We're building a better ClinicalTrials.gov. Check it out and tell us what you think!
Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

Study of NIVOLUMAB/IPILIMUMAB Maintenance in Unresectable Locally Advanced or Metastatic Urothelial Cancer (VEXILLUM)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT05219435
Recruitment Status : Recruiting
First Posted : February 2, 2022
Last Update Posted : December 5, 2022
Sponsor:
Collaborator:
Bristol-Myers Squibb
Information provided by (Responsible Party):
Spanish Oncology Genito-Urinary Group

Brief Summary:
Immunotherapy has improved clinical outcomes in metastatic urothelial carcinoma (mUC). Second-line treatment after progression to platinum-containing chemotherapy with immune checkpoint inhibitors (ICIs) have antitumor activity in advanced / metastatic UC and provide favorable safety profiles when compared with chemotherapy The study aims to determine if Nivolumab plus Ipilimumab maintenance therapy is effective in delaying disease progression in patients with unresectable locally advanced or metastatic urothelial cancer that did not progress during or following completion of first-line chemotherapy. Vexillum plans to recruit patients that achieve clinical benefit from first-line chemotherapy and may be candidates for maintenance immunotherapy to consolidate this benefit.

Condition or disease Intervention/treatment Phase
Urothelial Cancer Drug: Nivolumab Drug: Ipilimumab Phase 2

Detailed Description:

All enrolled patients should have received first-line chemotherapy and not progressed. After a treatment-free interval of 3-12 weeks from chemotherapy, patients will receive maintenance therapy with 4 cycles of Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg every three weeks (Q3W)(induction phase) followed by Nivolumab 480 mg every 4 weeks (Q4W)(consolidation phase) until unacceptable toxicity, disease progression (PD), investigator ́s decision, patient's consent withdrawal or death by any cause, whichever occurs first.

  • Induction phase (Total of 4 cycles Q3W)

    • Nivolumab at 1 mg/kg by intravenous (IV) infusion on D1 of each cycle.
    • Ipilimumab at 3 mg/kg by intravenous (IV) infusion on D1 of each cycle.
  • Consolidation phase (Cycles Q4W) ○ Nivolumab at a fixed dose of 480 mg by intravenous (IV) infusion on D1 of each cycle. The maximum duration of treatment with nivolumab will be 2 years, and patients will discontinue treatment at any time in case of unacceptable toxicity, disease progression (PD), investigator ́s decision, patient's consent withdrawal or death by any cause, whichever occurs first.

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 66 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: Patients will receive maintenance therapy with 4 cycles of Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg every three weeks (Q3W)(induction phase) followed by Nivolumab 480 mg every 4 weeks (Q4W)(consolidation phase) until unacceptable toxicity, disease progression (PD), investigator ́s decision, patient's consent withdrawal or death by any cause, whichever occurs first.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase II Non Randomized Clinical Trial of NIVOLUMAB/IPILIMUMAB Maintenance Following First-line Chemotherapy in Unresectable Locally Advanced or Metastatic Urothelial Cancer.
Actual Study Start Date : July 6, 2022
Estimated Primary Completion Date : March 2025
Estimated Study Completion Date : December 2025

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Nivolumab plus Ipilimumab
Patients will receive maintenance therapy with 4 cycles of Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg every three weeks (Q3W)(induction phase) followed by Nivolumab 480 mg every 4 weeks (Q4W)(consolidation phase) until unacceptable toxicity, disease progression (PD), investigator ́s decision, patient's consent withdrawal or death by any cause, whichever occurs first.
Drug: Nivolumab
Nivolumab at 1 mg/kg by intravenous (IV) infusion on D1 of each cycle. Nivolumab at a fixed dose of 480 mg by intravenous (IV) infusion on D1 of each cycle. The maximum duration of treatment with nivolumab will be 2 years, and patients will discontinue treatment at any time in case of unacceptable toxicity, disease progression (PD), investigator ́s decision, patient's consent withdrawal or death by any cause, whichever occurs first.
Other Name: Opdivo

Drug: Ipilimumab
Ipilimumab at 3 mg/kg by intravenous (IV) infusion on D1 of each cycle.
Other Name: Yervoy




Primary Outcome Measures :
  1. progression-free survival (PFS) [ Time Frame: Throughout the study period, approximately 12 months per patient from first study dose. ]
    PFS is defined as the time from the first dose of study treatment date until the first documentation disease progression or death from any cause, whichever occurs first. A subject who has not confirmed progression will be censored at the last known disease evaluation. Patients who have not progressed and start a new line of treatment will be censored at the date of the last adequate tumor assessment prior to starting the next line of therapy. Estimated by Kaplan Meier.

  2. progression-free survival (PFS) in PL-D1 positive patients [ Time Frame: Throughout the study period, approximately 12 months per patient from first study dose. ]
    subgroup analysis of PFS. Same definition of PFS as Outcome 1 applies.


Secondary Outcome Measures :
  1. Overall Survival (OS) [ Time Frame: Throughout the study period, approximately 12 months per patient from first study dose. ]
    Time from the first dose of study treatment date to the date of death and the proportion/percentage of patients alive at the end of follow-up. A subject who has not died will be censored at the last known date alive. Estimated by Kaplan Meier

  2. Clinical benefit rate (CBR) [ Time Frame: Throughout the study period, approximately 12 months per patient from first study dose. ]
    Percentage/proportion of patients with complete response (CR) or partial response (PR), according to ORR definition for the trial, or maintained stable disease (SD) as their overall best response throughout the study period, assessed by imaging follow-up (CT scan/MRI) and RECIST 1.1 criteria. Stable disease should be maintained for at least 4 months to be considered as a CBR event.

  3. Duration of response (DoR) [ Time Frame: Throughout the study period, approximately 12 months per patient from first study dose. ]
    Time from first confirmed response (CR or PR), according to ORR definition for the trial, to the date of the documented PD as determined using RECIST 1.1 criteria or death due to any cause, whichever occurs first.

  4. Post-chemotherapy PFS (cPFS) [ Time Frame: Throughout the study period, approximately 12 months per patient from first study dose. ]
    defined as the time from first dosing date of chemotherapy until the first documentation disease progression or death from any cause, whichever occurs first.

  5. Post-chemotherapy OS (cOS) [ Time Frame: Throughout the study period, approximately 12 months per patient from first study dose. ]
    Time from first dosing of chemotherapy date to the date of death and the proportion/percentage of patients alive at the end of follow-up.

  6. Frequency of adverse events [ Time Frame: Throughout the study period, approximately 12 months per patient from first study dose. ]
    Number of patients experiencing adverse events from the total of patients exposed to study drug

  7. Frequency of treatment-related adverse events [ Time Frame: Throughout the study period, approximately 12 months per patient from first study dose. ]
    Number of patients experiencing adverse events related to the study treatment from the total of patients exposed to study drug

  8. Quality of life (QoL) patient reported outcomes [ Time Frame: Throughout the study period, approximately 12 months per patient from first study dose. ]
    Patient reported outcomes assessed through the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30), version 3 and the EuroQoL five-dimensions, 5 level (EQ- 5D-5L) questionnaire. Median scores for both questionnaires will be provided.

  9. Objective response rate (ORR) [ Time Frame: Throughout the study period, approximately 12 months per patient from first study dose. ]
    Assessed by the investigator by imaging follow-up (CT scan/MRI) using the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. This will be considered as the percentage/proportion of patients with confirmed complete response (CR) or partial response (PR) as their overall best response throughout the study period. Objective responses will be assessed by the investigator according to the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

1. Male or female subjects ≥ 18 years old.

2- Written informed consent approved by the Independent Ethics Committee (IEC), prior to the performance of any trial activities.

3- Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.

4- Histologically confirmed, unresectable locally advanced or metastatic transitional cell carcinoma of the urothelium.

  • Also termed urothelial cell carcinoma [UCC] of the urinary tract; including renal pelvis, ureters, urinary bladder, and urethra).

    5- Stage IV disease (T4b, N0, M0; any T, N1-N3, M0; any T, any N, M1) at the start of first line chemotherapy.

    6- Prior first-line chemotherapy must have consisted of at least 4 cycles and no more than 6 cycles of gemcitabine plus cisplatin and/or gemcitabine plus carboplatin.

    7- Patient inclusion within the trial must occur within 3-12 weeks after the last dose of chemotherapy (3-12 weeks treatment-free interval).

    8- Only patients without progressive disease as per RECIST v1.1 guidelines after 4-6 cycles of chemotherapy will be allowed to be included. Baseline CT scan before inclusion should confirm that patients are on CR, PR or SD according to RECIST 1.1 criteria.

    9- Tumor tissue (formalin-fixed paraffin-embedded (FFPE) archival or recent acquisition) must be available at baseline.

Note: Fine Needle Aspiration [FNA] and bone metastases samples are not acceptable. If an insufficient amount of tumor tissue from an unresectable or metastatic site is available prior to the start of the screening phase, subjects must consent to allow the acquisition of additional tumor tissue. This may be discussed with the PI if a new biopsy is feasible.

10- Patients with adequate normal organ and marrow function as defined below:

  1. Haemoglobin ≥ 9.0 g/dL.
  2. Absolute neutrophil count (ANC) > 1500 per mm3.
  3. Platelet count ≥ 100,000 per mm3.
  4. Serum bilirubin ≤ 1.5 X institutional upper limit of normal (ULN) unless liver metastases are present, in which case it must be ≤ 2X ULN. This will not apply to patients with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of haemolysis or hepatic pathology); however, they will be allowed only in consultation with their physician.
  5. Serum transaminases (ALT, AST and GGT) ≤ 2.5X institutional upper limit of normal unless liver metastases are present, in which case it must be ≤ 3X ULN.
  6. Measured creatinine clearance (CL) > 30 mL/min or Calculated creatinine CL > 40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for the determination of creatinine clearance.

    11- Female subjects of childbearing potential (WOCBP) must provide a negative urine pregnancy test at screening, and must agree to use a medically accepted and highly effective birth control method (i.e. those with a failure rate less than 1%; refer to ANNEX III) for the duration of the study treatment and for 5 months after the last dose of study treatment.

A woman is considered of childbearing potential ( i.e. fertile) following menarche and until becoming post-menopausal unless permanently sterile. Women will be considered post-menopausal if they have been amenorrhoeic for 12 months without an alternative medical cause. The following age-specific requirements apply:

  1. Amenorrheic for ≥1 year in the absence of chemotherapy and/or hormonal treatments
  2. Luteinizing hormone (LH) and/or follicle stimulating hormone and/or estradiol levels in the post-menopausal range
  3. Radiation induced oophorectomy with last menses >1 year ago
  4. Chemotherapy induced menopause with >1 year interval since last menses
  5. Surgical sterilization (bilateral oophorectomy or hysterectomy)
  6. 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)
  7. 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, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).

    12- Willingness and ability of patients to comply with the protocol for the duration of the study including undergoing treatment as well as availability for scheduled visits and examinations including follow up.

    Exclusion Criteria:

    1. ECOG performance status of >1 (Karnofsky < 70%).
    2. Patients whose disease progressed by RECIST v1.1 on or after first-line chemotherapy for urothelial cancer in the advanced or metastatic setting.
    3. Prior immunotherapy with IL-2, IFN-a or treatment with any immune checkpoint inhibitor therapy (e.g, CTLA4, PD-1, or PD-L1 targeting agent) for the unresectable metastatic setting.

      Note: Patients may have received immunotherapy in the adjuvant setting as long as the last dose of adjuvant was administered at least 12 months prior to the first dose of trial treatment.

    4. Receipt of any type of systemic chemotherapy or anticancer therapy within 3 weeks before starting treatment.
    5. Previously identified allergy or hypersensitivity to components of the study treatment formulations.
    6. History of allogeneic organ transplant.
    7. Any non-cancer treatment with vaccines used for the prevention of infectious diseases (up to 1 month before or after any dose of ipilimumab and nivolumab).
    8. Major surgery (i.e. cystectomy) less than 28 days prior to the first dose of study treatment.
    9. Patients with known symptomatic central nervous system (CNS) metastases requiring steroids. Patients with previously diagnosed CNS metastases are eligible if they have completed their treatment and have recovered from the acute effects of radiation therapy or surgery prior to inclusion, have discontinued corticosteroid treatment for these metastases for at least 4 weeks, and are neurologically stable.
    10. Subjects that have a diagnosis of immunodeficiency or are receiving systemic steroid therapy or any other form of immunosuppressive therapy within 28 days prior to the first dose of trial treatment, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses (which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid).
    11. Active or prior documented autoimmune disease within the past 2 years which requires systemic therapy.

      Note: Subjects with vitiligo, Grave's disease, or psoriasis not requiring systemic treatment (within the past 2 years) are not excluded. Subjects with Type I diabetes mellitus are not excluded.

    12. Active or prior documented inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis).
    13. Inadequate haematological/organ function.
    14. Any of the following in the previous 6 months: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident, transient ischemic attack, deep vein thrombosis, or symptomatic pulmonary embolism.
    15. Persistence of any toxicities attributed to prior anti-cancer therapy, other than alopecia, that have not resolved to Grade 1 (NCI-CTCAE v5.0) or baseline before administration of study treatment.
    16. Active hepatitis B virus or hepatitis C virus.
    17. Vaccination within 4 weeks of the first dose of study treatment and while on trial is prohibited except for administration of inactivated vaccines (i.e. SARS-CoV-2 and Influenza vaccines will be permitted).
    18. Patients who have a known secondary malignancy that is progressing or has required active treatment within the past 2 years.

      Note: Patients with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ that have undergone potentially curative therapy are eligible.

    19. Pregnant or lactating females. Fertile and sexually active patients that are not willing to use the appropriate highly effective contraceptive methods.
    20. Any underlying medical or psychiatric disorder, which, in the opinion of the investigator, makes the administration of ipilimumab and nivolumab unsafe or interferes with the informed consent process or trial procedures.
    21. Participation in other studies involving investigational drug(s) within 4 weeks prior to inclusion. Observational studies are permitted.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05219435


Contacts
Layout table for location contacts
Contact: Federico Nepote 934344412 investigacion@mfar.net
Contact: Pau Donate 934344412 investigacion@mfar.net

Locations
Layout table for location information
Spain
Hospital Universitario Juan Ramón Jiménez Recruiting
Huelva, Andalucia, Spain, 21005
Contact: A responsible person designated by the Sponsor         
Contact       investigacion@mfar.net   
Principal Investigator: Principal investigator selected by the sponsor, M.D.; Ph.D.         
Hospital Universitario Virgen de la Macarena Recruiting
Sevilla, Andalucia, Spain, 41009
Contact: A responsible person designated by the Sponsor         
Contact       investigacion@mfar.net   
Principal Investigator: Principal investigator selected by the sponsor, M.D.; Ph.D.         
Hospital Clínico Universitario de Zaragoza Not yet recruiting
Zaragoza, Aragon, Spain, 50009
Contact: A responsible person designated by the Sponsor         
Contact       investigacion@mfar.net   
Principal Investigator: Principal investigator selected by the sponsor, M.D.; Ph.D.         
Hospital Universitario Central de Asturias Recruiting
Oviedo, Asturias, Spain, 33011
Contact: A responsible person designated by the Sponsor         
Contact       investigacion@mfar.net   
Principal Investigator: Principal investigator selected by the sponsor, M.D.; Ph.D.         
Hospital Virgen de la Salud de Toledo Not yet recruiting
Toledo, Castilla La Mancha, Spain, 45004
Contact: A responsible person designated by the Sponsor         
Contact       investigacion@mfar.net   
Principal Investigator: Principal investigator selected by the sponsor, M.D.; Ph.D.         
Complejo asistencial universitario de Salamanca Not yet recruiting
Salamanca, Castilla Y Leon, Spain, 37007
Contact: A responsible person designated by the Sponsor         
Contact       investigacion@mfar.net   
Principal Investigator: Principal investigator selected by the sponsor, M.D.; Ph.D.         
Hospital Clínic de Barcelona Not yet recruiting
Barcelona, Cataluña, Spain, 08036
Contact: A responsible person designated by the Sponsor         
Contact       investigacion@mfar.net   
Principal Investigator: Principal investigator selected by the sponsor, M.D.; Ph.D.         
Hospital General Universitario Gregorio Marañon Not yet recruiting
Madrid, Comunidad Autonoma De Madrid, Spain, 28007
Contact: A responsible person designated by the Sponsor         
Contact       investigacion@mfar.net   
Principal Investigator: Principal investigator selected by the sponsor, M.D.; Ph.D.         
Hospital Universitario 12 de Octubre Recruiting
Madrid, Comunidad Autónoma De Madrid, Spain, 28041
Contact: A responsible person delegated by the sponsor         
Contact       investigacion@mfar.net   
Principal Investigator: Principal investigator selected by the sponsor, M.D.; Ph.D.         
Hospital Universitario de la Ribera Recruiting
Alzira, Comunitat Valenciana, Spain, 46600
Contact: A responsible person designated by the Sponsor         
Contact       investigacion@mfar.net   
Principal Investigator: Principal investigator selected by the sponsor, M.D.; Ph.D.         
Hospital Clínico Universitario de Santiago de Compostela Recruiting
Santiago de Compostela, Galicia, Spain, 15706
Contact: A responsible person designated by the Sponsor         
Contact       investigacion@mfar.net   
Principal Investigator: Principal investigator selected by the sponsor, M.D.; Ph.D.         
Hospital Universitario Son Espases Recruiting
Palma De Mallorca, Islas Baleares, Spain, 07120
Contact: A responsible person designated by the Sponsor         
Contact       investigacion@mfar.net   
Principal Investigator: Principal investigator selected by the sponsor, M.D.; Ph.D.         
Sponsors and Collaborators
Spanish Oncology Genito-Urinary Group
Bristol-Myers Squibb
Investigators
Layout table for investigator information
Study Chair: Guillermo de Velasco Hospital Universitario 12 de Octubre
Layout table for additonal information
Responsible Party: Spanish Oncology Genito-Urinary Group
ClinicalTrials.gov Identifier: NCT05219435    
Other Study ID Numbers: SOGUG-2021-IEC(VEJ)-4
2021-005364-22 ( EudraCT Number )
First Posted: February 2, 2022    Key Record Dates
Last Update Posted: December 5, 2022
Last Verified: January 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Spanish Oncology Genito-Urinary Group:
metastatic
unresectable locally advanced
Additional relevant MeSH terms:
Layout table for MeSH terms
Nivolumab
Ipilimumab
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immune Checkpoint Inhibitors
Molecular Mechanisms of Pharmacological Action