1) To assess the antitumor activity of PHA-739358 administered as IV infusion according to two different dose schedules in metastatic HRPC patients progressing on standard docetaxel-based chemotherapy.2) To have a precise idea of the antitumor…
ID
Source
Brief title
Condition
- Prostatic disorders (excl infections and inflammations)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
PSA response rate within the first three months of treatment, defined as
proportion of patient achieving at least a 50% PSA decline from baseline
confirmed by a second PSA value, 4 or more weeks later.
Secondary outcome
Secondary:
* Duration of PSA response: defined as time from date of first 25% PSA decline
from baseline to the date of first PSA rise by 50% above the nadir, provided
that the increase is of at least 2 ng/ml or back to the baseline.
* 30% PSA reduction: defined as proportion of patient achieving at least a 30%
PSA decline from baseline confirmed by a second PSA value, 4 or more weeks
later.
* PSA velocity: i.e. rate of change in PSA levels during the first 3 months of
treatment.
* Progression Free Survival (PFS): defined as the time from the date of
randomization to the date of first documentation of progression, or of death
due to any cause, whichever comes first. Progression of disease will be defined
as described in the full protocol.
* Objective tumor response rate: proportion of patients with measurable disease
at baseline achieving partial or complete overall best response according to
RECIST criteria.
* Clinical benefit rate: proportion of patients with pain score >= 2 on a
10-point pain intensity scale and/or analgesic score >= 1 on a 5-point analgesic
scale at baseline achieving a clinical benefit defined as:
• a >= 2-point decrease of pain score during treatment accompanied by stable or
reduced analgesic score as compared to baseline, lasting at least 2 weeks
or
• a >= 1-point decrease of analgesic score accompanied by stable/ reduced pain
score as compared to baseline, lasting at least 2 weeks
and
• performance status score unchanged or decreased versus baseline.
* Overall Safety profile: characterized by type, frequency, severity (graded
using the National Cancer Institute Common Terminology Criteria for Adverse
Events [NCI CTCAE] Version 3.0), timing and relationship to study therapy of
adverse events and laboratory abnormalities. Dose delays/reductions will be
used as an additional parameter to evaluate schedule tolerability.
Background summary
PHA-739358 is a small ATP competitive molecule that selectively inhibits Aurora
A, B and C kinases, a family of proteins that regulate different steps in the
mitotic and meiotic processes, and that are overexpressed in several cancers,
including prostate cancer. PHA-739358 antitumor activity has been shown in
several in vitro and in vivo studies where tumor growth inhibition, regressions
and cures were observed. In the murine transgenic prostate carcinoma TRAMP
model, tumor regression >80% was seen in 3 out of 16 animals and disease
stabilizations in 10 out of 16 animals treated with PHA-739358.
Thus far, 6 clinical studies with PHA-739358 have been activated including two
phase I dose escalation studies in solid tumors testing two different treatment
schedules (6-h IV infusion on days 1, 8, and 15 every 4 weeks and 24-h IV
infusion on day 1 every 2 weeks), two phase I dose escalation studies in
hematological malignancies, one pilot phase II study in CML and one phase II
study in various solid tumors that has just started.
Clinical experience with PHA-739358 is too limited to draw any conclusion as
regards its potential in HRPC (4 heavily pretreated patients enrolled in phase
I , one showing a partial PSA decline (39%) and 4-month disease stabilization).
However, available data on overexpression of the PHA-739358 target in prostate
cancer samples, the tumor regressions/stabilizations observed with PHA-739358
in the TRAMP model in vivo, together with the predictable, manageable and
reversible toxicities observed thus far in patients with solid tumors, support
proceeding with clinical investigations of this new agent in HRPC patients
progressing during or after standard, taxotere-based, 1st-line chemotherapy for
which no standard therapy is available.
Study objective
1) To assess the antitumor activity of PHA-739358 administered as IV infusion
according to two different dose schedules in metastatic HRPC patients
progressing on standard docetaxel-based chemotherapy.
2) To have a precise idea of the antitumor activity of PHA-739358 in the
selected patient population (patients are stratified based on PSA response to
previous docetaxel based therapy), a control group has been inserted in step
2: mitoxantrone plus prednisone or an approved 2nd-line treatment if any agent
is registered for this indication before the 2nd step of the study is
activated.
Study design
This will be a Phase II, multi-center open-label, randomized study of
PHA-739358 in approximately 118 adult patients with metastatic HRPC progressing
on/after standard, docetaxel-based, 1st-line chemotherapy for HRPC.
Randomization will be stratified according to PSA response to prior
docetaxel-based therapy (50% decrease or more versus less than 25%). The study
will consist of two steps:
• In the first step of the study 58 patients will be randomized to one of two
PHA-739358 dose schedules in a 1:1 ratio, i.e. 330 mg/m2 administered as 6-h IV
Infusion on Days 1, 8, and 15 of a 28-day cycle (Arm A) or 500 mg/m2
administered as 24-h IV infusion on Days 1 and 15 of a 28-day cycle (Arm B).
The dose intensity for the two schedules tested is equivalent: 990 and 1000
mg/m2/28-day cycle for arm A and B, respectively. For each PHA-739358 treatment
schedule a two-step Simon*s Mini Max design will be used, allowing early
termination at the first step in case of inactivity of one or both schedules.
At completion of the first step, the best PHA-739358 schedule will be selected
for proceeding to the 2nd step based on the observation of the number of PSA
responses required to proceed (at least 3 out of 29 patients per arm) and
taking into consideration treatment effect on other efficacy and safety
secondary end-points points.
• Assuming at least one of the two PHA-739358 dose schedules meets the
requirements for proceeding to the 2nd-step of the study, a second
randomization will take place where 54 patients will be randomized in a 1:1
ratio to the PHA-739358 selected schedule or a control treatment (mitoxantrone
plus prednisone). The inclusion of a control group in this second step of the
study is aimed at keeping under control potential biases in the selection of
study population that may affect the observed outcome. In the theoretical
situation that before the start of the second part of the study another second
line treatment becomes available (following registration and if available) the
study design will be adapted and an amendment will be submitted to the Ethics
Committee.
Intervention
PHA-739358 will be dosed based on the patient's body surface area. De dose in
arm A is 330 mg/m2 administered on day 1, 8 and 15 (6 hours infusion) or in arm
B 500mg/m2 administered on day 1 and day 15 (24 hours infusion) in a 28-day
cycle. In the absence of hematloogical toxicity greater then Grade 1 (exclusing
nause, vomiting and) in cycle 1 the dose may be increased to 400mg/m2 in arm A
and to 580mg/m2 in arm B.
Study burden and risks
Patients will undergo a full medical examination including a X-ray of the
thorax. An electrocardiogram (ECG) and a scan (MUGA) to monitor the
hartfunction will be done. Also CT or MRI imaging is done to measure the tumor
size. This will be repeated every two cycles. Also a bonescan will be made to
measure the extension (bone metastasis) of the disease. This will be repeted
every 12 weeks. Furthermore blood samples will be taken for laboratory analysis.
In all patients frequent blood samples will be drawn (at least 2 times per 28
weeks). There is a risk for pain or bruising at the location of blood sampling.
Cardiac function will be monitored at regualar intevals with MUGA scan.
Viale Pasteur 10
20014 Nerviano (mil)
IT
Viale Pasteur 10
20014 Nerviano (mil)
IT
Listed location countries
Age
Inclusion criteria
1. Adult (age >= 18 years) male patients.
2. Histologically confirmed diagnosis of adenocarcinoma of the prostate.
3. Metastatic (stage D3 according to Jewett Staging System).
4. Hormone-refractory disease, progressing after 1st-line docetaxel-based chemotherapy. For patients with measurable disease, progression will be defined by RECIST criteria. For patients without any measurable disease, appearance of new bone lesions at bone scan and PSA progression, according to recommendations from the Prostate-Specific Antigen Working Group, will be required.
5. Patients receiving corticosteroids requested for concomitant disease other than HRPC should continue treatment at the same dose.
6. Patients receiving bisphosphonate therapy must have been on stable doses for at least 4 weeks prior to enrollment.
7. Patients who have not undergone surgical castration must continue on primary androgen deprivation with LHRH analogue, if any, and testosterone must be < 50 ng/dL.
8. Prior radiotherapy is allowed provided that no more than 25% of bone marrow reserve has been irradiated and a minimum of 4 weeks have elapsed between the end of prior radiotherapy and the entry into the trial.
9. ECOG performance status 0-2.
10. Life expectancy of at least 3 months.
11. Resolution of all acute toxic effects (excluding alopecia) of any prior surgery, radiotherapy, radio-surgery or chemotherapy to NCI CTC (Version 3.0) Grade >= 1.
12. Required baseline laboratory data include:
Absolute Neutrophils Count (ANC) >= 1.500/mm3 (>= 1,5 x 109/L)
Platelets >= 100.000/mm3 (>= 100 x 109/L)
Hemoglobin >= 10,0 g/dL
Serum Creatinine <=1,5 mg/dL ( <=133 *mol/L)
Serum Albumin >= 3,0 g/dL
Total Serum Bilirubin <= 1,5 x ULN
Liver Transaminases (AST/ALT) <= 2,5 x ULN; <= 5 x ULN if livermetastasis are present
Alkalische fosfatase (ALP) <= 2,5 x ULN; <= 5 x ULN if bonemetastasis are present
AST/ALT = aspartate aminotransferase/alanine aminotransferase, ULN = upper normal limit
13. Signed and dated informed consent indicating that the patient is aware of the neoplastic nature of his disease and has been informed of the procedures to be followed, the experimental nature of the therapy, potential benefits, side effects, discomforts, risks, and alternative treatments.
14. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests and other study indications or procedures.
Exclusion criteria
1. Current enrollment in another therapeutic clinical trial.
2. Use of other investigational drugs (drugs not marketed for any indication) within 30 days prior to treatment.
3. More than one prior chemotherapy line.
4. Known brain or leptomeningeal disease (baseline computerized tomography [CT] or Magnetic Resonance Imaging [MRI] scan of the brain required only in case of clinical suspicion of central nervous system metastases.
5. Other prior malignancy, except for adequately treated basal or squamous cell skin cancer or superficial bladder cancer, or any other cancer from which the patient has been disease-free for 5 years or greater.
6. Prior treatment with radiopharmaceuticals (e.g. Strontium-89, Samarium-153) within 8 weeks prior to enrollment.
7. Major surgery, within 4 weeks or not fully recovered prior to Day 1.
8. Patients must agree to have no intention to father a child during the study and in the following 3 months after the end of the treatment.
9. Uncontrolled hypertension with blood pressure exceeding 160/100 mmHg (Stage 2 hypertension according to the JNC 7/ NIH USA 2003 guideline).
10. Any of the following in the past 6 months: myocardial infarction, unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack, pulmonary embolism, deep vein thrombosis.
11. Cardiac dysrhythmias Grade >= 2 according to NCI CTCAE version 3.0.
12. Known active infections, including HIV positivity.
13. History of allergic reactions to a similar structural compound, biological agent, or formulation.
14. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration or may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the patient inappropriate for entry into this study.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2006-006136-21-NL |
| CCMO | NL19674.078.07 |