≥3 Adverse Events Related to Sunitinib
timeFrame: Date treatment consent signed to date off study, approximately 110 months and 28 days for the thymoma/thymic carcinoma group and 91 months and 11 days for the thymic carcinoma only group.
Other outcomes:
measure: Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0).
timeFrame: Date treatment consent signed to date off study, approximately 110 months and 28 days for the thymoma/thymic carcinoma group and 91 months and 11 days for the thymic carcinoma only group.
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center, 9000 Rockville Pike
state: Maryland
Study officials:
affiliation: National Cancer Institute (NCI)
name: Arun Rajan, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Detterbeck FC. Clinical value of the WHO classification system of thymoma. Ann Thorac Surg. 2006 Jun;81(6):2328-34. doi: 10.1016/j.athoracsur.2005.11.067.
citation: Engels EA, Pfeiffer RM. Malignant thymoma in the United States: demographic patterns in incidence and associations with subsequent malignancies. Int J Cancer. 2003 Jul 1;105(4):546-51. doi: 10.1002/ijc.11099.
citation: Falkson CB, Bezjak A, Darling G, Gregg R, Malthaner R, Maziak DE, Yu E, Smith CA, McNair S, Ung YC, Evans WK; Lung Cancer Disease Site Group of Cancer Care Ontario's Program in Evidence-Based Care. The management of thymoma: a systematic review and practice guideline. J Thorac Oncol. 2009 Jul;4(7):911-9. doi: 10.1097/jto.0b013e3181a4b8e0.
citation: Thomas A, Rajan A, Berman A, Tomita Y, Brzezniak C, Lee MJ, Lee S, Ling A, Spittler AJ, Carter CA, Guha U, Wang Y, Szabo E, Meltzer P, Steinberg SM, Trepel JB, Loehrer PJ, Giaccone G. Sunitinib in patients with chemotherapy-refractory thymoma and thymic carcinoma: an open-label phase 2 trial. Lancet Oncol. 2015 Feb;16(2):177-86. doi: 10.1016/S1470-2045(14)71181-7. Epub 2015 Jan 13. Erratum In: Lancet Oncol. 2015 Mar;16(3):e105. doi: 10.1016/S1470-2045(15)70095-1.