Trial of Sunitinib in Patients With Type B3 Thymoma or Thymic Carcinoma in Second and Further Lines (Style Trial) (Style)

Phase II Trial of Sunitinib in Patients With Type B3 Thymoma or Thymic Carcinoma in Second and Further Lines (Style Trial)

Study to investigate response to sunitinib in patients with thymic epithelial tumours who had progressive disease after at least one previous regimen of platinum-based chemotherapy.

Study Overview

• Status: Recruiting
• Conditions: Thymic Carcinoma; Type B3 Thymoma
• Intervention / Treatment: Drug: Sunitinib

Detailed Description

This trial will be conducted to assess the activity of Sunitinib in patients affected by advanced or recurrent B3 thymoma or thymic carcinoma progressing after at least one line of chemotherapy (including one platinum based regimen).

Taking into account the different biology and historically discrepant responses and survival of thymoma and thymic carcinoma, patients will be enrolled with these tumour types in two separate cohorts.

Sunitinib will be self orally administered at 50 mg once daily, is 50 mg taken orally once daily, for 4 consecutive weeks, followed by a 2-week rest period (schedule 4/2) to comprise a complete cycle of 6 weeks until tumour progression, unacceptable toxicity or other criteria for discontinuation is met.

Sunitinib dose reductions are permitted as per the approved product label for safety reasons.

Dose reductions should occur in 12.5 mg decrements. No more than 2 dose reductions are allowed. If more than 2 dose reductions are necessary (ie, reduction to less than 25 mg daily), the subject must be permanently discontinued (Section 7.2.2)

Possible dose reductions:

• Sunitinib at dose of 37,5 mg orally once daily for 4 weeks followed by 2 weeks rest-period in cycles of 6 weeks.
• Sunitinib at dose of 25 mg orally once daily for 4 weeks followed by 2 weeks rest-period in cycles of 6 weeks

• Study Type: Interventional
• Enrollment (Anticipated): 56
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Marina Chiara Garassino, MD; Phone Number: +390223903813; Email: marina.garassino@istitutotumori.mi.it
• Study Contact Backup: Name: Rosaria Gallucci, MSc; Phone Number: +390223903836; Email: rosaria.gallucci@istitutotumori.mi.it

Study Locations

• Italy
  • Milan, Italy, 20133
    • Recruiting
    • National Cancer Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Signed and dated IRB (Independent Review Board)/IEC (Independent Ethics Committee)-approved Informed Consent
2. Histological diagnosis of invasive recurrent or metastatic type B3 thymoma or thymic carcinoma. In case of presence of both histologies it will be classified based on the predominantly part. B2 thymoma with areas of B3 thymoma are eligible.
3. Patients must have had at least one prior platinum-containing chemotherapy regimen. There is no limit to the number of prior chemotherapy regimens or targeted agents received. Progressive disease should have been documented before entry into the study
4. Patients must have measurable disease, defined as at least one lesion that can be accurately measured according with RECIST 1.1 criteria
5. Availability of archival tissue (paraffine block or at least 10 unstained slides)
6. Patients must have recovered from toxicity related to prior therapy to at least grade 1 (defined by v.CTCAE 4.0)
7. Patients must not have had major surgery, radiation therapy, chemotherapy, biologic therapy (including any investigational agents), or hormonal therapy (other than replacement), within 4 weeks prior to entering the study
8. Age > 18 years
9. Life expectancy > 3 months
10. Performance status (ECOG) ≤ 2
11. Negative pregnancy test (if female in reproductive years)

12. Patients must have adequate organ and marrow function (as defined below). Patients must have returned to baseline or grade 1 from any acute toxicity related to prior therapy:

    • Absolute neutrophil count ≥ 1,500/mm
    • Hemoglobin ≥ 9 g/dL
    • Platelets ≥ 100,000/mm
    • Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) , except for patients affected by Gilbert's syndrome
    • AST(SGOT) (aspartate aminotransferase) /ALT(SGPT) (alanine transaminase) ≤ 3 x institutional ULN (5x if LFT (liver function test) elevations due to liver metastases)
    • Creatinine ≤ 1.5 x institutional ULN
13. Women of childbearing potential (WOCBP) must agree to follow instructions for method(s) of contraception before study entry, for all the duration of the study and for at least 8 weeks after the last dose of investigational drug (30 days for an ovarian cycle turnover plus the time required for the active metabolite of sunitinib to undergo five half-lives).
14. Males who are sexually active with WOCBP must agree to follow instructions for method(s) of before study entry, for all the duration of the study and for at least 16 weeks after the last dose of investigational drug (90 days for sperm turnover plus the time required for the active metabolite of sunitinib to undergo five half-lives).

Exclusion Criteria:

1. untreated CNS metastases. Patients with treated brain metastases are eligible if they are clinically stable with regard to neurologic function, off steroids after cranial irradiation (whole brain radiation therapy, focal radiation therapy, and stereotactic radiosurgery) ending at least 2 weeks prior to start of treatment, or after surgical resection performed at least 28 days prior to start of treatment. The patient may have no evidence of Grade ≥1 CNS haemorrhage based on pre-treatment Magnetic Resonance Imaging (MRI) or IV contrast CT scan (performed within 28 days before start of treatment)
2. Major surgery, other than diagnostic surgery, within 4 weeks prior to treatment
3. Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic therapy
4. Pregnant or breast feeding women
5. Previous (within the last 5 years) or current malignancies at other sites, except for adequately treated basal cell or squamous cell skin cancer or in situ carcinoma of the cervix uteri
6. Current enrollment in or participation in another therapeutic clinical trial within 4 weeks before treatment start.
7. Patients with uncontrolled or significant cardiovascular disease (AMI within 12 months, unstable angina within 6 months, NYHA (New York Heart Association) Class III, IV Congestive heart failure or left ventricular ejection fraction below local institutional lower limit of normal or below 45%,
8. Ongoing symptomatic cardiac dysrhythmias, uncontrolled atrial fibrillation, or prolongation of the Fridericia corrected QT (QTcF) interval defined as > 450 msec for males and > 470 msec for females, where QTcF = QT / 3√RR
9. Poorly controlled hypertension
10. History of cerebrovascular accident including transient ischemic attack within the past 12 months.
11. History of deep vein thrombosis (DVT) unless adequately treated with low molecular weight heparin
12. History of pulmonary embolism within the past 6 months unless stable, asymptomatic, and treated with low molecular weight heparin for at least 6 weeks.
13. Evidence of active bleeding or bleeding susceptibility; or medically significant hemorrhage within prior 30 days.
14. Receiving concomitant CYP3A4 inducers or strong CYP3A4 inhibitors
15. Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of sunitinib
16. Known HIV infection

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sunitinib; Sunitinib orally administered at 50 mg once daily for 4 consecutive weeks, followed by a 2-week rest period (schedule 4/2) to comprise a complete cycle of 6 weeks	Drug: Sunitinib; small-molecule, multi-targeted receptor tyrosine kinase (RTK) inhibitor; Other Names: Sutent

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Activity of Sunitinib	Best tumour response (Complete Response + Partial Response)	4 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival (PFS)	The PFS is defined as the time from the date of randomization to the date of documented progressive disease, recurrence or Death (whichever occurs first)	4 years
Overall Survival (OS)	The OS is defined as the time from the date of randomization to the date of death	4 years
Duration of activity of sunitinib	Complete Response + Partial Response + Stable Disease	4 years
Safety and toxicity profile of sunitinib	will be utilized the CTCAE v 4.0 criteria for assessment of toxicity and serious adverse event reporting.	4 years
Incidence of adverse events (AEs)	Incidence of adverse events (AEs) will be graded according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 4.0, laboratory values, physical examinations, vital signs.	4 years

Collaborators and Investigators

• Sponsor: Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
• Investigators: Principal Investigator: Marina Chiara Garassino, MD, National Cancer Institute (NCI)

Publications and helpful links

General Publications

• Kurup A et al. Phase II study of gefitinib treatment in advanced thymic malignancies. JCO 23 (16S, Part I of II, June 1 Supplement), ASCO 2005: Abs. 7068
• 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.
• Salter JT et al. Imatinib for the treatment of thymic carcinoma. JCO 26: ASCO 2008 (May 20 Supplement): Abs.
• 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.
• Wright CD. Management of thymomas. Crit Rev Oncol Hematol. 2008 Feb;65(2):109-20. doi: 10.1016/j.critrevonc.2007.04.005. Epub 2007 Jun 14.
• Giaccone G. Treatment of malignant thymoma. Curr Opin Oncol. 2005 Mar;17(2):140-6. doi: 10.1097/01.cco.0000152628.43867.8e.
• Serpico D, Trama A, Haspinger ER, Agustoni F, Botta L, Berardi R, Palmieri G, Zucali P, Gallucci R, Broggini M, Gatta G, Pastorino U, Pelosi G, de Braud F, Garassino MC. Available evidence and new biological perspectives on medical treatment of advanced thymic epithelial tumors. Ann Oncol. 2015 May;26(5):838-847. doi: 10.1093/annonc/mdu527. Epub 2014 Nov 19.
• Strobel P, Hartmann M, Jakob A, Mikesch K, Brink I, Dirnhofer S, Marx A. Thymic carcinoma with overexpression of mutated KIT and the response to imatinib. N Engl J Med. 2004 Jun 17;350(25):2625-6. doi: 10.1056/NEJM200406173502523. No abstract available.
• Bisagni G, Rossi G, Cavazza A, Sartori G, Gardini G, Boni C. Long lasting response to the multikinase inhibitor bay 43-9006 (Sorafenib) in a heavily pretreated metastatic thymic carcinoma. J Thorac Oncol. 2009 Jun;4(6):773-5. doi: 10.1097/JTO.0b013e3181a52e25.

Study record dates

Study Major Dates

• Study Start (Actual): March 2, 2017
• Primary Completion (Anticipated): May 31, 2022
• Study Completion (Anticipated): May 31, 2022

Study Registration Dates

• First Submitted: February 22, 2018
• First Submitted That Met QC Criteria: February 22, 2018
• First Posted (Actual): February 28, 2018

Study Record Updates

• Last Update Posted (Actual): June 9, 2021
• Last Update Submitted That Met QC Criteria: June 8, 2021
• Last Verified: June 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Lymphatic Diseases; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Thoracic Neoplasms; Neoplasms, Complex and Mixed; Carcinoma; Thymoma; Thymus Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Protein Kinase Inhibitors; Sunitinib
• Other Study ID Numbers: INT 165-16

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No