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

Study Overview
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Brief Summary
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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.

Detailed Description
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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

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

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

Intervention / Treatment
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* Biological: Nivolumab/Ipilimumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 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. Exclusion Criteria: 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 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nivolumab/Ipilimumab<br>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<br>* 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)<br>* Other names: Opdivo/Yervoy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | until 30 weeks after last patient first treatment, LPFT | 
| Remission Rates during TITAN treatment: RR1, RR2, RR2SD, RR3 | 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. 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. 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. RR3 is the subsequent remission event to RR2 for patients undergoing repeated nivolumab/ipiliumumab boost according to the algorithm described above. | until 30 weeks after last patient first treatment, LPFT | 
| 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. | 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 | TTR may be recorded several times per patient. | 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 | DOR may be recorded multiple times per patient. | 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. | 
| 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. | Time from first dosing date to the date of death. A subject who has not died will be censored at last known date alive. | 
| Safety: Adverse events assessment | Treatment Emergent Adverse Events according to CTC 4 | Continuously: Treatment Visit day 1/week 1 until Survival Visits/Follow-up Visits | 
| 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. | Screening Visit until Survival Visits/Follow-up Visits | 
| Patient reported outcomes | NCCN-FACT FKSI-19 (Version 2) | Treatment Visit day 1/week 1 until Survival Visits/Follow-up Visits 1 and 2 | 
| 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 | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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tailored immuno therapy, Nivolumab, Ipilimumab, boost