Phase 2 INSPIRE trial: Ipilimumab with Nivolumab in molecular-Selected patients with castration-resistant PRostate cancer
- Conditions
- advanced prostate cancermetastatic castration-resistant prostate cancer10038597
- Registration Number
- NL-OMON49591
- Lead Sponsor
- Radboud Universitair Medisch Centrum
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Completed
- Sex
- Not specified
- Target Recruitment
- 69
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.
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 sk
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method <p>Efficacy<br /><br>-disease control rate (DCR) of >6mo; this includes SD, PR or CR by best ORR in<br /><br>evaluable patients, all lasting longer than 6mo</p><br>
- Secondary Outcome Measures
Name Time Method <p>Safety (first secondary endpoint):<br /><br>- Percentage of Grade 3/4 and 5 treatment-related AE*s<br /><br><br /><br>Efficacy (second secondary endpoint):<br /><br>-Best objective response rate (ORR) per RECIST1.1 criteria<br /><br>-Biochemical response rate at week 13 and maximal PSA decline according to<br /><br>Prostate Cancer Working Group 3 criteria (PCWG3)<br /><br>-Radiographic progression free survival per irRECIST1.1 immune-related response<br /><br>criteria</p><br>