Sacituzumab Govitecan With or Without Atezolizumab Immunotherapy in Rare Genitourinary Tumors (SMART) Such as Small Cell, Adenocarcinoma, and Squamous Cell Bladder/Urinary Tract Cancer, Renal Medullary Carcinoma and Penile Cancer

A Phase II Study of Sacituzumab Govitecan With or Without Atezolizumab Immunotherapy in Rare Genitourinary Tumors (SMART) Such as Small Cell, Adenocarcinoma, and Squamous Cell Bladder/Urinary Tract Cancer, Renal Medullary Carcinoma and Penile Cancer

Background:

Rare tumors of the genitourinary (GU) tract can appear in the kidney, bladder, ureters, and penis. Rare tumors are difficult to study because there are not enough people to conduct large trials for new treatments. Two drugs-sacituzumab govitecan (SG) and atezolizumab-are each approved to treat other cancers. Researchers want to find out if the two drugs used together can help people with GU.

Objective:

To test SG, either alone or combined with atezolizumab, in people with rare GU tumors.

Eligibility:

Adults aged 18 years and older with rare GU tumors. These may include small cell carcinoma of the bladder; squamous cell carcinoma of the bladder; primary adenocarcinoma of the bladder; renal medullary carcinoma; or squamous cell carcinoma of the penis.

Design:

Participants will be screened. They will have a physical exam with blood and urine tests. They will have tests of heart function. They will have imaging scans. They may need a biopsy: A small needle will be used to remove a sample of tissue from the tumor.

Both SG and atezolizumab are given through a tube attached to a needle inserted into a vein in the arm.

All participants will receive SG on days 1 and 8 of each 21-day treatment cycle. Some participants will also receive atezolizumab on day 1 of each cycle.

Blood and urine tests, imaging scans, and other exams will be repeated during study visits.

Treatment may continue for up to 5 years.

Follow-up visits will continue for 5 more years.

Study Overview

• Status: Not yet recruiting
• Conditions: Squamous Cell Carcinoma of the Penis; Renal Medullary Carcinoma; Squamous Cell Carcinoma of the Bladder; Small Cell Carcinoma of the Bladder; Small Cell Carcinoma of the Urinary Tract; Squamous Cell Carcinoma of the Urinary Tract; Primary Adenocarcinoma of the Bladder; Primary Adenocarcinoma of the Urinary Tract
• Intervention / Treatment: Drug: Sacituzumab govitecan; Drug: Atezolizumab

Detailed Description

Background:

• Urothelial carcinoma (UC) represents the most common histology for tumors of the bladder and urinary tract.
• A minority of patients have primary tumors of the bladder/urinary tract consisting of rare histological variants, including small cell carcinoma, primary adenocarcinoma of the bladder (urachal or non-urachal), or squamous cell carcinoma. Some tumors may contain elements of UC mixed with these variants or may be entirely composed of such variants.
• Clear cell renal cell carcinoma (ccRCC) is the most common histology for cancers of the renal parenchyma. Renal medullary carcinoma is a rare histology of kidney cancer, which is associated with sickle cell trait and other hemoglobinopathies.
• Rare tumors of the genitourinary (GU) tract often have more aggressive clinical course, but lack standard of care treatment regimens, since these patient populations are poorly represented or excluded from most clinical trials.
• Sacituzumab govitecan (SG) is an antibody-drug conjugate of an IgG 1 monoclonal antibody targeting trophoblastic cell surface antigen 2 (Trop2) with a chemotherapeutic payload of SN-38. SN-38 is an active metabolite of irinotecan and acts as a topoisomerase I inhibitor.
• SG has demonstrated clinical activity in solid tumors. In phase II clinical trials, SG has demonstrated efficacy in metastatic UC after progression on platinum-based chemotherapy and immune checkpoint inhibitor (ICI) therapy.
• Atezolizumab is an anti- programmed death-ligand 1 (PD-L1) ICI that is approved for advanced/metastatic UC in patients ineligible to receive platinum therapy.
• There are currently no clinical trials for SG monotherapy or SG/atezolizumab combination in rare GU tumors.

Objective:

-To determine clinical efficacy of sacituzumab govitecan (SG), either alone or in combination with atezolizumab, as defined by objective response rate (ORR), in participants with rare metastatic non-prostate genitourinary tumors

Eligibility:

• Age >= 18 years
• ECOG performance status <= 1
• Histologically confirmed diagnosis of locally advanced (unresectable) or metastatic GU tumors of the following histologies: small cell carcinoma, squamous cell carcinoma, or primary adenocarcinoma of the bladder or urinary tract; or renal medullary carcinoma or squamous cell carcinoma of the penis.
• Participants must have locally advanced unresectable or metastatic disease on cross-sectional imaging.
• Participants may have received any prior programmed cell death protein 1 (PD-1)/PD-L1 axis ICI treatment.

Design:

• This is an open label, non-randomized phase II trial with two arms.
• All participants will receive SG.
• Participants without prior treatment with any PD-1/PD-L1 axis ICI (checkpoint inhibitor na(SqrRoot) ve) will be eligible to receive concurrent atezolizumab.
• SG will be administered intravenously (IV) at 10 mg/kg on D1 and D8 of 21-day cycles.
• Atezolizumab will be administered IV at 1200mg on D1 of 21-day cycles.
• Treatment will be given in 21-day cycles continuously for a maximum of 5 years, or until signs of progression or intolerable side effects.
• The accrual ceiling will be set at 60 to allow for inevaluable participants and screen failure.

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Lisa Ley, R.N.; Phone Number: (240) 858-3524; Email: lisa.ley@nih.gov
• Study Contact Backup: Name: Andrea B Apolo, M.D.; Phone Number: (301) 480-0536; Email: apoloab@mail.nih.gov

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center
      • Contact: Lisa Ley; Phone Number: 240-858-3524; Email: lisa.ley@nih.gov

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

• INCLUSION CRITERIA:

• Participants must have histologically confirmed diagnosis of a locally advanced unresectable or metastatic non-prostate genitourinary (GU) tumor of the following histologies:

  • Small cell carcinoma of the bladder or urinary tract
  • Squamous cell carcinoma of the bladder or urinary tract
  • Primary adenocarcinoma of the bladder or urinary tract (urachal or non-urachal)
  • Renal medullary carcinoma
  • Squamous cell carcinoma of the penis

Note: For the purposes of enrollment, the urinary tract is defined as the renal pelvis, ureter, bladder, and urethra.

• Pre-study treatment tissue availability (sufficient tissue for approximately 25 unstained slides is mandatory for enrollment. If tissue is determined to be insufficient/unsuitable, a fresh biopsy prior to study therapy will be required.
• Locally advanced unresectable or metastatic disease. Participants who have received prior treatment must have evidence of progressive disease (i.e., defined as new or progressive lesions evident on cross-sectional imaging).
• Participants must have measurable disease, per RECIST 1.1.
• Age >= 18 years.
• Eastern Cooperative Oncology Group (ECOG) performance status <= 1 (Karnofsky >= 70%.

• Participants must have adequate organ and marrow function as defined below:

  • Hemoglobin (Hgb) >= 9.0 g/dL
  • Absolute neutrophil count (ANC) >= 1,500/mcL
  • Platelets >= 100,000/mcL
  • Total bilirubin <= 1.5 x upper limit of normal (ULN) (<= 3 x ULN in participants with known/suspected Gilbert s disease)
  • AST (SGOT) / ALT (SGPT) <= 2.5 x ULN (or <= 5 x ULN if considered to be related to liver metastases by the PI)
  • Serum creatinine <= 2 x ULN or creatinine clearance >= 30 ml/min/1.73 m^2 (glomerular filtration rate [GFR] may be used in place of CrCl. Creatinine clearance or eGFR should be calculated per institutional standard)
  • Alkaline phosphatase <= 2.5 x ULN (or <= 5 x ULN if considered to be related to liver or bone metastases by the PI)
  • Serum albumin >= 25g/L
  • For participants not receiving therapeutic anticoagulation: INR or aPTT <= 1.5 x ULN
  • For participants receiving therapeutic anticoagulation: stable anticoagulant regimen
• Participants may have received any number of prior anti-cancer treatments or be treatment na(SqrRoot) ve (except for participants with small cell carcinoma of the bladder/urinary tract cancer, whom must have received a platinum-based combination regimen either as neoadjuvant, adjuvant or first-line treatment in the locally advanced/metastatic setting).

• Participants with treated central nervous system (CNS) lesions, provided that all of the following criteria are met:

  • Measurable disease, per RECIST v1.1, must be present outside the CNS.
  • The participant has no history of intracranial hemorrhage or spinal cord hemorrhage.
  • The participant has not undergone stereotactic radiotherapy within 1 week prior to initiation of study treatment, whole-brain radiotherapy (WBXRT) within 2 weeks prior to initiation of study treatment, or neurosurgical resection within 4 weeks prior to initiation of study treatment.
  • The participant has no ongoing requirement for corticosteroids as therapy for CNS disease.
  • The participant may be receiving anti-convulsant therapy if appropriate and the dose is considered stable.
• Participants with prior radionuclide treatment must have a washout period of at least 6 weeks prior to the first dose of study treatment.
• Participants with prior treatment with chemotherapy must have a washout period of 2 weeks prior to the first dose of study treatment.
• Participants with prior treatment with non-CNS-directed radiotherapy must have a washout period of 2 weeks prior to the first dose of study treatment (except palliative bone-directed radiotherapy which does not require any washout).
• Participants with prior treatment with a small molecule kinase inhibitor must have a washout period of at least 2 weeks or five half-lives of the compound or active metabolites, prior to the first dose of study treatment.
• Treatment with systemic immunostimulatory agents (including, but not limited to, interferon and interleukin 2 [IL-2]) must have a washout period of at least 4 weeks or 5 half-lives of the drug (whichever is longer) prior to the first dose of study treatment.
• Major surgical procedure, other than for diagnosis, must not occur within 4 weeks prior to the first dose of study treatment.

• Treatment with systemic immunosuppressive medication (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-TNF-alpha agents) must have a washout period of at least 2 weeks prior to initiation of study treatment or anticipation of need for systemic immunosuppressive medication during study treatment, with the following exceptions:

  • Participants who received acute, low-dose systemic immunosuppressant medication or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids for a contrast allergy) are eligible for the study.
  • Participants who received mineralocorticoids (e.g., fludrocortisone), corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible for the study.
• FDA-approved hormonal therapy for the treatment or prevention of other malignancies (e.g., breast cancer, prostate cancer) are allowed to be continued where in the opinion of the treating investigator stopping such therapies may increase the risk of disease progression. Potential drug-drug interactions with the hormonal agent will be assessed by the treating investigator prior to enrollment and hormonal agents that inhibit or induce UGT1A1 will be excluded while on trial.
• Human immunodeficiency virus (HIV)-infected participants are eligible if on stable dose of highly active antiretroviral therapy (HAART), a CD4 count >= 200 cells/microL, and an undetectable viral load.
• Hepatitis B virus (HBV) positive participants are eligible if they have been treated or are on an appropriate course of antivirals at study entry and with planned monitoring and management according to appropriate guidance. For previously treated patients or those with prior infection that has been cleared, prophylaxis is permitted, and hepatology consultation recommended.
• Participants with a history of hepatitis C virus (HCV) infection (i.e., positive HCV antibody test) must have been treated and cured (negative HCV RNA test at screening).

Participants with HCV infection who are currently on treatment are eligible if they have an undetectable HCV viral load.

• Women of child-bearing potential (WOCBP) must agree to use one (1) highly effective methods of contraception (e.g., intrauterine device [IUD], hormonal, surgical sterilization) prior to study entry, for the duration of study participation, and for up to 6 months after discontinuation of the study drug(s). Women must refrain from donating eggs during this same period.
• Men must agree to use an effective method of contraception (barrier, surgical sterilization) for the duration of the study treatment and up to 6 months after the last dose of the study drug(s) and must refrain from donating sperm during this same period.
• Breastfeeding participants must discontinue breastfeeding and/or not begin breastfeeding until 1 month after the last dose of study drug(s).
• Ability of participants to understand and the willingness to sign a written informed consent document.

EXCLUSION CRITERIA:

• History of severe hypersensitivity or allergic reactions attributed to compounds of similar chemical or biologic composition to SG, SN-38, irinotecan, or atezolizumab, or hypersensitivity to Chinese hamster ovary cell products.
• Symptomatic or untreated brain/CNS metastases.
• Pregnant women as evaluated by a positive serum or urine Beta-human chorionic gonadotropin (Beta-hCG) test at screening.
• Participants unwilling to accept blood products as medically indicated.

• Active or history of autoimmune disease or immune deficiency that might recur, which might affect vital organ function or require immune suppressive treatment including systemic corticosteroids. These conditions include myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjogren syndrome, Guillain-Barre syndrome, or multiple sclerosis, with the following exceptions:

  • Participants with a history of autoimmune-related hypothyroidism who are on thyroid-replacement hormone are eligible for the study.
  • Participants with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study.

  • Participants with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., participants with psoriatic arthritis are excluded) are eligible for the study provided all of following conditions are met:

    • Rash must cover < 10% of body surface area.
    • Disease is well controlled at baseline and requires only low-potency topical corticosteroids.
    • There has been no occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids within the previous 12 months.
• History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan. History of radiation pneumonitis in the radiation field (fibrosis) is permitted.
• Anticipation of need for a major surgical procedure during the study.
• Prior allogeneic stem cell or solid organ transplantation.
• Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during SG or atezolizumab treatment or within 5 months after the final dose of SG or atezolizumab. Note: Seasonal flu vaccines that do not contain a live virus and locally authorized/approved COVID-19 vaccines are permitted.
• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently) with the exception of participants with indwelling catheters (e.g., PleurX(R)) who are allowed.
• Uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L, calcium > 12 mg/dL or corrected serum calcium > ULN).
• Significant cardiovascular disease (such as New York Heart Association Class II or greater cardiac disease, myocardial infarction, cerebrovascular accident, unstable arrhythmia, or unstable angina) within 3 months prior to initiation of study treatment.
• Prior treatment with immune checkpoint blockade therapies, including anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies (for Arm 2 only).
• Participants with prior malignancy within the previous 2 years except for locally curable cancers that have been apparently cured such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the cervix, breast, or low risk Gleason 6 prostate cancer, among others.
• Participants with severe uncontrolled intercurrent illness that would limit compliance with study requirements, evaluated by history, physical exam, and chemistry panel.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm 1; Treatment with sacituzumab govitecan	Drug: Sacituzumab govitecan; Sacituzumab govitecan is administered IV at 10 mg/kg on days 1 and 8 of each 21-day cycle.
Experimental: Arm 2; Treatment with sacituzumab govitecan and atezolizumab	Drug: Sacituzumab govitecan; Sacituzumab govitecan is administered IV at 10 mg/kg on days 1 and 8 of each 21-day cycle.; Drug: Atezolizumab; Atezolizumab is administered IV at 1200 mg on day 1 each 21-day cycle.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective response rate (ORR)	Percentage of participants by best overall response (e.g., CR, PR, SD,PD) to therapy	On days 1 and 8 of each cycle and at every restaging (every 9 weeks) until the end of the study therapy and every 9 weeks during follow-up until PD.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of response (DoR)	Time from start of treatment to disease progression or death in participants who achieve CR or PR	On days 1 and 8 of each cycle and at every restaging (every 9 weeks) until the end of the study therapy and every 9 weeks during follow-up until PD.
Overall survival (OS)	Time from the start of treatment that participants are still alive.	Days 1 and 8 of each cycle, at EoT, at the Safety visit, at follow-up, and every 90 days for up to a total of 5 years after the end of therapy
Progression-free survival (PFS)	Duration of time from start of treatment to time of progression or death, whichever occurs first	At every restaging (every 9 weeks) until the end of the study therapy and every 9 weeks during follow-up until PD
Clinical benefit rate (CBR)	Percentage of participant who have achieved CR, PR, and SD while on treatment.	At every restaging (every 9 weeks) until the end of the study therapy and every 9 weeks during follow-up until PD
Safety of sacituzumab govitecan with or without atezolizumab	Adverse events (AEs) will be reported by type and grade of toxicity	From first dose through 30 days after last treatment

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Andrea B Apolo, M.D., National Cancer Institute (NCI)

Publications and helpful links

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Estimated): May 1, 2024
• Primary Completion (Estimated): November 1, 2027
• Study Completion (Estimated): November 1, 2028

Study Registration Dates

• First Submitted: December 2, 2023
• First Submitted That Met QC Criteria: December 7, 2023
• First Posted (Actual): December 8, 2023

Study Record Updates

• Last Update Posted (Estimated): April 26, 2024
• Last Update Submitted That Met QC Criteria: April 25, 2024
• Last Verified: April 2, 2024

More Information

Terms related to this study

• Keywords: Immunotherapy; Urothelial carcinoma; Programmed death-ligand 1; SN-38; Trophoblastic cell surface antigen 2
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms by Histologic Type; Neoplasms; Lung Diseases; Urogenital Neoplasms; Neoplasms by Site; Kidney Diseases; Urologic Diseases; Neoplasms, Glandular and Epithelial; Urinary Bladder Diseases; Endocrine System Diseases; Endocrine Gland Neoplasms; Genital Neoplasms, Male; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Thyroid Diseases; Head and Neck Neoplasms; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Lung Neoplasms; Neuroendocrine Tumors; Neoplasms, Squamous Cell; Penile Diseases; Neoplasms, Ductal, Lobular, and Medullary; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Genital Diseases, Male; Genital Diseases; Kidney Neoplasms; Carcinoma; Adenocarcinoma; Urinary Bladder Neoplasms; Small Cell Lung Carcinoma; Carcinoma, Squamous Cell; Urologic Neoplasms; Thyroid Neoplasms; Carcinoma, Neuroendocrine; Carcinoma, Small Cell; Penile Neoplasms; Carcinoma, Medullary; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Immunoconjugates; Atezolizumab; Sacituzumab govitecan
• Other Study ID Numbers: 10001535; 001535-C

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: .All collected IPD will be shared
• IPD Sharing Time Frame: Data from this study may be requested from other researchers at least 3 years after the completion of the primary endpoint.
• IPD Sharing Access Criteria: Data from this study may be requested by contacting the PI.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

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