A Phase 1b/2 Study of Docetaxel and Prednisone, With or Without ISIS 183750 (an eIF4E Inhibitor), in Patients With Castrate-Resistant Prostate Cancer
- Provide written informed consent prior to Screening.
- Age ≥ 18 years.
- Histological or cytological diagnosis of adenocarcinoma of the prostate.
- Metastatic disease for which no curative therapy exists and for which systemic
chemotherapy is indicated.
- Progression of disease despite either medical or surgical castration. If the patient
received medical androgen ablation, a castrate level of testosterone (> or = 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
- 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 (< or = 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.
- PSA > or = 2 ng/mL during the Screening period.
- Performance status of 0 or 1 on the ECOG Performance Status Scale.
- Have an estimated life expectancy of at least 12 weeks.
- Adequate organ function within 14 days prior to first study dose (ISIS EIF4E Rx or
docetaxel, whichever occurs first) including the following:
- Absolute neutrophil count (ANC) > or = 1.5 x 109/L.
- Platelet count > or = 100 x 109/L.
- Total bilirubin < or = 1.0 x upper limit of normal (ULN).
- Aspartate aminotransferase (AST) < or = 1.5 x ULN.
- Alanine aminotransferase (ALT) < or = 1.5 x ULN.
- Serum creatinine < or = 1.5 x ULN.
- Prothrombin time (PT) and international normalized ratio (INR) within normal
- Activated partial thromboplastin time (aPTT) within normal limits.
- 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.
- Have discontinued all previous therapies for cancer (except treatment with LHRH
analogues) as follows:
- Part 1: cytotoxic chemotherapy must be discontinued at least 4 weeks prior to
screening; Part 2: see Inclusion Criteria 11.
- Part 1: biological treatment (other than hormonal treatments) must be
discontinued for at least 6 weeks prior to screening; Part 2: see Inclusion
- Hormone therapies (e.g., abiraterone, MDV3100) must have been discontinued 4
weeks prior to screening.
- Radiotherapy must be discontinued at least 4 weeks prior to screening, and the
patient must have recovered from the acute effects of therapy.
- 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).
- 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.
- The patient is willing and able to comply with the study visit schedule and
procedures, and geographic proximity (Investigator's discretion) that allows adequate
- 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
- Pre-existing peripheral neuropathy > or = Common Terminology Criteria for Adverse
Events, Version 4.0 (CTCAE) Grade 2.
- 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).
- Have active infection or serious concomitant systemic disorder (for example, heart
failure) incompatible with the study (at the discretion of the Investigator).
- 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
- Presence of an underlying disease state associated with active bleeding.
- 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
- Concurrent treatment with other anticancer drugs.
- Inability to comply with protocol or study procedures.
- Previous therapy with strontium or samarium.
- Patients who have had irradiation of ≥ 25% of the bone marrow (e.g. pelvic
- Use of any herbal products, including saw palmetto within 1 week of screening and
throughout the study.
- 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.
- Known history of HIV, HCV, or chronic HBV infection.
- Previous treatment with a therapeutic antisense oligonucleotide or siRNA.
- Planned concomitant participation in another clinical trial of an experimental agent,
vaccine, or device.
- 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.