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

Phase 2

Completed

• Conditions: Urologic Neoplasms; Metastatic Bladder Cancer; Urinary Tract Neoplasms
• Interventions: Drug: OGX-427 600 mg; Drug: OGX-427 1000 mg; Drug: Placebo; Drug: Gemcitabine; Drug: Cisplatin; Drug: Carboplatin

• Registration Number: NCT01454089
• Lead Sponsor: Achieve Life Sciences

Brief Summary

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

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 All participants have an End of Treatment (EOT) visit when they are withdrawn from all study treatment (chemotherapy and maintenance).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.

Study Timeline

• Study Start: 2011-10
• Study First Submitted: 2011-10-05
• Study First Submitted QC: 2011-10-13
• Study First Posted: 2011-10-18
• Primary Completion: 2014-11
• Study Completion: 2014-11
• Disposition First Submitted: 2015-10-22
• Disposition First Submitted QC: 2015-10-22
• Disposition First Posted: 2015-11-16
• Status Verified: 2016-10
• Last Update Submitted: 2016-10-06
• Last Update Posted: 2016-10-07

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 183

Inclusion Criteria

1. Age ≥ 18 years at the time of consent

2. 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

3. 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

4. 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

5. Minimum of 21 days since prior major surgery or radiation therapy

6. Karnofsky performance status ≥ 70%

7. 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

8. If of child-bearing potential, willing to use contraceptives

9. Willing to give written informed consent

Exclusion Criteria

1. A candidate for potential curative surgery or radiotherapy
2. Intravesical therapy within the last 3 months
3. 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.
4. Peripheral neuropathy ≥ Grade 2
5. Known serious hypersensitivity to gemcitabine, cisplatin or carboplatin
6. 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
7. Cerebrovascular accident, myocardial infarction or pulmonary embolus within 6 months of randomization
8. 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
9. Pregnant or nursing (must have a negative serum or urine pregnancy test within 72 hours prior to randomization)
10. Participating in a concurrent clinical trial of an experimental drug, vaccine or device. Participation in an observational study is allowed

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
OGX-427 600 mg	OGX-427 600 mg	Standard chemotherapy (gemcitabine and cisplatin) in combination with OGX-427 (600 mg)
OGX-427 1000 mg	OGX-427 1000 mg	Standard chemotherapy (gemcitabine and cisplatin) in combination with OGX-427 (1000 mg)
Placebo	Placebo	Standard chemotherapy (gemcitabine and cisplatin) in combination with placebo
OGX-427 600 mg	Cisplatin	Standard chemotherapy (gemcitabine and cisplatin) in combination with OGX-427 (600 mg)
OGX-427 600 mg	Carboplatin	Standard chemotherapy (gemcitabine and cisplatin) in combination with OGX-427 (600 mg)
OGX-427 600 mg	Gemcitabine	Standard chemotherapy (gemcitabine and cisplatin) in combination with OGX-427 (600 mg)
OGX-427 1000 mg	Gemcitabine	Standard chemotherapy (gemcitabine and cisplatin) in combination with OGX-427 (1000 mg)
OGX-427 1000 mg	Carboplatin	Standard chemotherapy (gemcitabine and cisplatin) in combination with OGX-427 (1000 mg)
OGX-427 1000 mg	Cisplatin	Standard chemotherapy (gemcitabine and cisplatin) in combination with OGX-427 (1000 mg)
Placebo	Gemcitabine	Standard chemotherapy (gemcitabine and cisplatin) in combination with placebo
Placebo	Cisplatin	Standard chemotherapy (gemcitabine and cisplatin) in combination with placebo
Placebo	Carboplatin	Standard chemotherapy (gemcitabine and cisplatin) in combination with placebo

Primary Outcome Measures

Name	Time	Method
Overall Survival (OS)	Baseline to date of death by any cause (up to approximately 12 months)	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.

Secondary Outcome Measures

Name	Time	Method
Number of Participants With Treatment-emergent Adverse Events (AEs), Serious AEs, and Grade 3 or Higher AEs	From initiation of study drug to end of study (up to 8 months)	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.
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	Baseline to measured progressive disease (up to approximately 12 months)	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.
Overall Response Rate (ORR) and Disease Control Rate	Baseline to measured progressive disease (up to approximately 12 months)	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.)
Duration of Overall Response Rate	Baseline to measured progressive disease (up to approximately 12 months)	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).
Progression-free Survival (PFS)	Baseline to measured progressive disease (up to approximately 12 months)	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.
Change From Baseline in Serum Hsp27 levels by End of Treatment	Baseline, End of Treatment (up to approximately 12 months)	End of Treatment is last non-hemolyzed observation up to last dose + 30 days. Includes unscheduled and additional treatment visits. Hemolyzed samples were excluded.
Change From Baseline in Serum Clusterin Levels by End of Treatment	Baseline, End of Treatment (up to approximately 12 months)	End of Treatment is last observation up to last dose + 30 days. Includes unscheduled and additional treatment visits.
Change From Baseline in Circulating Tumor Cell (CTC) Count by End of Treatment	Baseline, End of Treatment (up to approximately 12 months)	End of Treatment is last observation up to last dose + 30 days. Includes unscheduled and additional treatment visits.
Serum OGX-427 Cmax and Trough Levels	Cycle 1 Day 1 through Cycle 6 Day 1, End of Treatment (up to approximately 12 months)	only C1 to C6, Ctrough and Cmax - as well report EOT Ctrough

Trial Locations

Locations (55)

Seattle Cancer Care Alliance; 🇺🇸 Seattle, Washington, United States

Montefiore Medical Center, Albert Einstein College of Medicine; 🇺🇸 Bronx, New York, United States

Columbia University Medical Center; 🇺🇸 New York, New York, United States

British Columbia Cancer Agency; 🇨🇦 Vancouver, British Columbia, Canada

Institute Jean Godinot; 🇫🇷 Reims, Champagne-Ardenne, France

CHUM-Hospital Notre Dame; 🇨🇦 Montreal, Quebec, Canada

Centre Hospitalier Régional et Universitaire - Hôpital; 🇫🇷 Bretonneau Tours, Centre, France

R. S. McLaughlin Durham Regional Cancer Center at Lakeridge Health; 🇨🇦 Oshawa, Ontario, Canada

Siteman Cancer Center, Washington University School of Medicine; 🇺🇸 St. Louis, Missouri, United States

Princess Margaret Hospital; 🇨🇦 Toronto, Ontario, Canada

Centre Hospitalier Universitaire de Rouen; 🇫🇷 Rouen, Haute-Normandie, France

Centre Hospitalier Universitaire, Institut Gustave Roussy; 🇫🇷 Villejuif Cedex, Ile-de-france, France

Centre Paul Papin; 🇫🇷 Angers Cedex 9, Pays De La Loire, France

Institut Paoli Calmettes; 🇫🇷 Marseille Cedex 9, Provence Alpes Cote D'Azur, France

Centre Antoine Lacassagne; 🇫🇷 Nice, Provence Alpes Cote d'Azur, France

Universitätsklinikum Heidelberg; 🇩🇪 Heidelberg, Baden-Wuerttemberg, Germany

Klinikum Rechts der Isar der Technischen Universität; 🇩🇪 München, Bayern, Germany

Johann-Wolfgang-Goethe-Universität Frankfurt; 🇩🇪 Frankfurt, Hessen, Germany

Medizinische Hochschule Hannover; 🇩🇪 Hannover, Niedeersachen, Germany

Hospital Clinic I Provincial de Barcelona; 🇪🇸 Barcelona, Spain

Universitätsklinikum des Saarlandes; 🇩🇪 Homburg, Saarland, Germany

Centrum Onkologii im. Prof. Franciszka Lukaszczyka w Bydgoszczy; 🇵🇱 Bydgoszcz, Kujawsko-Pomorskie, Poland

Centrum Onkologii Instytut im. M. Sklodowskiej-Curie; 🇵🇱 Warszawa, Mazowieckie, Poland

Akademicki Szpital Kliniczny im. J. Mikulicza-Radeckiego we Wroclawiu; 🇵🇱 Wroclaw, Dolnoslaskie, Poland

Uniwersyteckie Centrum Kliniczne; 🇵🇱 Gdansk, Pomorskie, Poland

Zaklad Opieki Zdrowotnej MSWiA z Warminsko-Mazurskim Centrum Onkologii w Olsztynie; 🇵🇱 Olsztyn, Warminski-Mazurskie, Poland

Urology Cancer Center and GU Research Network; 🇺🇸 Omaha, Nebraska, United States

Tom Baker Cancer Center; 🇨🇦 Calgary, Alberta, Canada

Unità Operativa di Oncologia Medica; 🇮🇹 Roma, Italy

Karmanos Cancer Institute; 🇺🇸 Detroit, Michigan, United States

Radiological Associates of Sacramento; 🇺🇸 Sacramento, California, United States

USC Norris Comprehensive Cancer Center; 🇺🇸 Los Angeles, California, United States

Yale University; 🇺🇸 New Haven, Connecticut, United States

Monter Cancer Center; 🇺🇸 Lake Success, New York, United States

Juravinski Cancer Centre; 🇨🇦 Hamilton, Ontario, Canada

Universitätsklinikum Jena; 🇩🇪 Jena, Thuringen, Germany

Medicale Centre René Gauducheau; 🇫🇷 St. Herblain Cedex, Pays de la Loire, France

Azienda Ospedaliero-Universitaria Policlinico di Modena; 🇮🇹 Modena, Italy

Institut Català D'Oncologia, Hospital Duran i Reynals; 🇪🇸 Madrid, Spain

Fondazione IRCCS Policlinico San Matteo Pavia; 🇮🇹 Pavia, Italy

NZOZ Europejskie Centrum Zdrowia Otwock; 🇵🇱 Otwock, Mazowieckie, Poland

Hospital del Mar; 🇪🇸 Barcelona, Spain

Universitätsklinikum Mainz; 🇩🇪 Mainz, Germany

Universitätsklinikum Magdeburg A.ö.R.; 🇩🇪 Magdeburg, Sachsen-Anhalt, Germany

Universitätsklinikum Dresden; 🇩🇪 Dresden, Sachsen, Germany

Hospital Santa Creu i Sant Pau; 🇪🇸 Barcelona, Spain

Hospital General Universitario Gregorio Marañon; 🇪🇸 Madrid, Spain

Hospital Universitario 12 de Octubre; 🇪🇸 Madrid, Spain

Hospital Vall d´Hebrón; 🇪🇸 Barcelona, Spain

Instituto Valenciano de Oncología-Fundación (IVO-FINCIVO); 🇪🇸 Valencia, Spain

City of Hope National Medical Center; 🇺🇸 Duarte, California, United States

Texas Oncology, P.A.; 🇺🇸 Dallas, Texas, United States

University of California Los Angeles; 🇺🇸 Los Angeles, California, United States

Cedars-Sinai Medical Center; 🇺🇸 Los Angeles, California, United States

Cross Cancer Center; 🇨🇦 Edmonton, Alberta, Canada