Clinical Trials /

Testing the Addition of MEDI4736 (Durvalumab) to Chemotherapy Before Surgery for Patients With High-Grade Upper Urinary Tract Cancer

NCT04628767

Description:

This phase III trial compares the effect of adding durvalumab to chemotherapy versus chemotherapy alone before surgery in treating patients with upper urinary tract cancer. Durvalumab is a monoclonal antibody that may interfere with the ability of tumor cells to grow and spread. Chemotherapy drugs, such as methotrexate, vinblastine, doxorubicin cisplatin, and gemcitabine work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Adding durvalumab to chemotherapy before surgery may work better in shrinking the tumor compared to chemotherapy alone.

Related Conditions:
  • Renal Pelvis and Ureter Urothelial Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Testing the Addition of MEDI4736 (Durvalumab) to Chemotherapy Before Surgery for Patients With High-Grade Upper Urinary Tract Cancer
  • Official Title: A Phase III Trial of MED14736 (Durvalumab) and Chemotherapy for Patients With High Grade Upper Tract Urothelial Cancer Prior to Nephroureterectomy

Clinical Trial IDs

  • ORG STUDY ID: NCI-2020-09850
  • SECONDARY ID: NCI-2020-09850
  • SECONDARY ID: EA8192
  • SECONDARY ID: EA8192
  • SECONDARY ID: U10CA180820
  • NCT ID: NCT04628767

Conditions

  • Renal Pelvis and Ureter Urothelial Carcinoma

Interventions

DrugSynonymsArms
CisplatinAbiplatin, Blastolem, Briplatin, CDDP, Cis-diammine-dichloroplatinum, Cis-diamminedichloridoplatinum, Cis-diamminedichloro Platinum (II), Cis-diamminedichloroplatinum, Cis-dichloroammine Platinum (II), Cis-platinous Diamine Dichloride, Cis-platinum, Cis-platinum II, Cis-platinum II Diamine Dichloride, Cismaplat, Cisplatina, Cisplatinum, Cisplatyl, Citoplatino, Citosin, Cysplatyna, DDP, Lederplatin, Metaplatin, Neoplatin, Peyrone''s Chloride, Peyrone''s Salt, Placis, Plastistil, Platamine, Platiblastin, Platiblastin-S, Platinex, Platinol, Platinol- AQ, Platinol-AQ, Platinol-AQ VHA Plus, Platinoxan, Platinum, Platinum Diamminodichloride, Platiran, Platistin, PlatosinArm A (durvalumab, chemotherapy)
Doxorubicin Hydrochloride5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8, 9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, hydrochloride, (8S-cis)- (9CI), ADM, Adriacin, Adriamycin, Adriamycin Hydrochloride, Adriamycin PFS, Adriamycin RDF, ADRIAMYCIN, HYDROCHLORIDE, Adriamycine, Adriblastina, Adriblastine, Adrimedac, Chloridrato de Doxorrubicina, DOX, DOXO-CELL, Doxolem, Doxorubicin HCl, Doxorubicin.HCl, Doxorubin, Farmiblastina, FI 106, FI-106, hydroxydaunorubicin, RubexArm A (durvalumab, chemotherapy)
DurvalumabImfinzi, Immunoglobulin G1, Anti-(Human Protein B7-H1) (Human Monoclonal MEDI4736 Heavy Chain), Disulfide with Human Monoclonal MEDI4736 Kappa-chain, Dimer, MEDI-4736, MEDI4736Arm A (durvalumab, chemotherapy)
Gemcitabine HydrochloridedFdCyd, Difluorodeoxycytidine Hydrochloride, FF 10832, FF-10832, FF10832, Gemcitabine HCI, Gemzar, LY-188011, LY188011Arm C (durvalumab, gemcitabine hydrochloride)
MethotrexateAbitrexate, Alpha-Methopterin, Amethopterin, Brimexate, CL 14377, CL-14377, Emtexate, Emthexat, Emthexate, Farmitrexat, Fauldexato, Folex, Folex PFS, Lantarel, Ledertrexate, Lumexon, Maxtrex, Medsatrexate, Metex, Methoblastin, Methotrexate LPF, Methotrexate Methylaminopterin, Methotrexatum, Metotrexato, Metrotex, Mexate, Mexate-AQ, MTX, Novatrex, Rheumatrex, Texate, Tremetex, Trexeron, Trixilem, WR-19039Arm A (durvalumab, chemotherapy)
PegfilgrastimFilgrastim SD-01, filgrastim-SD/01, Fulphila, HSP-130, Jinyouli, Neulasta, Neulastim, Pegfilgrastim Biosimilar HSP-130, Pegfilgrastim Biosimilar Pegcyte, Pegfilgrastim-jmdb, SD-01, SD-01 sustained duration G-CSFArm A (durvalumab, chemotherapy)
Vinblastine Sulfate29060 LE, 29060-LE, Exal, Velban, Velbe, Velsar, VINCALEUKOBLASTINEArm A (durvalumab, chemotherapy)

Purpose

This phase III trial compares the effect of adding durvalumab to chemotherapy versus chemotherapy alone before surgery in treating patients with upper urinary tract cancer. Durvalumab is a monoclonal antibody that may interfere with the ability of tumor cells to grow and spread. Chemotherapy drugs, such as methotrexate, vinblastine, doxorubicin cisplatin, and gemcitabine work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Adding durvalumab to chemotherapy before surgery may work better in shrinking the tumor compared to chemotherapy alone.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To compare event-free survival (EFS) between patients with upper tract urothelial cancer
      (UTUC) randomized to neoadjuvant accelerated methotrexate, vinblastine, adriamycin, cisplatin
      (aMVAC) alone or in combination with MEDI4736 (durvalumab). (Cisplatin eligible patients
      [Arms A and B]) II. Evaluation of pathologic complete response at radical nephroureterectomy
      (RNU) (pathologic complete response [pCR], pT0N0/ Nx). (Cisplatin ineligible patients [Arm
      C]).

      SECONDARY OBJECTIVES:

      I. To assess pathologic complete response (pCR) at surgery. (Cisplatin eligible cohort) II.
      Event-free survival (EFS) will be evaluated for the cisplatin ineligible cohort as a
      secondary endpoint. (Cisplatin ineligible cohort) III. Overall survival in all, and by post
      chemotherapy response (ypCR, yp =< T1N0, yp >= T2Nany). (All patients) IV. To evaluate
      disease-free survival (DFS) in each arm separately. (All patients) V. To evaluate
      cancer-specific survival of patients in each arm separately. (All patients) VI. To evaluate
      renal function outcomes following systemic treatment and following surgery ([RNU) in each arm
      separately. (All patients) VII. To evaluate safety and tolerability of neoadjuvant aMVAC
      alone or in combination with MEDI4736 (durvalumab) prior to RNU. (All patients)

      OUTLINE: Patients eligible for cisplatin are randomized to Arms A or B. Patients ineligible
      for cisplatin are assigned to Arm C.

      ARM A: Patients receive durvalumab intravenously (IV) over 60 minutes on day 1 of
      chemotherapy cycles 1 and 3. Patients also receive methotrexate IV over 2-3 minutes,
      vinblastine sulfate IV, doxorubicin IV, cisplatin IV over at least 2 hours on day 1.
      Treatments repeat every 14 days for up to 4 cycles in the absence of disease progression or
      unacceptable toxicity. Within 21- 60 days after completion of systemic treatment, patients
      with continued lack of radiographic presence of metastatic or unresectable disease undergo
      surgery.

      ARM B: Patients also receive methotrexate IV over 2-3 minutes, vinblastine sulfate IV,
      doxorubicin IV, cisplatin IV over at least 2 hours on day 1. Treatments repeat every 14 days
      for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Within 21-
      60 days after completion of systemic treatment, patients with continued lack of radiographic
      presence of metastatic or unresectable disease undergo surgery.

      ARM C: Patients receive durvalumab IV over 60 minutes on day 1 and gemcitabine hydrochloride
      IV over 30 minutes on days 1 and 8. Treatment repeats every 21 days for up to 4 cycles in the
      absence of disease progression or unacceptable toxicity. Within 21- 60 days after completion
      of systemic treatment patients with continued lack of radiographic presence of metastatic or
      unresectable disease undergo surgery.

      After completion of study treatment, patients are followed up within 30 days and then every
      3-6 months for up to 5 years from study entry.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A (durvalumab, chemotherapy)ExperimentalPatients receive durvalumab IV over 60 minutes on day 1 of chemotherapy cycles 1 and 3. Patients also receive methotrexate IV over 2-3 minutes, vinblastine sulfate IV, doxorubicin IV, cisplatin IV over at least 2 hours on day 1. Treatments repeat every 14 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Within 21- 60 days after completion of systemic treatment, patients with continued lack of radiographic presence of metastatic or unresectable disease undergo surgery.
  • Cisplatin
  • Doxorubicin Hydrochloride
  • Durvalumab
  • Methotrexate
  • Pegfilgrastim
  • Vinblastine Sulfate
Arm B (chemotherapy)Active ComparatorPatients also receive methotrexate IV over 2-3 minutes, vinblastine sulfate IV, doxorubicin IV, cisplatin IV over at least 2 hours on day 1. Treatments repeat every 14 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Within 21- 60 days after completion of systemic treatment, patients with continued lack of radiographic presence of metastatic or unresectable disease undergo surgery.
  • Cisplatin
  • Doxorubicin Hydrochloride
  • Methotrexate
  • Pegfilgrastim
  • Vinblastine Sulfate
Arm C (durvalumab, gemcitabine hydrochloride)ExperimentalPatients receive durvalumab IV over 60 minutes on day 1 and gemcitabine hydrochloride IV over 30 minutes on days 1 and 8. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Within 21- 60 days after completion of systemic treatment, patients with continued lack of radiographic presence of metastatic or unresectable disease undergo surgery.
  • Durvalumab
  • Gemcitabine Hydrochloride

Eligibility Criteria

        Inclusion Criteria:

          -  STEP 1 REGISTRATION AND RANDOMIZATION

          -  Patient must have the ability to understand and the willingness to sign a written
             informed consent document. Patients with impaired decision-making capacity (IDMC) who
             have a legally authorized representative (LAR) or caregiver and/or family member
             available will also be considered eligible

          -  Patient must have a diagnosis of high grade upper tract urothelial carcinoma proven by
             biopsy within 60 days prior to registration with one of the following:

               -  Upper urinary tract mass on cross-sectional imaging or

               -  Tumor directly visualized during upper urinary tract endoscopy before referral to
                  medical oncology

                    -  NOTE: Biopsy is standard of care (SOC) and required for enrollment to study.
                       This is vital for best practice

          -  Leukocytes >= 3,000/mcL (obtained =< 14 days prior to registration)

          -  Platelets >= 100,000/mcL (obtained =< 14 days prior to registration)

          -  Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (or =< 2.5 x ULN
             for patients with Gilbert's disease) (obtained =< 14 days prior to registration)

          -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
             [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
             =< 2.5 x institutional ULN (obtained =< 14 days prior to registration)

          -  Hemoglobin (Hgb) >= 9 g/dL (obtained =< 14 days prior to registration)

               -  NOTE: Packed red blood transfusion is allowed to achieve this parameter as per
                  treating investigator

          -  Patient must have no evidence of metastatic disease or clinically enlarged lymph nodes
             (>= 1.0 cm short axis) on imaging required within 28 days prior to registration
             (solitary slightly enlarged lymph node with negative biopsy is allowed)

               -  NOTE: Patients with elevated alkaline phosphatase, calcium or suspicious bone
                  pain/tenderness should also undergo baseline bone scans to evaluate for bone
                  metastasis

          -  Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral
             therapy with undetectable viral load within 6 months are eligible for this trial

               -  NOTE: These patients must be stable on their anti-retroviral regimen with
                  evidence of at least two undetectable viral loads within the past 6 months on the
                  same regimen; the most recent undetectable viral load must be within the past 12
                  weeks. They must have a CD4 count of greater than 250 cells/mcL over the past 6
                  months on this same anti-retroviral regimen and must not have had a CD4 count <
                  200 cells/mcL over the past 2 years, unless it was deemed related to the cancer
                  and/or chemotherapy induced bone marrow suppression. They must not be currently
                  receiving prophylactic therapy for an opportunistic infection and must not have
                  had an opportunistic infection within the past 6 months

               -  NOTE: For patients who have received chemotherapy in the past 6 months, a CD4
                  count < 250 cells/mcL during chemotherapy is permitted as long as viral loads
                  were undetectable during this same chemotherapy. They must have an undetectable
                  viral load and a CD4 count >= 250 cells/mcL within 7 days of registration

          -  For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral
             load must be undetectable on suppressive therapy, if indicated

               -  NOTE: Testing for HIV, hepatitis B or hepatitis C is not required unless
                  clinically indicated

          -  Patients with a history of hepatitis C virus (HCV) infection must have been treated
             and have undetectable viral load. For patients with HCV infection who are currently on
             treatment, they are eligible if they have an undetectable HCV viral load

          -  Patients with known history or current symptoms of cardiac disease, or history of
             treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac
             function using the New York Heart Association Functional Classification. To be
             eligible for this trial, patients should be class 2B or better

          -  Patient must have a body weight of > 30 kg

          -  Patient must have a life expectancy of >= 12 weeks

          -  Patient must have a creatinine clearance > 15 ml/min as by Crockroft-Gault or 24-hour
             creatinine clearance within 28 days prior to registration

               -  NOTE: Patients will be assigned to cisplatin-ineligible and cisplatin-eligible
                  cohorts based on their creatinine clearance, Eastern Cooperative Oncology Group
                  (ECOG) performance status, and grade (if any) of peripheral neuropathy and
                  hearing loss in keeping with SOC cisplatin contraindications. Patients that are
                  cisplatin-eligible will be randomized to either Arm A or Arm B

                    -  Patients that meet the following criteria will be assigned to the
                       cisplatin-ineligible Arm C:

                         -  Creatinine clearance of > 15 ml/min and =< 50 ml/min

                         -  Patient must have an absolute neutrophil count (ANC) >= 1,000/mcL
                            obtained < 14 days prior to registration

                         -  Patient must have ECOG performance status 0-2

                    -  Patients that meet the following criteria will be randomized to
                       cisplatin-eligible Arm A or Arm B:

                         -  Patient must have an absolute neutrophil count (ANC) >= 1,500/mcL
                            obtained < 14 days prior to registration

                         -  Patient must have ECOG performance status 0-1

                         -  Patient must have left ventricular ejection fraction (LVEF) >= 50% by
                            (either multigated acquisition scan [MUGA] or 2-D echocardiogram)
                            within 28 days prior to randomization

                         -  Patient must not have peripheral neuropathy >= grade 2 or hearing loss
                            >= grade 3

        Exclusion Criteria:

          -  Patients must not have any component of small cell carcinoma. Other variant histologic
             types are permitted provided the predominant (>= 50%) subtype is urothelial carcinoma

          -  Patients must not be pregnant or breast-feeding due to the potential harm to an unborn
             fetus and possible risk for adverse events in nursing infants with the treatment
             regimens being used. All patients of childbearing potential must have a blood test or
             urine study within 14 days prior to registration to rule out pregnancy. A patient of
             childbearing potential is defined as any patient, regardless of sexual orientation or
             whether they have undergone tubal ligation, who meets the following criteria: 1) has
             achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral
             oophorectomy; or 3) has not been naturally postmenopausal (amenorrhea following cancer
             therapy does not rule out childbearing potential) for at least 24 consecutive months
             (i.e., has had menses at any time in the preceding 24 consecutive months)

          -  Patients of childbearing potential and sexually active patients must not expect to
             conceive or father children by using accepted and effective method(s) of contraception
             or by abstaining from sexual intercourse from the time of registration, while on study
             treatment and for at least 6 months after the last dose of protocol treatment

          -  Patient must not have another active (or within 2 years) second malignancy other than
             resected non-melanoma skin cancers, resected in situ breast, cervical or other in situ
             carcinoma, and either clinically insignificant per the investigator (e.g. =< Gleason
             3+4) on surveillance or previously treated prostate cancer with no rising prostate
             specific antigen (PSA) and no plan to treat

               -  NOTE: Patients with a prior or concurrent malignancy whose natural history or
                  treatment does not have the potential to interfere with the safety or efficacy
                  assessment of the investigational regimen are eligible for this trial. Patients
                  in whom concomitant or prior bladder/urethra predominant (>= 50%) urothelial
                  carcinoma have been surgically resected and demonstrated to be only non-invasive
                  cancer (< cT1N0) are eligible regardless of time elapsed

          -  Patient must not have any uncontrolled illness including, but not limited to, ongoing
             or active infection including tuberculosis (clinical evaluation that includes clinical
             history, physical examination and radiographic findings, and tuberculosis [TB] testing
             in line with local practice), symptomatic congestive heart failure (CHF), myocardial
             infarction (MI) in last 3 months, or unstable angina pectoris, significant
             uncontrolled cardiac arrhythmia, liver cirrhosis, interstitial lung disease, or
             psychiatric illness/social situations that would limit compliance with study
             requirements

          -  Patient must not have received prior radiation therapy to >= 25% of the bone marrow
             for other diseases

          -  Patient must not have received prior systemic anthracycline therapy

               -  NOTE: Patients who have received prior intravesical chemotherapy at any time for
                  non-muscle invasive urothelial carcinoma of the bladder are eligible

          -  Patient must not have an active autoimmune disease requiring immunosuppressive therapy
             within 2 years prior to registration or a history of inflammatory bowel disease
             (inflammatory bowel disease [IBD], colitis, or Crohn's disease), systemic lupus
             erythematosus, Sarcoidosis syndrome, Wegener syndrome or immune-related pneumonitis or
             interstitial lung disease. Patients with well-controlled hyper/hypothyroidism, celiac
             controlled by diet alone, diverticulosis, diabetes mellitus type I, vitiligo,
             alopecia, psoriasis, eczema, lichen planus, or similar skin/mucosa condition are
             eligible

          -  Patient must not be on or have used immunosuppressive medication within 14 days before
             the first dose of MEDI4736 (MEDI4736 (durvalumab). The following are exceptions to
             this criterion:

               -  Intranasal, inhaled, intra-auricular, topical steroids, or local steroid
                  injections (e.g. intra-articular injection

               -  Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of
                  prednisone or its equivalent at the time of enrollment

               -  Steroids as premedications for hypersensitivity reactions (e.g. computed
                  tomography [CT] scan premedication)

          -  Patient must not have a concomitant primary urothelial carcinoma of the bladder and/or
             urethra

               -  NOTE: Patients in whom concomitant or prior bladder/urethra predominant (>= 50%)
                  urothelial carcinoma have been surgically resected and demonstrated to be only
                  non-invasive cancer (< cT1N0) are eligible regardless of time elapsed

          -  Patient must not have prior history of muscle-invasive urothelial carcinoma with or
             without systemic chemotherapy (T2-4a and/or N1) within 2 years prior to registration

               -  NOTE: Patients who have no evidence of disease (NED) for more than 2 years from
                  the latest therapy (surgery, radiation, chemotherapy, or clinical trial) are
                  eligible

          -  Patient must not have received live attenuated vaccine within 30 days prior to the
             first dose of MEDI4736 (durvalumab), while on protocol treatment and within 30 days
             after the last dose of MEDI4736 (durvalumab)

          -  Patient must not have had a major surgical procedure (as defined by the Investigator)
             within 28 days prior to the first dose of protocol therapy

          -  Patient must not have a history of allogenic organ transplantation
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Event-free survival (EFS) (Cisplatin eligible cohort)
Time Frame:From randomization to the earliest of systemic recurrence, disease progression, or death from any cause, assessed up to 5 years
Safety Issue:
Description:EFS events in this trial will be defined as disease recurring outside of the bladder, urethra, or contralateral upper tract.

Secondary Outcome Measures

Measure:pCR (Cisplatin-eligible cohort)
Time Frame:Up to 5 years
Safety Issue:
Description:
Measure:EFS (cisplatin-ineligible cohort)
Time Frame:From randomization to the earliest of systemic recurrence, disease progression, or death from any cause, assessed up to 5 years
Safety Issue:
Description:Will be characterized using the Kaplan-Meier method.
Measure:Overall survival (OS)
Time Frame:From registration to death from any cause, assessed up to 5 years
Safety Issue:
Description:OS will be evaluated by arm, post chemotherapy response (ypCR, stage yp =< T1N0, yp >= T2N0), as well as stage (ypCR and > ypCR) within and across treatment arms. Will be estimated using Kaplan-Meier method.
Measure:Urothelial cancer-free survival or disease-free survival
Time Frame:From the date of surgery to the earlier of a return of upper tract urothelial cancer (UTUC) or death from any cause, assessed up to 5 years
Safety Issue:
Description:A return of UTUC includes non-muscle invasive recurrences, pathologic T2 or higher muscle-invasive recurrences specifically in the urinary tract, metastatic disease outside the urinary tract, or death. Patients alive without documented UTUC will be censored at the date of last disease assessment.
Measure:Cancer-specific survival
Time Frame:From registration to death due to cancer; deaths due to other causes will be counted as competing events, assessed up to 5 years
Safety Issue:
Description:Cancer-specific survival will be analyzed using Gray's method and cumulative incidence estimates will be reported.
Measure:Renal function outcomes following systemic treatment and following radical nephroureterectomy
Time Frame:Post chemotherapy and post surgery
Safety Issue:
Description:The proportion of patients with renal insufficiency (creatinine [CrCl] < 60 ml/min) post chemotherapy and post nephroureterectomy as well as the proportion of patients with renal function improvement (CrCl < 60 ml/min at baseline and CrCl >= 60 ml/min on study) will be reported along with exact binomial confidence intervals. The distribution of changes in renal function post chemotherapy as well as post surgery from baseline will also be reported. The analysis of renal function outcomes will be performed among patients who receive at least one dose of study therapy.
Measure:Incidence of adverse events
Time Frame:Up to 30 days post surgery
Safety Issue:
Description:Toxicity will be evaluated in all treated patients.

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

November 16, 2020