Phase I/II Study of Ipilimumab Plus Nivolumab (IPI-NIVO) Combined With Sacituzumab Govitecan (SG)as First-line Treatment for Cisplatin-ineligible Metastatic Urothelial Carcinoma
Overview
- Phase
- Phase 1
- Intervention
- Sacituzumab govitecan
- Conditions
- Metastatic Urothelial Carcinoma
- Sponsor
- H. Lee Moffitt Cancer Center and Research Institute
- Enrollment
- 46
- Locations
- 1
- Primary Endpoint
- Phase 1: Maximum Tolerated Dose
- Status
- Active, Not Recruiting
- Last Updated
- 4 months ago
Overview
Brief Summary
The purpose of this study is to see how well the study drugs called Ipilimumab plus Nivolumab (IPI-NIVO) work when added to another study drug called Sacituzumab Govitecan for people who have metastatic bladder cancer.
Detailed Description
The phase I component of this study will evaluate fixed doses of ipilimumab and nivolumab (3 mg/kg and 1 mg/kg, respectively) IV every 3 weeks x 4 cycles combined with a starting dose of sacituzumab govitecan Level 1 of 8 mg/kg IV days 1,8 every 3 weeks (1 cycle) x 4 cycles. One dose escalation to 10 mg/kg and one dose reduction to dose level minus 1 of sacituzumab govitecan 6 mg/kg days 1,8 every 3 weeks is allowed. The phase II component will be conducted as two-stage trial enrolling 34 patients with a futility interim analysis after stage 1 (13 patients). After 4 cycles, patients will continue maintenance nivolumab 360 mg IV every Q 21 days along with RP2 dose of SG D1,8 Q21 days till progression of disease or intolerable toxicities or patient decision. Radiographic imaging is performed every 12 weeks to assess response.
Investigators
Eligibility Criteria
Inclusion Criteria
- •18 years of age or older
- •Able to understand and give written informed consent.
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- •Participants with histologically documented locally advanced or metastatic urothelial carcinoma. Upper and lower tract tumors are permitted and mixed histologies are permitted if urothelial carcinoma is the predominant histology (≥50%).
- •Ineligiblity for cisplatin-based chemotherapy, defined by any of the following: (a) Creatinine clearance (CL) \<60 mL/min. GFR should be calculated from serum/plasma creatinine using the Cockcroft-Gault formula. (b) CTCAE v5.0 Grade \> 1 hearing loss (c) CTCAE v5.0 Grade \> 1 neuropathy (d) NYHA Class \> II cardiac dysfunction
- •Adequate organ function laboratory values as defined per protocol
- •Have measurable disease by CT or MRI as per RECIST 1.1 criteria. Tumor lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
- •Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre- menopausal patients. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply: (a) Women \<50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy). (b) Women ≥50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses \>1 year ago, had chemotherapy-induced menopause with last menses \>1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).
- •Male participants must agree to use an adequate method of contraception starting with the first dose of study therapy through 7 months after the last dose of study therapy. Female participants if sexually active must agree to use dual methods of contraception during the study and for a minimum period of 5 months after the last dose of study drug.
Exclusion Criteria
- •Women who are pregnant or lactating.
- •Currently participating in or has participated in a study of an investigational agent or using an investigational device within 4 weeks prior to the first dose of trial treatment.
- •Prior chemotherapy for metastatic urothelial carcinoma at any time in the patient's medical history.
- •Small-cell carcinoma component
- •Prior chemotherapy for localized urothelial carcinoma completed within 12 months before registration. Has received anti-PD-1/PD-L1 therapy previously, except if used in earlier stage urothelial carcinoma such as non-muscle invasive bladder cancer (NMIBC) or muscle invasive bladder cancer (MIBC) as neoadjuvant or adjuvant therapy and completed \>3 months prior to registration.
- •Prior therapy with sacituzumab govitecan, irinotecan, or any topoisomerase I-containing regimen or antibody-drug conjugate
- •Received radiation therapy for bone metastasis ≤2 weeks, any other radiation therapy within 4 weeks before first dose of study treatment. Systemic treatment with radionuclides within 6 weeks before the first dose of study treatment. Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
- •Requires concomitant medication interfering with ABCA1 transporter or UGT1A1
- •Participants with Gilbert's disease.
- •An active second malignancy. Note: Participants with a history of malignancy that has been completely treated, with no evidence of active cancer for 3 years prior to enrollment, or subjects with surgically cured tumors with low risk of recurrence are allowed to- enroll.
Arms & Interventions
Phase 1 Dose Level -1
If dose reduction is indicated, participants will be treated at dose level -1: Ipilumumab 3mg/kg + Nivolumab 1mg/kg IV day 1 every 3 weeks for 4 cycles, followed by Nivolumab 360 mg every 3 weeks. Sacituzumab Govitecan 6 mg/kg IV will be administered days 1 and 8 every 3 weeks
Intervention: Sacituzumab govitecan
Phase 1 Dose Level 1
Participants will be treated at dose level 1: Ipilumumab 3mg/kg + Nivolumab 1mg/kg IV day 1 every 3 weeks for 4 cycles, followed by Nivolumab 360 mg every 3 weeks. Sacituzumab Govitecan 8 mg/kg IV will be administered days 1 and 8 every 3 weeks.
Intervention: Ipilimumab
Phase 1 Dose Level 1
Participants will be treated at dose level 1: Ipilumumab 3mg/kg + Nivolumab 1mg/kg IV day 1 every 3 weeks for 4 cycles, followed by Nivolumab 360 mg every 3 weeks. Sacituzumab Govitecan 8 mg/kg IV will be administered days 1 and 8 every 3 weeks.
Intervention: Nivolumab
Phase 1 Dose Level 1
Participants will be treated at dose level 1: Ipilumumab 3mg/kg + Nivolumab 1mg/kg IV day 1 every 3 weeks for 4 cycles, followed by Nivolumab 360 mg every 3 weeks. Sacituzumab Govitecan 8 mg/kg IV will be administered days 1 and 8 every 3 weeks.
Intervention: Sacituzumab govitecan
Phase 1 Dose Level 2
Participants will be treated at dose level 2: Ipilumumab 3mg/kg + Nivolumab 1mg/kg IV day 1 every 3 weeks for 4 cycles, followed by Nivolumab 360 mg every 3 weeks. Sacituzumab Govitecan 10 mg/kg IV will be administered days 1 and 8 every 3 weeks.
Intervention: Ipilimumab
Phase 1 Dose Level 2
Participants will be treated at dose level 2: Ipilumumab 3mg/kg + Nivolumab 1mg/kg IV day 1 every 3 weeks for 4 cycles, followed by Nivolumab 360 mg every 3 weeks. Sacituzumab Govitecan 10 mg/kg IV will be administered days 1 and 8 every 3 weeks.
Intervention: Nivolumab
Phase 1 Dose Level 2
Participants will be treated at dose level 2: Ipilumumab 3mg/kg + Nivolumab 1mg/kg IV day 1 every 3 weeks for 4 cycles, followed by Nivolumab 360 mg every 3 weeks. Sacituzumab Govitecan 10 mg/kg IV will be administered days 1 and 8 every 3 weeks.
Intervention: Sacituzumab govitecan
Phase 1 Dose Level -1
If dose reduction is indicated, participants will be treated at dose level -1: Ipilumumab 3mg/kg + Nivolumab 1mg/kg IV day 1 every 3 weeks for 4 cycles, followed by Nivolumab 360 mg every 3 weeks. Sacituzumab Govitecan 6 mg/kg IV will be administered days 1 and 8 every 3 weeks
Intervention: Ipilimumab
Phase 1 Dose Level -1
If dose reduction is indicated, participants will be treated at dose level -1: Ipilumumab 3mg/kg + Nivolumab 1mg/kg IV day 1 every 3 weeks for 4 cycles, followed by Nivolumab 360 mg every 3 weeks. Sacituzumab Govitecan 6 mg/kg IV will be administered days 1 and 8 every 3 weeks
Intervention: Nivolumab
Phase 2: Treatment at Maximum Tolerated Dose (MTD)
Participants will be treated at with Ipilumumab 3mg/kg + Nivolumab 1mg/kg IV day 1 every 3 weeks for 4 cycles, followed by Nivolumab 360 mg every 3 weeks plus the maximum tolerated dose of Sacituzumab Govitecan days 1 and 8 every 3 weeks.
Intervention: Ipilimumab
Phase 2: Treatment at Maximum Tolerated Dose (MTD)
Participants will be treated at with Ipilumumab 3mg/kg + Nivolumab 1mg/kg IV day 1 every 3 weeks for 4 cycles, followed by Nivolumab 360 mg every 3 weeks plus the maximum tolerated dose of Sacituzumab Govitecan days 1 and 8 every 3 weeks.
Intervention: Nivolumab
Phase 2: Treatment at Maximum Tolerated Dose (MTD)
Participants will be treated at with Ipilumumab 3mg/kg + Nivolumab 1mg/kg IV day 1 every 3 weeks for 4 cycles, followed by Nivolumab 360 mg every 3 weeks plus the maximum tolerated dose of Sacituzumab Govitecan days 1 and 8 every 3 weeks.
Intervention: Sacituzumab govitecan
Outcomes
Primary Outcomes
Phase 1: Maximum Tolerated Dose
Time Frame: Up to 12 months
Determine the Maximum Tolerated Dose (MTD)/ Recommended Phase 2 dose (RP2D) of Sacituzumab Govitecan when combined with Ipilimumab and Nivolumab
Phase 2: Overall Response Rate
Time Frame: Up to 30 months
Overall Response Rate (ORR) of Sacituzumab Govitecan with Ipilimumab and Nivolumab combination. ORR is defined as the rate of the best overall response as complete response (CR) or partial response (CR). OR will be summarized by the percentage of responses with a 95% confidence interval as calculated from Clopper-Pearson method.
Secondary Outcomes
- Phase 1: Overall Response Rate(Up to 12 months)
- Phase 1: Duration of Response (DOR)(Up to 12 months)
- Phase 1: Progression Free Survival (PFS)(Up to 12 months)
- Phase 2: Progression Free Survival (PFS)(Up to 30 months)
- Phase 2: Duration of Response (DOR)(Up to 30 months)
- Phase 2: Overall Survival (OS)(Up to 30 months)