| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic Castrate-refractory Prostate Cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Metastatic Castrate-refractory Prostate Cancer |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Male diseases of the urinary and reproductive systems [C12] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10036909 |
| E.1.2 | Term | Prostate cancer metastatic |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 primary objective of the safety lead-in portion of
this study is to assess the safety and tolerability of CV9104 and
to determine the dose for the randomised portion.
The primary objective of the randomised portion of the study is to compare the overall survival (OS) in the CV9104 treated group with the placebo group.
|
|
| E.2.2 | Secondary objectives of the trial |
- Comparison of safety: CV9104 to placebo
- Comparison of progression free survival (PFS) (PFS1, Prostate Cancer Working Group PCWG2 criteria) from randomisation until progression between the CV9104 treated group and the placebo group
- Comparison of PFS (PFS2, PCWG2 criteria) from date of first subsequent systemic therapy until progression between the CV9104 treated group and the placebo group
- Comparison of S-PFS from randomisation until second progression on first subsequent therapy between the CV9104 treated group and the placebo group
- Comparison of the maximum change in prostate specific antigen (PSA) during the vaccination period prior to the date of the first subsequent systemic therapy compared to baseline between the CV9104 treated group and the placebo group
For all secondary objectives - please refer to the study protocol. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male, age ≥ 18 years
2. Histologically confirmed castrate-refractory metastatic adenocarcinoma of the prostate with progressive disease
- after surgical castration; or during androgen suppression therapy, including a gonadoptropinreleasing hormone (GNRH) agonist or antagonist
and
- after at least 1 second-line anti-hormonal manipulation (e.g. antiandrogen; including combined androgen blockade followed by antiandrogen withdrawal)
and
- a serum testosterone level of < 50 ng/dL or < 1.7 nmol/L.
Progression will be confirmed either
- radiologically (nodal or other soft tissue progression, appearance of 2 or more new lesions on bone scan - to be confirmed by other imaging ifflare or trauma is suspected); or
- by 2 consecutive rises of PSA, measured at least 1 week apart, resulting at least in a 50% increase over the nadir and PSA > 2 ng/mL. The last of these PSA values must have been measured within 2 months prior to start of screening and
- In patients having received initial combined androgen blockade or haveshown a decline in PSA for ≥ 3 months after administration of an antiandrogen an antiandrogen withdrawal response must have been excluded after discontinuation of
antiandrogen therapy (e.g. bicalutamide, flutamide or nilutamide) for at least 6 weeks prior to randomisation. Patients with a confirmedprogression (PCWG2) after an antiandrogen withdrawal response are eligible. All patients must have discontinued antiandrogen treatment prior to randomization
3. Metastatic disease confirmed by imaging (bone scan, computed tomography [CT] or magnetic-resonance imaging [MRI]); ambiguous bone scan results should be confirmed by a second method.
4. Performance status: Eastern Cooperative Oncology Group (ECOG) 0 to 1.
5. Patients should be unlikely to need subsequent systemic therapy within the next 4 weeks (safety lead-in) or the next 3 months (randomised portion), in the opinion of the investigator.
6. Adequate organ function:
- Bone marrow function: haemoglobin ≥100 g/L; white
blood cell count ≥3.0 × 1.000.000.000/L; lymphocyte count ≥0.8 × 1.000.000.000/L; absolute neutrophil count ≥1.5 × 1.000.000.000/L; platelet count ≥100 × 1.000.000.000/L.
- Hepatic: aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 × upper limit of normal; bilirubin ≤1.5 × upper limit of normal.
- Renal: creatinine ≤2 mg/dL and creatinine clearance
≥45 mL/min/1.73m2.
7. Men of child producing potential must agree that together with their female partners they will use a highly effective method of contraception as defined in ICH (M3) resulting in a low failure rate (i.e. less than 1% per year) when used consistently and correctly. Those methods include implants, injectables, combined oral contraceptives, some intrauterine devices (IUDs), sexual abstinence or vasectomy. The contraception should be applied until 1 month after the last vaccination.
8. Patients requiring bisphosphonates or denosumab at the time of registration into the trial are eligible as long as therapy is initiated at least 28 days prior to first study treatment administration and it must be continued during the study unless contraindications arise.
9. Patient has provided written informed consent. |
|
| E.4 | Principal exclusion criteria |
1. Previous immunotherapy for PCA (e.g. sipuleucel-T
[Provenge®], experimental cancer vaccines or ipilimumab [Yervoy®]).
2. Estimated life expectancy of < 6 months due to PCA or concomitant disease.
3. Treatment with any investigational anticancer agents within 4 weeks or 5 half-lives according to what gives the longer range prior to first dose of study drug.
4. Acute pathologic fracture or spinal cord compression at screening.
5. Systemic immunosuppressive agents including systemic steroids or immunomodulating agents including herbal remedies (e.g. mistletoe extract) for the previous 28 days prior to the start of treatment or need for such immunosuppressive/-modulating treatment, exceptglucocorticoid replacement therapy for adrenal insufficiency. For other conditions where steroid therapy is allowed, see section on prior and concomitant therapy (Section 6.3).
6. Active skin disease (atopic eczema, psoriasis) in the areas for vaccine injection (upper arms or thighs) preventing the administration of i.d. injections into areas of healthy skin.
7. Concurrent major surgery or planned surgery.
8. Prior splenectomy or prior allogeneic bone marrow
transplant.
9. History of or current autoimmune disorders such as sarcoidosis, lupus erythematosus, rheumatoid arthritis,
glomerulonephritis systemic vasculitis, autoimmune
hepatitis, Sjögren syndrome, scleroderma, polymyalgia rheumatica, arteriitis temporalis, calcinosis, Raynauds disease, esophageal dysmotility, sclerodactyly and telangiectasia (CREST) syndrome (limited cutaneous scleroderma), dermatomyositis, Morbus Crohn and colitis ulcerosa except autoimmune thyroiditis with only thyroid hormone replacement or vitiligo or Diabetes Mellitus type 1.
10. Primary or secondary immune deficiency.
11. Allergies to any components of the study drug including allergy to protamine sulfate (e.g. allergy to protamine-containing insulins) or fish allergy.
12. Allergies to penicillins or other β-lactam antibiotics
13. Active infections requiring anti-infectious therapy at the time of randomization.
14. Seropositive for human immunodeficiency virus, hepatitis B virus (except after hepatitis B vaccination) or hepatitis C virus infection.
15. Uncontrolled urinary retention or hydronephrosis (to be confirmed by ultrasound, bladder scan or other adequate imaging method). Patients with urinary retention can be enrolled after adequate treatment, see section 6.3.
16. Uncontrolled medical condition considered as high risk for the treatment with an investigational drug (e.g. unstable Diabetes Mellitus, vena-cava-syndrome, uncontrolled pleural effusion, acute pulmonary embolism).
17. Known brain metastases or leptomeningeal involvement.
18. Symptomatic congestive heart failure (New York Heart Association 3 or 4), unstable angina pectoris or myocardial infarction, significant cardiac arrhythmia, history of stroke or transient ischemic attack, all within 6 months prior to enrolment or severe hypertension according to WHO criteria or uncontrolled hypertension at the time of enrolment (systolic blood pressure ≥ 180 mm Hg).
19. History of seizures, encephalitis or multiple sclerosis.
20. Active drug abuse or chronic alcoholism.
21. Inability to provide informed consent due to mental
impairment.
The following are additional exclusion criteria only for
patients participating in the randomised part of the trial:
22. Previous chemotherapy for metastatic PCA.
23. Previous anti-hormonal treatment with abiraterone or any other investigational anti-hormonal treatment.
24. Cancer related pain requiring opioid narcotics within 28 days before enrolment or an average pain score of > 3 on a visual analogue scale.
25. Presence of visceral metastases.
26. History of other malignancies other than PCA over the last 5 years (except basal cell carcinoma of the skin). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Safety Lead-in: Occurrence of dose-limiting toxicity (DLT)
during the first 4 weeks of treatment (after administration of
3 weekly vaccinations and 1 week observation period)
Randomised Portion: Overall survival time from the time of
randomisation
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Occurrence of dose-limiting toxicity (DLT)
during the first 4 weeks of treatment (after administration of
3 weekly vaccinations and 1 week observation period)
OS time from randomisation: Throughout the study |
|
| E.5.2 | Secondary end point(s) |
Secondary Safety Endpoints:
1. Adverse events and related AEs;
2. Serious AEs and related SAEs;
3. Adverse events with NCI-CTCAE toxicity grades ≥ 3 ;
4. Related AEs with NCI-CTCAE toxicity grades ≥ 3 ;
5. Premature discontinuation of study treatment (overall);
6. Premature discontinuation of study treatment due to AE;
7. Adverse events of Special Interest (AESI)
8. Laboratory results (including laboratory values with NCI-CTCAE toxicity grades ≥ 3);
9. Vital signs;
10. Physical examination;
11. ECOG status;
12. ECG;
13. Deaths and deaths within 30 days after randomisation.
Secondary Efficacy Endpoints:
1. Percent change to maximal and to minimal PSA from baseline and before start of first subsequent systemic therapy.
2. Percent change to maximal and to minimal PSA from start of first systemic therapy to end of first subsequent systemic therapy.
3. Overall progression-free survival, radiographic progression-free survival and PSA progression-free survival from date of randomisation (PFS1).
4. Overall progression-free survival, radiographic progression-free survival and PSA progression-free survival from start date of first subsequent systemic therapy (PFS2)
5. Overall progression-free survival, radiographic progression-free survival and PSA progression-free survival from randomisation to second progression on first subsequent systemic therapy (S-PFS).
6. Time from date of randomisation to second progression on first subsequent systemic therapy.
7. Time from randomisation to start of first subsequent systemic therapy.
8. Cellular immune response rates against the 6 RNActive®-encoded antigens.
9. Humoral immune response rates against the 6 RNActive®-encoded antigens (PSA, PSMA, PSCA, PAP, STEAP and MUC-1) dependent on availability and functionality of assays.
10. Overall immune response rates against the 6 RNActive®-encoded antigens
11. Time to symptom progression based on FACT-P total score and subscores
12. Change and area under the curve from baseline of EQ-5D total score and pain sub-score. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Adverse events and related AEs /Serious AEs and related SAEs/ Adverse events with NCI-CTCAE toxicity grades ≥3 /Related AEs with NCI-CTCAE toxicity grades ≥3/Premature discontinuation of study treatment (overall)/Premature discontinuation of study treatment due to AE/
Overall progression-free survival, radiographic progression-free survival and PSA progression-free survival from date of randomisation: Throughout the study
Laboratory results /Vital signs /Physical examination /ECOG status: At all visits
ECG: At Screening and EoT visit
For further timepoints refer to protocol, schedule of assessments.
|
|
| 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 | No |
| 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 | Yes |
| 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 |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| 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 | Yes |
| 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
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 50 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| European Union |
| Switzerland |
|
| 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
|
| The study will be terminated after the results of the primary statistical analysis are available and after 75% of death events have occurred or when all remaining patients have been followed up for at least 12 months after the primary statistical analysis, whatever comes first. |
|
| 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 | 7 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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