A Study of Intravesical Apaziquone as a Surgical Adjuvant in Participant Undergoing Transurethral Resection Bladder Tumor (TURBT)

A Multicenter, Multi-Arm, Randomized, Multi-Dose, Placebo-Controlled, Double-Blind, Phase 3 Study of Intravesical Apaziquone (EOquin®) as a Surgical Adjuvant in the Immediate Postoperative Period in Patients Undergoing Transurethral Resection for Non- Muscle Invasive Bladder Cancer

This is a Phase 3, randomized, multicenter, multi-arm, placebo-controlled, double-blind study of apaziquone in participants with ≤4 non-muscle invasive bladder cancer (NMIBC), ≤3.5 centimeters (cm) in diameter, all of which must had been fully resected at TURBT.

In addition to Screening, participants underwent an assessment of urothelial carcinoma of the bladder via cystoscopy for clinically apparent tumor Ta, G1-G2.

Following TURBT on Day 1, eligible participants were randomized to one of three treatment arms in a 1:1:1 ratio.

Arm 1 : One dose of Apaziquone. Arm 2 : Two Doses of Apaziquone. Arm 3 : Placebo. Primary endpoint was to evaluate the Time to Recurrence with either a one instillation of 4 mg apaziquone or two instillations of 4 milligram (mg) apaziquone relative to placebo instillation following TURBT in a participant with NMIBC who received TURBT.

This is a Phase 3, randomized, multicenter, multi-arm, placebo-controlled, double-blind study of apaziquone in participants with ≤4 non-muscle invasive bladder tumors, ≤3.5 cm in diameter, all of which must have been fully resected at TURBT.

In addition to Screening, participants underwent an assessment of urothelial carcinoma of the bladder via cystoscopy for clinically apparent tumor Ta, G1-G2.

Following TURBT on Day 1, eligible participants were randomized to one of three treatment arms in a 1:1:1 ratio :

Arm 1 : One Dose of Apaziquone:

• Day 1: administration of 4 mg of apaziquone 60±30 minutes post-TURBT
• Day 15 (±5 days): administration of placebo

Arm 2 : Two Doses of Apaziquone :

• Day 1: administration of 4 mg of apaziquone 60±30 minutes post-TURBT
• Day 15 (±5 days): administration of 4 mg of apaziquone

Arm 3: Placebo :

• Day 1 : administration of placebo 60±30 minutes post-TURBT
• Day 15 (±5 days) : administration of placebo

Once randomized, Day 1 study drug instillation occurred 60 ±30 minutes post TURBT. Participants returned on Day 15 (±5 days) for a second instillation unless their pathology results showed non Ta, G1-G2 histology; in the absence of local pathology results by the Day 15 visit, participants received a second instillation of study drug. All histology specimens were reviewed by a local pathology laboratory and all clinical treatment decisions and study analyses were based on the local pathology review. Participants whose pathology was other than Ta, G1-G2 were followed for safety at Day 35 (±5 days) from the last dose of study drug and then discontinued from the study.

Participants with pathology confirmed Ta, G1-G2 disease were followed according to the schedule below :

• Cystoscopic examination and urine cytology every 90 days (±10 days) (calculated from date of TURBT) through 24 months for tumor recurrence and progression.
• If at any time during the 24 months follow up period there was a tumor recurrence, the participant continued on study with follow-up cystoscopic examination and urine cytology every 90 days (±10 days) (calculated from date of TURBT) through the end of 24 months. Participants with a recurrence were permitted to have a follow-up TURBT.
• If at any time during the 24 months follow up period there was a tumor recurrence and/or participant started on another therapy, the participant was followed by telephone, for safety every 90 days (±10 days) (calculated from date of TURBT) through the end of 24 months.

Duration of Study: The duration of the study for each participant was approximately 24 months including:

• Screening Period : 30-days
• Treatment Period : Day 1 and Day 15 (±5 days)
• Safety and Follow-up Period: 24-months

1. Participant must have had a diagnosis with urothelial carcinoma of the bladder with clinically apparent tumor Ta, G1-G2.
2. Participant had ≤4 tumors, none of which exceeded 3.5 cm in diameter.
3. Participant must have been willing to give written informed consent, able to adhere to dosing and visit schedules, and meet all study requirements.
4. Participant was at least 18 years of age at randomization.
5. Participant must have been willing to practice two forms of contraception, one of which must have been a barrier method, from study entry until at least 35 days after the last dose of the study drug.
6. Female participant of childbearing potential must have had a negative pregnancy test within 30 days prior to randomization. Female participant who was postmenopausal for at least 1 year (defined as more than 12 months since last menses) or were surgically sterilized did not require this test.

Exclusion Criteria:

1. Participant had an active concurrent malignancy/life-threatening disease. If there was a history of prior malignancies/life-threatening diseases, the participant was to be disease-free for at least 5 years. Participant with other prior malignancies less than 5 years before study entry could have still been enrolled if they had received treatment resulting in complete resolution of the cancer and currently had no clinical, radiologic, or laboratory evidence of active or recurrent disease.

2. Participant had positive urine cytology for malignancy at Screening.

3. Participant had an active uncontrolled infection, including a urinary tract infection, underlying medical condition, or other serious illness that would impair the ability of the participant to receive protocol treatment.

4. Participant had used any investigational drugs, biologics, or devices within 30 days prior to study treatment or planned to use any of these during the course of the study.

5. Participant had any prior intravesical chemotherapy, immunotherapy, or previous exposure to apaziquone.

6. Participant had or has ever had

   • Upper tract Transitional Cell Carcinoma (TCC).
   • Urethral tumor (prostatic urethra included).
   • Any invasive bladder tumor known to be other than tumor Ta, G1-G2.
   • Any evidence of lymph node or distant metastasis.
   • Any bladder tumor with histology other than TCC.
   • Carcinoma in situ (CIS).

7. Participant had a tumor in a bladder diverticulum.

8. Participant had received any pelvic radiotherapy (including external beam and/or brachytherapy.)

9. Participant had a bleeding disorder or a screening platelet count <100×10^9/L.

10. Participant had screening hemoglobin <10 milligrams per deciliter (mg/dL).

11. Participant had any unstable medical condition that would make it unsafe to undergo TURBT.

12. Participant had a history of interstitial cystitis.

13. Participant had a history of allergy to red color food dye.

14. For a participant with a recurrent tumor, the participant had at least a 6-month cystoscopically-confirmed tumor-free interval between the last tumor recurrence and screening cystoscopic examination.

15. Participant was pregnant or breast-feeding.