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Multidisciplinary Approach for Poor Prognosis Sinonasal Tumors in Inoperable Patients

This study is currently recruiting participants. (see Contacts and Locations)
Verified November 2016 by Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
Sponsor:
Collaborator:
Regione Lombardia
Information provided by (Responsible Party):
Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
ClinicalTrials.gov Identifier:
NCT02099188
First received: March 14, 2014
Last updated: November 23, 2016
Last verified: November 2016
  Purpose

Sinonasal tumors are rare diseases, as they account for the 0.2 % - 0.8 % of all tumors. For patients with inoperable tumors, the prognosis is poor and the current therapy is a combined-modality treatment that is both more effective and associated with less morbidity.

This study proposes innovative integration of multiple modality of treatment modulated by histology, molecular profile and response to induction CT.


Condition Intervention Phase
Unresectable Sinonasal Tumors
Drug: Cisplatin
Drug: Docetaxel
Drug: 5-fluorouracil
Drug: Etoposide
Drug: Adriamycin
Drug: Ifosfamide
Drug: Leucovorin
Radiation: Radiotherapy - Patients needing Elective Nodal Volume (ENI)
Radiation: Radiotherapy - Patients not needing ENI
Radiation: Radiotherapy - Patients needing curative neck irradiation
Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Multidisciplinary Approach for Poor Prognosis Sinonasal Tumors: Phase II Study of Chemotherapy, Photon and Heavy Ion Radiotherapy Integration for More Effective and Less Toxic Treatment in Inoperable Patients

Further study details as provided by Fondazione IRCCS Istituto Nazionale dei Tumori, Milano:

Primary Outcome Measures:
  • Progression Free Survival (PFS) [ Time Frame: PFS will be assessed at 5 years. ]
    Progression Free Survival (PFS) at 5 years, defined as the time from enrollment to progression of disease or death for any cause; last date of follow up will be registered for patients alive not in progression.


Secondary Outcome Measures:
  • Overall survival (OS) [ Time Frame: Overall survival will be assessed at the following time frames: 3 months, 6 months, 9 months, 12 months, 18 months, 24 months, 30 months, 36 months, 48 months, 60 months, 72 months, 84 months, 96 months. ]
    Overall survival defined as the time from enrollment (ITT population) or treatment start (PP population) to the date of death from any causes; last date of follow up will be registered for patients alive.

  • Ocular function preservation by visual field tests. [ Time Frame: At the enrollment. During follow-up after: 3 months, 12 months, 24 months, 36 months, 48 months, 60 months, 72 months, 84 months, 96 months. ]
    Ocular function preservation by visual field tests.

  • Hearing preservation performed by audiogram test. [ Time Frame: At the enrollment. During follow-up after: 3 months, 12 months, 24 months, 36 months, 48 months, 60 months, 72 months, 84 months, 96 months. ]
    Hearing preservation performed by audiogram test.

  • Overall safety profile of the whole treatment. [ Time Frame: From the day of the Informed Consent Form signature through to 90 days after the last dose of the last therapy administered (i.e., radiotherapy and/or chemotherapy). ]
    Overall safety profile of the whole treatment characterized by type, severity graded using the National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] Version 4.03), timing and relationship to study therapy of adverse events and laboratory abnormalities collected.

  • Objective Response Rate [ Time Frame: After the end of 1st, 3rd and 5th cycle of induction therapy and before the radiotherapy. During f-up at the following time frames: 3 months, 6 months, 9 months, 12 months, 18 months, 24 months, 30 months, 36 months, 48 months, 60 months. ]
    Objective Response Rate (CR and PR by RECIST criteria version 1.1)

  • Adverse events and laboratories abnormalities. [ Time Frame: During the treatments. F-up at the following time frames: 3 months, 6 months, 9 months, 12 months, 18 months, 24 months, 30 months, 36 months, 48 months, 60 months, 72 months, 84 months, 96 months. ]
    Adverse events (characterized by type, severity, timing) and laboratories abnormalities (graded using the National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] Version 4.03), induced by radiotherapy (both photon RT and heavy ion RT).


Estimated Enrollment: 25
Study Start Date: November 2013
Estimated Study Completion Date: January 2024
Estimated Primary Completion Date: January 2020 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Multimodality treatment

Squamocellular Carcinoma, Sinonasal Undifferentiated Carcinoma:

  • Docetaxel at 75 mg/m2 as IV infusion on Day 1 q3w
  • Cisplatin at 80 mg/m2 as IV infusion on Day 1 q3w
  • 5-fluorouracil at 800 mg/m2/day as IV infusion from Day 1 to Day 4 q3w

Small cell carcinoma neuroendocrine type, Pure neuroendocrine carcinoma and grade III-IV Esthesioneuroblastoma.

  • Cisplatin at 33 mg/m2/day as IV infusion from Day 1 to Day 3 q3w.
  • Etoposide at 150 mg/m2/day as IV infusion from Day 1 to Day 3 q3w . Second cycle and every other cycle
  • Adriamycin at 20 mg/m2/day as IV infusion from Day 1 to Day 3 q3w.
  • Ifosfamide at 3000 mg/m2/day as IV infusion from Day 1 to Day 3 q3w.

Intestinal Type Adenocarcinoma with functional p53.

  • Leucovorin* at 250 mg/m2/day as IV infusion from Day 1 to Day 5 q3w.
  • Cisplatin at 100 mg/m2 as IV infusion on Day 2 q3w
  • 5-fluorouracil at 800 mg/m2/day as IV infusion from Day 2 to Day 5 q3w

Followed by radiotherapy

Drug: Cisplatin
80 mg/m2 or 33 mg/m2/day or 100 mg/m2 - Concentrate for solution for infusion
Drug: Docetaxel
75 mg/m2 - Concentrate for solution for infusion
Drug: 5-fluorouracil
800 mg/m2/day - Concentrate for solution for infusion
Drug: Etoposide
150 mg/m2/day - Concentrate for solution for infusion
Drug: Adriamycin
20 mg/m2/day - Powder for solution for infusion
Drug: Ifosfamide
3000 mg/m2/day - Powder for solution for infusion
Drug: Leucovorin
250 mg/m2/day - Powder for solution for infusion
Radiation: Radiotherapy - Patients needing Elective Nodal Volume (ENI)

LR-PTV: 50.4-54 Gy with 1.8-2 Gy per fraction will be prescribed. This volume will always be treated with photons IMRT.

  1. Particle boost with ENI:

    HR-PTV: carbon ions 18 - 21 Gy (relative biological effectiveness, RBE) in fractions of 3 Gy (RBE) without concomitant chemotherapy IR-PTV: this volume is optional, if used it will receive the first 3 fractions i.e. 9 Gy (RBE) of the boost.

  2. Photons boost with ENI. HR-PTV: at least 70 Gy with 2-2.12 Gy per fraction and 66 Gy at 2Gy per fraction in radical setting will be prescribed. IR-PTV: 59.4-60 Gy with 1.8 Gy-2 Gy per fraction will be prescribed.
Radiation: Radiotherapy - Patients not needing ENI
  1. Treatment with particles. IR-PTV: this volume can be larger or equal to HR-PTV according to individual situations. 50.4-54 Gy with 1.8-2 Gy per fraction will be prescribed to IR-PTV with protontherapy with concomitant chemotherapy. HR-PTV: carbon ions 18 - 21 Gy (RBE) in fractions of 3 Gy (RBE) without concomitant chemotherapy. The first 3 fractions may be given to the bigger IR-PTV.
  2. Treatment with photons. HR-PTV: at least 70 Gy with 2-2.12 Gy per fraction and 66 Gy at 2Gy per fraction in radical setting will be prescribed. IR-PTV: 59.4-60 Gy with 1.8 Gy-2 Gy per fraction will be prescribed.
Radiation: Radiotherapy - Patients needing curative neck irradiation

LR-PTV: 50.4-54 Gy with 1.8-2 Gy per fraction will be prescribed. This volume will always be treated with photons IMRT.

  1. Particle boost. HR-PTV: carbon ions 18 - 21 Gy (RBE) in fractions of 3 Gy (RBE) without concomitant chemotherapy IR-PTV: this volume is optional, if used it will receive the first 3 fractions i.e. 9 Gy (RBE) of the boost.
  2. Photons boost. HR-PTV: at least 70 Gy with 2-2.12 Gy per fraction and 66 Gy at 2Gy per fraction in radical and postoperative setting will be prescribed. IR-PTV: 59.4-60 Gy with 1.8 Gy-2 Gy per fraction will be prescribed.

Detailed Description:

So far, surgery followed by radiotherapy (RT) has been the usual approach for advanced disease. Technical improvements in surgical approaches have been reported, providing less invasive surgery with lower morbidity. However, there are cases of unresectable tumors where the needs of novel strategies is higher.

New therapeutic strategies are needed to obtain more efficient treatment with less morbidity. Some studies explored the role and feasibility of induction chemotherapy (CT) and the prognostic value of response to CT. Histology and molecular pattern can guide the type of administered CT. The first drives the choice of drug to be associated with Cisplatin, while mutational status of p53 (wild type, WT vs mutated, MUT) is a predictive value for response to CT with Cisplatin plus 5-Fluorouracil and Leucovorin in ITAC.

Moreover, proton/carbon ion beam therapy, compared to conventional photon therapy, provides a more accurate and intense dose to tumor area, with potentially higher control of disease.

Treatment outcomes for unresectable paranasal sinus carcinoma are poor, and combined-modality treatment is needed to find out novel therapeutic strategies.

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Signed and dated IEC-approved Informed Consent.
  2. Diagnosis of sinonasal tumor with the following histotypes:

    • Squamous Cell Carcinoma (SCC);
    • Sinonasal Undifferentiated Carcinoma (SNUC);
    • Small Cell Carcinoma Neuroendocrine Type (SmCCNET);
    • Pure Sinonasal Neuroendocrine Carcinoma (SNEC);
    • Intestinal Type Adenocarcinoma (ITAC) with a functional p53 gene;
    • Esthesioneuroblastoma with differentiation grade III-IV by Hyams.
  3. AJCC stage T4b.
  4. Unresectable disease.
  5. ECOG performance status 0-2.
  6. Adequate bone marrow, renal and hepatic functionality, defined as haemoglobin >10 g/dL, neutrophils >1500/mmc, platelets > 100.000/mmc, creatinine value ≤ 1.5 x ULN or calculated creatinine clearance (by Cockcroft and Gault's formula) > 60 mL/min, transaminases values < 1.5 times over the upper limit of normal (ULN).
  7. Polychemotherapy treatment clinical feasibility as per Investigator's Judgment.
  8. Male or female patients ≥ 18 years of age.
  9. Negative pregnancy test (if female in reproductive years).
  10. Agreement upon the use of effective contraceptive methods (hormonal or barrier method of birth control, or abstinence) prior to study entry and for the duration of study participation, if men and women of child producing potential.

Exclusion Criteria:

  1. Previous radiotherapy or chemotherapy for head and neck district tumors (surgical treatment relapses are admitted).
  2. Metastatic disease.
  3. Cardiac, pulmonary, infective, neurological disease or any other medical condition that could interfere with treatment.
  4. Unable and unwilling to comply with scheduled visits, therapy plans, and laboratory tests required in this protocol.
  5. Previous diagnosis of other malignant neoplasm in the last 3 years (in situ cervical cancer or completely excised basocellular/squamocellular skin cancer are always admitted).
  6. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the patient inappropriate for entry into this study or could compromise protocol objectives in the opinion of the Investigator and/or the Sponsor.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02099188

Contacts
Contact: Lisa Licitra, MD +39 02 2390 ext 2805 lisa.licitra@istitutotumori.mi.it
Contact: Paolo Bossi paolo.bossi@istitutotumori.mi.it

Locations
Italy
Presidio Ospedaliero Spedali Civili di Brescia Recruiting
Brescia, BS, Italy, 25125
Principal Investigator: Piero Nicolai, MD         
Fondazione IRCCS Istituto Nazionale Tumori Recruiting
Milano, MI, Italy, 20133
Principal Investigator: Lisa Licitra, MD         
Ospedale Cà Granda - Niguarda Not yet recruiting
Milano, MI, Italy, 20162
Principal Investigator: Alberto G. Dragonetti, MD         
IRCCS Policlinico San Matteo Recruiting
Pavia, PV, Italy, 27100
Principal Investigator: Marco Benazzo, MD         
A.O. Ospedale di Circolo e Fondazione Macchi Recruiting
Varese, VA, Italy, 21100
Principal Investigator: Paolo Castelnuovo, MD         
Azienda Ospedaliera "Maggiore della Carità" Recruiting
Novara, Italy, 28100
Principal Investigator: Letizia Deantonio, MD         
Sponsors and Collaborators
Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
Regione Lombardia
Investigators
Study Director: Lisa Licitra, MD Fondazione IRCCS Istituto Nazionale Tumori
Principal Investigator: Piero Nicolai, MD Presidi Ospedalieri Spedali Civili di Brescia
Principal Investigator: Paolo Castelnuovo, MD A.O. Ospedale di Circolo e Fondazione Macchi
Principal Investigator: Marco Benazzo, MD IRCCS Policlinico San Matteo
Principal Investigator: Alberto G. Dragonetti, MD Ospedale Cà Granda - Niguarda
Principal Investigator: Letizia Deantonio, MD Azienda Ospedaliera "Maggiore della Carità"
  More Information

Responsible Party: Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
ClinicalTrials.gov Identifier: NCT02099188     History of Changes
Other Study ID Numbers: SINTART2
2013-000580-93 ( EudraCT Number )
Study First Received: March 14, 2014
Last Updated: November 23, 2016

Additional relevant MeSH terms:
Docetaxel
Etoposide phosphate
Isophosphamide mustard
Liposomal doxorubicin
Cisplatin
Fluorouracil
Etoposide
Ifosfamide
Doxorubicin
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Antimetabolites
Antimetabolites, Antineoplastic
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents, Phytogenic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Antineoplastic Agents, Alkylating
Alkylating Agents
Antibiotics, Antineoplastic

ClinicalTrials.gov processed this record on March 24, 2017