| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic Castrate-Resistant Prostate Cancer |
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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] - Male diseases of the urinary and reproductive systems [C12] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.1 |
| 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) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10062904 |
| E.1.2 | Term | Hormone-refractory 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 |
| The primary objective of this study is to confirm the effect of tasquinimod on delaying disease progression or death compared with placebo. |
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| E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study are:
• To determine the effect of tasquinimod on OS, time to symptomatic progression, additional radiological and clinical efficacy endpoints, quality of life (QoL) parameters, and safety as compared with placebo.
• To assess the pharmacokinetics of tasquinimod in men with metastatic CRPC.
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Single coded serum and blood samples may be retained for possible future analysis beyond the end of the study.
DNA/ RNA biobank samples for pharmacogenomic assessment will only be collected for those patients who have agreed to it by signing a separate pharmacogenetics and pharmacogenomics ICF.
Further analyses of biomarkers, pharmacogenetics and pharmacogenomics from the biobank samples will be performed outside the scope of the main study and reported separately.
Analyses may include:
exploratory biomarkers for assays of mechanistic markers (eg, soluble receptor for advanced glycation end products [RAGE], TSP‑1, S100A9, and angiokine proteins or peptides) and for cytokine profiling
Screening for analysis of genes of relevance for the pathology of prostate cancer in order to correlate individual patient DNA sequence variation with safety, tolerability, pharmacokinetics, and potential clinical benefit.
Analysis of gene expression of relevance for the mechanism of tasquinimod (eg, genes for soluble RAGE, TSP-1, S100A9, angiokines, and cytokines) and those of relevance for safety, tolerability, pharmacokinetics, and potential clinical benefit.
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| E.3 | Principal inclusion criteria |
1. Age at least 18 years at the time of signing the informed consent form. For patients in Taiwan the minimum age is 20 years.
2. Histologically confirmed diagnosis of adenocarcinoma of the prostate.
3. Evidence of bone metastatic disease on radiographic examination, whether from bone scan or other imaging modality.
4. Castrate levels of serum testosterone (≤50 ng/dL or 1.7 nmol/L).
5. Evidence of progressive disease defined by any of the following criteria:
• Increasing serum PSA levels as defined by the PCWG2, determined by 2 consecutive measurements and confirmed by a third. If the third measurement is below the second, then a fourth measurement must be greater than the second. The confirming third or fourth measurement must be ≥2 ng/mL. Measurements must be, the most recent values within 15 months [(preferably with 14 days, but with at least 7 days between each measurement].)
• Progression of soft tissue metastasis documented within 6 weeks of enrollment (computed tomography [CT] scan or magnetic resonance imaging [MRI])
• Progression of bone disease (at least 1 new bone lesion as measured by bone scan within the past 12 weeks)
6. Karnofsky score ≥70%.
7. Laboratory values as follows:
• Hemoglobin ≥100 g/L (>10 g/dL)
• Absolute neutrophil count ≥1500/μL
• Platelets ≥100 000/μL
• Serum creatinine ≤1.5 times the upper limit of normal (ULN)
• Total bilirubin ≤1.5 times ULN
• Aspartate aminotransferase and alanine aminotransferase ≤3 times ULN
8. If sexually active with partner of childbearing potential, patient will agree to use adequate contraceptive methods (barrier contraceptive with spermicide or vasectomy) while on study drug. The adequate contraceptive method should be continued for 14 days after the patient stops taking study drug.
9. No evidence (within 5 years) of prior malignancies (except successfully treated basal cell or squamous cell carcinoma of the skin).
10. Able to swallow and retain oral medication.
11. Able to adhere to the study visit schedule and other protocol requirements.
12. Ability to comprehend the full nature and purpose of the study, including possible risks and side effects; ability to cooperate with the investigator and to comply with the requirements of the entire study.
13. Able (or patient’s legal guardian, if applicable) to sign and date the written informed consent after being informed of the full nature and purpose of the study, including possible risks and side effects, and given ample time and opportunity to read and understand this information.
Inclusion criteria for the open-label extension treatment phase: In order to be enrolled in the OLE treatment phase, each patient must meet all of the OLE inclusion criteria. The open-label Day 1 visit should be at the planned patient visit following unblinding and within no more than 4 months after this amendment is approved and becomes effective at the study site.
1. Received tasquinimod or placebo treatment in the randomized doubleblind treatment phase of this study.
2. Willing and able to give informed consent for OLE treatment.
3. All of the safety related inclusion criteria for the main study, numbers 6 to 8 and 10 to 12 above.
4. No evidence (within 5 years) of prior malignancies (except successfully treated basal cell or squamous cell carcinoma of the skin) or, in case of occurrence of a cancer during the study, the option to switch to the OLE treatment phase will be done on a case-by-case basis taking into account the benefit/risk for the patient. |
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| E.4 | Principal exclusion criteria |
1. Prior cytotoxic chemotherapy for the treatment of prostate cancer within 2 years or within 4 weeks for Estracyt (estramustine) prior to study treatment.
2. Previous anticancer therapy using radiation, biologics or vaccines, including abiraterone, TAK-700 (Orteronel), or MDV3100 within 4 weeks prior or sipuleucel-T (Provenge) within 2 weeks prior to the start of study treatment. If radiation therapy is applied after baseline scan, a new baseline scan needs to be done at least 4 weeks after the radiation therapy.
3. Previous therapy with antiandrogens within 4 weeks (within 6 weeks for bicalutamide eg, Casodex®) prior to study treatment.
4. Concurrent use of other anticancer agents or treatments, with the following exceptions:
• Ongoing treatment with luteinizing hormone-releasing hormone (LHRH) agonists or antagonists, denosumab (Prolia) or bisphosphonate (eg, zoledronic acid) is allowed. Ongoing treatment should be kept at a stable schedule; however, if medically required, a change of dose, compound, or both is allowed.
5. Any treatment modalities involving major surgery within 4 weeks prior to the start of study treatment.
6. Prostate cancer pain that requires ongoing treatment with narcotic analgesics or warrants the initiation of radio- or chemotherapy.
7. Ongoing treatment with warfarin unless the international normalized ratio (INR) is well controlled and below 4 (Section 4.6.8.1).
8. Maintenance treatment with corticosteroids corresponding to a prednisolone or prednisone dose above 10 mg/day. The dose must have been stable for at least 5 days.
9. Systemic exposure to ketoconazole or other strong cytochrome P450 (CYP) 3A4 isozyme inhibitors or inducers within 14 days prior to the start of study treatment. Systemic exposure to amiodarone is not allowed within 1 year prior to the start of study treatment.
10. Ongoing treatment with sensitive CYP1A2 substrate or CYP1A2 substrate with narrow therapeutic range at the start of study treatment.
11. Ongoing treatment with CYP3A4 substrate with narrow therapeutic range at the start of study treatment.
12. Simultaneous participation in any other study involving treatment with investigational drugs or having received treatment with investigational drugs less than 4 weeks prior to the start of study treatment.
13. Myocardial infarction, percutaneous coronary intervention, acute coronary syndrome, coronary artery bypass graft, class III/IV congestive heart failure, cerebrovascular accident, transient ischemic attack, or limb claudication at rest, within 6 months prior to start of study treatment and ongoing symptomatic dysrhythmias, unstable angina, uncontrolled hypertension, and uncontrolled atrial or ventricular arrhythmias.
14. History of pancreatitis.
15. Known brain or epidural metastases.
16. Known positive serology for HIV (patients with known history of HIV will be excluded because of potential for unforeseen toxicity and morbidity in an immunocompromised host).
17. Chronic hepatitis with advanced, decompensated hepatic disease or cirrhosis of the liver or history of a chronic viral hepatitis or known viral hepatitis carrier (patients who have recovered from hepatitis will be allowed to enter the study).
18. Patients with active tuberculosis (TB), or with known, untreated latent TB. (Country-specific TB therapy should have been given for at least 30 days prior to the start of study treatment and the patient should intend to complete the entire course of that therapy.)
19. Any condition, including other active or latent infections, medical or psychiatric conditions, or the presence of laboratory abnormalities, which could confound the ability to interpret data from the study or places the patient at unacceptable risk if he participates in the study.
20. Any patient who in the opinion of the investigator should not participate in the study.
Exclusion criteria for the open-label extension treatment phase: Patients meeting any of the following criteria will be excluded from being enrolled in the OLE treatment phase:
1. Having met any of the reasons for withdrawal from study treatment.
2. Having met any of the safety related exclusion criteria for the main study, numbers 6 to 20 above. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint is progression-free survival (PFS) defined as the time from the date of randomization to the date of radiological progression or death. Radiological progression is defined by any of the following criteria:
• Progression of soft tissue lesions according to the Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1)
• Progression of bone lesions detected with bone scan according to Prostate Cancer Working Group 2 (PCWG2) criteria
• Radiologically confirmed spinal cord compression or pathological fracture due to malignant progression
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary endpoint is PFS, defined as the time from the date of randomization to the date
of radiological progression or death. |
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| E.5.2 | Secondary end point(s) |
• OS
• Time to radiological progression
• Time to symptomatic progression (including death due to prostate cancer)
• Time to first radiological or symptomatic progression
• Time to first radiological or symptomatic progression or death (due to any cause)
• Time to initiation of salvage systemic therapy, including chemotherapy, or palliative
radiation
• Time to new soft tissue lesion
• Time to progression due to soft tissue lesions (according to RECIST 1.1)
• Time to skeletal related events
• Time to new bone lesion
• Time to opiate use for cancer pain
• QoL measured by the Functional Assessment of Cancer Therapy-Prostate (FACT-P)
questionnaire and by the EuroQol 5-Dimension QoL Instrument (EQ-5D)
• Changes in Karnofsky score
• Changes in visual analog scale (VAS) for tumor-related pain
• Changes in serum PSA over time
• Changes in BAP over time
• Changes in VEGF over time
• Population pharmacokinetics of tasquinimod
• Safety
• Time to radiological progression, OS, time to symptomatic progression, and QoL (including FACT-P, EQ-5D, and VAS) are all key secondary endpoints. Data on OS and QoL will be collected for all patients for the duration of the study (including the Follow-up Phase).
• For patients experiencing symptomatic progression without radiological evidence of
progression, scans of soft tissue and bone lesions should continue to be collected until
radiological progression, according to the definition of the primary endpoint, has been
documented.
• For patients experiencing radiological progression without symptomatic evidence of
progression, all efforts should be made to collect the date of symptomatic disease
progression according to the protocol definition (Section 4.4.1.1.4).
After the formal final statistical analysis, and upon request, the following ancillary endpoints for the OLE/FUE phase of the study will be provided:
- Safety
- Initiation of new anticancer therapies
- Overall survival |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| disease progression and symptomatic progression |
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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 | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | Yes |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 145 |
| 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 |
| Argentina |
| Australia |
| Belgium |
| Brazil |
| Bulgaria |
| Canada |
| Chile |
| China |
| Colombia |
| Czech Republic |
| Estonia |
| France |
| Germany |
| Greece |
| India |
| Israel |
| Italy |
| Korea, Republic of |
| Latvia |
| Lebanon |
| Lithuania |
| Mexico |
| Netherlands |
| New Zealand |
| Panama |
| Peru |
| Poland |
| Romania |
| Slovakia |
| Spain |
| Sweden |
| Taiwan |
| Turkey |
| Ukraine |
| United Kingdom |
| United States |
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| 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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| Not applicable. Last subject, last visit = end of trial |
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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 |
| 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 | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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