| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Castration Resistant Prostate Cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 13.1 |
| 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) |
|
| 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 |
| To compare overall survival of subjects with castration resistant prostate cancer (CRPC), that have progressed during or following docetaxel treatment, when randomized to treatment with bone-directed radiotherapy followed by ipilimumab vs bone-directed radiotherapy followed by placebo. |
|
| E.2.2 | Secondary objectives of the trial |
• Compare progression free survival (PFS)
• Compare pain response
• Characterize safety profile
+ Exploratory Objectives:
• Estimate PSA response rate
• Characterize the kinetics of tumor burden among subjects with measurable disease
• Characterize PSA kinetics
• Estimate changes in Quality of Life (QoL) as measured by the Medical Outcome Study Short Form Health Survey (SF-36)
• Estimate changes in pain intensity as measured by the Brief Pain Inventory Short Form (BPI-SF)
• Perform pharmacokinetic (PK) analysis
• Determine presence of Human Anti-Human Antibodies (HAHA)
• Assess the effect of Ipilimumab on ECG parameters |
|
| 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 |
(1) An ECG sub-study will be performed at selected sites to assess the effects of ipilimumab on ECG parameters. All subjects from participating sites will have triplicate 12-lead ECGs performed at Day 1 (2 triplicate ECGs, separated by at least 15 minutes, prior to Dose 1), Week 7 (pre- and post-dose), and at the Week 24 Induction visit. The ECG sub-study will continue until study closure or ECG data from 200 subjects has been collected. (See protocol section 6.3.2).
(2) Biomarker Amendment 06 (version 1.0 dated 16-Nov-09) - Site Specific
The objective of this Amendment is to permit the collection of blood samples for use in exploratory research studies or to test previously identified potential biomarkers of immunotherapy efficacy.The main objective of this amendment is to explore the potential role of circulating tumor cells (CTC) and absolute lymphocyte count (ALC) as biomarkers of ipilimumab efficacy.
(3) Serum Biomarker Amendment 13 (version 1.0 dated 18-Mar-11) -
Site Specific
The objective of this amendment is to utilize residual serum samples
from CA184043 central lab testing in order to investigate the potential
biomarker value of CRP, cytokines, NKG2D ligand,
anti-tumor antibodies, and other biomarkers, to predict clinical activity
as measured by efficacy endpoints of ipilimumab in radiation treated
CRPC patients.
|
|
| E.3 | Principal inclusion criteria |
1) Signed Written Informed Consent
a) Willing and able to give informed consent.
2) Target Population
a) Histologic or cytologic confirmation of adenocarcinoma of the prostate;
Note: Every effort should be made to obtain the original pathology report diagnosing prostate cancer. If the original pathology report cannot be obtained then written documentation, in the form of a letter from the referring physician or a clinic note from the CA184043 investigator, must be entered into the subject’s medical record.
b) At least 1 symptomatic bone metastasis which can be irradiated, or at least 1 asymptomatic bone metastasis which, in the clinical judgment of the investigator, is appropriate to be irradiated (eg, risk of fracture or cord compression);
c) Have been treated by orchiectomy or are receiving a GnRH agonist/antagonist, and have a testosterone level less than 50 ng/dl (1.74 nmol/L);
d) If applicable, must have discontinued anti-androgens at least 2 weeks prior to randomization. Medications considered to be anti-androgens include; Flutamide, Bicalutamide (Casodex), nilutamide, aminoglutethimide, ketoconazole, diethylstilbestrol, megestrol acetate (Megace), and finasteride (Proscar). Additionally, any natural substance that might have anti-androgen activity, including but not limited to St John’s Wort, Saw Palmetto, or PC-SPES, must be discontinued prior to randomization;
e) Must have received at least 1 prior regimen containing docetaxel for the treatment of metastatic CRPC, consisting of at least 2 cycles of docetaxel;
f) ECOG Performance Status: Subjects must have ECOG PS 0 - 1.
g) Subjects must have progressed while receiving, or within 6 months of receiving, a
docetaxel-containing regimen. If the subject received additional anti-cancer
therapy after docetaxel, they must also demonstrate signs of progression on that
therapy. For eligibility purposes, progressive disease is defined by any one of the
following;
i) Rising PSA values at a minimum of 1-week intervals and a 2.0 ng/mL
minimum starting value
ii) Progression per bone scan: the appearance of 2 or more new lesions
iii) Progression per target lesions/measurable disease: nodal or visceral disease
progression, per modified RECIST. Only lymph nodes greater than 2 cm will
be considered to assess a change in size qualifying for disease progression.
3) Age and Sex
a) Men ≥ 18 years of age or minimum age of consent per local regulations.
|
|
| E.4 | Principal exclusion criteria |
1) Sex and Reproductive Status
a) Sexually active fertile men not using effective birth control if their partners are women of child-bearing potential (WOCBP).
2) Target Disease Exceptions
a) History of brain metastasis.
3) Medical History and Concurrent Diseases
a) Autoimmune disease: subjects with a documented history of inflammatory bowel disease, including ulcerative colitis and Crohn's disease are excluded from this study, as are subjects with a history of rheumatoid arthritis, systemic progressive sclerosis (scleroderma), Systemic Lupus Erythematosus, autoimmune vasculitis (eg, Wegener’s Granulomatosis);
b) Motor neuropathy considered of autoimmune origin (eg, Guillain-Barre Syndrome);
c) Patients with a prior history of pelvic (prostate) radiation associated with significant radiation proctitis within 12 months prior to the planned first infusion of blinded study drug. For the purpose of this protocol, radiation proctitis is defined as diarrhea that reached a level of Grade 2 or Grade 3, that occurred within 1 month of radiation treatment, and that was of 7 days duration or longer.
d) Dementia, altered mental status, or any psychiatric condition that would prohibit the understanding or rendering of informed consent or completing questionnaires;
e) A serious uncontrolled medical disorder that, in the opinion of the investigator, would impair the ability of the subject to receive protocol therapy;
f) Prior malignancy active within the previous 3 years except for locally curable cancers that have been apparently cured and needing no subsequent therapy, such as basal or squamous cell skin cancer, or superficial bladder cancer;
g) Known HIV or Hepatitis B or Hepatitis C infection, based on testing performed
during the CA184043 screening period.
4) Physical and Laboratory Test Findings
a) Inadequate hematologic function defined by an absolute neutrophil count (ANC) < 1,500/mm³, a platelet count < 100,000/mm³, or a hemoglobin level < 9 g/dL;
b) Inadequate hepatic function defined by a total bilirubin level ≥ 2.5 times the upper limit of normal (ULN), AST and ALT levels ≥ 2.5 times the ULN or ≥ 5 times the ULN if liver metastases are present;
c) Inadequate renal function defined by a serum creatinine level ≥ 2.5 times the ULN;
d) Inadequate creatinine clearance defined as less than 50 mL/min;
e) Usage of greater than 120 mg of oral morphine (or equivalent) over a 24 hour period within 3 days of randomization, unless narcotic usage is necessitated by a symptomatic bone lesion that is likely to be palliated by protocol-specified radiotherapy.
5) Prohibited Treatments and/or Therapies
a) More than 2 prior cytotoxic chemotherapy regimens for metastatic CRPC. Note: for purposes of eligibility, all docetaxel-containing regimens are considered to be one regimen.
b) Chronic use of immunosuppressants and/or systemic corticosteroids (used in the management of cancer or non-cancer-related illnesses). However, during the course of the study, use of corticosteroids is allowed if used for treating irAEs, or adrenal insufficiencies, or if administered at doses of prednisone 5 mg BID or equivalent;
c) Any non-oncology vaccine therapy used for the prevention of infectious diseases (for up to 4 weeks prior to or after any dose of blinded study drug);
d) Prior treatment with any inhibitor or agonist of T cell costimulation;
e) Prior strontium or samarium;
f) Prior treatment on BMS study CA180227: A Randomized Double-Blind Phase 3 Trial Comparing Docetaxel Combined with Dasatinib to Docetaxel Combined with Placebo in Castration-Resistant Prostate Cancer.
6) Other Exclusion Criteria
a) Prisoners or subjects who are involuntarily incarcerated;
b) Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Time Frame: is assessed at each study visit while on treatment and every
12 weeks in the post-treatment Follow-up Phase |
|
| E.5.2 | Secondary end point(s) |
Compare progression free survival (PFS) [ Time Frame: Assessed at each
study visit while on treatment and every 12 weeks in the post-treatment
Follow-up Phase until alternative treatment is initiated ]
Compare pain response [ Time Frame: Assessed at screening, weeks 12,
18, 24, and at the End of Treatment visit ]
Characterize safety profile [ Time Frame: Assessed at each study visit
while on treatment and for 70 days following the last dose of study
drug] |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | Yes |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Immunogenicity sample testing (HAHA); QoL; ECG substudy |
|
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 48 |
| 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 |
| Austria |
| Belgium |
| Brazil |
| Canada |
| Chile |
| Colombia |
| Czech Republic |
| Denmark |
| France |
| Germany |
| Greece |
| Hungary |
| Ireland |
| Israel |
| Italy |
| Mexico |
| Netherlands |
| Peru |
| Poland |
| Puerto Rico |
| Romania |
| Russian Federation |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| 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 | 3 |
| 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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