Tailored ImmunoTherapy Approach With Nivolumab in Subjects With Metastatic or Advanced Transitional Cell Carcinoma

NCT03219775 | Unknown Phase 2 DMC

• 1 other identifier: 0416-ASG
• Study Type: interventional
• Target: 169
• Locations: 2 countries
• Sites: 27

Brief Summary

TITAN-TCC (0416-ASG) is a Phase 2, open-label study of nivolumab (BMS-936558) monotherapy with additional nivolumab/ipilimumab "boost" cycles in previously untreated\* and platinum-based pretreated, 2nd and 3rd line, advanced or metastatic transitional cell carcinoma subjects. Nivolumab is a fully human PD-1 antibody which blocks the respective immune checkpoint in a ligand (PD-L1/PD-L2) independent manner. \[\*Update from Jan-2020: First-line cohort was stopped and the inclusion of these patients was terminated\]

Conditions

Transitional Cell Carcinoma; Advanced Cancer; Metastatic Cancer

Keywords

tailored immuno therapy; Nivolumab; Ipilimumab; boost

Outcome Measures

Primary Outcomes (1)

• Objective Response Rate (ORR)

  The primary objective will be measured by the primary endpoint of ORR (based on investigator assessments) among all treated subjects, first line subjects and second line subjects. It is defined as the number of subjects with a best overall response of CR or PR divided by the number of all treated subjects, first line subjects or second line subjects. Best overall response is defined as the best response designation, as determined by investigator, recorded between the date of first dose and the date of objectively documented immunotherapy resistance per RECIST v1.1 or the date of subsequent therapy, whichever occurs first.

  max. months

Secondary Outcomes (10)

• Remission Rates (RR)

  max. 68 months

• Time to Immunotherapy Resistance (TIR)

  max. 68 months

• Time to Response (TTR)

  max. 68 months

• Duration of Response (DOR)

  max. 68 months

• Progression free survival (PFS)

  max. 68 months

Other Outcomes (2)

• Immune monitoring (Exploratory Endpoint)

  max. 68 months

• PD-L1 and PD-L2

  max. 68 months

Study Arms (1)

Nivolumab/Ipilimumab

EXPERIMENTAL

* Induction: Mono-Therapy with Nivolumab * If CR/PR: Nivolumab Maintenance Mono-Therapy * If SD/PD: Nivolumab/Ipilimumab "Boost 1+2"-Combination Therapy * If CR/PR: Nivolumab Maintenance Mono-Therapy * If SD/PD: Nivolumab/Ipilimumab "Boost 3+4"-Combination Therapy * If CR/PR/SD: Nivolumab Maintenance Mono-Therapy

Biological: Nivolumab/Ipilimumab

Interventions

Nivolumab/Ipilimumab BIOLOGICAL

* Induction: Mono-Therapy with Nivolumab (240 mg i.V. / Q2W x 4) * If CR/PR: Nivolumab Maintenance Mono-Therapy (240 mg i.V. / Q2W) * If SD/PD: Nivolumab/Ipilimumab "Boost 1+2"-Combination Therapy (Nivo1 mg/kg i.V. and Ipi3 mg/kg i.V. / Q3W x 2)\* * If CR/PR: Nivolumab Maintenance Mono-Therapy (240 mg i.V. / Q2W) * If SD/PD: Nivolumab/Ipilimumab "Boost 3+4"-Combination Therapy (Nivo 1 mg/kg i.V. and Ipi 3 mg/kg i.V. / Q3W x 2) * If CR/PR/SD: Nivolumab Maintenance Mono-Therapy (240 mg i.V. / Q2W) * since June 5, 2019, the treatment in all four "boost" cycles (1+2) and (3+4) is performed with nivolumab 1 mg/kg + ipilimumab 3 mg/kg (NIVO1/IPI3)

Also known as: Opdivo/Yervoy

Nivolumab/Ipilimumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Signed Written Informed Consent
• Subjects or legally acceptable representatives must have signed and dated an IRB/IEC approved written informed consent form in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol related procedures that are not part of normal subject care.
• Subjects or legally acceptable representatives must be willing and able to comply with scheduled visits, treatment schedule, laboratory testing, and other requirements of the study.
• Target Population
• Histological evidence of metastatic or surgically unresectable transitional cell carcinoma of the bladder, urethra, ureter, or renal pelvis. Minor histologic variants of transitional cell carcinoma (e.g. squamous cell, comprising \<50 % of the tumor overall) are acceptable.
• Subjects must have advanced or surgically unresectable TCC (cT4b, any N or any T, N2-N3 or any M1) or having progressed during or after platinum-based first line therapy and up to 1 further treatment line (2nd and 3rd line cohort). Subjects, who have received neoadjuvant or adjuvant cisplatin based chemotherapy are eligible and considered first line provided that progression has occurred \>12 months from last therapy \[for chemoradiation and adjuvant treatment\] or \>12 months from last surgery \[for neoadjuvant treatment\]; in all other patients who received cisplatin based neoadjuvant and/or adjuvant chemotherapy and progression within 12 months this will be considered one line of therapy. \[\*Update January 2020:First-line cohort has been stopped since 31-Jan-2019 and wont be restarted\]
• KPS of at least 70% (See Appendix 1)
• Measurable disease as per RECIST v1.1 (See Appendix 2)
• Formalin-fixed paraffin embedded tumor tissue obtained within 2 years prior to screening must be available and received by the central pathology (tumor block is preferred, alternatively 15 unstained slides). Note that:
• Fine Needle Aspiration \[FNA\] and bone metastases samples (without soft tissue component) are not acceptable for submission).
• Tumor lesions used for newly acquired biopsies should not be target lesions, unless there are no other lesions.
• Age and Reproductive Status
• Males and Females, ≥ 18 years of age
• Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of study drug.
• Women must not be breastfeeding

You may not qualify if:

• Target Disease Exceptions
• Any history of or current CNS metastases. Baseline imaging of the brain by MRI (preferred) or CT scan is required within 28 days prior to registration in 2nd/3rd line patients only.
• Medical History and Concurrent Diseases
• Prior systemic treatment with more than two different chemotherapy regimen (Sequential chemotherapy as a planned sequence to optimize response will count as 1 regimen)
• Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti CTLA 4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways.
• Any active or recent history of a known or suspected autoimmune disease or recent history of a syndrome that required systemic corticosteroids (\> 10 mg daily prednisone equivalent) or immunosuppressive medications except for syndromes which would not be expected to recur in the absence of an external trigger. Subjects with vitiligo or type I diabetes mellitus or residual hypothyroidism due to autoimmune thyroiditis only requiring hormone replacement are permitted to enroll.
• Any condition requiring systemic treatment with corticosteroids (\> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days prior to first dose of study drug. Inhaled steroids and adrenal replacement steroid doses \> 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
• Prior malignancy active within the previous 3 years except for
• locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast.
• Patients in active surveillance for prostate cancer
• Human immunodeficiency virus (HIV) infection or known acquired immunodeficiency syndrome (AIDS).
• Any positive test for hepatitis B or hepatitis C virus indicating acute or chronic infection.
• Known medical condition (eg, a condition associated with diarrhea or acute diverticulitis) that, in the investigator's opinion, would increase the risk associated with study participation or study drug administration or interfere with the interpretation of safety results.
• Major surgery (eg, nephrectomy) less than 28 days prior to the first dose of study drug.
• Anti-cancer therapy less than 28 days prior to the first dose of study drug or palliative, focal radiation therapy less than 14 days prior to the first dose of study drug.

Sponsors & Collaborators

• AIO-Studien-gGmbH: lead
• Bristol-Myers Squibb: collaborator

Study Sites (27)

Univ. Klinik für Innere Medizin

Graz, 8036, Austria

Location

Ordensklinikum Linz - KH Barmherzige Schwestern

Linz, 4010, Austria

Location

Universitätsklinikum Salzburg

Salzburg, 5020, Austria

Location

KH der Barmherzigen Brüder Wien

Vienna, 1020, Austria

Location

Landesklinikum Wiener Neustadt

Wiener Neustadt, 2700, Austria

Location

Universitätsklinikum Jena und Poliklinik für Urologie

Jena, Thuringia, 07747, Germany

Location

Uniklinik der RWTH Aachen

Aachen, 52074, Germany

Location

Vivantes Klinikum Neukölln

Berlin, 12351, Germany

Location

Studienzentrum Bayenthal

Cologne, 50968, Germany

Location

Uniklinik C.-G.-Dresden

Dresden, 01307, Germany

Location

Universitätsklinikum Düsseldorf

Düsseldorf, 40225, Germany

Location

Helios Klinikum Erfurt

Erfurt, 99089, Germany

Location

Universitätsklinikum Erlangen

Erlangen, 91054, Germany

Location

Chirurgische Universitätsklinik Freiburg

Freiburg im Breisgau, 79106, Germany

Location

Überörtliche Gemeinschaftspraxis für Urologie GbR

Fürth, 90763, Germany

Location

Greifswald Universitätsklinikum

Greifswald, 17475, Germany

Location

Universitätsklinikum Heidelberg Chirurgische Klinik Klinik für Urologie

Heidelberg, 69120, Germany

Location

Marien Hospital

Herne, 44625, Germany

Location

Urologie Herzberg

Herzberg am Harz, 37412, Germany

Location

Universitätsklinikum Magdeburg

Magdeburg, 39120, Germany

Location

UKGM Marburg

Marburg, 35033, Germany

Location

Klinikum der Universität München - Großhadern

München, 81377, Germany

Location

Universitätsklinikum Münster

Münster, 48149, Germany

Location

Universtätsmedizin Rostock

Rostock, 18057, Germany

Location

Universitätsklinikum Ulm

Ulm, 89075, Germany

Location

Kliniken Nordoberpfalz AG, Klinikum Weiden

Weiden, 92637, Germany

Location

Urologie Praxis am Wasserturm

Würselen, 52146, Germany

Location

Related Publications (3)

• Grimm MO, Schostak M, Grun CB, Loidl W, Pichler M, Zimmermann U, Schmitz-Drager B, Steiner T, Roghmann F, Niegisch G, Bolenz C, Schmitz M, Baretton G, Leucht K, Schumacher U, Foller S, Zengerling F, Meran J; TITAN-TCC Study Group. Nivolumab + Ipilimumab as Immunotherapeutic Boost in Metastatic Urothelial Carcinoma: A Nonrandomized Clinical Trial. JAMA Oncol. 2024 Jun 1;10(6):755-764. doi: 10.1001/jamaoncol.2024.0938.

  PMID: 38722641 DERIVED

• Grimm MO, Grun CB, Niegisch G, Pichler M, Roghmann F, Schmitz-Drager B, Baretton G, Schmitz M, Bolenz C, Foller S, Leucht K, Schumacher U, Schostak M, Meran J, Loidl W, Zengerling F. Tailored immunotherapy approach with nivolumab with or without ipilimumab in patients with advanced transitional cell carcinoma after platinum-based chemotherapy (TITAN-TCC): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2023 Apr;24(4):347-359. doi: 10.1016/S1470-2045(23)00053-0. Epub 2023 Feb 28.

  PMID: 36868252 DERIVED

• Grimm MO, Schmitz-Drager BJ, Zimmermann U, Grun CB, Baretton GB, Schmitz M, Foller S, Leucht K, Schostak M, Zengerling F, Schumacher U, Loidl W, Meran J. Tailored Immunotherapy Approach With Nivolumab in Advanced Transitional Cell Carcinoma. J Clin Oncol. 2022 Jul 1;40(19):2128-2137. doi: 10.1200/JCO.21.02631. Epub 2022 Mar 11.

  PMID: 35275706 DERIVED

MeSH Terms

Conditions

Carcinoma, Transitional Cell; Neoplasm Metastasis

Interventions

Nivolumab; Ipilimumab

Condition Hierarchy (Ancestors)

Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Marc-Oliver Grimm, Prof. Dr.

  Jena University Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 4, 2017
• First Posted: July 18, 2017
• Study Start: July 6, 2017
• Primary Completion: September 16, 2021
• Study Completion: February 18, 2023
• Last Updated: November 3, 2021

Record last verified: 2021-11

Locations

AU (5); DE (22)