Prospective, randomized, neoadjuvant phase II study with combination immuno-oncology in primary clear cell renal cell cancer at risk for recurrence or distant metastases (NESCIO-trial; M21NSC; CA209-6DJ)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis Stichting

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Male Urogenital Diseases [C12], Diseases [C] - Female Urogenital Diseases and Pregnancy Complications [C13]

Trial duration

5 Jan 2022 → ongoing

Decision date (initial)

2024-08-22

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2024-515514-40-00

EudraCT number

2021-002360-51

ClinicalTrials.gov

NCT05148546

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Pharmacogenetic, Safety, Therapy

To investigate the rate of pathological responses following different neoadjuvant immunotherapy combinations in high-risk non-metastatic clear cell RCC in an adaptive trial design

Secondary objectives 4

1. To describe the safety and feasibility of neoadjuvant IO approach in high-risk non-metastatic clear cell renal cell cancer patients
2. To investigate the objective response rate according to RECIST 1.1
3. To assess EFS, RFS, rate of metastasis and local recurrence at 5 years after start of treatment
4. To investigate surgical morbidity according Clavien Dindo classification

Conditions and MedDRA coding

Resectable intermediate to high-risk clear cell RCC (according to RECIST 1.1) that can be biopsied, no history of distant metastases, naïve for CTLA-4/PD-1/PD-L1/LAG-3 directed immunotherapy, and more than 18 years old

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. Adults at least 18 years of age
2. World Health Organization (WHO) Performance Status 0 or 1
3. Histologically confirmed resectable clear cell RCC (measurable according to RECIST 1.1), that can be biopsied, and no history of distant metastases
4. Intermediate to high risk will be based on clinical TNM and biopsy nuclear grade. These are: 1. cT1b-cT2a grade 4 cN0 cM0 2. cT2b grade 3-4 cN0 cM0 3. cT3 any grade cN0 cM0 4. cT4 any grade cN0 cM0 5. cT any cN1 (fully resectable) cM0
5. No other malignancies, except adequately treated and a cancer-related life-expectancy of more than 5 years
6. Patient willing to undergo triple tumor biopsies and extra blood withdrawal during screening and in case of relapse
7. No prior immunotherapy targeting CTLA-4, PD-1 or PD-L1, or LAG-3
8. No immunosuppressive medications within 2 weeks prior start immunotherapy
9. Screening laboratory values must meet the following criteria: WBC ≥ 2.0x109/L, Neutrophils ≥1.5x109/L, Platelets ≥100 x109/L, Hemoglobin ≥5.5 mmol/L, Creatinine ≤1.5x ULN, AST ≤ 1.5 x ULN, ALT ≤ 1.5 x ULN, Bilirubin ≤1.5 X ULN, normal CK and Troponin T, normal LDH
10. Women of childbearing potential must use appropriate method(s) of contraception. They 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
11. Women of childbearing potential 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 treatment
12. Women who are not of childbearing potential (i.e., who are postmenopausal), or surgically sterile as well as azoospermic men do not require contraception
13. Patient is capable of understanding and complying with the protocol requirements and has signed the Informed Consent document.

Exclusion criteria 18

1. Distantly metastasized RCC
2. Brain metastases (based on symptoms)
3. Non-clear cell RCC
4. No measurable lesion according to RECIST 1.1
5. Subjects with any active autoimmune disease or a documented history of autoimmune disease, or history of syndrome that required systemic steroids or immunosuppressive medications, except for subjects with vitiligo or resolved childhood asthma/atopy
6. Prior CTLA-4 or PD-1/PD-L1 or LAG-3 targeting immunotherapy
7. Radiotherapy prior or post-surgery
8. Patients will be excluded if they test positive for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody), indicating acute or chronic infection; if treated and being at least one year free from HCV patients are allowed to participate
9. Patients will be excluded if they have known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
10. Allergies and Adverse Drug Reactions (like mastocytosis)
11. History of severe hypersensitivity reaction to any monoclonal antibody
12. Underlying medical conditions that, in the Investigator's opinion, will make the administration of study drug(s) hazardous or obscure the interpretation of toxicity or adverse events;
13. Pregnant or nursing
14. Concurrent medical condition requiring the use of immunosuppressive medications, or immunosuppressive doses of systemic or absorbable topical corticosteroids;
15. Use of other investigational drugs before study drug administration 30 days and 5 half-times before study inclusion
16. Relatlimab-specifik exclusion criteria: Participants with history of myocarditis, regardless of etiology.
17. Relatlimab-specifik exclusion criteria: Troponin T (TnT) > 2 × institutional ULN. Participants with TnT levels between > 1 to 2 × ULN will be permitted if a repeat levels within 24 hours are ≤ 1 ULN. If TnT levels are between >1 to 2 × ULN within 24 hours, the participant may undergo a cardiac consultation and be considered for treatment, following cardiologist recommendation. When repeat levels within 24 hours are not available, a repeat test should be conducted as soon as possible. If TnT repeat levels beyond 24 hours are < 2 × ULN, the participant may undergo a cardiac consultation and be considered for treatment, following cardiologist recommendation. Notification of the decision to enroll the participant following cardiologist recommendation has to be made to the BMS Medical Monitor or designee.
18. Relatlimab-specifik exclusion criteria:Left ventricular ejection fraction (LVEF) assessment with documented LVEF < 50% by either transthoracic echocardiogram (TTE) or multigated acquisition (MUGA) scan (TTE preferred test) within 6 months prior to start of study treatment.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Pathologic response rate, defined as the proportion of patients demonstrating a complete pathologic or partial pathologic response, according to central revision (pathology of NKI)

Secondary endpoints 7

1. Safety, as measured by the frequency of immune-related adverse events leading to postponing of surgery for > 2 weeks
2. Objective response rate, defined as the proportion of patients demonstrating a complete or partial response according to RECIST 1.1, at week 6
3. Recurrence Free Survival (RFS), defined as the time from randomization to recurrence or death from any cause, whichever occurs first. Subjects last known to be alive, who have not experienced recurrence, will be censored
4. Event-free survival (EFS), defined as the time from randomization to recurrence, distant metastasis, or death from any cause, whichever occurs first. Subjects who are event-free at the end of follow-up will be censored
5. Rate of distant metastases, defined as the proportion of patients starting treatment who experience distant metastases during follow-up
6. Rate of local recurrences, defined as the proportion of patients starting treatment who experience a local recurrence during follow-up
7. Surgical morbidity following neoadjuvant immunotherapy (according Clavien Dindo classification)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis Stichting

Sponsor organisation

Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis Stichting

Address

Plesmanlaan 121

City

Amsterdam

Postcode

1066 CX

Country

Netherlands

Scientific contact point

Organisation

Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis Stichting

Contact name

Haanen

Public contact point

Organisation

Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis Stichting

Contact name

Haanen

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 3 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications