E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Metastatic castrate resistant prostate cancer (prostate adenocarcinoma) |
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E.1.1.1 | Medical condition in easily understood language |
Prostate cancer that has spread to other parts of the body that continues to grow and spread despite using hormone therapy (anti-androgen therapy). |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10001198 |
E.1.2 | Term | Adenocarcinoma of the prostate metastatic |
E.1.2 | System Organ Class | 100000004864 |
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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 |
The trial is testing to see if metastatic prostate cancer patients who are no longer responding to their current treatment or previous treatment will respond to combination treatment of Nivolumab and Ipilimumub. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives are to find out what the potential benefits of nivolumab and ipilimumab treatment are by measuring: - The overall survival rate of patients - iRECIST Radiological Response rate - The progression-free survival of patients via imaging - The progression-free survival of patients via the blood marker PSA - The frequency and severity of side effects of treatment. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Inclusion criteria for Pre-Screening (Assessment of ImS): • Metastatic castrate resistant prostate cancer. • Histologically confirmed prostate adenocarcinoma. • Patient has archival prostate cancer tissue available or has disease amenable to biopsy and is willing to undergo a new biopsy for assessment of ImS. Disease amenable to biopsy is: o Soft tissue lesion meeting RECIST criteria that in the opinion of clinician and interventional radiologist is safe to biopsy, or o Bone lesion that is deemed suitable to biopsy by a suitably trained clinician. • Men ≥18 years. • Adequate venous access for administration of treatment and collection blood samples for exploratory biological samples. • Life expectancy of >6 months. • Has had or is having ≥1 line of systemic treatment for CRPC, or is currently having first line systemic treatment for mCRPC. • Reasonable expectation that the patient does currently, or will within the next 3 months, have progressive disease and fulfil all eligibility criteria for trial treatment
Inclusion Criteria for Main Study (Treatment): • Metastatic castrate resistant prostate cancer. • Histologically confirmed prostate adenocarcinoma. • Immunogenic signature positive disease • Patients with disease amenable to biopsy must be willing to have a new biopsy (if new biopsy was not required for assessment of ImS). • WHO performance status of 0-1. • Adequate haematological status. • Adequate liver and renal function. • Has had 1 line of systemic treatment for CRPC. • Documented prostate cancer progression within 6 months prior to screening for the Main Study • Ongoing androgen deprivation with serum testosterone <1.73 nmol/L.
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E.4 | Principal exclusion criteria |
Exclusion criteria for Assessment of ImS: • Any history of autoimmune disease, with the exception of patients with a history of autoimmune-related hyperthyroidism or hypothyroidism who are in remission or on a stable dose of thyroid-replacement hormone • Patients with prior allogeneic stem cell or solid organ transplantation • Active invasive malignancy in the previous 2 years excluding non-melanoma skin cancer. • History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organising pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis on screening chest CT scan (History of radiation pneumonitis in the radiation field is permitted). • Patients with interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity • Patients with the following risk factors for bowel perforation: o History of acute diverticulitis or intra-abdominal abcess in the last 3 years o History of GI obstruction or abdominal carcinomatosis • History of grade ≥2 peripheral neuropathy. • Prior treatment with Sipuleucel-T, immune checkpoint targeting agents or other novel immune-oncology agents • Significant cardiovascular disease, such as New York Heart Association cardiac disease (Class II or greater), myocardial infarction within 3 months prior to enrolment, unstable arrhythmias, or unstable angina. • Patients with uncontrolled Type 1 diabetes mellitus. Patients controlled on a stable insulin regimen are eligible. • Patients with uncontrolled adrenal insufficiency. • Known active hepatitis B or C infection. • Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness.
Exclusion criteria for treatment: All exclusion criteria to exclude patients from Assessment of ImS apply • Patients with risk factors for bowel perforation. • Patients must not have had systemic corticosteroid therapy (>10mg daily prednisone equivalent) for 14 days prior to study entry, or concomitant use of other immunosuppressive medications. The use of inhaled corticosteroids, physiologic replacement doses of glucocorticoids (i.e., for adrenal insufficiency), and mineralocorticoids (e.g., fludrocortisone) is allowed. • Administration of a live, attenuated vaccine within 4 weeks prior to enrolment or anticipation that such a live, attenuated vaccine will be required during the study. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint of the trial is to assess the composite response rate (CRR): patients will be considered as having had a treatment response if any one of the following criteria are satisfied: • Radiological response (Modified RECIST 1.1) • PSA response ≥50% confirmed by a second PSA test at least 4 weeks later (PCWG3 2016) • Conversion of CTC count from ≥5 cells/7.5ml at baseline to <5 cells/7.5ml at 9 weeks confirmed by a second CTC test at least 4 weeks later (PCWG3 2016) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
CRR will be reported upon completion of treatment (proportion and 95% confidence interval) and an exact test will be performed to compare the CRR to the hypothesised rate of 20% for ineffective treatment effect. |
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E.5.2 | Secondary end point(s) |
The secondary endpoints of the trial are:
1. Overall survival (OS) 2. Radiological progression free survival (RPFS) 3. iRECIST Radiological Response rate 4. PSA progression free survival 5. Frequency and severity of adverse events
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. OS is defined as the time from registration to death from any cause. Patients without documented death at the time of the final analysis will be censored at the date of the last follow-up. OS will be analysed using Kaplan-Meier plots and median OS. OS rates (with 95% confidence intervals) will be calculated upon completion of treatment.
2. RPFS is defined as the time from registration to objective disease progression or death from any cause. Patients without documented death or documented progression time at the time of the final analysis will be censored at the date of the last follow-up. RPFS will be analysed using Kaplan-Meier plots and median RPFS. RPFS rates (with 95% confidence intervals) will be calculated upon completion of treatment. |
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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 | Yes |
E.6.7 | Pharmacodynamic | Yes |
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 | No |
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 | No |
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.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 15 |
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 | No |
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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The end of the trial will be 5 years after registration of the final patient, or once all patients have progressed or died, whichever is sooner. |
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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 | 6 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | 29 |
E.8.9.2 | In all countries concerned by the trial years | 6 |
E.8.9.2 | In all countries concerned by the trial months | 5 |
E.8.9.2 | In all countries concerned by the trial days | 29 |