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Ramucirumab and Carbo-Paclitaxel for Untreated Thymic Carcinoma / B3 Thymoma With Carcinoma (RELEVENT) (RELEVENT)

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ClinicalTrials.gov Identifier: NCT03921671
Recruitment Status : Recruiting
First Posted : April 19, 2019
Last Update Posted : May 6, 2019
Sponsor:
Information provided by (Responsible Party):
Marina Garassino, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

Brief Summary:
This is a multicentric study. All patients with TET (thymic epithelial tumors) of any histological type will participate in the study. This is an open-label phase 2 study that will follow a Green-Dahlberg 2-stage design whose objective is to evaluate the activity and safety of the combination of ramucirumab (10 mg / kg) + carboplatin (AUC 5) and paclitaxel (200 mg / m2) in patients with relapsed and / or metastatic thymic carcinoma/ thymoma B3, in the first line (RELEVENT trial).

Condition or disease Intervention/treatment Phase
Thymic Carcinoma Thymoma Combination Product: Ramucirumab Phase 2

Detailed Description:

Clinical and quality of life data will be collected for all treated patient. Based on the histological evaluation performed by each participating center, patients will be screened for inclusion in one of the three studies, based on the following criteria:

  • TOPS studies only: all patients with A, AB, B1, B2, B3 without areas of carcinoma histology that do not have a fresh tissue sample and screen failures of the RELEVENT and BIOTET study;
  • BIOTET only: all patients with A, AB, B1, B2, B3 without areas of histology of the carcinoma that have a fresh tissue sample;
  • RELEVENT only: all patients with thymoma B3 and areas of carcinoma and patients with thymic carcinoma who do not have a fresh tissue sample;
  • RELEVENT and BIOTET: all patients with thymoma B3 and areas of carcinoma and patients with thymic carcinoma who meet the inclusion / exclusion criteria and for whom a fresh tissue sample is available.Finally, the RELEVENT and BIOTET study patients will continue the observational follow-up of the TOPS study, once the clinical and biological study procedures have been completed.

All patients, regardless of histological status, will be invited to participate in the clinical follow up observational and collection of PROMIS 29 in scope of the prospective TET study (TOPS).

Patients with thymic carcinoma or thymoma B3 with areas of carcinoma will receive a centralized pathological review of the tumour block or slides and will be screened to participate in the Phase II RELEVENT pharmacological study.Histological diagnosis will be confirmed before screening.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Intervention Model: Single Group Assignment
Intervention Model Description: Green-Dahlberg 2-stage design
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Improving Treatment Strategies in Thymic Epithelial Tumors: a TYME Collaborative Effort
Actual Study Start Date : November 1, 2018
Estimated Primary Completion Date : July 16, 2020
Estimated Study Completion Date : July 16, 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Thymus Cancer

Arm Intervention/treatment
Experimental: Ramucirumab +carboplatin+ paclitaxel
All patient will receive the combination of ramucirumab (10 mg / kg) + carboplatin (AUC 5) and paclitaxel (200 mg / m2) in patients with recurrent and / or metastatic thymic carcinoma or thymoma B3 with area of carcinoma, in the first line.
Combination Product: Ramucirumab
Combination of ramucirumab (10 mg / kg) + carboplatin (AUC 5) and paclitaxel (200 mg / m2) in patients with carcinoma thymic (or thymoma B3 with areas of carcinoma), relapsed and / or metastatic, in the first line.
Other Name: CARBOPLATIN (AUC 5) + PACLITAXEL(200 mg / m2)




Primary Outcome Measures :
  1. Best tumour response (CR+PR) [ Time Frame: 6 months ]
    Objective tumor response will be assessed according to RECIST 1.1.


Secondary Outcome Measures :
  1. Progression Free Survival (PFS) [ Time Frame: 4 years ]
    Disease progression will be established as the radiological progression according to RECIST 1.1 or through clinical assessment in case radiological evaluation is not feasible or as death from any cause due to clinical condition. PFS will be estimated through Kaplan-Meier method

  2. Overall Survival (OS) [ Time Frame: 4 years ]
    OS will be estimated through Kaplan-Meier method


Other Outcome Measures:
  1. Comprehensive analysis of tumor mutational status on paraffin-embedded tissue [ Time Frame: 4 years ]
    Targeted re-sequencing of genes mutated in TETs in order to define the prognostic role of somatic mutations and their potential association to prognosis or response to therapy

  2. Comprehensive analysis of single nucleotide polymorphism in blood [ Time Frame: 4 years ]
    Genome-wide approach using a platform able to investigate more than 4 million SNP in order to find potential association with prognosis or response to therapy

  3. Analysis of circulating micro-RNA [ Time Frame: 4 years ]
    Analysis of micro-RNA in plasma and their evaluation as possible biomarker associated with prognosis or response to therapy

  4. Quality of life analysis through collection of Patients Reported Outcome (PROs) [ Time Frame: 4 years ]
    Web based PROs will be administered at each visit and data about compliance will be collected



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Ages Eligible for Study:   18 Years to 100 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. provision of written informed consent before treatment initiation
  2. pathologically confirmed thymic carcinoma and B3 thymomas, with areas of carcinoma locally advanced as per central histological revision, recurrent and/or metastatic, not amenable to potentially curative treatments.
  3. age>= 18 years old
  4. provision of archival or fresh tissue (block or at least 15 charged slides 4μM of thickness).
  5. Blood and plasma sampling at baseline and at first clinical revaluation
  6. measurable disease (defined according to Response Evaluation Criteria in Solid Tumours [RECIST] version 1.1);7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1;

8. adequate hematologic function, as evidenced by an absolute neutrophil count (ANC) ≥1500/μL, haemoglobin

≥9 g/dL (5.58 mmol/L), and platelets ≥100,000/μL; 9. adequate coagulation function as defined by International Normalized Ratio (INR) ≤ 1.5, and a partial thromboplastin time (PTT) ≤ 5 seconds above the ULN (unless receiving anticoagulation therapy). Patients receiving warfarin must be switched to low molecular weight heparin and have achieved stable coagulation profile prior to first dose of protocol therapy 10. adequate hepatic function as defined by a total bilirubin ≤1.5times the upper limit of normal (ULN), (Except for patients with Gilbert's syndrome who may only be included in the total bilirubin is < 3.0 x ULN or direct bilirubin < 1.5 x ULN) and aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3.0 times the upper limit of normal (or 5.0 times the ULN in the setting of liver metastases) 11. adequate renal function as defined by a serum creatinine ≤1.5 times the ULN, or creatinine clearance (measured via 24-hour urine collection) ≥40 mL/minute (that is, if serum creatinine is >1.5 times the ULN, a 24-hour urine collection to calculate creatinine clearance must be performed). The patient's urinary protein is

≤1+ on dipstick or routine urinalysis (UA; if urine dipstick or routine analysis is ≥2+, a 24-hour urine collection for protein must demonstrate <1000 mg of protein in 24 hours to allow participation in this protocol).

12. sexually active patients, must be postmenopausal, surgically sterile, or using effective contraception (hormonal or barrier methods). Female patients of childbearing potential must have a negative serum pregnancy test within 7 days prior to first dose of protocol therapy. 13. Prior radiation therapy is allowed.

  • In case of chest radiotherapy a 28 days interval is needed between the end of the radiation treatment and the start of treatment .
  • In the case of focal or palliative radiation treatment a 7 days interval is needed from last radiation treatment to start of treatment (and provided that 25% or less of total bone marrow had been irradiated).
  • In the case of CNS radiation a minimum of 14 days interval is needed from the end of radiation treatment to start of treatment.

Exclusion Criteria:

  1. previous systemic treatment for locally advanced/metastatic thymic carcinoma/B3 thymomas; patients treated in the neoadjuvant or adjuvant setting can be enrolled after discussion with PI
  2. 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)
  3. any Grade 3-4 GI bleeding within 3 months prior to first dose of protocol therapy
  4. peripheral neuropathy ≥ G2History of deep vein thrombosis (DVT), pulmonary embolism (PE), or any other significant thromboembolism (venous port or catheter thrombosis or superficial venous thrombosis are not considered "significant") during the 3 months prior to first dose of protocol therapy.
  5. patient has experienced hemoptysis (defined as bright red blood or ≥ 1/2 teaspoon) within 2 months prior to first dose of protocol therapy
  6. radiographic evidence of intra-tumour cavitation, radiologically documented evidence of major blood vessel invasion or encasement by cancer
  7. history of uncontrolled hereditary or acquired thrombotic disorder
  8. The patient has:

    • cirrhosis at a level of Child-Pugh B (or worse) or
    • cirrhosis (any degree) and a history of hepatic encephalopathy or clinically meaningful ascites resulting from cirrhosis. Clinically meaningful ascites is defined as ascites from cirrhosis requiring diuretics or paracentesis.
  9. clinically relevant congestive heart failure (NYHA II-IV) or symptomatic or poorly controlled cardiac arrhythmia
  10. The patient has experienced any arterial thromboembolic events, including but not limited to myocardial infarction, transient ischemic attack, cerebrovascular accident, or unstable angina, within 6 months prior to first dose of protocol therapy.uncontrolled or poorly-controlled hypertension (>160 mmHg systolic or > 100 mmHg diastolic for >4 weeks) despite standard medical management.
  11. serious or no healing wound, ulcer, or bone fracture within 28 days prior to start of treatment
  12. significant bleeding disorders, vasculitis, or experienced grade 3/4 gastrointestinal (GI) bleeding within 3 months prior to start of treatment
  13. history of GI perforation and / or fistulae within 6 months prior to start of treatment
  14. bowel obstruction, history or presence of inflammatory enteropathy or extensive intestinal resection, Crohn's disease, ulcerative colitis, or chronic diarrhoea
  15. peripheral neuropathy ≥grade 2 (NCI-CTCAE v 4.0)
  16. serious illness or medical condition(s) including, but not limited to, the following: -Known human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS)- related illness.

    • Active or uncontrolled clinically serious infection.
    • Previous or concurrent malignancy except for basal or squamous cell skin cancer and/or in situ carcinoma of the cervix, or other solid tumours treated curatively and without evidence of recurrence for at least 3 years prior to start of treatment.
    • Uncontrolled metabolic disorders or other non-malignant organ or systemic diseases or secondary effects of cancer that induce a high medical risk and/or make assessment of survival uncertain.
    • Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration and in the judgment of the investigator would make the patient ineligible for entry into this study.
    • significant third-space fluid retention (for example, ascites or pleural effusion), and is not amenable for required repeated drainage
  17. known allergy or hypersensitivity reaction to any of the treatment components
  18. known history of active drug abuse
  19. patient is pregnant or breastfeeding
  20. major surgery within 28 days prior to first dose of protocol therapy, or minor surgery/subcutaneous venous access device placement within 7 days prior to first dose of protocol therapy
  21. elective or planned major surgery to be performed during the course of the clinical trial
  22. patient is receiving concurrent treatment with other anticancer therapy
  23. patient is receiving chronic antiplatelet therapy, including aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs, including ibuprofen, naproxen, and others), dipyridamole or clopidogrel, or similar agents.

Once-daily aspirin use (maximum dose 325 mg/day) is permitted.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03921671


Contacts
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Contact: Lital Hollander, 02 3901 4640 lital.hollander@marionegri.it
Contact: MARTINA IMBIMBO, MD +39022390

Locations
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Italy
Fondazione IRCCS Istituto Nazionale dei Tumori Recruiting
Milan, Italy
Contact: Miriam Fink    +390223902757    miriam.fink@istitutotumori.mi.it   
Sponsors and Collaborators
Marina Garassino
Investigators
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Principal Investigator: MARINA GARASSINO, MD Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

Publications of Results:

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Responsible Party: Marina Garassino, Principal Investigator, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
ClinicalTrials.gov Identifier: NCT03921671     History of Changes
Other Study ID Numbers: NT-TET1-7371
2017-004494-13 ( EudraCT Number )
First Posted: April 19, 2019    Key Record Dates
Last Update Posted: May 6, 2019
Last Verified: May 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: hospital records; clinical and office charts, laboratory and pharmacy records, diaries, microfiches, radiographs, and correspondence. Data collection will be performed using electronic CRFs exclusively. No paper CRFs are provided to study investigators.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Analytic Code
Time Frame: From the first patient enrolled, to the end of the study
Access Criteria:

Direct access to source data will be granted to authorised representatives from the Sponsor, host institution and the regulatory authorities to permit trial-related monitoring, audits and inspections.

Access to the study clinical data entry platform will be granted to trial staff through a computer-based credential generation system in the following manner:


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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by Marina Garassino, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano:
metastatic or relapsed non-pre-treated disease

Additional relevant MeSH terms:
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Carcinoma
Thymoma
Thymus Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Complex and Mixed
Thoracic Neoplasms
Neoplasms by Site
Lymphatic Diseases
Paclitaxel
Albumin-Bound Paclitaxel
Carboplatin
Ramucirumab
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action