This study has been transitioned to CTIS with ID 2024-513186-39-00 check the CTIS register for the current data. Primary objective:To evaluate the efficacy of nivolumab in combination with ipilimumab in molecular pre-selected patients with…
ID
Source
Brief title
Condition
- Reproductive neoplasms male malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Efficacy
-disease control rate (DCR) of >6mo; this includes SD, PR or CR by best ORR in
evaluable patients, all lasting longer than 6mo
Secondary outcome
Safety (first secondary endpoint):
- Percentage of Grade 3/4 and 5 treatment-related AE*s
Efficacy (second secondary endpoint):
-Best objective response rate (ORR) per RECIST1.1 criteria
-Biochemical response rate at week 13 and maximal PSA decline according to
Prostate Cancer Working Group 3 criteria (PCWG3)
-Radiographic progression free survival per irRECIST1.1 immune-related response
criteria
Background summary
A promising novel treatment modality is immunotherapy utilizing agents that
inhibit negative regulatory immune-checkpoints (immune checkpoint blockade,
[ICB]), or stimulate co-stimulatory checkpoints. Single agent ICB has been only
limited successful in patients with metastatic castration-resistant prostate
cancer (mCRPC), with single agent ICB benefitting a minority of patients.
Ipilimumab, a CTLA-4 inhibitor, has activity in only a subgroup of patients in
both the pre-chemotherapy (CA184-095) and post-chemotherapy (CA184-043)
setting. Among the anti-PD-1/PD-L1 inhibitors, the nivolumab cohort of the
phase 1 study (CA209-003) included 17 patients with advanced CRPC with no
activity witnessed, of which 13 were evaluable for radiographic response.
Interim data from the phase 2 Keynote-199 trial of single-agent pembrolizumab
for 198 patients with measurable disease, with and without PD-L1 expression
showed an overall ORR of 5% with 2 CR and 7 PR. 20% of patients in all three
cohorts witnessed a clinical meaningful disease control rate (DCR) of at least
6 months. It has become clear that an all-comer population yields too few
responses from monotherapy ICB, and alternative strategies for successful
implementation of ICB are needed in this type of cancer.
Combinatory ICB consisting of anti-PD-1 and CTLA-4, has been established as a
treatment modality to increase response rates at the cost of substantial
treatment-related adverse effects (TRAE). This is seen in the phase II
Checkmate-650 trial with nivolumab in combination with ipilimumab. Here, an
all-comer population of mCRPC patients were treated with Nivolumab 1 mg/kg and
Ipilimumab 3 mg/kg Q3W for 4 doses, followed by a maintenance dose of Nivolumab
480mg Q4W. Beneficial responses were observed in 18% of patients, but this
immunotherapeutic regimen appeared too toxic for further development, with only
29% receiving all four combinations, due to discontinuation for toxicity in 43
of 90 patients (48%). A recent trial in 15 patients with mCRPC testing a Q3W
regimen of 3mg/kg nivolumab and 1mg/kg ipilimumab showed a more beneficial
toxicity profile, and could be considered a clinically feasible protocol in a
mCRPC patient population.
In previous work we assessed which histopathological and molecular
characteristics could potentially be used to select for those susceptible for
ICB. Unsupervised clustering of genomic aberrations from whole genome
sequencing data from 197 patients was used to define 3 distinct immune-genomic
clusters of mCRPC A) MSI signature with high tumour mutational burden; B) BRCA
signature with many deletions and a higher than average mutational burden; C)
tandem duplications. Our unsupervised clustering of whole-genome sequencing
data validates supervised molecular patient classification and stratification.
In addition, we demonstrated with multiplex immunohistochemistry, that presence
of tumour infiltrating T-cells (CD4/CD8 cytotoxic T-cells) are associated with
increased neo-antigen load through MSI or other genomic aberrations. Our data
indicates that ±25% of mCRPC patients would be ideal candidates for
biomarker-enriched immunotherapy trials with combination ICB.
Study objective
This study has been transitioned to CTIS with ID 2024-513186-39-00 check the CTIS register for the current data.
Primary objective:
To evaluate the efficacy of nivolumab in combination with ipilimumab in
molecular pre-selected patients with metastatic castration-resistant prostate
cancer. Susceptible patients are selected for MMRd/high mutational burden/BRCA
signature/tandem duplicator phenotype
-cohort 1 will assess the efficacy of the combination in mCRPC patients naïve
for ICB
-cohort 2 will assess the efficacy of the combination in patients with prior
progression to monotherapy ICB (CTLA-4 or anti-PD1/PDL1)
Secondary (translational) objective:
To further optimize and validate predictive and early response immunogenic
signatures from biomarkers in tissue and blood, associating with an objective
response and disease control (DCR) of at least 6 months.
Study design
Open-label phase 2 trial to evaluate the effects of 4 cycles of combinatory ICB
followed by monotherapy nivolumab in patients with an immunogenic mCRPC,
defined as:
-MMRd
-high mutational burden
-BRCA signature
-tandem duplicator phenotype
1) Efficacy:
-disease control rate (DCR) of >6mo; this includes a SD, PR or CR by best ORR
in evaluable patients, all lasting longer than 6mo (first primary endpoint):
-best objective response rate (ORR) per RECIST1.1 criteria
-biochemical response rate at week 13 and maximal PSA decline according to
Prostate Cancer Working Group 3 criteria (PCWG3)
-radiographic progression free survival per iRECIST immune-related response
criteria
2) Safety: Percentage of Grade 3/4 and 5 treatment-related AE*s. Percentage of
events leading to discontinuation. Percentage of treatment-related grade 1/2
and 3/4 toxicities.
3) Correlative research: Longitudinal blood samples (ctDNA response, TCR
richness/diversity, T-cell diversity and functionality) and tissue pre-
on-therapy and optional post-progression collection (NGS, RNA sequencing,
multiplex immunohistochemistry).
CT and bone scintigraphy scans are required for response evaluation, at
baseline at week 6, then every 13 weeks until confirmed disease progression per
iRECIST and PCWG3 criteria. Tumour biopsies/material preservation is required
at baseline and following the second cycle (4 weeks).
Intervention
Cohort 1 and 2:
Treatment with a combinatory regimen of nivolumab 3mg/kg and ipilimumab 1mg/kg
(Q3w, for 4 times), followed by nivolumab 480mg flat dose (Q4w) for up to one
year
Study burden and risks
We anticipate that early molecular profiling will increase the odds that
patient will benefit from
personalized therapy, in this case immunotherapy. Patients with MMR deficiency,
high mutational burden, or certain groups of patients harbouring DNA damage
repair defects, may benefit from checkpoint immunotherapy. Patients may have
better response and duration of response than when given in a later disease
state. Therefore, we anticipate that early molecular characterization and
treatment will lead to better outcome, and better quality of life.
Personalizing cancer treatment has many advantages, but sequencing germline DNA
as reference material for interpreting cancer genetics may have consequences
that extend beyond providing cancer care for an individual patient. In
sequencing germline DNA, mutations may be encountered that are associated with
increased susceptibility not only to hereditary cancer syndromes but also to
other diseases; in those cases, disclosing germline data could be clinically
relevant and even lifesaving. On the other hand knowledge of germline mutations
that confer a certain risk, also needs acknowledging with regard to the
emotional and cognitive difficulties regarding the disclosure of unsolicited
findings. The risk assessment for unsolicited findings are at least 1% of
patients. These unsolicited findings have to be confirmed by a validated test
and patients will be counseled by a genetic counselor. The informed consent
signed by the patients will contain the information that all such findings will
be reported to the patient. There is a very low risk for biopsy associated
complications, this being approximately 1-5% for grade 1-2 CTCAE toxicity, with
<1% for hospitalization due to bleeding, pain or infection. Patients cannot
decide on the specific research that is carried out with their biomaterials.
Immunotherapy
ICB by nivolumab or ipilimumab leads to T-cell activation, with the potential
for clinical inflammatory AEs primarily involving the skin
(dermatitis/pruritus), GI tract (diarrhea/colitis), liver (hepatitis),
endocrine glands (eg, hypophysitis and adrenal or thyroid abnormalities), and
other less frequent organs (eg, uveitis/episcleritis). The majority of these
inflammatory AEs initially manifest during treatment; however, a minority could
occur weeks to months after discontinuation of ipilimumab. The majority of the
inflammatory AEs is reversible with the guidance issued below. When severe
inflammatory AEs occur, ipilimumab or nivolumab should be permanently
discontinued, and systematic high-dose corticosteroid therapy should be
initiated.
Geert Grooteplein Zuid 8
Nijmegen 6500HB
NL
Geert Grooteplein Zuid 8
Nijmegen 6500HB
NL
Listed location countries
Age
Inclusion criteria
1. Written informed consent.
2. Histological diagnosis of adenocarcinoma of the prostate. Patients who have
no histological diagnosis must be willing to undergo a biopsy to prove prostate
adenocarcinoma.
3. Metastatic Castration-Resistant Prostate Cancer (mCRPC), metastatic disease
defined either by measurable disease by RECIST1.1 criteria and/or presence of
bone-metastatic disease evaluable per PCWG3 criteria. For cohort 1, measurable
disease is compulsory.
4. An immunogenic phenotype, consisting of one of the next criteria:
1, mismatch repair deficiency and/or a high mutational burden of >7 mutations
per Mb (cluster A);
2, BRCA2 inactivation and/or BRCAness signature (cluster B);
3, a tandem duplication signature (cluster C).
5. Age >=18 years.
6. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 - 1.
7. PSA >= 2 ng/ml.
8. Documented willingness to use an effective means of contraception while
participating in the study and for 7 months post last dose of treatment.
9. Documented ongoing castrate serum testosterone <50 ng/dL (<2.0 nM).
10. Received prior castration by orchiectomy and/or ongoing Luteinizing
Hormone-Releasing Hormone (LH-RH) agonist treatment.
11. Progression of disease by PSA utilizing PCWG3 criteria and at least another
of the following criteria;
a. Bone scan: disease progression as defined by at least 2 new lesions on bone
scan.
b. Soft tissue disease progression defined by modified RECIST 1.1.
c. Clinical progression with worsening pain and the need for palliative
radiotherapy for bone metastases.
12. Having a biopsiable metastatic lesion and willingness to undergo a
baseline* and on-treatment tumour biopsy for next-generation sequencing and
biomarker analyses. *When sufficient FFPE material is available from a biopsy
in castrate-state, one may apply for a waiver for a new baseline biopsy.
Exclusion criteria
1. Prior treatment with checkpoint immunotherapy (CTLA-4, or PD-1 and PD-L1
antagonists) for cohort 1. For cohort 2 patients may have prior treatment with
monotherapy CTLA-4 or PD-1 or PD-L1.
2. Surgery, chemotherapy within 4 weeks prior to trial entry / randomisation
into the study. Any other therapies for prostate cancer, other than GnRH
analogue therapy and osteoporosis preventing agents, are not allowed.
3. Radiotherapy within 2 weeks prior to trial entry. Radiation-related side
effects higher than grade 1, or above baseline.
4. Participation in another interventional clinical trial and any concurrent
treatment with any investigational drug within 4 weeks prior to trial entry /
randomisation.
5. History of seizure or any condition that may predispose to seizure
including, but not limited to underlying brain injury, stroke, primary brain
tumours, brain metastases, or alcoholism.
6. Untreated or symptomatic brain or leptomeningeal involvement.
7. Inadequate organ and bone marrow function as evidenced by: a. haemoglobin
<6.2 mmol/L b. Absolute neutrophil count <1.0 x 109/L c. Platelet count < 75 x
109/L d. Albumin <30 g/dL. e. AST / SGOT and/or ALT / SGPT >= 2.5 x ULN (>= 5 x
ULN if liver metastases present) f. Total bilirubin >= 1.5 x ULN (except for
patient with documented Gilbert*s disease) g. Serum Creatinine > 1.5 x ULN
8. Any of the following cardiac criteria; a. Any clinically significant
abnormalities in rhythm, conduction, or morphology of a resting ECG (e.g.,
complete left bundle branch block, third degree heart block)
c. Experience of any of the following procedures or conditions in the preceding
six months: coronary artery bypass graft, angioplasty, vascular stent,
myocardial infarction, congestive heart failure NYHA >= Grade2
d. Uncontrolled hypotension defined as - systolic blood pressure (BP) <90mmHg
and/or diastolic BP <50mmHg
9. Clinically significant history of liver disease consistent with Child-Pugh
Class B or C, including viral or other hepatitis, current alcohol abuse, or
cirrhosis.
10. History of clinically relevant auto-immune disease (including Crohn*s
disease or ulcerative colitis). Any other finding giving reasonable suspicion
of a disease or condition that contraindicates the use of nivolumab or
ipilimumab or that may affect the interpretation of the results or renders the
patients at high risk from treatment complications.
10. Need for chronic corticosteroid therapy of >10 mg of prednisolone or >0.5mg
of dexamethasone per day or an equivalent dose of other anti-inflammatory
corticosteroid. Patients in which corticosteroids cannot be stopped prior to
entering the trial are allowed a maximum of 10mg of prednisolone per day or
equivalent. In the case of corticosteroid discontinuation, a 2-week (14 days)
washout is required with a mandatory PSA check prior to starting the trial. If
the PSA has declined compared to the value obtained prior to stopping
corticosteroids, patients will not be eligible for study. Patients can only
enter the study with a confirmed PSA increase.
11. Malignancies other than prostate cancer within 3 years prior to trial entry
/ randomization, except for adequately treated basal or squamous cell skin
cancer and non-muscle invasive bladder cancer.
12. Active second malignancy, except basal or squamous cell skin cancer and
non-muscle invasive bladder cancer. Other treated malignancies with curative
intent, including colorectal cancer, may be included following PI consent.
13. Unresolved clinically significant toxicity from prior therapy except for
alopecia and Grade 1 peripheral neuropathy.
14. Inability to comply with study and follow-up procedures.
15. Patients with predominant small cell or neuroendocrine prostate cancer are
not eligible.
16. Patients without measurable lesion per RECIST1.1, and with a superscan on
bone scintigraphy not evaluable per PCWG3 criteria, are not eligible.
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 | CTIS2024-513186-39-00 |
| EU-CTR | CTIS2024-513186-39-01 |
| EudraCT | EUCTR2020-001240-25-NL |
| CCMO | NL73634.091.20 |