This study has been transitioned to CTIS with ID 2024-515514-40-00 check the CTIS register for the current data. The primary objective is to investigate the rate of pathological responses following different neoadjuvant immunotherapy combinations in…
ID
Source
Brief title
Condition
- Renal and urinary tract neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The rate of pathological responses following different neoadjuvant
immunotherapy combinations in high-risk non-metastatic clear cell RCC in an
adaptive trial design and the safety and feasibility of neoadjuvant IO approach
in high-risk non-metastatic clear cell renal cell cancer patients
Secondary outcome
Secondary objectives:
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 rate at 5 years
after start of treatment
4. To investigate surgical morbidity according to Clavien Dindo classification
Exploratory objectives:
Collection of peripheral blood and tissue collection (both fresh frozen and
paraffin embedded) on pretreatment biopsies and post-treatment partial/total
nephrectomies to correlate with pathological response rate and RFS for:
1. investigation of immune infiltrate and changes upon neoadjuvant
immunotherapy by (multiplex) IHC/IF/
2. investigation of predictive transcriptomics for response
3. investigation of TMB, frameshift mutations, INDELs, HERV-E
4. ctDNA (methylated DNA) to early predict response to treatment or progression
5. Collect fresh tumor materials for TIL isolation, TCR seq, sc RNA seq
Background summary
From neoadjuvant monotherapy and combination immunotherapy studies it has
become clear that upfront immunotherapy can induce impressive pathological
responses. The observation from OpACIN, that most of the stage III melanoma
patients did not receive 4 courses ipilimumab 3mg/kg + nivolumab 1mg/kg due to
treatment-related toxicities, but also the observation of a very high response
rate after 2 courses in the neo-adjuvant arm, indicated, that stage 3 melanoma
patients benefit already from only 2 infusions.
In addition, in several tumor types combination of ipilimumab plus nivolumab
appear superior to monotherapy anti-PD-1, including melanoma and HNSSC. In
NSCLC, single agent nivolumab led to a high major pathological response rate
[42], while combination ipilimumab plus nivolumab was too toxic [43]. In
mismatch repair (MMR) deficient colorectal cancer, 100% of patients treated so
far in the NICHE trial [21] show a major pathological response and so far, none
of these have progressed/relapsed post-surgery. In MMR proficient colorectal
cancer and bladder cancer combination immunotherapy is also highly effective.
These data have resulted in the initiation of several neoadjuvant phase I/II
studies in primary RCC, which are currently ongoing. A phase I neoadjuvant
trial in patients with RCC has investigated the lymphocytic infiltration,
safety and early efficacy of pembrolizumab (NCT02212730). In addition, two
safety and efficacy studies investigate neoadjuvant nivolumab, one in the
non-metastatic setting and one as pre- and post-operative therapy in metastatic
RCC (ADAPTeR) (NCT02575222; NCT02446860). Another neoadjuvant phase 1b study
tests safety and efficacy of durvalumab plus tremelimumab in advanced RCC
(NCT02762006).
Furthermore, data are emerging that help rationally design a neoadjuvant
combination trial. Specifically, LAG-3 is upregulated in RCC TIL exposed to
anti-PD-1 (more than any other inhibitory receptors like TIM-3) [10]. Targeting
LAG-3 in combination with anti-PD-1 (or ipi/nivo) may be another next logical
step.
Another example for future combination is based on data from CD73, an ecto-5*-
nucleotidase, which is highly expressed in clear cell renal cell cancer and
maybe a marker for cancer stem cells or highly aggressive cells [11]. Recent
data indicate that targeting the adenosine A2A receptor by ciforadenant could
induce ORR in refractory RCC patients pointing towards the importance of
targeting the CD39-CD73-A2AR axis [12].
We here propose to randomize patients to cohorts treated with nivolumab alone,
ipilimumab + nivolumab, and relatlimab + nivolumab, using an adaptive trial
design. In the future other promising combinations can be added, whereas
treatments arms with no or little activity can be stopped
Study objective
This study has been transitioned to CTIS with ID 2024-515514-40-00 check the CTIS register for the current data.
The primary objective is 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. And to study the
safety and feasibility of neoadjuvant IO approach in high-risk non-metastatic
clear cell renal cell cancer patients. To investigate the objective response
rate according to RECIST 1.1
To assess EFS, RFS, rate of metastasis and local recurrence rate at 5 years
after start of treatment and to investigate surgical morbidity according to
Clavien Dindo classification.
Study design
This is an adaptive design, randomized controlled, open-label three-arm phase 2
trial (including a Simon stage 2 design) consisting of 60 intermediate to
high-risk clear cell RCC patients randomized 1:1:1 to receive 2 courses
nivolumab 360 mg q3wk (arm A), 2 courses ipilimumab 1 mg/kg + nivolumab 3 mg/kg
q3wk (arm B), or 2 courses of nivolumab 360 mg + relatlimab 360 mg q3wks (arm
C), prior to surgery at week 7 (23 patients per arm). After 42 patients (14 per
arm) an interim analysis will be performed. Patients will be stratified
according to treatment center.
After 27 patients (9 per arm) an interim analysis will be performed about the
observed efficacy and toxicity within each arm, and based on this information,
the study will be continued.
Intervention
Tumor nephrectomy at 7 weeks
Study burden and risks
Currently, there is no standard systemic adjuvant immunotherapy for RCC
approved. In that way this trial offers an opportunity for the high relapse
risk patient population. However, participation in this trial also sets the
patients at high risk of developing immune related adverse events. Algorithms
have been developed to treat patients developing irAEs. Recovery is commonly
observed (except for endocrine irAE) and depends on the fast onset of the
advised immunosuppression.
Systemic recurrences and overall survival could be improved by treatment with
ipilimumab + nivolumab based on strong data in advanced clear cell RCC patients.
To ensure the safety of these patients, a data safety monitoring board will be
installed
An interim analysis will be planned using a Simon two-stage approach within
arms A, B and arm C separately with the focus on response rate and will be
presented and discussed with the DSMB. In the first stage, 14 patients per arm,
thus in total 42 patients, will be accrued. If there are 0-1 responses within
the 14 patients per arm, then this arm will be closed. Otherwise, 9 additional
patients will be accrued for a total of 23 patients.
Plesmanlaan 121
Amsterdam 1066 CX
NL
Plesmanlaan 121
Amsterdam 1066 CX
NL
Listed location countries
Age
Inclusion criteria
• Adults at least 18 years of age
• World Health Organization (WHO) Performance Status 0 or 1
• Histologically confirmed resectable clear cell RCC (measurable according to
RECIST 1.1), that can be biopsied, and no history of distant metastases
• 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
• No other malignancies, except adequately treated and a cancer-related
life-expectancy of more than 5 years
• Patient willing to undergo triple tumor biopsies and extra blood withdrawal
during screening and in case of relapse
• No prior immunotherapy targeting CTLA-4, PD-1 or PD-L1, or LAG-3
• No immunosuppressive medications within 2 weeks prior start immunotherapy
• 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
• 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
• 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
• Women who are not of childbearing potential (i.e., who are postmenopausal),
or surgically sterile as well as azoospermic men do not require contraception
• Patient is capable of understanding and complying with the protocol
requirements and has signed the Informed Consent document.
Exclusion criteria
• Distantly metastasized RCC • Brain metastases (based on symptoms) • Non-clear
cell RCC • No measurable lesion according to RECIST 1.1 • 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 • Prior CTLA-4 or PD-1/PD-L1 or LAG-3 targeting immunotherapy •
Radiotherapy prior or post-surgery • 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 • Patients will be excluded if they have known history of testing
positive for human immunodeficiency virus (HIV) or known acquired
immunodeficiency syndrome (AIDS) • Allergies and Adverse Drug Reactions (like
mastocytosis) • History of severe hypersensitivity reaction to any monoclonal
antibody • 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; • Pregnant or nursing •
Concurrent medical condition requiring the use of immunosuppressive
medications, or immunosuppressive doses of systemic or absorbable topical
corticosteroids; • Use of other investigational drugs before study drug
administration 30 days and 5 half-times before study inclusion
Relatlimab-specific exclusion criteria • Participants with history of
myocarditis, regardless of etiology. • 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. • 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.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2024-515514-40-00 |
| EudraCT | EUCTR2021-002360-51-NL |
| ClinicalTrials.gov | NCT05148546 |
| CCMO | NL77681.031.21 |