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.

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.

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.