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A Study Evaluating the Efficacy and Safety of Multiple Immunotherapy-based Treatment Combinations in Patients With Locally Advanced or Metastatic Urothelial Carcinoma After Failure With Platinum-Containing Chemotherapy

NCT03869190

Description:

A Phase Ib/II, open-label, multicenter, randomized, umbrella study in participants with locally advanced or metastatic Urothelial Carcinoma (UC) who have progressed during or following a platinum-containing regimen. The study is designed with the flexibility to open new treatment arms as new treatments become available, close existing treatment arms that demonstrate minimal clinical activity or unacceptable toxicity, or modify the participant population (e.g., with regard to prior anti-cancer treatment or biomarker status).

Related Conditions:
  • Urothelial Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Study Evaluating the Efficacy and Safety of Multiple Immunotherapy-based Treatment Combinations in Patients With Locally Advanced or Metastatic Urothelial Carcinoma After Failure With Platinum-Containing Chemotherapy
  • Official Title: A Phase Ib/II, Open-Label, Multicenter, Randomized Umbrella Study Evaluating the Efficacy and Safety of Multiple Immunotherapy-based Treatment Combinations in Patients With Locally Advanced or Metastatic Urothelial Carcinoma After Failure With Platinum-Containing Chemotherapy (MORPHEUS-mUC)

Clinical Trial IDs

  • ORG STUDY ID: WO39613
  • NCT ID: NCT03869190

Conditions

  • Urothelial Carcinoma

Interventions

DrugSynonymsArms
AtezolizumabAtezolizumab
Enfortumab VedotinAtezolizumab + Enfortumab Vedotin
NiraparibAtezolizumab + Niraparib
Hu5F9-G4Atezolizumab + Hu5F9-G4
IsatuximabAtezolizumab + Isatuximab
LinagliptinAtezolizumab + Linagliptin
TocilizumabAtezolizumab + Tocilizumab

Purpose

A Phase Ib/II, open-label, multicenter, randomized, umbrella study in participants with locally advanced or metastatic Urothelial Carcinoma (UC) who have progressed during or following a platinum-containing regimen. The study is designed with the flexibility to open new treatment arms as new treatments become available, close existing treatment arms that demonstrate minimal clinical activity or unacceptable toxicity, or modify the participant population (e.g., with regard to prior anti-cancer treatment or biomarker status).

Trial Arms

NameTypeDescriptionInterventions
AtezolizumabActive ComparatorParticipants will receive atezolizumab until unacceptable toxicity or loss of clinical benefit, as determined by the investigator after an integrated assessment of radiographic and biochemical data, local biopsy results (if available), and clinical status.
  • Atezolizumab
Atezolizumab + Enfortumab VedotinExperimentalParticipants will receive atezolizumab and Enfortumab Vedotin (EV) until unacceptable toxicity or loss of clinical benefit, as determined by the investigator after an integrated assessment of radiographic and biochemical data, local biopsy results (if available), and clinical status.
  • Atezolizumab
  • Enfortumab Vedotin
Atezolizumab + NiraparibExperimentalParticipants will receive atezolizumab and Niraparib (Nira) until unacceptable toxicity or loss of clinical benefit, as determined by the investigator after an integrated assessment of radiographic and biochemical data, local biopsy results (if available), and clinical status.
  • Atezolizumab
  • Niraparib
Atezolizumab + Hu5F9-G4ExperimentalParticipants will receive atezolizumab and Hu5F9-G4 until unacceptable toxicity or loss of clinical benefit, as determined by the investigator after an integrated assessment of radiographic and biochemical data, local biopsy results (if available), and clinical status.
  • Atezolizumab
  • Hu5F9-G4
Atezolizumab + IsatuximabExperimentalParticipants will receive atezolizumab and Isatuximab (Isa) until unacceptable toxicity or loss of clinical benefit, as determined by the investigator after an integrated assessment of radiographic and biochemical data, local biopsy results (if available), and clinical status.
  • Atezolizumab
  • Isatuximab
Atezolizumab + LinagliptinExperimentalParticipants will receive atezolizumab and Linagliptin (Lina) until unacceptable toxicity or loss of clinical benefit, as determined by the investigator after an integrated assessment of radiographic and biochemical data, local biopsy results (if available), and clinical status.
  • Atezolizumab
  • Linagliptin
Atezolizumab + TocilizumabExperimentalParticipants will receive atezolizumab and Tocilizumab (TCZ) until unacceptable toxicity or loss of clinical benefit, as determined by the investigator after an integrated assessment of radiographic and biochemical data, local biopsy results (if available), and clinical status.
  • Atezolizumab
  • Tocilizumab

Eligibility Criteria

        Inclusion Criteria:

          -  Histologically documented, locally advanced or metastatic UC (also termed TCC or
             urothelial cell carcinoma of the urinary tract; including renal pelvis, ureters,
             urinary bladder, and urethra)

          -  Availability of a representative tumor specimen that is suitable for determination of
             PD-L1 and/or additional biomarker status by means of central testing

          -  Disease progression during or following treatment with no more than one
             platinum-containing regimen for inoperable, locally advanced or metastatic UC or
             disease recurrence

          -  ECOG Performance Status of 0 or 1

          -  Measurable disease (at least one target lesion) according to RECIST v1.1

          -  Adequate hematologic and end-organ function

          -  Negative HIV test at screening

          -  Negative total hepatitis B core antibody (HBcAb) test and hepatitis C virus (HCV)
             antibody at screening

          -  Tumor accessible for biopsy

          -  For women of childbearing potential: agreement to remain abstinent or use
             contraceptive measures and agreement to refrain from donating eggs

          -  For men: agreement to remain abstinent or use contraceptive measures, and agreement to
             refrain from donating sperm

        Exclusion Criteria:

          -  Prior treatment with a T-cell co-stimulating therapy or a CPI including anti-CTLA-4,
             anti-PD-1, and anti-PD-L1 therapeutic antibodies

          -  Prior treatment with any of the protocol-specified study treatments including
             treatment with poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor,
             nectin-4 targeting agents, signal regulatory protein alpha-targeting agents, or agents
             that block CD38

          -  Treatment with investigational therapy within 28 days prior to initiation of study
             treatment

          -  Any approved anti-cancer therapy, including chemotherapy or hormonal therapy, within 3
             weeks prior to initiation of study treatment

          -  Eligibility only for the control arm

          -  Prior allogeneic stem cell or solid organ transplantation

          -  Treatment with systemic immunostimulatory agents within 4 weeks or 5 half-lives of the
             drug (whichever is longer) prior to the initiation of study treatment

          -  Treatment with systemic immunosuppressive medication within 2 weeks prior to
             initiation of study treatment or anticipation of need for systemic immunosuppressant
             medication during study treatment

          -  Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study
             treatment, or anticipation of need for such a vaccine during atezolizumab treatment or
             within 5 months after the last dose of atezolizumab

          -  Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent
             drainage procedures

          -  Uncontrolled tumor-related pain

          -  Uncontrolled or symptomatic hypercalcemia

          -  Symptomatic, untreated, or actively progressing CNS metastases

          -  History of leptomeningeal disease

          -  Active or history of autoimmune disease or immune deficiency

          -  History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced
             pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis

          -  History of malignancy other than UC within 2 years prior to screening, with the
             exception of malignancies with a negligible risk of metastasis or death

          -  Active tuberculosis

          -  Severe infection within 4 weeks prior to initiation of study treatment

          -  Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation
             of study treatment

          -  Significant cardiovascular disease

          -  Grade 3 or greater hemorrhage or bleeding event within 28 days prior to initiation of
             study treatment

          -  Major surgical procedure, other than for diagnosis, within 4 weeks prior to initiation
             of study treatment

          -  Pregnancy or breastfeeding, or intention of becoming pregnant during the study

          -  Additional drug-specific exclusion criteria might apply
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective Response Rate (ORR)
Time Frame:Baseline until disease progression or loss of clinical benefit (approximately 4 years)
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Progression Free Survival (PFS)
Time Frame:Randomization until the first occurrence of disease progression or death from any cause, which ever occurs first, through the end of study (approximately 4 years) as determined by the investigator according to RECIST 1.1
Safety Issue:
Description:
Measure:Overall Survival (OS)
Time Frame:Randomization to death from any cause, through the end of study (approximately 4 years)
Safety Issue:
Description:
Measure:Overall Survival (at specific time-points)
Time Frame:12 months
Safety Issue:
Description:
Measure:Duration of Response (DOR)
Time Frame:Randomization until first occurrence of a documented objective response to the first recorded occurrence of disease progression or death from any cause (whichever occurs first), through end of study (approximately 4 years)
Safety Issue:
Description:
Measure:Disease Control Rate (DCR)
Time Frame:Baseline through end of study (approximately 4 years)
Safety Issue:
Description:
Measure:Percentage of Participants with Adverse Events
Time Frame:Baseline to end of study (approximately 4 years)
Safety Issue:
Description:
Measure:Serum Concentration of Atezolizumab
Time Frame:Day 1, Cycle 1 pre-treatment and 30 mins post-infusion; Day 1 of Cycles 2, 4, 8, 12, and 16 pre-treatment (Cycles = 21 or 28 days); within 30 days after last dose.
Safety Issue:
Description:
Measure:Serum and Plasma Concentration of Enfortumab Vedotin
Time Frame:Day 1, Cycle 1 pre-treatment and at end of infusion; Day 8 Cycle 1 pre-treatment; Day 1 of Cycles 2, 4, 8, 12 and 16 pre-treatment (Cycles = 21 days); within 30 days after last dose.
Safety Issue:
Description:
Measure:Plasma Concentration of Niraparib
Time Frame:Day 1, Cycle 1 pre-treatment and 2 hours after administration; Day 1 of Cycle 4, 2 hours after administration (Cycle = 21 days); within 30 days after last dose.
Safety Issue:
Description:
Measure:Serum Concentration of Hu5F9-G4
Time Frame:Day 1 and 8, Cycle 1 pre-treatment and 1 hour after infusion; Day 22 of Cycle 1 pre-treatment; Day 1 of Cycles 2, 4 8 and 16 (Cycle = 28 days); within 30 days after last dose.
Safety Issue:
Description:
Measure:Plasma Concentration of Isatuximab
Time Frame:Day 1, Cycles 1 and 4 pre-treatment and at end of infusion; Day 1 of Cycles 2, 6, 8, 10, 12 and 16 pre-treatment (Cycle = 21 days); within 30 days after last dose.
Safety Issue:
Description:
Measure:Plasma Concentration of Linagliptin
Time Frame:Day 1, Cycle 1, 2 hours after administration; Day 15, Cycle 1 pre-treatment; Day 1 Cycle 2, pre-treatment (Cycle = 21 days).
Safety Issue:
Description:
Measure:Serum Concentration of Tocilizumab
Time Frame:Day 1, Cycle 1 pre-treatment and at end of infusion; Day 1 of Cycles 2, 4, 6, 8, 10, 12, 14, 16 and every fourth cycle thereafter, pre-treatment (Cycles = 28 days); within 30 days after last dose.
Safety Issue:
Description:

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Hoffmann-La Roche

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