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

Primary Purpose

Metastatic Urothelial Carcinoma

Status
Recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Ipilimumab
Nivolumab
Sacituzumab govitecan
Sponsored by
H. Lee Moffitt Cancer Center and Research Institute
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Metastatic Urothelial Carcinoma focused on measuring mUC, Bladder cancer

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Moffitt Cancer CenterRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Experimental

Experimental

Experimental

Arm Label

Phase 1 Dose Level 1

Phase 1 Dose Level 2

Phase 1 Dose Level -1

Phase 2: Treatment at Maximum Tolerated Dose (MTD)

Arm Description

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.

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.

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

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.

Outcomes

Primary Outcome Measures

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
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.

Secondary Outcome Measures

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)
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.
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.
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.
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.
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.

Full Information

First Posted
April 26, 2021
Last Updated
June 30, 2023
Sponsor
H. Lee Moffitt Cancer Center and Research Institute
Collaborators
Bristol-Myers Squibb, Gilead Sciences
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1. Study Identification

Unique Protocol Identification Number
NCT04863885
Brief Title
Combination of Ipi/Nivo Plus Sacituzumab Govitecan in Metastatic Cisplatin Ineligible Urothelial Carcinoma Patients
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
June 2023
Overall Recruitment Status
Recruiting
Study Start Date
April 30, 2021 (Actual)
Primary Completion Date
April 2024 (Anticipated)
Study Completion Date
April 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
H. Lee Moffitt Cancer Center and Research Institute
Collaborators
Bristol-Myers Squibb, Gilead Sciences

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Metastatic Urothelial Carcinoma
Keywords
mUC, Bladder cancer

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Sequential Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
46 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Phase 1 Dose Level 1
Arm Type
Experimental
Arm Description
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.
Arm Title
Phase 1 Dose Level 2
Arm Type
Experimental
Arm Description
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.
Arm Title
Phase 1 Dose Level -1
Arm Type
Experimental
Arm Description
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
Arm Title
Phase 2: Treatment at Maximum Tolerated Dose (MTD)
Arm Type
Experimental
Arm Description
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 Type
Drug
Intervention Name(s)
Ipilimumab
Other Intervention Name(s)
Yervoy
Intervention Description
Participants will receive Ipilimumab 3 mg/kg
Intervention Type
Drug
Intervention Name(s)
Nivolumab
Other Intervention Name(s)
Opdivo
Intervention Description
Participants will receive Nivoumab 1mg/kg
Intervention Type
Drug
Intervention Name(s)
Sacituzumab govitecan
Other Intervention Name(s)
Trodelvy
Intervention Description
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.
Primary Outcome Measure Information:
Title
Phase 1: Maximum Tolerated Dose
Description
Determine the Maximum Tolerated Dose (MTD)/ Recommended Phase 2 dose (RP2D) of Sacituzumab Govitecan when combined with Ipilimumab and Nivolumab
Time Frame
Up to 12 months
Title
Phase 2: Overall Response Rate
Description
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.
Time Frame
Up to 12 months
Secondary Outcome Measure Information:
Title
Phase 1: Overall Response Rate
Description
Overall Response Rate is defined as the rate of the best overall response as complete response (CR) or partial response (PR)
Time Frame
Up to 12 months
Title
Phase 1: Duration of Response (DOR)
Description
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.
Time Frame
Up to 12 months
Title
Phase 1: Progression Free Survival (PFS)
Description
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.
Time Frame
Up to 12 months
Title
Phase 2: Progression Free Survival (PFS)
Description
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.
Time Frame
Up to 12 months
Title
Phase 2: Duration of Response (DOR)
Description
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.
Time Frame
Up to 12 months
Title
Phase 2: Overall Survival (OS)
Description
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.
Time Frame
Up to 12 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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. 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Rohit K Jain, MD, MPH
Organizational Affiliation
Moffitt Cancer Center
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Guru Sonpavde, MD
Organizational Affiliation
Dana-Farber Cancer Institute
Official's Role
Principal Investigator
Facility Information:
Facility Name
Moffitt Cancer Center
City
Tampa
State/Province
Florida
ZIP/Postal Code
33612
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Trey Poehlman
Phone
813-745-0118
Email
Trey.Poehlman@moffitt.org
First Name & Middle Initial & Last Name & Degree
Rohit K Jain, MD, MPH

12. IPD Sharing Statement

Links:
URL
https://moffitt.org/clinical-trials-research/clinical-trials/?source=footer
Description
Moffitt Cancer Center Clinical Trials website

Learn more about this trial

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

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