Clinical Trials /

CV301 Combined With PD-1/L1 Blockade in Patients With Locally Advanced or Metastatic Urothelial Bladder Cancer

NCT03628716

Description:

This is a Phase 2, single-arm, multi-institutional clinical trial designed to study the combination of CV301 with atezolizumab in the first-line treatment of UC not eligible for cisplatin-containing chemotherapy (Cohort 1) and in the second-line treatment of UC previously treated with standard first-line cisplatin-based chemotherapy (Cohort 2).

Related Conditions:
  • Urothelial Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: CV301 Combined With PD-1/L1 Blockade in Patients With Locally Advanced or Metastatic Urothelial Bladder Cancer
  • Official Title: A Phase 2, Multicenter, Single-Arm Trial of CV301 in Combination With PD-1/L1 Blockade in Patients With Locally Advanced or Metastatic Urothelial Bladder Cancer

Clinical Trial IDs

  • ORG STUDY ID: CV301-BLD-001
  • NCT ID: NCT03628716

Conditions

  • Bladder Cancer

Interventions

DrugSynonymsArms
CV301CV301 + Atezolizumab
AtezolizumabCV301 + Atezolizumab

Purpose

This is a Phase 2, single-arm, multi-institutional clinical trial designed to study the combination of CV301 with atezolizumab in the first-line treatment of UC not eligible for cisplatin-containing chemotherapy (Cohort 1) and in the second-line treatment of UC previously treated with standard first-line cisplatin-based chemotherapy (Cohort 2).

Detailed Description

      This is a Phase 2, single-arm, multi-institutional clinical trial designed to study the
      combination of CV301 with atezolizumab in the first-line treatment of UC not eligible for
      cisplatin-containing chemotherapy (Cohort 1) and in the second-line treatment of UC
      previously treated with standard first-line cisplatin-based chemotherapy (Cohort 2). The
      trial will be performed using an optimal two-stage design within each cohort.

      Stage 1, Cohort 1: Enroll 14 subjects. If objective response is not achieved in at least four
      patients, the cohort will be stopped for futility. If objective response is achieved in at
      least four subjects, the cohort will proceed to stage 2. If any patient is not evaluable for
      the primary endpoint, the patient may be replaced.

      Stage 1, Cohort 2: Enroll 13 subjects. If objective response is not achieved in at least
      three patients, the cohort will be stopped for futility. If objective response is achieved in
      at least three subjects, the cohort will proceed to stage 2. If any patient is not evaluable
      for the primary endpoint, the patient may be replaced.

      Stage 2, Cohort 1: Enroll an additional 19 subjects. If any patient is not evaluable for the
      primary endpoint, the patient may be replaced until a total of 33 patients are evaluable for
      the primary endpoint.

      Stage 2, Cohort 2: Enroll an additional 22 subjects. If any patient is not evaluable for the
      primary endpoint, the patient may be replaced until a total of 35 patients are evaluable for
      the primary endpoint.
    

Trial Arms

NameTypeDescriptionInterventions
CV301 + AtezolizumabExperimentalSubject receiving combination treatment with CV301 + Atezolizumab
  • CV301
  • Atezolizumab

Eligibility Criteria

        Inclusion Criteria:

          1. Age ≥ 18 years at date of ICF signature having the ability to comply with protocol.

          2. Histologically or cytologically documented locally advanced (T4b, any N; or any T, N
             2−3) or metastatic (M1, Stage IV; or metastatic recurrence after locoregional
             treatment) UC (including renal pelvis, ureters, urinary bladder, urethra)

               1. Patients with mixed histologies were required to have a dominant transitional
                  cell pattern.

               2. Locally advanced bladder cancer that was inoperable on the basis of involvement
                  of the pelvic sidewall or adjacent viscera (clinical stage T4b) or bulky nodal
                  metastasis (N2−N3).

          3. Life expectancy ≥ 12 weeks.

          4. Measurable disease, as defined by RECIST v1.1. Previously irradiated lesions cannot be
             counted as target lesions unless there has been demonstrated progression in the lesion
             since radiotherapy and no other lesions are available for selection as target lesions.

          5. Demonstrate adequate organ function.

          6. For female patients of childbearing potential and male patients with partners of
             childbearing potential, agreement (by patient and/or partner) to use a highly
             effective form(s) of contraception (i.e., one that results in a low failure rate [< 1%
             per year] when used consistently and correctly) and to continue its use for 5 months
             after the last dose of atezolizumab.

          7. Representative formalin-fixed paraffin-embedded (FFPE) tumor specimens in paraffin
             blocks (blocks preferred) or 10-15 unstained slides, with an associated pathology
             report.

             For Cohort 1:

          8. Untreated with chemotherapy

          9. Have at least one of the following:

               1. ECOG (Eastern Cooperative Oncology Group) performance status of 2.

               2. Glomerular filtration rate calculated as creatinine clearance (Cockroft-Gault
                  formula) of ≥20 mL/min and less than 60 mL/min

               3. Hearing loss or neuropathy of any cause Common Terminology Criteria for Adverse
                  Events (CTCAE) Grade ≥2

             For Cohort 2:

         10. Disease progression during or following treatment with at least one
             platinum-containing regimen (e.g., GC, MVAC, CarboGem, carboplatin-paclitaxel) for
             inoperable locally advanced or metastatic urothelial carcinoma or disease recurrence,
             as defined by:

               1. Regimen is defined as patients receiving at least one cycle of a
                  platinum-containing regimen with response assessment. Patients who received one
                  cycle of a platinum-containing regimen but discontinued due to toxicity are also
                  eligible.

               2. Patients who received prior adjuvant/neoadjuvant chemotherapy and progressed
                  within 12 months of treatment with a platinum-containing adjuvant/neoadjuvant
                  regimen are considered as second-line patients.

         11. ECOG (Eastern Cooperative Oncology Group) performance status of < 2

         12. Calculated creatinine clearance (Cockroft-Gault formula) of ≥20 mL/min

        Exclusion Criteria:

          1. Any approved anti-cancer therapy, including chemotherapy, within 3 weeks prior to
             initiation of trial treatment; the following exceptions are allowed:

               1. Palliative radiotherapy for bone metastases or non-target soft tissue lesions
                  completed >7 days prior to baseline imaging.

               2. Hormone-replacement therapy or oral contraceptives.

          2. Treatment with any other investigational agent or participation in another clinical
             trial with therapeutic intent within 28 days prior to screening given that all AEs
             related to prior treatment have resolved to baseline or Grade 1.

          3. Active central nervous system (CNS) metastases as determined by computed tomography
             (CT) or magnetic resonance imaging (MRI) evaluation during screening and prior
             radiographic assessments or Leptomeningeal disease.

          4. Uncontrolled tumor-related pain:

               1. Patients requiring pain medication must be on a stable regimen at trial entry.

               2. Symptomatic lesions amenable to palliative radiotherapy (e.g., bone metastases or
                  metastases causing nerve impingement) should be treated prior to trial entry.

               3. Asymptomatic metastatic lesions whose further growth would likely cause
                  functional deficits or intractable pain (e.g., epidural metastasis that is not
                  currently associated with spinal cord compression) could be considered for
                  loco-regional therapy if appropriate prior to enrollment.

          5. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent
             drainage procedures (once monthly or more frequently)

             a. Patients with indwelling catheters (e.g., PleurX) are allowed.

          6. Uncontrolled hypercalcemia (>1.5 mmol/L ionized calcium or Ca >12 mg/dL or corrected
             serum calcium >ULN) or symptomatic hypercalcemia requiring continued use of
             bisphosphonate therapy or denosumab:

               1. Patients who are receiving bisphosphonate therapy or denosumab specifically to
                  prevent skeletal events and who did not have a history of clinically significant
                  hypercalcemia are eligible.

               2. Patients who are receiving denosumab prior to enrollment have to be willing and
                  eligible to receive a bisphosphonate instead while in the trial.

          7. Malignancies other than urothelial carcinoma within 3 years prior to Day 1, with the
             exception of those with a negligible risk of metastasis or death treated with expected
             curative outcome (such as adequately treated carcinoma in situ of the cervix, basal or
             squamous cell skin cancer, or ductal carcinoma in situ treated surgically with
             curative intent) or localized prostate cancer treated with curative intent and no
             intent for further treatment or incidental prostate cancer (T1/T2b, Gleason score ≤7
             undergoing active surveillance and treatment naive).

          8. Pregnant and lactating women.

          9. History of severe allergic, anaphylactic, or other hypersensitivity reactions to
             chimeric or humanized antibodies or fusion proteins, or aminoglycoside antibiotics or
             egg products, poxvirus-based vaccinations, or beef or bovine meat.

         10. Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster
             ovary cells or any component of the atezolizumab formulation.

         11. History of autoimmune disease, including but not limited to myasthenia gravis,
             myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis,
             inflammatory bowel disease, vascular thrombosis associated with anti-phospholipid
             syndrome, granulomatosis with polyangiitis, Sjogren's syndrome, Guillain-Barre
             syndrome, multiple sclerosis, vasculitis, or glomerulonephritis.

               1. Patients with a history of autoimmune-related hypothyroidism on a stable dose of
                  thyroid replacement hormone are eligible for this trial.

               2. Patients with controlled Type I diabetes mellitus on a stable dose of insulin
                  regimen are eligible for this trial.

               3. Patients with history of vitiligo and controlled psoriasis are eligible for the
                  trial.

         12. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis
             obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active
             pneumonitis on screening chest CT scan

             a. History of radiation pneumonitis in the radiation field (fibrosis) is permitted.

         13. Positive test for Human Immunodeficiency Virus (HIV).

         14. Patients with active hepatitis B virus (HBV; chronic or acute, defined as having a
             positive hepatitis B surface antigen [HBsAg] test at screening) or hepatitis C virus
             (HCV)

               1. Patients with past HBV infection or resolved HBV infection (defined as the
                  presence of hepatitis B core antibody [HBcAb] and absence of HbsAg, negative
                  polymerase chain reaction (PCR) for HBV) are eligible. HBV Deoxyribonucleic Acid
                  (DNA) PCR must be obtained in these patients prior to Day 1.

               2. Patients positive for HCV antibody are eligible only if polymerase chain reaction
                  is negative for HCV Ribonucleic Acid (RNA) prior to enrollment.

         15. Active tuberculosis.

         16. Signs or symptoms clinically significant of infection within 2 weeks prior to Day 1.

         17. Received therapeutic oral or intravenous (IV) antibiotics within 1 week prior to Day 1

             a. Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary
             tract infection or to prevent chronic obstructive pulmonary disease exacerbation) are
             eligible.

         18. Significant cardiovascular disease, which includes but is not limited to New York
             Heart Association (NYHA) Heart Failure Class II or greater, myocardial infarction
             within the previous 3 months, unstable arrhythmias, unstable angina.

             a. Patients with known coronary artery disease, congestive heart failure not meeting
             the above criteria, or left ventricular ejection fraction < 50% on a stable medical
             regimen that was optimized in the opinion of the treating physician, in consultation
             with a cardiologist if appropriate, are eligible.

         19. Major surgical procedure other than for diagnosis within 28 days prior to Day 1 or
             anticipation of need for a major surgical procedure during the course of the trial.

         20. Prior allogeneic stem cell or solid organ transplant.

         21. Administration of a live, attenuated vaccine within 4 weeks before Day 1 or
             anticipation that such a live attenuated vaccine would be required during the trial

             a. Influenza vaccination may be given during influenza season only (approximately
             October to March). Patients cannot receive live, attenuated influenza vaccine (e.g.,
             FluMist®) within 4 weeks prior to Day 1 or at any time during the trial.

         22. Any other diseases, metabolic dysfunction, physical examination finding, or clinical
             laboratory finding giving reasonable suspicion of a disease or condition that
             contraindicated the use of an investigational drug or that could affect the
             interpretation of the results or render the patient at high risk from treatment
             complications.

         23. Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including
             anti−CTLA-4, anti−PD-1, and anti−PD-L1 therapeutic antibodies

         24. Treatment with systemic immunostimulatory agents (including but not limited to IFNs,
             interleukin [IL]-2) within 6 weeks or five half-lives of the drug, whichever was
             shorter, prior to Day 1.

         25. Treatment with systemic corticosteroids or other systemic immunosuppressive
             medications (including but not limited to prednisone, dexamethasone, cyclophosphamide,
             azathioprine, methotrexate, and anti−tumor necrosis factor [anti-TNF] agents) within 2
             weeks prior to Day 1, or anticipated requirement for systemic immunosuppressive
             medications during the trial

             a. Patients who receive acute, low-dose, systemic corticosteroid medications (e.g., a
             one-time dose of dexamethasone for nausea) or for prevention of hypersensitivity
             reactions to contrast agents may be enrolled in the trial.

         26. The use of inhaled, nasal, ophthalmic, intra-articular, auricular or topical
             corticosteroids, physiologic replacement doses of glucocorticoids (i.e., for adrenal
             insufficiency), and mineralocorticoids (e.g. Fludrocortisone for adrenal
             insufficiency) is allowed.
      
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:up to 24 month
Safety Issue:
Description:The proportion of subjects with an ORR (complete (CR) or partial (PR) response) based on RECIST 1.1 evaluations as performed by the investigator

Secondary Outcome Measures

Measure:Progression Free survival (PFS)
Time Frame:at 6, 9 , 12, 18 and 24 months
Safety Issue:
Description:The time interval from first treatment to objective tumor progression or death
Measure:Overall Survival (OS)
Time Frame:12, 18 and 24 months
Safety Issue:
Description:Time interval from first treatment to death of any cause
Measure:Duration of Response
Time Frame:up to 24 month
Safety Issue:
Description:The time from response (CR or PR, whichever comes first) to investigator assessed progression using RECIST 1.1 or death
Measure:TEAEs
Time Frame:up to 24 month
Safety Issue:
Description:Incidence of any Treatment-Emergent Adverse Events

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Bavarian Nordic

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