E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
(metastatic) castration-resistant prostate cancer |
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E.1.1.1 | Medical condition in easily understood language |
(metastatic) castration-resistant prostate cancer |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
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/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)
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Het evalueren van de werkzaamheid van nivolumab in combinatie met ipilimumab bij moleculair voorgeselecteerde patiënten met uitgezaaid castratie-resistente prostaatkanker. Gevoelige patiënten worden geselecteerd op MMRd / hoge mutatie last / tandem duplicator-fenotype
-cohort 1 zal de werkzaamheid van de combinatie beoordelen bij mCRPC-patiënten die niet eerder met ICB zijn behandeld
-cohort 2 zal de werkzaamheid van de combinatie beoordelen bij patiënten met eerdere progressie op monotherapie ICB (CTLA-4 of anti-PD1 / PDL1) |
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E.2.2 | Secondary objectives of the trial |
Translational: 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. |
Translationeel: het verder optimaliseren en valideren van voorspellende en immunogene vroege respons profielen van biomarkers in weefsel en bloed, geassocieerd met een objectieve respons en DCR van ten minste 6 maanden. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 >10 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 (see section 4.5).
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.
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E.4 | Principal 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, for the use of concomitant steroids on this trial please refer to section 12.1. 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.
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E.5 End points |
E.5.1 | Primary end point(s) |
Efficacy endpoint: disease control rate (DCR) of >6mo; this includes SD, PR or CR by best ORR in evaluable patients, all lasting longer than 6mo |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
At inclusion, Wk 7, Wk 17, Wk 29, Wk 41, and 30 days after last dose |
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E.5.2 | Secondary end point(s) |
1) Safety endpoint: percentage of Grade 3/4 and 5 treatment-related AE’s
2) Efficacy endpoint: best objective response rate (ORR) per RECIST1.1 criteria
3) Efficacy endpoint: biochemical response rate at week 13 and maximal PSA decline according to Prostate Cancer Working Group 3 criteria (PCWG3)
4) Efficacy endpoint: radiographic progression free survival per irRECIST1.1 immune-related response criteria |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) At inclusion, Wks 1, 4, 7, 10, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49 and at end of treatment
2) At inclusion, Wk 7, Wk 17, Wk 29, Wk 41, and 30 days after last dose
3) BRR at Wk 13, PSA at inclusion, Wks 1, 4, 7, 10, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49 and at end of treatment
4) At inclusion, Wk 7, Wk 17, Wk 29, Wk 41, and 30 days after last dose |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Finding predictive and prognostic biomarkers of disease |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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last study assessment for the last subject on study or if the sponsor terminates the study, whichever comes first. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |