A Phase 2 Study Comparing Chemotherapy in Combination With OGX-427 or Placebo in Patients With Bladder Cancer

Study Overview
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Brief Summary
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The primary objective of this study is to ascertain whether there is evidence of longer survival relative to the control arm for three comparisons: 600 mg OGX-427 Arm to control Arm; 1000 mg OGX-427 Arm to control Arm; and pooled 600 mg and 1000 mg OGX-427 Arms to control Arm.

Detailed Description
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Following 3 loading doses, participants receive chemotherapy and study drug on a 21-day cycle during the Treatment Period (Chemotherapy Period) until disease progression, completion of 6 cycles, toxicity or voluntary participant withdrawal. Participants who do not have documented disease progression and have completed a minimum of four cycles of chemotherapy continue to receive weekly Study Drug maintenance therapy during the Maintenance Period until disease progression or the participant fulfills one of the other reasons for withdrawal from protocol treatment, unless they have been discontinued from protocol treatment for unacceptable toxicity related to study drug. All participants have an End of Treatment (EOT) visit when they are withdrawn from all study treatment (chemotherapy and maintenance). All participants are followed until documented disease progression. Once disease progression is documented, participants enter a Survival Follow-up Period during which data are collected regarding further cancer therapy, secondary malignancy, and survival status.

Official Title
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A Randomized, Double-blind Phase 2 Study Comparing Gemcitabine and Cisplatin in Combination With OGX-427 or Placebo in Patients With Advanced Transitional Cell Carcinoma

Conditions
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Urologic Neoplasms, Metastatic Bladder Cancer, Urinary Tract Neoplasms

Intervention / Treatment
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* Drug: OGX-427 600 mg
* Drug: OGX-427 1000 mg
* Drug: Placebo
* Drug: Gemcitabine
* Drug: Cisplatin
* Drug: Carboplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years at the time of consent Histologically documented metastatic or locally inoperable advanced transitional cell carcinoma (TCC) of the urinary tract (bladder, urethra, ureter and renal pelvis) (T4b, N2, N3 or M1 disease) NOTE: Certain mixed histologies that are predominately (≥ 50%) TCC are eligible: squamous, adenocarcinoma, and undifferentiated. Mixed undifferentiated histology requires immunohistochemistry (IHC) consistent with a TCC origin. Mixed small-cell histologies are excluded 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 Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria No prior systemic chemotherapy with the following exceptions: Prior use of radiosensitizing single agent therapy is allowed Prior neoadjuvant and adjuvant chemotherapy may be allowed Minimum of 21 days since prior major surgery or radiation therapy Karnofsky performance status ≥ 70% Required laboratory values at baseline: absolute neutrophil count (ANC) ≥ 1.5 x 10^9 cells/L platelet count ≥ 125 x 10^9/L calculated creatinine clearance ≥ 60 mL/minute bilirubin ≤ 1.5 x upper limit of normal (ULN; ≤ 2.5 x ULN if secondary to Gilbert's disease) aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 x ULN If of child-bearing potential, willing to use contraceptives Willing to give written informed consent Exclusion Criteria: A candidate for potential curative surgery or radiotherapy Intravesical therapy within the last 3 months Documented brain metastasis or carcinomatous meningitis, treated or untreated. NOTE: Brain imaging is not required unless the patient has symptoms or physical signs of central nervous system (CNS) disease. Peripheral neuropathy ≥ Grade 2 Known serious hypersensitivity to gemcitabine, cisplatin or carboplatin Current serious, uncontrolled medical condition such as congestive heart failure, angina, hypertension, arrhythmia, diabetes mellitus, infection, etc. or any condition such as a psychiatric illness which in the opinion of the investigator would make the patient unacceptable for the protocol Cerebrovascular accident, myocardial infarction or pulmonary embolus within 6 months of randomization Active second malignancy (except non-melanomatous skin cancer): active secondary malignancy is defined as a current need for cancer therapy or a high possibility (> 30%) of recurrence during the study Pregnant or nursing (must have a negative serum or urine pregnancy test within 72 hours prior to randomization) Participating in a concurrent clinical trial of an experimental drug, vaccine or device. Participation in an observational study is allowed

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: OGX-427 600 mg<br>Standard chemotherapy (gemcitabine and cisplatin) in combination with OGX-427 (600 mg) | Drug: OGX-427 600 mg<br>* Patients will receive three loading doses of 600 mg Study Drug within a 9-day period. Following the loading dose period, patients will receive weekly Study Drug infusions (600 mg IV) on Days 1, 8 and 15 of each 21-day cycle.<br>* Other names: apatorsen;Drug: Gemcitabine<br>* Patients will receive gemcitabine (1000 mg/m^2) for up to 6 cycles administered IV on Days 1 and 8 of each 21-day cycle following Study Drug infusion. The Cycle 1, Day 1 administration of chemotherapy must occur within 5 days of the third loading dose of Study Drug.<br>Drug: Cisplatin<br>* Following the administration of gemcitabine on Day 1, cisplatin (70 mg/m^2) will be administered IV for up to 6 cycles. The Cycle 1, Day 1 administration of chemotherapy must occur within 5 days of the third loading dose of Study Drug.<br>Drug: Carboplatin<br>* Following the administration of gemcitabine on Day 1, cisplatin (70 mg/m^2) is to be administered IV for up to 6 cycles; however, carboplatin could be substituted for cisplatin for some unacceptable toxicities. The Cycle 1, Day 1 administration of chemotherapy must occur within 5 days of the third loading dose of Study Drug.<br>|
| Experimental: OGX-427 1000 mg<br>Standard chemotherapy (gemcitabine and cisplatin) in combination with OGX-427 (1000 mg) | Drug: OGX-427 1000 mg<br>* Patients will receive three loading doses of 600 mg Study Drug within a 9-day period. Following the loading dose period, patients will receive weekly Study Drug infusions (1000 mg IV) on Days 1, 8 and 15 of each 21-day cycle.<br>* Other names: apatorsen;Drug: Gemcitabine<br>* Patients will receive gemcitabine (1000 mg/m^2) for up to 6 cycles administered IV on Days 1 and 8 of each 21-day cycle following Study Drug infusion. The Cycle 1, Day 1 administration of chemotherapy must occur within 5 days of the third loading dose of Study Drug.<br>Drug: Cisplatin<br>* Following the administration of gemcitabine on Day 1, cisplatin (70 mg/m^2) will be administered IV for up to 6 cycles. The Cycle 1, Day 1 administration of chemotherapy must occur within 5 days of the third loading dose of Study Drug.<br>Drug: Carboplatin<br>* Following the administration of gemcitabine on Day 1, cisplatin (70 mg/m^2) is to be administered IV for up to 6 cycles; however, carboplatin could be substituted for cisplatin for some unacceptable toxicities. The Cycle 1, Day 1 administration of chemotherapy must occur within 5 days of the third loading dose of Study Drug.<br>|
| Active Comparator: Placebo<br>Standard chemotherapy (gemcitabine and cisplatin) in combination with placebo | Drug: Placebo<br>* Patients will receive three loading doses of placebo within a 9-day period. Following the loading dose period, patients will receive weekly placebo infusions (IV) on Days 1, 8 and 15 of each 21-day cycle.<br>Drug: Gemcitabine<br>* Patients will receive gemcitabine (1000 mg/m^2) for up to 6 cycles administered IV on Days 1 and 8 of each 21-day cycle following Study Drug infusion. The Cycle 1, Day 1 administration of chemotherapy must occur within 5 days of the third loading dose of Study Drug.<br>Drug: Cisplatin<br>* Following the administration of gemcitabine on Day 1, cisplatin (70 mg/m^2) will be administered IV for up to 6 cycles. The Cycle 1, Day 1 administration of chemotherapy must occur within 5 days of the third loading dose of Study Drug.<br>Drug: Carboplatin<br>* Following the administration of gemcitabine on Day 1, cisplatin (70 mg/m^2) is to be administered IV for up to 6 cycles; however, carboplatin could be substituted for cisplatin for some unacceptable toxicities. The Cycle 1, Day 1 administration of chemotherapy must occur within 5 days of the third loading dose of Study Drug.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | OS is defined as the time from randomization to death from any cause; OS was censored on date of last contact for participants still alive at time of analysis. | Baseline to date of death by any cause (up to approximately 12 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-emergent Adverse Events (AEs), Serious AEs, and Grade 3 or Higher AEs | Treatment-emergent AEs are defined as and AE that occurred after the first dose of study drug up to 30 days after the last dose of study drug. AEs were graded using National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Treatment-emergent AEs could have occurred during loading dose period, chemotherapy period, maintenance period, and treatment period A detailed summary of adverse events is located in the Reported Adverse Event Module. | From initiation of study drug to end of study (up to 8 months) | 
| Number of Participants With ≥ 1 Hematology Abnormality and ≥ 1 Grade 3 or Higher Hematology Abnormality |  | Screening through End of Study Visit (Within 30 [±7] days following withdrawal of study treatment) | 
| Number of Participants With ≥ 1 Chemistry Laboratory Abnormality and ≥ 1 Grade 3 or Higher Chemistry Laboratory Abnormality |  | Screening through End of Study Visit (Within 30 [±7] days following withdrawal of study treatment) | 
| Number of Participants With ≥ 1 Urinalysis Abnormality and ≥ 1 Grade 3 or Higher Urinalysis Abnormality |  | Screening through End of Study Visit (Within 30 [±7] days following withdrawal of study treatment) | 
| Best Objective Tumor Response | Complete Response (CR): Complete disappearance of all measurable and non-measurable disease with no new lesions. Any pathological lymph node (target or non-target) must have a reduction in short axis to < 10 mm). All markers of disease must have normalized. Partial Response (PR): A decrease from baseline of ≥ 30% of the diameter(s) of all target measurable lesions with no unequivocal progression of non-measurable lesions and no new lesions. Stable Disease (SD): Does not qualify for CR, PR, or progression. Disease Progression (PD): If at least one of following criteria is met: 1. Appearance of any new lesion or site of disease. 2. A 20% increase in the sum of the diameter(s) of target measurable lesions over either the smallest sum observed or over baseline if no decrease during therapy has occurred. The sum must also demonstrate an absolute increase of at least 5 mm. 3. Unequivocal progression of non-target lesions alone. | Baseline to measured progressive disease (up to approximately 12 months) | 
| Overall Response Rate (ORR) and Disease Control Rate | Participants were defined as having an overall response if their best response is either confirmed CR, confirmed PR, unconfirmed CR or unconfirmed PR. ORR was defined as the percent of participants who had an overall response. Participants were defined as having disease control if their best response is confirmed CR, confirmed PR, unconfirmed CR, unconfirmed PR or SD. The disease control rate (DCR) was defined as the percent of participants with disease control. (See Best Objective Tumor Response Outcome Measure above for response category definitions.) | Baseline to measured progressive disease (up to approximately 12 months) | 
| Duration of Overall Response Rate | Overall response was defined has having a response of Complete Response (CR) or Partial Response (PR). (See Best Objective Tumor Response Outcome Measure above for response category definitions.) Duration of Response is defined as the duration from the first overall response to the first Stable Disease (SD) or Disease Progression (PD), whichever happens first. If no SD or PD, subject is censored at the last tumor assessment (prior to other anti-cancer therapy if applicable). | Baseline to measured progressive disease (up to approximately 12 months) | 
| Progression-free Survival (PFS) | PFS was defined as the time from randomization to the date of disease progression or death, whichever occurred first, before or after treatment discontinuation. For participants still on study and those who remained alive and had not progressed after treatment discontinuation, PFS was censored on the date of the last tumor assessment. | Baseline to measured progressive disease (up to approximately 12 months) | 
| Change From Baseline in Serum Hsp27 levels by End of Treatment | End of Treatment is last non-hemolyzed observation up to last dose + 30 days. Includes unscheduled and additional treatment visits. Hemolyzed samples were excluded. | Baseline, End of Treatment (up to approximately 12 months) | 
| Change From Baseline in Serum Clusterin Levels by End of Treatment | End of Treatment is last observation up to last dose + 30 days. Includes unscheduled and additional treatment visits. | Baseline, End of Treatment (up to approximately 12 months) | 
| Change From Baseline in Circulating Tumor Cell (CTC) Count by End of Treatment | End of Treatment is last observation up to last dose + 30 days. Includes unscheduled and additional treatment visits. | Baseline, End of Treatment (up to approximately 12 months) | 
| Serum OGX-427 Cmax and Trough Levels | only C1 to C6, Ctrough and Cmax - as well report EOT Ctrough | Cycle 1 Day 1 through Cycle 6 Day 1, End of Treatment (up to approximately 12 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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bladder, urinary tract, transitional cell carcinoma, metastatic bladder cancer, chemotherapy