Phase 2 Study of Docetaxel +/- OGX-427 in Patients With Relapsed or Refractory Metastatic Bladder Cancer

The Borealis-2 Clinical Trial: A Randomized Phase 2 Study Comparing Docetaxel Alone to Docetaxel in Combination With OGX-427 in Patients With Relapsed or Refractory Metastatic Urothelial Carcinoma After Receiving a Platinum-containing Regimen: Hoosier Cancer Research Network GU12-160

This is a randomized, open-label Phase 2 clinical trial to evaluate whether suppression of Hsp27 (Heat shock protein 27) production using OGX-427, a second-generation antisense oligonucleotide (ASO), in combination with docetaxel can prolong survival time compared to docetaxel alone in participants with locally advanced or metastatic urothelial carcinoma (UC) that are relapsed or refractory after receiving a platinum-containing regimen.

Study Overview

• Status: Completed
• Conditions: Bladder Cancer; Urothelial Carcinoma
• Intervention / Treatment: Drug: OGX-427; Drug: Docetaxel

Detailed Description

OUTLINE: This is a multi-center study.

Eligible patients will be stratified based on time from prior systemic chemotherapy (< 3 vs ≥ 3 months) and Bellmunt prognostic factors criteria, which include Eastern Cooperative Oncology Group (ECOG) performance status >0, hemoglobin <10g/dL, and presence of liver metastases (0 versus 1-3 risk factors). Within the strata, participants will be randomly assigned with equal probability to either the investigational arm (Arm A: docetaxel + OGX-427) or the control arm (Arm B: docetaxel alone).

INVESTIGATIONAL ARM OGX-427 + DOCETAXEL (Arm A):

LOADING DOSE PERIOD:

Participants randomized onto the investigational arm (Arm A) will receive OGX-427 beginning with a loading dose period prior to the initiation of docetaxel treatment. The first dose of OGX-427 for the loading dose period must be administered within 5 working days of registration and randomization.

During the loading dose period, participants will receive three separate administrations of 600 mg OGX-427 intravenously (IV) (days -9 to -1). There must be at least one "non-infusion" day between each administration of OGX-427 (i.e., every other day) during the loading dose period and between the third loading dose of OGX-427 and day 1 of cycle 1. There should be no more than 7 days between the last loading dose and day 1 of cycle 1.

TREATMENT PERIOD:

During the treatment period, participants randomized to this arm will receive:

• OGX-427 600 mg IV weekly on days 1, 8, and 15 of each 21-day cycle. OGX-427 must be administered prior to docetaxel on day 1 of each cycle.
• Docetaxel (75 mg/M2) IV on day 1 of each 21-day cycle. Docetaxel should be administered immediately following the completion of the OGX-427 infusion.

OGX-427 MAINTENANCE:

Following completion of 10 cycles of docetaxel, 600 mg OGX-427 will continue to be administered by IV weekly as maintenance therapy for participants who do not have disease progression (i.e., stable disease or better). Participants without documented disease progression who have discontinued from study treatment not due to toxicity related to OGX-427 can also continue to receive OGX-427 maintenance as long as they have completed disease assessments following at least 2 cycles of chemotherapy. Maintenance with OGX-427 will continue until disease progression or unacceptable toxicity.

CONTROL ARM - DOCETAXEL ALONE (Arm B):

TREATMENT PERIOD:

During the treatment period, participants randomized to this arm will receive:

- Docetaxel (75 mg/M2) IV on day 1 of each 21-day cycle. The first dose of docetaxel must be administered within 5 working days of registration and randomization. Participants will continue to receive docetaxel on day 1 of each 21-day cycle until disease progression, unacceptable toxicity related to docetaxel, voluntary patient withdrawal, or a maximum of 10 docetaxel cycles.

FOLLOW-UP FOR BOTH ARMS:

Imaging studies will be performed every 6 weeks (i.e., after completion of cycles 2, 4, 6, 8 and 10) until disease progression and with any sign or symptom of new or worsening disease; computed tomography scan (CT) of chest/abdomen/pelvis is preferred but magnetic resonance imaging scan(MRI) is acceptable, especially for participants with increased risk of contrast-related nephropathy or other contraindications. For Arm A, scans will be performed every 2 cycles (6 weeks) +/1 week during the 21-day cycles of docetaxel administration and every 6 weeks during maintenance OGX-427 administration until disease progression; for Arm B, scans will be performed every 6 weeks during the 21-day cycles of docetaxel administration until disease progression. All scans should be completed before the subsequent cycle is scheduled to begin. Bone scans will be repeated, if positive at baseline, every 6 weeks during the first 4 cycles of treatment (i.e., at the end of cycles 2 and 4) and then every 12 weeks thereafter until disease progression (i.e., at the end of cycle 8, at end of treatment, and during maintenance with OGX-427 [Arm A only]).

All participants will have an End of Treatment (EOT) visit when they discontinue study treatment. All participants will be followed until documented disease progression.

Once disease progression is documented, participants will enter a survival follow-up period. All participants must be followed for survival as the primary endpoint. During the survival follow-up period, data will be collected every three months regarding further cancer therapy, secondary malignancy, and survival status.

Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

Life Expectancy: Greater than 3 months

Hematopoietic:

• Absolute neutrophil count(ANC)≥ 1,500/mcL
• Hemoglobin ≥ 8 g/dL
• Platelets ≥ 100,000/mcL

Hepatic:

• Bilirubin ≤ 1.1 x upper limit of normal (ULN) (≤ 2.0 x ULN if secondary to Gilbert's disease)
• Aspartate transaminase (AST), serum glutamic oxaloacetic transaminase (SGOT)/alanine transaminase (ALT), serum glutamic pyruvic transaminase (SGPT) ≤ 1.5 X institutional ULN

Renal:

• Serum creatinine ≤ 1.5 x ULN

Cardiac:

• Symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or myocardial infarction within 3 months of randomization.

• Study Type: Interventional
• Enrollment (Actual): 200
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama Hematology Oncology Clinic at Medical West
  • California
    • Duarte, California, United States, 91010
      • City of Hope: Duarte
    • Lancaster, California, United States, 93534
      • City of Hope: Antelope Valley
    • Los Angeles, California, United States, 90089
      • USC: Norris Comprehensive Cancer Center
    • Los Angeles, California, United States, 90095
      • UCLA: Jonsson Comprehensive Cancer Center
  • Indiana
    • Goshen, Indiana, United States, 46527
      • IU Health Goshen Hospital
    • Indianapolis, Indiana, United States, 46202
      • Indiana University Melvin & Bren Simon Cancer Center
    • Indianapolis, Indiana, United States, 46219
      • IU Health Central Indiana Cancer Centers
    • Muncie, Indiana, United States, 47303
      • IU Health at Ball Memorial Hospital
  • Maryland
    • Baltimore, Maryland, United States, 21231
      • Johns Hopkins University: Sidney Kimmel Comprehensive Cancer Center
    • Baltimore, Maryland, United States, 21201
      • University of Maryland: Greenebaum Cancer Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana-Farber Cancer Institute
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Cancer Center
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Siteman Cancer Center
  • Nebraska
    • Omaha, Nebraska, United States, 68114
      • Nebraska Cancer Specialists
  • New Hampshire
    • Manchester, New Hampshire, United States, 03102
      • Dartmouth-Hitchcock Medical Center: Norris Cotton Cancer Center
  • New Jersey
    • Basking Ridge, New Jersey, United States, 07920
      • Memorial Sloan-Kettering Cancer Center: Basking Ridge
    • Hackensack, New Jersey, United States, 07601
      • John Theurer Cancer Center: Hackensack University Medical Center
    • New Brunswick, New Jersey, United States, 08903
      • Rutgers Cancer Institute of New Jersey
  • New Mexico
    • Albuquerque, New Mexico, United States, 87131
      • University of New Mexico Cancer Center: Albuquerque
    • Las Cruces, New Mexico, United States, 88011
      • University of New Mexico Cancer Center: Las Cruces
  • New York
    • Buffalo, New York, United States, 14263
      • Roswell Park Cancer Institute
    • Commack, New York, United States, 11725
      • Memorial Sloan-Kettering Cancer Center: Commack
    • New York, New York, United States, 10016
      • New York University Clinical Cancer Center
    • New York, New York, United States, 10065
      • Memorial Sloan-Kettering Cancer Center: Main Campus
    • Rochester, New York, United States, 14642
      • University of Rochester Medical Center
    • Rockville Centre, New York, United States, 11570
      • Memorial Sloan-Kettering Cancer Center: Rockville Centre
    • Sleepy Hollow, New York, United States, 10591
      • Memorial Sloan-Kettering Cancer Center: Sleepy Hollow
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • University Hospitals Seidman Cancer Center
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic: Taussig Cancer Institute
    • Mentor, Ohio, United States, 44060
      • Lake Health: University Hospitals Seidman Cancer Center
    • Orange Village, Ohio, United States, 44122
      • UHHS Chagrin Highlands: Seidman Cancer Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Thomas Jefferson University: Kimmel Cancer Center
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • MUSC Hollings Cancer Center
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Froedtert & Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Participants must have histologically documented metastatic or locally inoperable advanced urothelial carcinoma (bladder, urethra, ureter and renal pelvis) (T4b, N2, N3, or M1 disease. NOTE: Aberrant differentiation such as squamous, glandular (adenocarcinoma), and micropapillary are eligible unless the tumor is considered a pure histological variant according to the pathology report. Participants with small cell histology are not eligible.
• Participants must have measurable disease defined as at least one target lesion that has not been irradiated and can be accurately measured in at least one dimension by RECIST v1.1 criteria.
• Participants must have received prior systemic chemotherapy treatment for metastatic urothelial carcinoma. NOTE: Up to 2 prior systemic chemotherapeutic regimens given in the metastatic disease setting for urothelial carcinoma are allowed.

• Specifically, subjects must meet one or more of the following criteria:

  1. Progression during or after treatment with a regimen that includes a platinum salt (e.g., carboplatin or cisplatin) OR
  2. Disease recurrence within one year after neoadjuvant or adjuvant platinum-based systemic chemotherapy, measured from the date of last dose of chemotherapy or surgery until the day the informed consent is signed
• Participants must be ≥18 years since no dosing or adverse event data are currently available on the use of OGX-427 in participants <18 years of age.
• Minimum of 21 days have elapsed since prior major surgery, with recovery from any adverse events.
• Minimum of 14 days have elapsed since any prior radiation therapy, with recovery from any adverse events.
• The effects of OGX-427 on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
• Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

• History of treatment with docetaxel in any setting. Participants treated with prior paclitaxel are eligible.
• Prior enrollment in the OncoGenex Phase 2 Study OGX-427-02.
• Participants may not be receiving other investigational agents.
• Participants with known brain or spinal cord metastases are excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. NOTE: Brain imaging is not required unless the patient has symptoms or physical signs of central nervous system (CNS) disease.
• History of allergic reactions or severe hypersensitivity reactions to drugs formulated with polysorbate 80 or antisense oligonucleotides.
• Peripheral neuropathy ≥Grade 2.
• Uncontrolled intercurrent illness including, but not limited to ongoing or active infection or psychiatric illness/social situations that would limit compliance with study requirements.
• Cerebrovascular accident or pulmonary embolus within 3 months of randomization.
• Pregnant women and breast feeding women are excluded from this study because of the risk to a fetus due to docetaxel chemotherapy and OGX-427 systemic treatment (fertility toxicology studies have not been completed for OGX-427).
• Active second malignancy (except non-melanomatous skin cancer or incidental prostate cancer found on cystectomy): active secondary malignancy is defined as a current need for cancer therapy or a high possibility (>30%) of recurrence during 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

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Experimental Arm: Arm A; Three doses of 600 mg OGX-427 will be administered IV during the loading dose period (days -9 to -1). Following completion of the loading dose period, 600 mg OGX-427 will be given IV weekly on days 1, 8, and 15 of each 21-day cycle.	Drug: OGX-427; Three doses of 600 mg OGX-427 will be administered IV during the loading dose period (days -9 to -1). Following completion of the loading dose period, 600 mg OGX-427 will be given IV weekly on days 1, 8, and 15 of each 21-day cycle. OGX-427 must be administered prior to docetaxel on day 1 of each cycle. Following completion of 10 cycles of docetaxel, 600 mg OGX-427 will continue to be administered by IV weekly as maintenance therapy in Arm A participants who do not have disease progression (i.e., stable disease or better). Participants without documented disease progression who have discontinued from study treatment not due to toxicity related to OGX-427 can also continue to receive OGX-427 maintenance as long as they have completed disease assessments following at least 2 cycles of chemotherapy. Maintenance with OGX-427 will continue until disease progression or unacceptable toxicity.; Drug: Docetaxel; For Arm A Only: Docetaxel should be administered immediately following the completion of the OGX-427 infusion. For Both Arms: Docetaxel (75 mg/M2) will be administered IV on Day 1 of each 21 day cycle for a maximum of 10 cycles.
Active Comparator: Control Arm: Arm B; Docetaxel (75 mg/M2) will be administered IV on day 1 of each 21 day cycle for a maximum of 10 cycles.	Drug: Docetaxel; For Arm A Only: Docetaxel should be administered immediately following the completion of the OGX-427 infusion. For Both Arms: Docetaxel (75 mg/M2) will be administered IV on Day 1 of each 21 day cycle for a maximum of 10 cycles.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival	To determine whether docetaxel administered in combination with OGX-427 provides a survival benefit compared to docetaxel alone.	36 Months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety and Toxicity of Regimen	To compare the safety and toxicity of OGX-427 in combination with docetaxel to that of docetaxel alone. A summary of per-patient maxiumy grade adverse events of any type is included in the Outcome Measure. Full adverse event information will be submitted further in the record.	36 Months
Overall Response Rate	To compare overall response rate (ORR) between the treatment arms.	Every 6 weeks
Overall Survival (OS) According to Baseline Serum Hsp27 Level.	A subgroup analysis to determine the median overall survival time based on baseline Hsp27 levels.	36 months
Hsp27 Expression in Archival Tissue	To evaluate the association of urothelial carcinoma expression of Hsp27 measured by immunohistochemistry (IHC) in archival tissue with clinical outcomes.	Cycle 1
Effect of Therapy Regimen on Circulating Tumor Cells (CTCs)and Correlative Analysis of Telomerase Activity	To evaluate the effect of therapy with docetaxel and OGX-427 on peripheral blood circulating tumor cells (CTCs) enumeration and expression of Hsp27 and other relevant proteins via immunoflourescence, and levels of telomerase by quantitative polymerase chain reaction (PCR), and explore their relation with clinical outcomes.	Prior to screening, prior to first loading dose, and prior to cycles 1, 2, 3 and 5

Collaborators and Investigators

• Sponsor: Noah Hahn, M.D.
• Collaborators: Hoosier Cancer Research Network; Achieve Life Sciences

Publications and helpful links

General Publications

• Jonathan E. Rosenberg, Noah M. Hahn, Meredith M. Regan, Cindy Jacobs, Patricia S. Stewart, Toni K. Choueiri. The Borealis-2 clinical trial: A randomized phase II study of OGX-427 plus docetaxel versus docetaxel alone in relapsed/refractory metastatic urothelial cancer. J Clin Oncol 31, 2013 (suppl; abstr TPS4588^) http://abstracts2.asco.org/AbstView_132_114639.html
• Choueiri TK, Hahn NM, Pal SK, Alva AS, Dreicer R, Starodub A, Sonpavde G, Hoffman-Censits JH, Picus J, Balar AV, Guancial EA, Regan MM, Jacobs C, Stewart PS, Rosenberg JE. The Borealis-2 clinical trial: A randomized phase 2 study of OGX-427 (apatorsen) plus docetaxel versus docetaxel alone in relapsed/refractory metastatic urothelial cancer. J Clin Oncol 32:5s, 2014 (suppl; abstr TPS4593^)
• Choueiri TK, Hahn NM, Alva AS, Lauer RC, Dreicer R, Picus J, Pili R, Balar AV, Sonpavde G, Hoffman-Censits JH, Guancial EA, Alter R, Regan MM, Jacobs C, Stewart PS, Pal SK, Rosenberg JE. The Borealis-2 clinical trial: A randomized phase 2 study of OGX-427 (Apatorsen) plus docetaxel versus docetaxel alone in relapsed/refractory metastatic urothelial cancer. J Clin Oncol 33:5s, 2015 (suppl; abstr TPS4577)

Helpful Links

• Hoosier Cancer Research Network Website

Study record dates

Study Major Dates

• Study Start: April 1, 2013
• Primary Completion (Actual): October 1, 2017
• Study Completion (Actual): October 1, 2017

Study Registration Dates

• First Submitted: January 25, 2013
• First Submitted That Met QC Criteria: January 29, 2013
• First Posted (Estimate): January 31, 2013

Study Record Updates

• Last Update Posted (Actual): July 11, 2022
• Last Update Submitted That Met QC Criteria: July 7, 2022
• Last Verified: July 1, 2022

More Information

Terms related to this study

• Keywords: Docetaxel; OGX-427
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Urologic Diseases; Neoplasms, Glandular and Epithelial; Urinary Bladder Diseases; Carcinoma; Urinary Bladder Neoplasms; Carcinoma, Transitional Cell; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Docetaxel
• Other Study ID Numbers: GU12-160