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Carcinoma, Renal CellPhase 2TITAN-RCCNCT02917772

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

A Phase 2 study testing Nivolumab/Ipilimumab in people with Carcinoma, Renal Cell and Clear-cell Metastatic Renal Cell Carcinoma, run by AIO-Studien-gGmbH at 35 sites in 8 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Nivolumab/Ipilimumab
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
200 participants
Where
35 sitesin 8 countries
Study dates
Oct 2016to Oct 2022
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
Show all 27Show fewer
  • 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
  • Hemoglobin less than the lower limit of normal (LLN)
  • Corrected calcium concentration greater than the upper limit of normal (ULN)
  • Absolute neutrophil count greater than the ULN
  • Platelet count greater than the ULN
  • If none of the above factors are present, subjects are not eligible (favorable-risk).
  • 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
  • Women of childbearing potential (WOCBP) must agree to follow instructions for method(s) of contraception for a period of 30 days (duration of ovulatory cycle) plus the time required for the investigational drug to undergo five half-lives. The terminal half lives of nivolumab and ipilimumab are up to 25 days and 18 days, respectively. WOCBP should use an adequate method to avoid pregnancy for 23 weeks (30 days plus the time required for nivolumab to undergo five half-lives) after the last dose of investigational drug.
  • Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for a period of 90 days (duration of sperm turnover) plus the time required for the investigational drug to undergo five half-lives. The terminal half lives of nivolumab and ipilimumab are up to 25 days and 18 days, respectively. Males who receive nivolumab combined with ipilimumab who are sexually active with WOCBP must continue contraception for 31 weeks (90 days plus the time required for nivolumab to undergo five half-lives) after the last dose of investigational drug.
  • Azoospermic males and WOCBP who are continuously not heterosexually active are exempt from contraceptive requirements. However, WOCBP must still undergo pregnancy testing as described in this section.

Who cannot join

  • 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.
Show all 27Show fewer
  • 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
  • Any of the following laboratory test findings:
  • WBC < 2,000/mm3
  • Neutrophils < 1,500/mm3
  • Platelets < 100,000/mm3
  • AST or ALT > 3 x ULN (> 5 x ULN if liver metastases are present)
  • Total Bilirubin > 1.5 x ULN (except subjects with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL)
  • Serum creatinine > 1.5 x upper limit of normal (ULN) or creatinine clearance < 40 mL/min (measured or calculated by Cockroft-Gault formula)
  • Allergies and Adverse Drug Reaction
  • History of severe hypersensitivity reaction to any monoclonal antibody or any constituent of the product.
  • Other Exclusion Criteria
  • Patients who are unable to consent because they do not understand the nature, significance and implications of the clinical trial and therefore cannot form a rational intention in the light of the facts.
  • Patient who has been incarcerated or involuntarily institutionalized by court order or by the authorities.

Trial locations and contacts

35 sites in 8 countries.

35 sites in 8 countries

Spain7 sites

  • Hospital de la Santa Creu i Sant Pau

    Barcelona

  • Hospital 12 de Octubre

    Madrid

  • Hospital Ramón y Cajal

    Madrid

  • Hospital Universitario Central de Asturias

    Oviedo

  • Complejo Hospitalario de Navarra

    Pamplona

  • Hospital Universitario Marques de Valdecilla

    Santander

  • Hospital Virgen del Rocio

    Seville

Other trials in Spain

Germany6 sites

  • Charité Universitätsmedizin Berlin

    Berlin

  • Universitätsklinikum Carl Gustav Carus

    Dresden

  • Universitätsklinikum Düsseldorf

    Düsseldorf

  • Universitätsklinikum

    Düsseldorf

  • Universität des Saarlandes Medizinische Fakultät

    Homburg/Saar

  • Universitätsklinikum Jena und Poliklinik für Urologie

    Jena, Thuringia, 07747

Other trials in Germany

France5 sites

  • CHD Vendée

    La Roche-sur-Yon

  • Centre Hôpitalier Lyon Sud

    Lyon

  • Hôpitaux Universitaires de Strasbourg Hôpital Civil

    Strasbourg

  • Institut Claudius Regaud

    Toulouse

  • Institut Gustave Roussy

    Villejuif

Other trials in France

Italy5 sites

  • Azienda USL8 Arezzo U.O.C. Oncologia Medica

    Arezzo

  • Fondazione IRCCS Istituto Nazionale dei Tumori

    Milan

  • IRCCS Fondazione Policlinico San Matteo

    Pavia

  • Azienda Ospedaliera San Camillo Forlanini

    Roma

  • Policlinico Universitario A. Gemelli

    Roma

Other trials in Italy

Czechia4 sites

  • Fakultní nemocnice Hradec Králové

    Hradec Králové

  • Fakultní nemocnice Olomouc

    Olomouc

  • FN Motol

    Prague

  • Všeobecné fakultní nemocnice

    Prague

Other trials in Czechia

United Kingdom4 sites

  • Broomfield Hospital

    Chelmsford

  • Charing Cross Hospital

    London

  • Kent Oncology Centre

    Maidstone

  • Royal Preston Hospital

    Preston

Other trials in United Kingdom

Austria2 sites

  • Ordensklinikum Linz Barmherzige Schwestern

    Linz

  • AKH Wien Universitätsklinik für Innere Medizin I

    Vienna

Other trials in Austria

Belgium2 sites

  • ZNA Middelheim

    Antwerp

  • CHR Verviers

    Verviers

Other trials in Belgium

About this study

Official title: A Phase II Single Arm Clinical Trial of a Tailored ImmunoTherapy Approach With Nivolumab in Subjects With Metastatic or Advanced Renal Cell Carcinoma

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.

Read the detailed description

The primary object is to estimate the Objective response rate (ORR) based on investigator assessment using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 of the TITAN regimen in untreated (1st line) and pretreated (2nd line) subjects with International Metastatic RCC Database Consortium (IMDC) intermediate and high risk, advanced Renal cell carcinoma (RCC) with clear cell component

Being tested
Nivolumab/Ipilimumab
Keywords
tailored immuno therapy, Nivolumab, Ipilimumab, boost
Medical subject headings
Carcinoma, Renal Cell, Clear-cell metastatic renal cell carcinoma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Nivolumab/IpilimumabBiological

    Also called Opdivo/Yervoy

    • 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)
Study groups in NCT02917772
Study groupRoleWhat they receive
Nivolumab/IpilimumabExperimental* 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
Receives: Biological: Nivolumab/Ipilimumab

What is being measured

The primary outcome is the main question the study is designed to answer.

  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.

    Measured: until 30 weeks after last patient first treatment, LPFT

Secondary outcomes (10)

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

    All as assessed by investigators among all treated subjects, first line subjects, and second line subjects. Furthermore, patients with IMDC intermediate and high risk will be analysed separately.

    Measured: until 30 weeks after last patient first treatment, LPFT

  2. Remission Rates during TITAN treatment: RR1, RR2, RR2SD, RR3

    1. RR1: Number of patients with CR/PR during nivolumab monotherapy (induction and maintenance, the latter only including protocol defined pseudoprogressors) divided by all treated patients.
    2. RR2: Remission rate after progression during nivolumab monotherapy. It is defined as the number of patients with CR/PR after receiving nivolumab/ipilimumab "boost" cycles for initial progression during nivolumab monotherapy divided by all patients receiving "boosts" for this situation.
    3. RR2SD: Remission rate after stable disease during nivolumab monotherapy. It is defined as the number of patients with CR/PR after receiving nivolumab/ipilimumab "boost" cycles for initial stable disease during nivolumab monotherapy divided by all patients receiving "boosts" for this situation.
    4. RR3 is the subsequent remission event to RR2 for patients undergoing repeated nivolumab/ipiliumumab "boost" according to the algorithm described above.

    Measured: until 30 weeks after last patient first treatment, LPFT

  3. Time to Immunotherapy Resistance: TIR

    Subjects with disease progression despite 4 nivolumab/ipilimumab combination "boost" cycles or within 3 months after the last "boost" cycle will be considered immunotherapy resistant.

    Measured: 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.

  4. Time-to-Response: TTR

    TTR may be recorded several times per patient.

    Measured: 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.

  5. Duration of Response: DOR

    DOR may be recorded multiple times per patient.

    Measured: 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.

  6. Overall survival:OS

    OS is defined as the time from first dosing date to the date of death. A subject who has not died will be censored at last known date alive.

    Measured: Time from first dosing date to the date of death. A subject who has not died will be censored at last known date alive.

  7. Safety: Adverse events assessment

    Treatment Emergent Adverse Events according to CTC 4

    Measured: Continuously: Treatment Visit day 1/week 1 until Survival Visits/Follow-up Visits

  8. Safety: Frequency of abnormal laboratory parameters

    Treatment Period: Within 72 hrs prior to re-dosing to include CBC w/ differential, AST, ALT, ALP, T.Bili, BUN or serum urea level, creatinine. Ca, Mg, Na, K, Cl, LDH, glucose, amylase, lipase, TSH (with reflexive Free T4 and Free T3).

    Follow-up Period: On site/local CBC w/differential, AST, ALT, ALP, T.Bili, BUN or serum urea level, creatinine and TSH for X01, repeat at X02 if study drug related toxicity persists.

    Measured: Screening Visit until Survival Visits/Follow-up Visits

  9. Patient reported outcomes

    NCCN-FACT FKSI-19 (Version 2)

    Measured: Treatment Visit day 1/week 1 until Survival Visits/Follow-up Visits 1 and 2

  10. Exploratory objectives: Immune monitoring

    • To monitor immunogenicity of nivolumab and nivolumab/ipilimumab "boosts" with regard to prediction of response as well as immune related adverse events, including:
    • frequency, differentiation and activation of blood-circulating CD4+ and CD8+ T cells (CD27, CD28, CD45RA, CD45RO, CD57, CD95, CD69, CD25, IFN-γ, TNF- α, IL-4, IL 17, IL-10, CD107a)
    • frequency of blood-circulating dendritic cells (HLA-DR, slan, CD1c, CD11c, CD123, CD141, CD303), myeloid-derived suppressor cells (HLA-DR, CD11b, CD14, CD15, CD33), and regulatory T cells (FoxP3, CD25, CD45RA, CD127)
    • expression of molecules involved in immune checkpoint modulation (ICOS, PD-1, PD-L1, CTLA-4) on blood-circulating dendritic cells and T cells
    • To determine the presence of autoantibodies in the serum of RCC patients
    • To explore the expression of PD-L1 and PD-L2 in tumor tissues of mRCC patients and correlation with efficacy parameters

    Measured: Taken together with Laboratory Tests: Prior to induction (Baseline), Prior to Nivo dose 4, Prior to Nivo dose 8, Prior to 6th nivo maintenance dosing

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted28 Sep 2016 (estimated)
  2. Study startOct 2016
  3. Primary completionOct 2021
  4. Study completionOct 2022

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
200 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02917772
Sponsor's protocol ID
0216-ASG
Acronym
TITAN-RCC
Status last verified
Oct 2022
First submitted
27 Sep 2016
Last updated
6 Oct 2022
Results posted
No
Data monitoring committee
No
Individual data sharing
No

Publications

  • 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.

    PubMed 37844597

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Nivolumab/Ipilimumab in people with Carcinoma, Renal Cell and Clear-cell Metastatic Renal Cell Carcinoma, run by AIO-Studien-gGmbH at 35 sites in 8 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 27 inclusion and 27 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 6 Oct 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 35 sites in Spain, Germany, France, Italy, Czechia and 3 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Objective Response Rate (ORR) (time frame: until 30 weeks after last patient first treatment, LPFT). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02917772, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 6 Oct 2022.

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