A Study of Tremelimumab Combined With the Anti-PD-L1 MEDI4736 Antibody in Malignant Mesothelioma (NIBIT-MESO-1)

• ClinicalTrials.gov Identifier: NCT02588131
• Recruitment Status: Unknown
• First Posted: October 27, 2015
• Last Update Posted: October 27, 2015
• Sponsor: Italian Network for Tumor Biotherapy Foundation
• Collaborator: AstraZeneca
• Information provided by (Responsible Party): Italian Network for Tumor Biotherapy Foundation

Tracking Information

• First Submitted Date: October 26, 2015
• First Posted Date: October 27, 2015
• Last Update Posted Date: October 27, 2015
• Study Start Date: October 2015
• Estimated Primary Completion Date: June 2016 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 26, 2015)

immune-related (ir)- objective response rate (ORR) [ Time Frame: 60 weeks ]

proportion of subjects with complete response [CR] or partial Response [PR]) according to the ir-modified-RECIST or ir-RECIST 1.1 in pleural or peritoneal subjects, respectively.

• Original Primary Outcome Measures: Same as current
• Change History: No Changes Posted

Current Secondary Outcome Measures (submitted: October 26, 2015)

• Immune-related-Disease control rate (ir-DCR) [ Time Frame: 60 weeks ]
  proportion of subjects with ir-CR, ir-PR, ir-stable disease according to the ir-modified-RECIST or ir-RECIST 1.1 in pleural or peritoneal subjects, respectively
• Disease control rate (DCR) [ Time Frame: 60 weeks ]
  proportion of subjects with CR, PR, stable disease according to the modified-RECIST or RECIST 1.1 in pleural or peritoneal subjects, respectively
• Immune-related-progression-free-survival (PFS) [ Time Frame: 60 weeks ]
  ir-PFS per ir-modified-RECIST or ir-RECIST-1.1 for pleural or peritoneal mesothelioma respectively, will be defined as the time between the date of randomization and the date of progression or death
• progression-free-survival (PFS) [ Time Frame: 60 weeks ]
  PFS per modified-RECIST or RECIST-1.1 for pleural or peritoneal mesothelioma respectively, will be defined as the time between the date of randomization and the date of progression or death
• Overall survival (OS) [ Time Frame: 120 weeks ]
  Overall Survival (OS) is defined as the time from randomization until the date of death. For those subjects who have not died, OS will be censored at the recorded last date of subject contact, and for subjects with a missing recorded last date of contact, OS will be censored at the last date the subject was known to be alive.
• Safety (adverse events) [ Time Frame: 120 weeks ]
  The safety endpoints include adverse events (AEs) and serious adverse events (SAEs). Reporting of safety, extent of exposure, concomitant medications and discontinuation of study therapy will be based on all subjects who received at least 1 dose of treatment. Toxicity will be registered according to the NCICTC v 4.0
• Immune-related-ORR based on PD-L1 tumor expression [ Time Frame: 60 weeks ]
  proportion of subjects with PD-L1 positive or negative tumor expression who achieved a complete response [CR] or partial Response [PR]) according to the ir-modified-RECIST or ir-RECIST 1.1 in pleural or peritoneal subjects, respectively.
• Immune-related-Disease control rate based on PD-L1 tumor expression [ Time Frame: 60 weeks ]
  proportion of subjects with PD-L1 positive or negative tumor expression who achieved a CR, PR, stable disease according to the ir-modified-RECIST or ir-RECIST 1.1 in pleural or peritoneal subjects, respectively
• Immune-related-progression- free-survival based on PD-L1 tumor expression [ Time Frame: 60 weeks ]
  ir-PFS per ir-modified-RECIST or ir-RECIST-1.1 for pleural or peritoneal mesothelioma respectively, will be defined in subjects with PD-L1 positive or negative tumor expression as the time between the date of randomization and the date of progression or death
• Overall survival based on PD-L1 tumor expression [ Time Frame: 120 weeks ]
  Overall Survival (OS) is defined in subjects with PD-L1 positive or negative tumor expression as the time from randomization until the date of death. For those subjects who have not died, OS will be censored at the recorded last date of subject contact, and for subjects with a missing recorded last date of contact, OS will be censored at the last date the subject was known to be alive.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of Tremelimumab Combined With the Anti-PD-L1 MEDI4736 Antibody in Malignant Mesothelioma (NIBIT-MESO-1)
• Official Title: A Single Arm, Phase II Clinical Study of Tremelimumab Combined With the Anti-PD-L1 MEDI4736 Monoclonal Antibody in Unresectable Malignant Mesothelioma Subjects: The NIBIT-MESO-1
• Brief Summary: This phase 2, open-label, single arm study aims to evaluate the efficacy of tremelimumab in combination with the anti-PD-L1 MEDI4736 in patients with unresectable malignant mesothelioma subjects
• Detailed Description: The prognosis of malignant mesothelioma (MM) patients remains dismal and effective treatment represents a high un-met medical need. Investigators have recently reported promising clinical activity of the anti-CTLA-4 mAb tremelimumab in pre-treated MM patients: disease control rate (DCR) was 31%, and survival rate at 1- and 2-years were 48.3% and 36.7%, respectively. These initial findings were corroborated by a second study in which, based on retrospective pharmacokinetic analyses, an intensified schedule of tremelimumab was utilized. Fifty-two % of patients achieved a DCR (median duration 10.9 months). These intriguing clinical results and the emerging efficacy of immunomodulatory mAb targeting the PD-1/PD-L1 axis in different tumor types, prompted us to design the NIBIT-MESO-1 study aimed to investigate the efficacy of tremelimumab combined with the anti-PD-L1 MEDI4736 in MM patients.
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Pleural Mesothelioma
• Peritoneal Mesothelioma

Intervention

Drug: tremelimumab plus MEDI4736

tremelimumab1 mg/kg i.v over 60 minutes plus MEDI 4736 20 mg/kg i.v every four weeks for 4 doses, then MEDI4736 20 mg/kg IV every four weeks for additional 9 doses.

Other Name: MEDI4736 (durvalumab)

Study Arms

Experimental: tremelimumab plus MEDI4736

Tremelimumab in combination with MEDI4736

Intervention: Drug: tremelimumab plus MEDI4736

Publications *

• Calabrò L, Morra A, Fonsatti E, Cutaia O, Amato G, Giannarelli D, Di Giacomo AM, Danielli R, Altomonte M, Mutti L, Maio M. Tremelimumab for patients with chemotherapy-resistant advanced malignant mesothelioma: an open-label, single-arm, phase 2 trial. Lancet Oncol. 2013 Oct;14(11):1104-1111. doi: 10.1016/S1470-2045(13)70381-4. Epub 2013 Sep 11.
• Calabrò L, Ceresoli GL, di Pietro A, Cutaia O, Morra A, Ibrahim R, Maio M. CTLA4 blockade in mesothelioma: finally a competing strategy over cytotoxic/target therapy? Cancer Immunol Immunother. 2015 Jan;64(1):105-12. doi: 10.1007/s00262-014-1609-9. Epub 2014 Sep 19. Review.
• Calabrò L, Morra A, Fonsatti E, Cutaia O, Fazio C, Annesi D, Lenoci M, Amato G, Danielli R, Altomonte M, Giannarelli D, Di Giacomo AM, Maio M. Efficacy and safety of an intensified schedule of tremelimumab for chemotherapy-resistant malignant mesothelioma: an open-label, single-arm, phase 2 study. Lancet Respir Med. 2015 Apr;3(4):301-9. doi: 10.1016/S2213-2600(15)00092-2. Epub 2015 Mar 26.
• Antonia et al. A Phase Ib study of MEDI4736, a programmed cell death ligand-1 (PD-L1) antibody, in combination with tremelimumab, a cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) antibody, in patients with advanced non-small cell lung cancer (NSCLC). ASCO 2015 (Abstract #3014).
• Calabrò L, Rossi G, Morra A, Rosati C, Cutaia O, Daffinà MG, Altomonte M, Di Giacomo AM, Casula M, Fazio C, Palmieri G, Giannarelli D, Covre A, Maio M. Tremelimumab plus durvalumab retreatment and 4-year outcomes in patients with mesothelioma: a follow-up of the open label, non-randomised, phase 2 NIBIT-MESO-1 study. Lancet Respir Med. 2021 Apr 9. pii: S2213-2600(21)00043-6. doi: 10.1016/S2213-2600(21)00043-6. [Epub ahead of print]
• Calabrò L, Morra A, Giannarelli D, Amato G, D'Incecco A, Covre A, Lewis A, Rebelatto MC, Danielli R, Altomonte M, Di Giacomo AM, Maio M. Tremelimumab combined with durvalumab in patients with mesothelioma (NIBIT-MESO-1): an open-label, non-randomised, phase 2 study. Lancet Respir Med. 2018 Jun;6(6):451-460. doi: 10.1016/S2213-2600(18)30151-6. Epub 2018 May 15.

Recruitment Information

• Recruitment Status: Unknown status
• Estimated Enrollment (submitted: October 26, 2015): 40
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: March 2018
• Estimated Primary Completion Date: June 2016 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Willing and able to give written informed consent.
• Histologic diagnosis of malignant mesothelioma.
• Subjects who have refused a first line platinum-based chemotherapy, or subjects in progression of disease after a maximum of one line of platinum-based therapy for advanced disease.
• Disease not amenable to curative surgery.
• Measurable disease, per modified Response Evaluation Criteria in Solid Tumor [RECIST] for pleural mesothelioma or RECIST version 1.1 for peritoneal mesothelioma).
• Life expectancy ≥ 12 weeks.
• ECOG performance status of 0 or 1
• Normal laboratory tests
• Negative screening tests for HIV, Hepatitis B, and Hepatitis C.
• Availability of archival tumor tissue or feasibility to perform a new tumor biopsy at screening phase.
• Men and women, of and over 18 years old. Women of childbearing potential (WOCBP) must use appropriate method(s) of contraception. WOCBP should use an adequate method to avoid pregnancy for 180 days after the last dose of investigational drug.

Exclusion Criteria:

• Involvement in the planning and/or conduct of the study.
• Participation in another clinical study with an investigational product during the last 6 weeks.
• Any previous treatment with a CTLA4, PD-1 or PD-L1 inhibitor, including tremelimumab or MEDI4736.
• History of another primary malignancy except for: malignancy treated with curative intent and with no known active disease ≥3 years before the first dose of study drug and of low potential risk for recurrence. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease. Adequately treated carcinoma in situ without evidence of disease eg, cervical cancer in situ.
• Receipt of the last dose of anti-cancer therapy ≤ 6 weeks prior to the first dose of study drug.
• Mean QT interval corrected for heart rate (QTc) ≥470 ms using Bazett's Correction.
• Current or prior use of immunosuppressive medication within 28 days before the first dose of tremelimumab and MEDI4736, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid.
• Any unresolved toxicity (CTCAE grade >2) from previous anti-cancer therapy.
• Any prior Grade >3 immune-related adverse event (irAE) while receiving any previous immunotherapy agent, or any unresolved irAE >Grade 1. Active or prior documented autoimmune or inflammatory disorders
• History of primary immunodeficiency or allogeneic organ transplant.
• History of hypersensitivity to tremelimumab or MEDI4736 or any excipient.
• Uncontrolled intercurrent illness including, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active bleeding diatheses
• Known history of previous clinical diagnosis of tuberculosis.
• History of leptomeningeal carcinomatosis.
• Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving tremelimumab and MEDI4736.
• Symptomatic or uncontrolled brain metastases requiring concurrent treatment, inclusive of but not limited to surgery, radiation and/or corticosteroids.
• Subjects with uncontrolled seizures.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Italy

Administrative Information

• NCT Number: NCT02588131
• Other Study ID Numbers: NIBIT-MESO-1
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Italian Network for Tumor Biotherapy Foundation
• Study Sponsor: Italian Network for Tumor Biotherapy Foundation
• Collaborators: AstraZeneca

Investigators

• Principal Investigator: Luana Calabro', MD, PhD; Medical Oncology and Immunotherapy Division, Univeristy Hospital os Siena, Siena, Italy

• PRS Account: Italian Network for Tumor Biotherapy Foundation
• Verification Date: October 2015