| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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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 | 18.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10060862 |
| E.1.2 | Term | Prostate cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 |
Primary objective (phase I):
To establish a safe and tolerable dose for RO5503781 given in combination with abiraterone.
Primary objective (phase II):
To establish whether the efficacy of the combination of RO5503781 with abiraterone
and prednisolone merits further study in patients with mCRPC. The primary endpoint will be radiological progression free survival.
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| E.2.2 | Secondary objectives of the trial |
Secondary objectives:
1. To investigate the efficacy of the addition of RO5503781 to abiraterone as measured by PSA response rate.
2. To investigate the efficacy of the addition of RO5503781 to abiraterone as measured by radiological
response rate.
3. To investigate the efficacy of the addition of RO5503781 to abiraterone as measured by biochemical and radiological progression free survival (time to biochemical or radiological progression or death
whichever occurs first).
4. To investigate the efficacy of RO5503781 in patients who are progressing radiologically on abiraterone as measured by PSA response rate.
5. To investigate the pharmacokinetics of RO5503781 and abiraterone when given in combination.
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| E.2.3 | Trial contains a sub-study | No |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Translational sub studies:
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| E.3 | Principal inclusion criteria |
1. Histologically proven adenocarcinoma of the prostate with documented
metastases (where the metastatic lesions are confined to 1 or 2 lesions on a bone scan these must be confirmed by a second modality (eg. CT, MRI or biopsy).
2. Availability of archival tumour samples. Where patients are willing to undergo a biopsy as part of the study, these specimens may be used as an alternative where no archival specimen is available.
3. Proven disease progression since last change in therapy defined by at least one of the following:
a.PSA progression. This must be based on a series of at least 3 successively increasing readings each taken at least 7 days apart. The 3rd reading must be >= 2ng/ml. In the event where an intermediate reading is lower than a previous reading, then the patient will still be eligible (ie. the 3 readings do not need to be consecutive). The first of the three readings must have been obtained after commencing the previous systemic therapy, or, in the case of androgen receptor antagonists, after discontinuing.
b. Radiographic progression since commencing last systemic anti-cancer therapy as defined by RECIST 1.1 (Eisenhauer et al. 2009 Eur J Cancer. 4 5:2 2 8) for non-bone disease or the appearance of 2 or more new lesions on a bone scan.
4. Castrate levels of serum testosterone (<1.7nmol/l).
5. On-going castration therapy.
6. Male aged 18 or over.
7. ECOG PS = 0 or 1.
8. Hb>= 10g/dL; platelets >= 150 x 109/L; neutrophils >=1.5 x109/L.
9. Bilirubin < 1.5 x ULN; ALT and/ or AST < 2.5 x ULN.
10. Serum potassium ≥LLN; Alb ≥ 30 g/L
11.Serum creatinine < 1.5 x ULN or a calculated creatinine clearance ≥ 60 mL/min
12.Able to swallow study drugs.
13.Life expectancy > 3 months.
14.Provision of written informed consent.
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| E.4 | Principal exclusion criteria |
1. Prior cytotoxic chemotherapy for castration resistant prostate cancer (patients may have received previous or ongoing bisphosphonates, eg. zoledronate, or denosumab).
2. Prior ketoconazole, abiraterone, MDV3100 (enzalutamide), TAK-700 (orteronel) or other novel anti-hormonal.
3. Uncontrolled hypertension (bp≥ 160 / 95 mmHg)
4. Significant heart disease as evident by MI or arterial thrombotic events in past six months, severe unstable angina, or new york heart association class (NYHA) III or IV heart failure or class II to IV heart failure or cardic ejection fraction measurement of <50%.
5. Other anticancer therapy (apart from LHRH agonist / antagonist) within 4 weeks (6 weeks for bicalutamide). This includes radiotherapy and therapeutic radionucleotides. Where patients are receiving bisphosphonates or denosumab they must have been on a stable dose for at least 6 weeks prior to starting study drug.
6. The requirement for strong opiates to control cancer related pain in the two weeks before study entry (codeine and tramadol are permitted).
7. Patient with a partner of child-bearing potential who is not using a highly effective method of contraception, who is unwilling to use condoms during the study and for 30 days after the last dose of study drug.
8. Patients with known coagulopathy, platelet disorder or history of non-drug induced thrombocytopenia.
9. Patients receiving oral or parenteral anti-coagulants/anti-platelet agents (chronic daily treatment with aspirin with doses >325 mg po daily, clopidogrel, low molecular weight heparin, or dagibatran, etc.) prior to the start of study therapy are excluded. Patients may receive anticoagulant flushes for maintenance of indwelling catheters.
10. Patients with known bone marrow disorders which may interfere with bone marrow recovery (due to tumor involvement, fibrosis) (eg. Concomitant myelodysplastic syndrome)
11. Patients who refuse blood products.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary:
(Phase I). Safety and tolerability of combination therapy defined by CTCAEv4.
(Phase II). Radiological progression free survival from start of study treatment. Radiological progression is defined by the PCWG2 criteria (see section 4.6).
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
(Phase I) All patients entered into the study will be accounted for. The analysis will focus on the incidence of dose limiting toxicities which will be summarized by dose cohort. In addition, worst recorded toxicity grade for each patient on the NCI-CTCAE toxicity scale (version 4.0) during RO5503781 treatment will be summarized by dose cohort.
(Phase II) This analysis will be conducted at the end of the minimum follow-up period once the required number of events (70) for progression-free survival have been observed. |
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| E.5.2 | Secondary end point(s) |
Secondary:
1. PSA response rate.
2. Radiological response rate in patients with measurable disease (RECIST 1.1).
3. PSA response rate after addition of RO5503781to abiraterone in patients experiencing radiological progression on abiraterone alone.
4. Biochemical and radiological PFS (ie. time to first of radiological or biochemical progression (as per PCWG2) or death).
5. PK of RO5503781 and abiraterone
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. PSA response rate. At the end of the minimum follow up period.
2. Radiological response rate in patients with measurable disease (RECIST 1.1). At the end of the minimum follow up period.
3. PSA response rate after addition of RO5503781to abiraterone in patients experiencing radiological progression on abiraterone alone. At the end of the minimum follow up period.
4. Biochemical and radiological PFS (ie. time to first of radiological or biochemical progression (as per PCWG2) or death). At the end of the minimum follow up period.
5. PK of RO5503781 and abiraterone. After the final patient has contributed to the PK sampling and the results of the analyses have been provided |
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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 | Yes |
| 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) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| First administration in combination with abiterone acetate and prednisolone. |
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| 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 | Yes |
| 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 | 20 |
| 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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For the purposes of Clinical Trial Authorisation, the trial is deemed to have ended 30 days after the last patient remaining on treatment receives the last dose of RO5503781 or placebo.
For the purposes of Main REC approval, the study end date is deemed to be the date of the last data capture. |
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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 | 0 |
| E.8.9.1 | In the Member State concerned days | 3 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 3 |
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