| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic castrate-resistant prostate cancer |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 13.1 |
| 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 | 13.1 |
| 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) |
|
| 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 |
In Part 1, the primary objective is to examine the safety and tolerability of ISIS 183750 in combination with
docetaxel and prednisone in order to determine the ISIS 183750 dose for evaluation in Part 2.
In Part 2, the primary objective is to estimate the progression-free survival in patients treated with ISIS 183750 in
combination with docetaxel and prednisone. |
|
| E.2.2 | Secondary objectives of the trial |
Part 1:
• To characterize the plasma and urine PK parameters of ISIS 183750 in the absence and presence of docetaxel
• To characterize the plasma PK parameters for docetaxel in the presence of ISIS 183750
• To explore anticancer effects of ISIS 183750 in combination with docetaxel and
prednisone
Part 2:
• To estimate overall survival
• To estimate the effect of treatment on PSA parameters including:
- Percent change from baseline to the end of the 4th treatment cycle
- Maximum post-baseline percent reduction
- Time to PSA progression
• To examine tumor response by RECIST version 1.1 including:
- Percent change of tumor size from baseline to the end of the 4th treatment cycle
- Objective tumor response rate
- Duration of objective tumor response for responding patients
- Time to tumor progression
• To determine the 7-day plasma trough levels of ISIS 183750
• To determine the safety and tolerability of ISIS 183750 in combination with docetaxel and prednisone |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients with castrate-resistant prostate cancer are eligible to be included in the study only if they meet all of the
following criteria:
1. Provide written informed consent prior to Screening.
2. Age ≥ 18 years.
3. Histological or cytological diagnosis of adenocarcinoma of the prostate.
4. Metastatic disease for which no curative therapy exists and for which systemic
chemotherapy is indicated.
5. Progression of disease despite either medical or surgical castration. If the patient
received medical androgen ablation, a castrate level of testosterone (≤ 50 ng/dL)
must have been present concurrent with disease progression. Progressive disease is
defined as any one of the following:
• Rising serum PSA levels: two consecutive increases in PSA levels documented
over a previous reference value obtained at least one week apart with the value of
the third point being ≥ 2 ng/mL. If the third PSA level is less than the second, an
additional fourth test to confirm a rising PSA (i.e., the fourth value is ≥ the second
value and is ≥ 2 ng/mL) is acceptable.
• Progressive measurable disease defined as an increase in the sum of the diameters of measurable lesions over
the smallest sum observed or the appearance of one or more new lesions as assessed by CT scan.
• Bone progressions: appearance of 2 or more new lesions on bone scan or other
imaging.
6. If patient did not have a surgical orchiectomy:
• The patient must be on androgen suppression treatment (e.g. LHRH agonist), have
a castrate level of testosterone (≤ 50 ng/dL), and must be willing to continue the
treatment throughout the study.
• The patient must have discontinued treatment with anti-androgens (discontinued
≥ 4 weeks for flutamide and ≥ 6 weeks for nilutamide or bicalutamide prior to
Screening) and have documented disease progression following discontinuation.
7. PSA ≥ 2 ng/mL during the Screening period.
8. Performance status of 0 or 1 on the ECOG Performance Status Scale.
9. Have an estimated life expectancy of at least 12 weeks.
10. Adequate organ function within 14 days prior to first study dose (ISIS 183750 or
docetaxel, whichever occurs first) including the following:
a. Absolute neutrophil count (ANC) ≥ 1.5 x 10(9)/L.
b. Platelet count ≥ 100 x 10(9)/L.
c. Total bilirubin ≤ 1.0 x upper limit of normal (ULN).
d. Aspartate aminotransferase (AST) ≤ 1.5 x ULN.
e. Alanine aminotransferase (ALT) ≤ 1.5 x ULN.
f. Serum creatinine ≤ 1.5 x ULN.
g. Prothrombin time (PT) and international normalized ratio (INR) within normal limits.
h. Activated partial thromboplastin time (aPTT) within normal limits.
11. Part 1: Have had no more than 1 prior chemotherapy or biological therapy regimen (approved or
experimental; all previous hormonal therapies are allowed and not counted as biological therapy for this
inclusion criterion) for prostate cancer. This does not include treatments that may have been received in the
adjuvant or
neoadjuvant setting. A regimen is defined as two or more consecutive cycles of
treatment.
Part 2: Have had no prior chemotherapy or biological therapy (approved or
experimental; all previous hormonal therapies are allowed and not counted as
biological therapy for this inclusion criterion) in any setting for prostate cancer.
12. Have discontinued all previous therapies for cancer (except treatment with LHRH
analogues) as follows:
a. Part 1: cytotoxic chemotherapy must be discontinued at least 4 weeks prior to
screening; Part 2: see Inclusion Criteria 11.
b. Part 1: biological treatment (other than hormonal treatments) must be discontinued for at least 6 weeks prior to
screening; Part 2: see Inclusion Criteria 11.
c. Hormone therapies (e.g., abiraterone, MDV3100) must have been discontinued 4 weeks prior to screening.
d. Radiotherapy must be discontinued at least 4 weeks prior to screening, and the
patient must have recovered from the acute effects of therapy.
13. Recovery from all toxicities of prior therapy to ≤ Grade 2 by NCI CTCAE, version
4.0 (Exception: any toxicity that in the view of the Investigator is not a clinically
significant safety risk for further therapy administration, including, but not limited
to: anemia, fatigue, erectile dysfunction, hot flashes, lymphedema of an extremity,
dizziness, cough, and urinary incontinence).
14. Men of reproductive potential must agree to use an effective form of contraception, as determined by the
Investigator, during the treatment period of the study and for 10 weeks following the last dose of study drug.
15. The patient is willing and able to comply with the study visit schedule and
procedures, and geographic proximity (Investigator’s discretion) that allows
adequate follow-up. |
|
| E.4 | Principal exclusion criteria |
Patients will be excluded from the study if they meet any of the following criteria:
1. Treatment with another investigational drug or device within 4 weeks or biological
agent within 6 weeks before Screening or 5 half-lives of study agent, whichever is
longer.
2. Pre-existing peripheral neuropathy ≥ Common Terminology Criteria for Adverse
Events, Version 4.0 (CTCAE) Grade 2.
3. Patients with treated or untreated parenchymal brain metastases or leptomeningeal disease. Currently active
malignant epidural disease is also excluded. Previously treated epidural disease does not exclude the patient from
the study. (Note: CT or MRI of brain is not needed to rule these out unless the patient has clinical symptoms
suggestive of CNS metastases).
4. Have active infection or serious concomitant systemic disorder (for example, heart
failure) incompatible with the study (at the discretion of the Investigator).
5. Presence or history of other malignancies except non-melanoma skin cancer or solid tumors curatively treated
at least 5 years previously with no subsequent evidence of recurrence.
6. Presence of an underlying disease state associated with active bleeding.
7. Ongoing therapy with oral or parenteral anticoagulants (e.g., heparin, warfarin/coumadin). Low-dose
anticoagulants for maintenance of catheter patency
and low dose aspirin (≤ 325 mg/day) and nonsteroidal antiinflammatory agents are
not exclusionary.
8. Concurrent treatment with other anticancer drugs.
9. Inability to comply with protocol or study procedures.
10. Previous therapy with strontium or samarium.
11. Patients who have had irradiation of ≥ 25% of the bone marrow (e.g. pelvic
irradiation).
12. Use of any herbal products, including saw palmetto within 1 week of screening and throughout the study.
13. Initiation of treatment with bisphosphonates, or change in dose, within 4 weeks of assignment to dosing in
this study. Patients taking bisphosphonates should not have their dosing regimen altered during the study unless
medically warranted.
14. Known history of HIV, HCV, or chronic HBV infection.
15. Previous treatment with a therapeutic antisense oligonucleotide or siRNA.
16. Planned concomitant participation in another clinical trial of an experimental agent, vaccine, or device.
17. Have any other medical conditions that, in the opinion of the Investigator, would
make the patient unsuitable for enrollment, or could interfere with the patient
participating in or completing the study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy endpoint is the progression-free survival, with progression defined as:
• PSA progression according to PCWG2 criteria (including the recommendation
that rising PSA alone as the basis for progression should be avoided),
• Tumor progression in lung, liver, lymph nodes and other soft tissue, by modified
RECIST 1.1 criteria,
• Bone progression defined as two or more new lesions on bone scan,
• Worsening symptoms and/or
• Death
|
|
| 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 | Yes |
| E.6.7 | Pharmacodynamic | No |
| 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) | 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 |
|
| 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Part 1:uncontrolled, open-label, dose escalation; Part 2:randomized, open-label |
|
| 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 | Yes |
| E.8.2.3.1 | Comparator description |
| Part 2: IMP+docetaxel+prednison versus docetaxel+prednison |
|
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 19 |
| 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 | Information not present in EudraCT |
| 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 |
|
| 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
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| 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 | 5 |
| 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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