| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| metastatic castrate resistant prostate cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Patients with advanced prostate cancer that have pain. |
|
| 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 | 14.0 |
| E.1.2 | Level | LLT |
| 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) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.0 |
| 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 |
Ascertain whether the investigational arm has a greater proportion of
patients with durable pain palliation as compared to the control arm. |
|
| E.2.2 | Secondary objectives of the trial |
Ascertain whether patients randomized to the investigational arm have a
longer time to pain progression as compared to patients randomized to
the control arm. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Age≥18years on the date of consent
2.Histological or cytological diagnosis of adenocarcinoma of the prostate
3.Metastatic disease at screening on a chest, abdomen or pelvic CT or bone scan
4.Concurrent pain and analgesic use that is viewed by the Investigator to be related to prostate cancer
5.Received at least 4cycles of prior docetaxel-based first-line chemotherapy for metastatic disease based on a q3 week schedule of docetaxel(NOTE:patients treated on a weekly or alternate schedule for first-line docetaxel must have received an accumulated dose of docetaxel of at least 300mg/M2)
6.For patients to receive docetaxel retreatment,a response during first-line docetaxel therapy as defined by one or more of the following must have occurred:
a.At least a 30%decrease in the sum of the longest diameter of measurable lesions with no unequivocal progression of existing lesions and no appearance of any new lesions.Measurable disease is defined as either nodes≥20 mm or visceral/soft tissue lesions≥10 mm
b.PSA response(30% reduction compared to the baseline level prior to initiating first-line docetaxel therapy)
c.Clinical response(classified by the treating Physician or Investigator as a reduction in pain or analgesic use or improvement in performance status).The type and basis of the clinical response(s) must be determined by the Investigator when obtaining the disease history
7.Current progressive disease during or after completing first-line docetaxel treatment as defined by one or more of the criteria below:
a.Progressive measurable disease:at least a 20% increase in the sum of the longest diameters of measurable lesions over the smallest sum observed –or the appearance of one or more new lesions as assessed by CT scan during or after completing first-line docetaxel treatment. Measurable lesions include nodal lesions≥20 mm in diameter or visceral/soft-tissue lesions≥10 mm in diameter.OR
b.Bone Scan Progression:appearance of 2 or more new lesions on bone scan during or after completing first-line docetaxel treatment.OR
c.Increasing serum PSA level:Three increasing PSA measurements obtained during or after completing first-line docetaxel treatment and at least one week apart are required.If the third PSA value is less than the second, an additional fourth test to confirm a rising PSA is acceptable. A minimum starting value of 5.0 ng/mL is required for study randomization
8.Baseline laboratory values at screening visit:
a.Creatinine≤1.5xupper limit of normal (ULN)
b.Bilirubin≤1.1 x ULN (unless elevated secondary to conditions such as Gilbert’s disease)
c.SGOT (AST)≤1.5 x ULN
d.Castrate serum testosterone level (<50 ng/dL-or-<1.7 nmol/L).
9.Must be willing to continue primary androgen suppression with luteinizing hormone releasing hormone (LHRH) analogues throughout the study, if not treated with bilateral orchiectomy
10.Adequate bone marrow function defined as ANC≥1.5 x 109 cells /L and platelet count≥100 x 109 /L at screening visit
11.Karnofsky score≥70%(See Appendix 16.2) at screening visit
12.For patients to receive docetaxel retreatment, at least 6 weeks has passed since receiving the last dose of docetaxel at the time of randomization
13.At least 21days have passed since completing radiotherapy at the time of randomization
14.At least 21days have passed since completing any cytotoxic agent or investigational agent, including ASOs(except custirsen which is an exclusion criterion), at the time of randomization
15.Has recovered from any docetaxel therapy-related neuropathy to≤ grade 1
16.Has recovered from all therapy related toxicity to≤grade 2 (except alopecia,anemia and any signs or symptoms of androgen deprivation therapy)
17.Patient can tolerate starting dose of 75 mg/M2 docetaxel or 25 mg/M2 cabazitaxel
18.Patient must have remained on the same bisphosphonate or denosumab usage for a minimum of 21days prior to randomization and be willing to not add, delete or change their current bisphosphonate or denosumab usage throughout the study (unless the deletion or change is for toxicity associated with usage) to assure that pain assessments are not confounded by changing their bisphosphonate or denosumab usage.
19.If on steroids at screening, patient must be on prednisone 5 mg BID for a total of 10mg/day. Patients on steroids(but not on prednisone or on a dose of prednisone other than 5mg BID at screening),must have their steroid treatment adjusted to oral prednisone 5 mg BID for a minimum of 21 days prior to randomization to assure that baseline pain assessments are not confounded by changes in steroid usage.NOTE:Patients who are not taking steroids or cannot tolerate prednisone are eligible for the study.Patients not receiving prednisone at screening, but able to tolerate prednisone, will begin oral prednisone (5mg BID for a total of 10 mg/day) on the morning of Day1 of Cycle1.
20.Written informed consent must be obtained prior to any protocol-specific procedures being performed.
|
|
| E.4 | Principal exclusion criteria |
1.More than two interruptions in first-line docetaxel therapy. An
interruption will be defined as more than 6 weeks between doses.
2.For patients receiving docetaxel retreatment, evidence of disease
progression while on or within 6 weeks of receiving the last dose of firstline
docetaxel therapy based on one of the following:
a.Radiographic imaging (at least a 20% increase in the sum of the
longest diameters of measurable lesions over the smallest sum observed
–or the appearance of one or more new lesions as assessed by CT scan
or ≥ 2 new lesions on bone scan. Measurable disease is defined as either
nodes ≥ 20 mm or visceral/soft tissue lesions ≥10 mm.)
b.Clinical deterioration (determined by the treating Physician or
Investigator, when obtaining the disease history, such as clinically
significant pain progression or decreased performance status).
NOTE:Patients with increasing PSA levels while receiving first-line docetaxel are not excluded.
3.Life expectancy less than 12 weeks.
4.Previously participated in any clinical trial evaluating custirsen.
5.Received any other cytotoxic chemotherapy as a second-line treatment after first-line docetaxel-based therapy.
6.Not on any opioid analgesic regimen for their prostate cancer-related
pain
7.Receiving more than one drug within each of the separate categories
of long-acting opioid, short-acting opioid, and non-opioid (See Section
6.6.1)
8.Receiving any analgesic specified in Appendix 16.7.1 as unacceptable
for this study.
9.Received any cycling or intermittent or continuous hormonal treatment 28 days prior to randomization with the exception of the continuous
LHRH analogues required in Inclusion Criteria #9.
10.History of, or current documented brain metastasis or carcinomatous meningitis, treated or untreated. (Brain imaging in asymptomatic patients is not required.)
11.Known epidural disease unless it has been treated and there is no
progression in the treated area.
12.Requiring ongoing treatment during the study with St John's Wort, or with medications known to be either strong CYP3A inhibitors or strong CYP3A inducers (Refer to Section 6.6.11).
13.Active second malignancy (except non melanomatous skin or
superficial bladder cancer) defined as requiring cancer therapy or at high
risk of reoccurrence during the study.
14.Uncontrolled or acute medical conditions such as myocardial
infarction, congestive heart failure, stroke or treatment of a major active infection within 3 months prior to randomization, as well as current uncontrolled hypertension, angina or a serious arrhythmia; and/or significant concurrent medical illness that in the opinion of the
Investigator would preclude protocol therapy.
15.Planned concomitant participation in another clinical trial of an
experimental agent, vaccine or device. Concomitant participation in
observational studies is acceptable.
16.Inability to communicate and read in English, Spanish or French.
Note:Upon review of source documentation, enrollment of a patient who
did not meet the inclusion or exclusion criteria will be classified as a
protocol violation.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint to be ascertained for each patient is whether
durable pain palliation has been observed (yes or no). Durable pain
palliation is defined as having a reduction in pain for a minimum of 12
weeks duration. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary endpoint analysis will be based on baseline and study
treatment pain status and analgesic use status until the end of durable
pain palliation status period or pain progression (whichever is first) is
documented. Seven daily assessments are planned at baseline.
Assessments while on study will occur daily for 6 days just prior to Day 1
of each 21-day treatment cycle, starting with the 6-day assessment
interval prior to Day 1, Cycle 2 (see Section 4.2). |
|
| E.5.2 | Secondary end point(s) |
Pain progression is defined as having one of the criteria below for two
consecutive assessment intervals :
1.After Cycle 3, Day 1: An increase in the mean worst pain score of
greater than 2 points above the baseline mean worst pain score.
2.After Cycle 3, Day 1: An increase in analgesic usage compared to
baseline levels determined at randomization (regardless of whether the
patient has achieved pain palliation or not) as defined by:
a.an increase in the mean total daily opioid dosage of either the longacting opioid or the short-acting opioid by more than 33%, that is also an increase of more than a 15 mg morphine-equivalent dose above the mean baseline daily dose
OR
b.the addition of any new opioid not previously defined in the baseline
analgesic regimen. (NOTE: This does not include a replacement opioid
for an intolerance or severe adverse event unless the replacement opioid dose is more than 33% above the baseline opioid level using morphineequivalent doses in Table 15)
OR
c.the addition of any new non-opioid not previously defined in the
baseline analgesic regimen with a mean total daily dose > 80% of the
maximum recommended total daily dose (Note: This does not include a
replacement non-opioid for an intolerance or severe adverse event or
changes in dosage for the non-opioid defined in the baseline analgesic
regimen as it will not be considered significant enough to indicate pain
progression)
3.At any time after randomization: Receipt of any radiation therapy for
pain palliation. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Due to the potential for an initial "flare" that can occur within the first
six weeks of treatment, pain progression will be evaluated only after the
completion of Cycle 2 (i.e. after Cycle 3, Day 1), except in cases requiring
radiation for pain palliation prior to completion of Cycle 2.
The secondary objective will be formally analyzed only if the primary
endpoint meets statistical criterion. |
|
| 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 | No |
| 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) | 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 | 15 |
| 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 |
| Canada |
| France |
| Spain |
| United Kingdom |
| United States |
|
| 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
|
Patients will continue study treatment until pain progression,
unacceptable toxicity, completion of 10 cycles or other specific criteria
for withdrawal.
After completion of study treatment, patients will be followed until pain
progression is documented. Patients will also be followed for safety
evaluations, for documentation of further treatment for prostate cancer
and for survival status. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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