Clinical Trials /

AGEN1884 Plus AGEN2034 Combined With Cisplatin-Gemcitabine for Muscle-Invasive Bladder Cancer

NCT04430036

Description:

This is a phase II trial to evaluate the tolerability, efficacy, and immune outcomes of AGEN1884 plus AGEN2034 concurrent with cisplatin and gemcitabine in the neoadjuvant treatment of muscle-invasive, non-metastatic bladder cancer prior to radical cystectomy.

Related Conditions:
  • Bladder Urothelial Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: AGEN1884 Plus AGEN2034 Combined With Cisplatin-Gemcitabine for Muscle-Invasive Bladder Cancer
  • Official Title: A Phase II Trial of Neoadjuvant AGEN1884 Plus AGEN2034 in Combination With Cisplatin-Gemcitabine for Muscle-Invasive Bladder Cancer Prior to Radical Cystectomy

Clinical Trial IDs

  • ORG STUDY ID: CTMS 19-0193
  • SECONDARY ID: HSC20200027H
  • NCT ID: NCT04430036

Conditions

  • Urinary Bladder Neoplasms

Interventions

DrugSynonymsArms
AGEN1884anti-CTLA-4 antibodyContinued Dosing
AGEN2034Anti-PD-1Continued Dosing
CisplatinGemzar, Platinol® and Platinol®-AQContinued Dosing
GemcitabineGebina, Gemalata, Gembin, Gembine, Gembio, Gemcel, GemcetinContinued Dosing

Purpose

This is a phase II trial to evaluate the tolerability, efficacy, and immune outcomes of AGEN1884 plus AGEN2034 concurrent with cisplatin and gemcitabine in the neoadjuvant treatment of muscle-invasive, non-metastatic bladder cancer prior to radical cystectomy.

Detailed Description

      We will begin with an initial safety run-in to establish the safety of the combination prior
      to expansion to the full planned phase II. The overall phase II will be an open-label, single
      arm study in two stages to evaluate the efficacy of the combination in pathologic downstaging
      of MIBC. Patients will receive four 21-day cycles of neoadjuvant therapy consisting of
      cisplatin and gemcitabine plus AGEN2034 in all 4 cycles and AGEN1884 in cycles 1 and 3.
      Patients will proceed to radical cystectomy within 10 weeks after the final dose of this
      therapy. The primary endpoint of pathologic tumor downstaging will be assessed at the time of
      cystectomy.
    

Trial Arms

NameTypeDescriptionInterventions
Safety Run-InExperimentalThe safety run-in of the study will first enroll three patients at the chosen dose and schedule of the combination. These first 3 patients will be followed to completion of day 1 cycle 2 of neoadjuvant therapy in the final patient in this cohort prior to enrollment and assessed for DLTs.If there are no DLTs in the first 3 patients, we will proceed to further accrual to stage I of phase II. If there is 1 DLT in the initial 3 patients, we will enroll 3 additional patients to the safety run-in. If a second DLT is experienced, the study will be terminated. If there is only 1 DLT in the 6 patients treated, further accrual can proceed.
  • AGEN1884
  • AGEN2034
  • Cisplatin
  • Gemcitabine
Initial DosingExperimentalAGEN1884 plus AGEN2034 with doses as defined from Phase I with cisplatin 70 mg/m2 day 1 and gemcitabine 1000 mg/m2 days 1 and 8 to a maximum of 4 cycles, for 17 participants.
  • AGEN1884
  • AGEN2034
  • Cisplatin
  • Gemcitabine
Continued DosingExperimentalAGEN1884 plus AGEN2034 with doses as defined from Phase I with cisplatin 70 mg/m2 day 1 and gemcitabine 1000 mg/m2 days 1 and 8 to a maximum of 4 cycles for an additional 19 participants.
  • AGEN1884
  • AGEN2034
  • Cisplatin
  • Gemcitabine

Eligibility Criteria

        Inclusion Criteria

          1. Diagnosis of muscle-invasive, non-metastatic urothelial carcinoma of the bladder,
             cT2-4, N0-1, M0

          2. Eligible to receive cisplatin-based chemotherapy, with eligibility defined as meeting
             any of the following criteria:

               1. Eastern Cooperative Oncology Group performance status of ¬0-1

               2. Creatinine clearance (CrCl) of >50 mL/min, as measured by 24-hour urine
                  collection or estimated by the CKD-EPI equation. Patients with CrCl between 50 -
                  60 mL/min are eligible for the study but will receive split dose cisplatin

               3. Grade < 2 hearing loss

               4. Grade < 2 peripheral neuropathy

               5. New York Heart Association Class </= II heart failure

          3. Eligible to receive gemcitabine as dosed here

          4. Patients must have organ and marrow function meeting the criteria below:

             Absolute neutrophil count > 2,000/mcL Hemoglobin > 9.0 mg/mL Platelets > 100,000/mcL
             Total bilirubin within normal limits or known to be elevated due to a benign
             conjugation defect such as Gilbert's syndrome, as evidenced by normal conjugated
             bilirubin level AST/ALT < 3X institutional normal limits Creatinine clearance (CrCl) >
             50 mL/min/1.73m2, as measured with 24 hr urine collection or estimated by CKD-EPI,
             whichever is greater

          5. Signed, written informed consents to allow transfer of tumor tissue and production of
             peptides and to receive experimental treatment and monitoring if agreeable, or
             monitoring without experimental treatment otherwise

          6. Age ≥18 years

          7. Available fresh tissue from surgical excision. If fresh tissue is not available,
             archival tissue may be used.

          8. Female subjects of childbearing potential must have a negative serum pregnancy test at
             screening (within 72 hours of first dose of study medication). Non-childbearing
             potential (other than by medical reasons) is defined as 1 of the following:

          9. ≥ 45 years of age and amenorrheic for >1 year by self-report.

         10. Amenorrheic for >2 years without a hysterectomy and oophorectomy, and
             follicle-stimulating hormone value in the postmenopausal range upon pretrial
             (screening) evaluation.

         11. Status post-hysterectomy, -oophorectomy, or -tubal ligation. If of childbearing
             potential, female subjects must be willing to use adequate birth control during the
             study, starting with the screening visit through 120 days after the last dose of study
             therapy.

        Male subjects with a female partner(s) of childbearing potential must agree to use a condom
        throughout the trial, starting with the screening visit through 120 days after the last
        dose of study therapy. Males with pregnant partners must agree to use a condom; no
        additional method of contraception is required for the pregnant partner.

        Note: Abstinence is acceptable for both female and male subjects if this is the subject's
        established and preferred contraception method.

        Exclusion Criteria

          1. Subjects must not have received anticancer medications or investigational drugs within
             the following intervals before first dose of study drug:

             a. ≤ 14 days for chemotherapy not used as SOC as defined here, targeted small molecule
             therapy, anticancer hormone therapy, or radiation therapy, with the following
             exceptions: i. Bisphosphonates and denosumab are permitted. ii. Novel imaging agents
             that have Phase I safety data and have not demonstrated therapeutic activity are
             permitted.

             b. ≤ 28 days for prior cancer immunotherapy, except intravesical therapy c. Prior use
             of a checkpoint inhibitor, ie anti-PD-1, anti-PD-L1, or anti-CTLA-4 antibody d. ≤ 28
             days for prior monoclonal antibody used for anticancer therapy, with the exception of
             denosumab e. ≤ 7 days for immunosuppressive treatment for any reason, with the
             following exceptions: i. Physiologic steroid replacement for adrenal insufficiency
             (e.g., <10 mg prednisone per day) is permitted.

             ii. Use of inhaled or topical corticosteroid for radiographic procedures is permitted.

             f. Systemic corticosteroids < 7 days are not allowed except as defined above. g. ≤ 28
             days before first dose of study drug for all other investigational study drugs or
             devices

          2. Has persisting toxicity related to prior therapy of National Cancer Institute Common
             Terminology Criteria for Adverse Events version 5.0 (NCI-CTCAE) Grade >1 severity.

             Note: Sensory neuropathy or alopecia of Grade ≤2 is acceptable.

          3. Has known severe hypersensitivity reactions to fully human monoclonal antibodies
             (NCI-CTCAE Version 5.0 Grade ≥3), any history of anaphylaxis, or uncontrolled asthma.

          4. Active or history of any autoimmune disease (subjects with diabetes type 1, vitiligo,
             psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are
             eligible). Patients with a history of inflammatory bowel disease (including Crohn's
             disease and ulcerative colitis) and autoimmune disorders such as rheumatoid arthritis,
             systemic progressive sclerosis [scleroderma], Systemic Lupus Erythematosus or
             autoimmune vasculitis [e.g., Wegener's Granulomatosis] are excluded from this study.

          5. Any condition requiring systemic treatment with corticosteroids (>10mg daily
             prednisone equivalents) or other immunosuppressive medications within 14 days prior to
             first dose of study drug. Inhaled steroids and adrenal replacement steroids doses
             >10mg daily prednisone equivalents are permitted in the absence of active autoimmune
             disease.

          6. Uncontrolled intercurrent illness, including but not limited to uncontrolled
             infection, interstitial lung disease or active, non-infectious pneumonitis,
             symptomatic congestive heart failure, unstable angina pectoris, uncontrolled cardiac
             arrhythmia, or social situations that would limit compliance with study requirements
             in the opinion of the treating investigator or medical monitor.

          7. History of intolerance or allergic reactions attributed to compounds of similar
             chemical or biologic composition to AGEN1884 or AGEN2034.

          8. Women who are pregnant or breastfeeding.

          9. Receipt of a live vaccine within 30 days prior to the first dose of study drug.

         10. Inability to adhere to the protocol.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Pathologic tumor downstaging of >T2 to pT0
Time Frame:22 Days
Safety Issue:
Description:pT0 or pCR, defined as eradication of all tumor from resected bladder and lymph node tissue, following neoadjuvant chemotherapy

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:The University of Texas Health Science Center at San Antonio

Trial Keywords

  • muscle-invasive, non-metastatic

Last Updated

June 10, 2020