Safety and Tolerability Study of ISIS EIF4E Rx in Combination With Docetaxel and Prednisone (CRPC)

A Phase 1b/2 Study of Docetaxel and Prednisone, With or Without ISIS 183750 (an eIF4E Inhibitor), in Patients With Castrate-Resistant Prostate Cancer

The purpose of this study is to examine the safety, tolerability and progression-free survival of patients with Castrate-Resistant Prostate Cancer treated with ISIS EIF4E Rx in combination with docetaxel and prednisone.

Study Overview

• Status: Completed
• Conditions: Castrate-Resistant Prostate Cancer
• Intervention / Treatment: Drug: ISIS EIF4E Rx; Drug: ISIS EIF4E Rx; Drug: ISIS EIF4E Rx; Drug: Prednisone; Drug: Docetaxel

• Study Type: Interventional
• Enrollment (Actual): 113
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Hungary
  • Budapest, Hungary, 1122
    • National Institute of Oncology
  • Budapest, Hungary, 1032
    • Szent Janos Hospital and Unified Hospitals of North Buda
  • Budapest, Hungary, 1082
    • Semmelweis University Faculty of Medicine
  • Pecs, Hungary, 7624
    • University of Pecs, Institute of Oncology
  • Szekesfehervar, Hungary, 8000
    • Fejer County St. Gyorgy Hospital, Dept of Oncology
• Poland
  • Bialystok, Poland, 15-027
    • Ewa Pilecka Clinical Oncology Department and Outpatient Chemotherapy Unit, Bialostockie M.Sklodowska-Curie Oncology Centre in Bialystok
  • Grudziadz, Poland, 86-300
    • Regionalny Szpital Specjalistyczny im. dr Wladyslawa Bieganskiego, Oddzial Onkologii Klinicznej
  • Olsztyn, Poland, 10-228
    • Department of Chemotherapy, Health Care Facility of the Ministry of Internal Affairs and Administration and Warminsko-Mazurskie Oncology Centre in Olsztyn
  • Opole, Poland, 45-060
    • Clinical Oncology Department and Day Hospitalization Unit, Independent Public Healthcare Facility T. Koszarowski Opolskie Oncology Centre in Opole
  • Warsaw, Poland, 02-781
    • Department of Urologic Oncology, Maria Sklodowska-Curie Institute of Oncology
  • Warsaw, Poland, 04-125
    • Clinical Oncology Department/Chemotherapy Department, MAGODENT Non-Public Healthcare Facility, Branch Facility No. 4
• Puerto Rico
  • San Juan, Puerto Rico, 00927
    • Fundacion de Investigacion de Diego
• Romania
  • Alba Iulia, Romania, 510077
    • Alba Lulia Emergency County Hospital
  • Baia Mare, Romania, 430031
    • Dr Constantin Opris Emergency County Hospital
  • Brasov, Romania, 500366
    • S.C. Rapid Diagnosis Polyclinic SRL
  • Bucharest, Romania, 22328
    • Fundeni Clinical Institute
  • Bucharest, Romania, 50659
    • "Prof. Dr Th Burghele" Clinical Hospital
  • Cluj-Napoca, Romania, 400058
    • SC Medisprof SRL
  • Constanta, Romania, 900635
    • S.C. Provita 2000 SRL
  • Craiova, Romania, 200385
    • SC Oncolab SRL, Medical Oncology Dept
• Russian Federation
  • Chelyabinsk, Russian Federation, 454087
    • State Therapeutical and Prophylactic Institution: Chelyabinsk Regional Clinical Oncology Center, Chemotherapy Department
  • Kursk, Russian Federation, 305035
    • State Medical Institution: Kursk Regional Oncological Center, Chemotherapy Dept
  • Moscow, Russian Federation, 105077
    • State Medical Institution of the City of Moscow: Municipal Clinical Hospital #57 under Moscow Department for Healthcare
  • Moscow, Russian Federation, 129128
    • Non-State Medical Institution: Central Clinical Hospital #2 n.a. N.A. Semashko under OJSC Russian Railways, Chemotherapy Dpmt
  • Obninsk, Russian Federation, 249036
    • Federal State Budget Institution: "Medical Radiological Research Center" under the Ministry of Health Care and Social Development of the Russian Federation
  • St Petersburg, Russian Federation, 197022
    • St. Petersburg State Medical Institution: St. Petersburg Municipal Oncological Center, Department of Urologic Oncology
  • St. Petersburg, Russian Federation, 197758
    • Russian Research Center for Radiology and Surgical Technologies
• United States
  • Arkansas
    • Fayetteville, Arkansas, United States, 72703
      • Highlands Oncology Group
  • California
    • San Bernardino, California, United States, 92404-4816
      • San Bernardino Urological Associates
  • Colorado
    • Fort Collins, Colorado, United States, 80528
      • Fort Range Cancer Center
  • Connecticut
    • Norwalk, Connecticut, United States, 06850
      • Norwalk Hospital- Whittingham Cancer Center
  • Florida
    • Lakeland, Florida, United States, 33805
      • Lakeland Regional Cancer Center
    • Miami, Florida, United States, 33136
      • University of Miami, Miller School of Medicine - Sylvester Comprehensive Cancer Center
  • Kentucky
    • Lexington, Kentucky, United States, 40503
      • Central Baptist Hospital Clinical Research Center
  • Louisiana
    • Shreveport, Louisiana, United States, 71103
      • Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center
  • New York
    • New York, New York, United States, 10019
      • St. Luke's - Roosevelt Hospital Center
    • Rochester, New York, United States, 14642
      • James P. Wilmont Cancer Center - University of Rochester Medical Center
  • Ohio
    • Canton, Ohio, United States, 44718
      • Gabrail Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 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 imaging.

• 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 limits.
  • 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 Criteria 11.
  • 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 follow-up.

Exclusion Criteria:

• 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.
• 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 recurrence.
• 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 exclusionary.
• 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 irradiation).
• 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part 1 Cohort 1	Drug: ISIS EIF4E Rx; 800 mg ISIS EIF4E Rx administered as a 3-hour intravenous infusion on Days 1, 8 and 15 of each 21 day cycle.; Drug: ISIS EIF4E Rx; 1000 mg ISIS EIF4E Rx administered as a 3-hour intravenous infusion on Days 1, 8 and 15 of each 21 day cycle.; Drug: ISIS EIF4E Rx; (Dose identified in Part 1)ISIS EIF4E Rx administered as a 3-hour intravenous infusion on Days 1, 8 and 15 of each 21 day cycle.; Drug: Prednisone; 5 mg administered orally twice daily on days 1, 8, 15 and 22 of each cycle; Drug: Docetaxel; 75 mg/m2 administered as a 1-hour intravenous infusion on day 1 of each cycle
Experimental: Part 1 Cohort 2	Drug: ISIS EIF4E Rx; 800 mg ISIS EIF4E Rx administered as a 3-hour intravenous infusion on Days 1, 8 and 15 of each 21 day cycle.; Drug: ISIS EIF4E Rx; 1000 mg ISIS EIF4E Rx administered as a 3-hour intravenous infusion on Days 1, 8 and 15 of each 21 day cycle.; Drug: ISIS EIF4E Rx; (Dose identified in Part 1)ISIS EIF4E Rx administered as a 3-hour intravenous infusion on Days 1, 8 and 15 of each 21 day cycle.; Drug: Prednisone; 5 mg administered orally twice daily on days 1, 8, 15 and 22 of each cycle; Drug: Docetaxel; 75 mg/m2 administered as a 1-hour intravenous infusion on day 1 of each cycle
Experimental: Part 2 Arm A	Drug: Prednisone; 5 mg administered orally twice daily on days 1, 8, 15 and 22 of each cycle; Drug: Docetaxel; 75 mg/m2 administered as a 1-hour intravenous infusion on day 1 of each cycle
Experimental: Part 2 Arm B	Drug: ISIS EIF4E Rx; 800 mg ISIS EIF4E Rx administered as a 3-hour intravenous infusion on Days 1, 8 and 15 of each 21 day cycle.; Drug: ISIS EIF4E Rx; 1000 mg ISIS EIF4E Rx administered as a 3-hour intravenous infusion on Days 1, 8 and 15 of each 21 day cycle.; Drug: ISIS EIF4E Rx; (Dose identified in Part 1)ISIS EIF4E Rx administered as a 3-hour intravenous infusion on Days 1, 8 and 15 of each 21 day cycle.; Drug: Prednisone; 5 mg administered orally twice daily on days 1, 8, 15 and 22 of each cycle; Drug: Docetaxel; 75 mg/m2 administered as a 1-hour intravenous infusion on day 1 of each cycle

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Progression free survival	At the end of each 21 day cycle

Collaborators and Investigators

• Sponsor: Ionis Pharmaceuticals, Inc.

Study record dates

Study Major Dates

• Study Start: November 1, 2010
• Primary Completion (Actual): May 1, 2013
• Study Completion (Actual): December 1, 2013

Study Registration Dates

• First Submitted: November 2, 2010
• First Submitted That Met QC Criteria: November 3, 2010
• First Posted (Estimated): November 4, 2010

Study Record Updates

• Last Update Posted (Actual): October 6, 2023
• Last Update Submitted That Met QC Criteria: October 4, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: Castrate-Resistant Prostate Cancer
• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Genital Neoplasms, Male; Prostatic Diseases; Urogenital Diseases; Male Urogenital Diseases; Genital Diseases, Male; Genital Diseases; Prostatic Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Inflammatory Agents; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Docetaxel; Prednisone
• Other Study ID Numbers: ISIS 183750-CS3

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes