Combination of Ipi/Nivo Plus Sacituzumab Govitecan in Metastatic Cisplatin Ineligible Urothelial Carcinoma Patients

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Metastatic Urothelial Carcinoma
• Intervention / Treatment: Drug: Ipilimumab; Drug: Nivolumab; Drug: Sacituzumab govitecan

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.

• Study Type: Interventional
• Enrollment (Estimated): 46
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Florida
    • Tampa, Florida, United States, 33612
      • Moffitt Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.
• Known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they have stable CNS disease for at least 4 weeks prior to the first dose of study drug and all neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids greater than 20 mg of prednisone daily for brain metastases (or the equivalent) for at least 7 days prior to trial treatment. All participants with carcinomatous meningitis are excluded regardless of clinical stability.
• Active cardiac disease as defined in protocol.
• Active chronic inflammatory bowel disease (ulcerative colitis, Crohn's disease) and participants with a history of bowel obstruction.
• Prior history of clinically significant bleeding, intestinal obstruction, or GI perforation within 6 months of enrollment.
• Must be at least 2 weeks beyond high dose systemic corticosteroids (however, low dose corticosteroids ≤10 mg prednisone or equivalent daily are permitted for reasons outside of CNS disease provided the dose is stable for 4 weeks).
• Active infection requiring systemic treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment. Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or chronic obstructive pulmonary disease exacerbation) are eligible for the study
• Active autoimmune disease requiring systemic treatment with steroids or other immunosuppressive agent or any condition that in the Investigator's judgment precludes treatment with IPI-NIVO
• Received a live vaccine within 30 days prior to the first dose of study drug(s)
• History or evidence of interstitial lung disease (ILD) or non-infectious pneumonitis
• Known history of HIV-1/2 with uncontrolled viral load and on medications that may interfere with SN-38 metabolism.
• Known active Hepatitis B or Hepatitis C (In subjects with a history of HBV, hepatitis B core antibody (HBcAb) testing is required and if positive, then HB DNA testing will be performed and if positive the patient will be excluded).
• Other concurrent medical or psychiatric conditions that, in the Investigator's opinion, may be likely to confound study interpretation or prevent completion of study procedure and follow-up examinations.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: Ipilimumab; Participants will receive Ipilimumab 3 mg/kg; Other Names: Yervoy; Drug: Nivolumab; Participants will receive Nivoumab 1mg/kg; Other Names: Opdivo; Drug: Sacituzumab govitecan; Participants will be treated at 1 of 2 dose levels of Sacituzumab govitecan, either at 8 mg/kg, 10 mg/kg, or 6 mg/kg.; Other Names: Trodelvy
Experimental: 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.	Drug: Ipilimumab; Participants will receive Ipilimumab 3 mg/kg; Other Names: Yervoy; Drug: Nivolumab; Participants will receive Nivoumab 1mg/kg; Other Names: Opdivo; Drug: Sacituzumab govitecan; Participants will be treated at 1 of 2 dose levels of Sacituzumab govitecan, either at 8 mg/kg, 10 mg/kg, or 6 mg/kg.; Other Names: Trodelvy
Experimental: 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	Drug: Ipilimumab; Participants will receive Ipilimumab 3 mg/kg; Other Names: Yervoy; Drug: Nivolumab; Participants will receive Nivoumab 1mg/kg; Other Names: Opdivo; Drug: Sacituzumab govitecan; Participants will be treated at 1 of 2 dose levels of Sacituzumab govitecan, either at 8 mg/kg, 10 mg/kg, or 6 mg/kg.; Other Names: Trodelvy
Experimental: 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.	Drug: Ipilimumab; Participants will receive Ipilimumab 3 mg/kg; Other Names: Yervoy; Drug: Nivolumab; Participants will receive Nivoumab 1mg/kg; Other Names: Opdivo; Drug: Sacituzumab govitecan; Participants will be treated at 1 of 2 dose levels of Sacituzumab govitecan, either at 8 mg/kg, 10 mg/kg, or 6 mg/kg.; Other Names: Trodelvy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 1: Maximum Tolerated Dose	Determine the Maximum Tolerated Dose (MTD)/ Recommended Phase 2 dose (RP2D) of Sacituzumab Govitecan when combined with Ipilimumab and Nivolumab	Up to 12 months
Phase 2: Overall Response Rate	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.	Up to 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 1: Overall Response Rate	Overall Response Rate is defined as the rate of the best overall response as complete response (CR) or partial response (PR)	Up to 12 months
Phase 1: Duration of Response (DOR)	Duration of Response will be calculated as the date of the first evaluation showing documented response, partial response (PR) or complete response (CR), to the date of the first progressive disease (PD) or death.	Up to 12 months
Phase 1: Progression Free Survival (PFS)	Progression Free Survival defined as the time from start of treatment to the first event of death or progressive disease (PD) per RECIST 1.1.	Up to 12 months
Phase 2: Progression Free Survival (PFS)	Progression Free Survival defined as the time from start of treatment to the first event of death or progressive disease (PD) per RECIST 1.1.	Up to 12 months
Phase 2: Duration of Response (DOR)	Duration of Response will be calculated as the date of the first evaluation showing documented response, partial response (PR) or complete response (CR), to the date of the first progressive disease (PD) or death.	Up to 12 months
Phase 2: Overall Survival (OS)	Overall Survival defined as the length of time from start of treatment until death by any cause. Participants will be evaluated using Kaplan- Meier estimation for survival for up to 6 months after discontinuation of study treatment; patients surviving longer than 6 months will be censored.	Up to 12 months

Collaborators and Investigators

• Sponsor: H. Lee Moffitt Cancer Center and Research Institute
• Collaborators: Bristol-Myers Squibb; Gilead Sciences
• Investigators: Principal Investigator: Rohit K Jain, MD, MPH, Moffitt Cancer Center; Principal Investigator: Guru Sonpavde, MD, Dana-Farber Cancer Institute

Publications and helpful links

Helpful Links

• Moffitt Cancer Center Clinical Trials website

Study record dates

Study Major Dates

• Study Start (Actual): April 30, 2021
• Primary Completion (Estimated): October 11, 2024
• Study Completion (Estimated): October 1, 2025

Study Registration Dates

• First Submitted: April 26, 2021
• First Submitted That Met QC Criteria: April 26, 2021
• First Posted (Actual): April 28, 2021

Study Record Updates

• Last Update Posted (Actual): February 13, 2024
• Last Update Submitted That Met QC Criteria: February 12, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Bladder cancer; mUC
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Carcinoma; Carcinoma, Transitional Cell; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Immunoconjugates; Nivolumab; Ipilimumab; Sacituzumab govitecan
• Other Study ID Numbers: MCC-20943; CA209-63Y (Other Identifier: Bristol-Myers Squibb)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No