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.
- 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
- 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
- Prior chemotherapy for metastatic urothelial carcinoma at any time in the patient's
- 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
- 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.