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

NCT02917772 | Completed Phase 2

• 1 other identifier: 0216-ASG
• Study Type: interventional
• Target: 200
• Locations: 8 countries
• Sites: 35

Brief Summary

TITAN RCC (0216-ASG) is a Phase 2, open-label study of nivolumab monotherapy with additional nivolumab/ipilimumab "boost" cycles in previously untreated and pretreated (2nd line), advanced or metastatic renal cell carcinoma (mRCC) subjects with intermediate and high risk disease according to IMDC.

Conditions

Carcinoma, Renal Cell; Clear-cell Metastatic Renal Cell Carcinoma

Keywords

tailored immuno therapy; Nivolumab; Ipilimumab; boost

Outcome Measures

Primary Outcomes (1)

• Objective Response Rate (ORR)

  (RECIST 1.1) by CT or MRI measured at week 8 (+/- 1 week) and week 16 (+/- 1 week), 28 (+/- 1 week) and then every 12 weeks (+/- 1 week). 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. For subjects without documented immunotherapy refractory disease or subsequent therapy, all available response designations will contribute to the ORR determination.

  until 30 weeks after last patient first treatment, LPFT

Secondary Outcomes (10)

• General considerations: RR, TTR, DoR, PFS, TIR (Time to Immunotherapy Resistance), OS

  until 30 weeks after last patient first treatment, LPFT

• Remission Rates during TITAN treatment: RR1, RR2, RR2SD, RR3

  until 30 weeks after last patient first treatment, LPFT

• Time to Immunotherapy Resistance: TIR

  Time from first dosing date to the date of documented tumor progression based on investigator assessments (per RECIST 1.1) despite 4 "boost" cycles or within 3 months after the last "boost" cycle, or death due to any cause.

• Time-to-Response: TTR

  Time from first dosing date or initiation of nivolumab/ipilimumab "boost" cycles to the date of the first confirmed response thereafter, as assessed by the IRC.

• Duration of Response: DOR

  Time from first confirmed response (CR or PR) to the date of the documented progressive disease as determined using RECIST 1.1 criteria or death due to any cause, whichever occurs first.

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 8) * If CR/PR: Nivolumab Maintenance Mono-Therapy (240 mg i.V. / Q2W) * If SD/PD: Nivolumab/Ipilimumab "Boost 1+2"-Combination Therapy (Nivo 3 mg/kg i.V. and Ipi 1 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 3 mg/kg i.V. and Ipi 1 mg/kg i.V. / Q3W x 2) * If CR/PR/SD: Nivolumab Maintenance Mono-Therapy (240 mg i.V. / Q2W)

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 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 must be willing and able to comply with scheduled visits, treatment schedule, laboratory testing, and other requirements of the study.
• Target Population
• Histological confirmation of RCC with a clear-cell component.
• Advanced (not amenable to curative surgery or radiation therapy) or metastatic (AJCC Stage IV) RCC
• One (anti-angiogenic or temsirolimus) \[to be eligible for 2nd line tier\] or no prior systemic therapy for RCC \[to be eligible for 1st line tier\] with the following exception:
• One prior adjuvant or neoadjuvant therapy for completely resectable RCC if such therapy did not include an agent that targets VEGF or VEGF receptors as well as CTLA-4- or PD-1/PD-L1 immune checkpoint inhibitors, respectively, and if recurrence occurred at least 6 months after the last dose of adjuvant or neoadjuvant therapy.
• KPS of at least 70%
• Measurable disease as per RECIST v1.1
• Tumor tissue (FFPE archival or recent acquisition) must be received by the central vendor (block or unstained slides). (Note: Fine Needle Aspiration \[FNA\] and bone metastases samples are not acceptable for submission).
• Patients with intermediate and poor risk categories will be eligible for the study.
• To be eligible as intermediate or poor-risk, at least one of the following prognostic factors as per the International Metastatic RCC Database Consortium (IMDC) criteria must be present:
• KPS equal to 70%
• Less than 1 year from initial diagnosis of RCC (eg, nephrectomy or first diagnostic biopsy) to registration (1st line) or to start of first-line targeted therapy (2nd line), respectively

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.
• Medical History and Concurrent Diseases
• Prior systemic treatment with more than one of the following drugs: mTOR, VEGF or VEGF receptor targeted therapy (including, but not limited to, temsirolimus, everolimus, sunitinib, pazopanib, axitinib, tivozanib, and bevacizumab).
• 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.
• 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.
• Presence of any toxicities attributed to prior anti-cancer therapy, other than alopecia, that have not resolved to Grade 1 (NCI CTCAE v4) or baseline before administration of study drug.
• Physical and Laboratory Test Findings

Sponsors & Collaborators

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

Study Sites (35)

Ordensklinikum Linz Barmherzige Schwestern

Linz, Austria

Location

AKH Wien Universitätsklinik für Innere Medizin I

Vienna, Austria

Location

ZNA Middelheim

Antwerp, Belgium

Location

CHR Verviers

Verviers, Belgium

Location

Fakultní nemocnice Hradec Králové

Hradec Králové, Czechia

Location

Fakultní nemocnice Olomouc

Olomouc, Czechia

Location

FN Motol

Prague, Czechia

Location

Všeobecné fakultní nemocnice

Prague, Czechia

Location

CHD Vendée

La Roche-sur-Yon, France

Location

Centre Hôpitalier Lyon Sud

Lyon, France

Location

Hôpitaux Universitaires de Strasbourg Hôpital Civil

Strasbourg, France

Location

Institut Claudius Regaud

Toulouse, France

Location

Institut Gustave Roussy

Villejuif, France

Location

Universitätsklinikum Jena und Poliklinik für Urologie

Jena, Thuringia, 07747, Germany

Location

Charité Universitätsmedizin Berlin

Berlin, Germany

Location

Universitätsklinikum Carl Gustav Carus

Dresden, Germany

Location

Universitätsklinikum Düsseldorf

Düsseldorf, Germany

Location

Universitätsklinikum

Düsseldorf, Germany

Location

Universität des Saarlandes Medizinische Fakultät

Homburg/Saar, Germany

Location

Azienda USL8 Arezzo U.O.C. Oncologia Medica

Arezzo, Italy

Location

Fondazione IRCCS Istituto Nazionale dei Tumori

Milan, Italy

Location

IRCCS Fondazione Policlinico San Matteo

Pavia, Italy

Location

Azienda Ospedaliera San Camillo Forlanini

Roma, Italy

Location

Policlinico Universitario A. Gemelli

Roma, Italy

Location

Hospital de la Santa Creu i Sant Pau

Barcelona, Spain

Location

Hospital 12 de Octubre

Madrid, Spain

Location

Hospital Ramón y Cajal

Madrid, Spain

Location

Hospital Universitario Central de Asturias

Oviedo, Spain

Location

Complejo Hospitalario de Navarra

Pamplona, Spain

Location

Hospital Universitario Marques de Valdecilla

Santander, Spain

Location

Hospital Virgen del Rocio

Seville, Spain

Location

Broomfield Hospital

Chelmsford, United Kingdom

Location

Charing Cross Hospital

London, United Kingdom

Location

Kent Oncology Centre

Maidstone, United Kingdom

Location

Royal Preston Hospital

Preston, United Kingdom

Location

Related Publications (1)

• Grimm MO, Esteban E, Barthelemy P, Schmidinger M, Busch J, Valderrama BP, Charnley N, Schmitz M, Schumacher U, Leucht K, Foller S, Baretton G, Duran I, de Velasco G, Priou F, Maroto P, Albiges L; TITAN-RCC study group. Tailored immunotherapy approach with nivolumab with or without nivolumab plus ipilimumab as immunotherapeutic boost in patients with metastatic renal cell carcinoma (TITAN-RCC): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2023 Nov;24(11):1252-1265. doi: 10.1016/S1470-2045(23)00449-7. Epub 2023 Oct 13.

  PMID: 37844597 DERIVED

MeSH Terms

Conditions

Carcinoma, Renal Cell; Clear-cell metastatic renal cell carcinoma

Interventions

Nivolumab; Ipilimumab

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Kidney Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Kidney Diseases; Urologic Diseases; Male Urogenital Diseases

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.

  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: September 27, 2016
• First Posted: September 28, 2016
• Study Start: October 1, 2016
• Primary Completion: October 1, 2021
• Study Completion: October 1, 2022
• Last Updated: October 6, 2022

Record last verified: 2022-10

Data Sharing

• IPD Sharing: Will not share

Locations

CZ (4); IT (5); ES (7); AU (2); BE (2); DE (6); FR (5); GB (4)