Brief Title
Enfortumab Vedotin and Pembrolizumab in People With Bladder Cancer
Official Title
Enfortumab Vedotin in Combination With Pembrolizumab for Locally Advanced and/or Node Positive Urothelial Carcinoma Prior to Surgery (EV-ECLIPSE)
Brief Summary
This study will test whether enfortumab vedotin combined with pembrolizumab is an effective
treatment for people with bladder cancer (urothelial carcinoma) involving the lymph nodes who
are going to have surgery to remove their cancer (cystectomy). The researchers will look at
whether treatment with enfortumab vedotin and pembrolizumab before surgery can get rid of
cancer within the lymph nodes. They will also try to find out if this combination of drugs is
effective at shrinking participants' cancer before their surgery.
The researchers think that a combination of enfortumab vedotin and pembrolizumab may help
people with this disease because both drugs are designed to help the immune system attack and
kill cancer cells. The researchers think the drugs may be more effective if given in
combination rather than on their own.
Study Phase
Phase 2
Study Type
Interventional
Primary Outcome
Pathologic complete response rate (pCR Rate)
Secondary Outcome
Event free survival (EFS)
Condition
Urothelial Carcinoma
Intervention
Enfortumab vedotin
Study Arms / Comparison Groups
enfortumab vedotin in combination with pembrolizumab
Description: Enfortumab vedotin will be administered at 1.25 mg/kg on day 1 and day 8 of each 21-day cycle, for up to 6 cycles. Patients can proceed to surgery prior to completion of cycle 6 at the discretion of the investigator and urologist if toxicities prevent completion of 6 cycles of treatment. Enfortumab vedotin will be capped at a maximum dose of 125 mg for each infusion (for patients who weigh > 100 kg). Pembrolizumab will be administered on day 1 of each cycle, every 21 days, for 6 cycles. After completion of 3 cycles patients with have imaging assessment, and patients with progression of disease as measured by distant metastases will be removed from the study. At completion of cycle 6, patients will have repeat imaging assessment and proceed to cystectomy within 4-8 weeks. Following cystectomy, patients will resume pembrolizumab monotherapy on day 1 of each 21-day cycle for an additional 11 doses (Cycles 7-17), to complete 1 year of pembrolizumab therapy.
Publications
* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Recruitment Information
Recruitment Status
Drug
Estimated Enrollment
23
Start Date
June 2, 2022
Completion Date
June 2024
Primary Completion Date
June 2024
Eligibility Criteria
Inclusion Criteria:
- Male/female participants who are at least 18 years of age on the day of signing
informed consent with histologically confirmed diagnosis of muscle invasive bladder
cancer (previously known as transitional cell) carcinoma (i.e., cancer of the bladder,
renal pelvis, ureter, or urethra)
- Clinical Stage T2-T4, N1-N3, M0 OR cT1, N2-N3, M0
- Pathology:
- Representative urothelial carcinoma FFPE tumor specimens (tumor blocks or 20
unstained slides). Patients with < 20 slides may be enrolled after discussion
with the principal investigator.
- Muscle invasive urothelial carcinoma of the bladder histologically confirmed at
the enrolling institution from TURBT. (Urothelial carcinoma invading into the
prostatic stroma with no histologic muscle invasion is allowed provided the
extent of disease is confirmed via imaging and/or EUA.)
- Evidence of urothelial carcinoma from FNA of lymph node OR lymphadenopathy
suspicious for nodal disease on cross-sectional imaging, MRI, or u/s.
- Node positivity for eligibility will be defined as imaging read with suspicious
lymph node ≥ 1.0 cm in the short axis, with biopsy, as documented by the
radiologist at the treating center. While biopsy to confirm lymph node
involvement is preferred, patients without biopsy proven urothelial carcinoma in
lymph nodes may be enrolled if imaging shows a lymph node ≥ 1.0 cm in the short
axis, and with confirmation from the study principal investigator.
- Deemed medically appropriate for radical cystectomy with treatment response achieved,
as per MSK or participating site Attending Urologic Oncologist
- Platinum eligible and ineligible patients are permitted on study
- No prior treatments for muscle invasive or metastatic urothelial carcinoma
- Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
Evaluation of ECOG is to be performed within 7 days prior to the first dose of study
intervention.
- Estimated glomerular filtration rate (eGFR) ≥ 30 ml/min/1.73 m2 using the CKD-EPI
equation: eGFR = 141 x min(Scr/k, 1)a x max (Scr/k, 1)-1.209 x 0.993Age x 1.018 [if
female] x 1.159 [if black]
°Scr is serum creatinine, k is 0.7 for females and 0.9 for males, a is -0.329 for
females and -0.411 for males, min indicates the minimum of Scr/k or 1, and max
indicates the maximum of Scr/k or 1
- Be willing and able to provide written informed consent for the trial
- Contraception requirements:
1. Male participants:
A male participant must agree to use a contraception as detailed in Appendix 3 of
this protocol during the treatment period and for at least 120 days following the
last dose of treatment, corresponding to time needed to eliminate any study
treatment(s) (e.g. 5 terminal half-lives for pembrolizumab and enfortumab
vedotin) plus an additional 90 days (a spermatogenesis cycle) after the last dose
of study treatment and refrain from donating sperm during this period.
2. Female participants:
A female participant is eligible to participate if she is not pregnant (see Appendix 3),
not breastfeeding, and at least one of the following conditions applies:
i. Not a woman of childbearing potential (WOCBP) as defined in Appendix 3 OR ii. A WOCBP
who agrees to follow the contraceptive guidance in Appendix 3 during the treatment period
and for at least [90 days (corresponding to time needed to eliminate any study treatment(s)
(pembrolizumab and enfortumab vedotin) plus 30 days (a menstruation cycle)] after the last
dose of study treatment.
- Have adequate organ function as defined in the following table (Table 1). Specimens
must be collected within 14 days prior to the start of study treatment either prior to
consent or at the study screening visit.
- Hematological
- Absolute neutrophil count (ANC) ≥1500/μL
- Platelets ≥100 000/μL
- Hemoglobin ≥9.0 g/dL or ≥5.6 mmol/La
- Renal
°Measured or calculatedb creatinine clearance (GFR can also be used in place of
creatinine or CrCl) GFR or CrCl of ≥ 30 mL/min
- Hepatic
- Total bilirubin ≤1.5 ×ULN OR direct bilirubin ≤ULN for participants with total
bilirubin levels >1.5 × ULN
- AST (SGOT) and ALT (SGPT) ≤ 2.5 × ULN
- Coagulation °International normalized ratio (INR) OR prothrombin time (PT) Activated
partial thromboplastin time (aPTT) ≤1.5 × ULN unless participant is receiving
anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended
use of anticoagulants
ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); AST
(SGOT)=aspartate aminotransferase (serum glutamic oxaloacetic transaminase); GFR=glomerular
filtration rate; ULN=upper limit of normal.
a Criteria must be met without erythropoietin dependency and without packed red blood cell
(pRBC) transfusion within last 2 weeks. b eGFR as calculated by the CKD-EPI equation can be
used in place of the creatinine clearance
Note: This table includes eligibility-defining laboratory value requirements for treatment;
laboratory value requirements should be adapted according to local regulations and
guidelines for the administration of specific chemotherapies
Exclusion Criteria:
- Evidence of NYHA functional class III or IV heart disease
- Any of the following within 6 months prior to study drug administration: myocardial
infarction, severe/unstable angina, coronary/peripheral artery bypass graft,
symptomatic congestive heart failure, cerebrovascular accident, or transient ischemic
attack
- On-going cardiac dysrhythmias of NCI CTCAE Version 5.0 grade ≥ 2. However, stable
atrial fibrillation controlled medically or with a device (i.e. pacemaker) or prior
ablation is allowed
- Pre-existing sensory grade ≥ 2 neuropathy
- Major surgical procedure within 28 days prior to Cycle 1, Day 1 or anticipation of
need for a major surgical procedure aside from cystectomy during the course of the
study. Transurethral resection or other urinary tract diagnostic procedures,
excisional biopsy, IR-guided biopsy, or MEDIPORT placement are NOT defined as major
surgical procedures.
- Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.
- A WOCBP who has a positive urine pregnancy test within 72 hours prior to allocation.
If the urine test is positive or cannot be confirmed as negative, a serum pregnancy
test will be required.
Note: in the event that 72 hours have elapsed between the screening pregnancy test and the
first dose of study treatment, another pregnancy test (urine or serum) must be performed
and must be negative in order for subject to start receiving study medication.
- Is currently enrolled in another therapeutic trial. Patients cannot receive concurrent
treatment on another clinical trial; Patients are allowed to enroll on supportive care
trials or non-treatment trials (e.g. QOL, dietary survey studies) concurrently
- Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with
an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4,
OX 40, CD137).
- Has received prior systemic anti-cancer therapy including investigational agents
within 4 weeks prior to allocation.
- Prior treatment with an antibody drug conjugate for bladder cancer directed
therapy
- Prior systemic chemotherapy (prior intravesical therapy is allowed)
- Prior radiation therapy to the bladder
- Has received prior radiotherapy within 2 weeks of start of study intervention.
Participants must have recovered from all radiation-related toxicities, not require
corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted
for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease.
- Has received a live vaccine or live-attenuated vaccine within 30 days prior to the
first dose of study drug. 1. Examples of live vaccines include, but are not limited
to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow
fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza
vaccines for injection are generally killed virus vaccines and are allowed; however,
intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not
allowed. Administration of killed vaccines is allowed. COVID-19 vaccination is
permitted.
°Influenza vaccination should be given during influenza season only (approximately
October to March). Patients must not receive live, attenuated influenza vaccine (e.g.,
FluMist®) within 4 weeks prior to Cycle 1, Day 1 or at any time during the study.
- Has receieved intravesical bacillus Calmette-Guerin (BCG) within 4 weeks before Cycle
1, Day 1 14.
- Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
(in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of
immunosuppressive therapy within 7 days prior to the first dose of study drug.
- Has a history of poorly controlled human immunodeficiency virus (HIV) infection or
acquired immunodeficiency syndrome (AIDS) related illness. Patients with a history of
an aids-defining opportunistic infection within the last 12 months or who are on
prophylactic antimicrobials related to underlying HIV are not eligible. Patients with
a history of HIV and a CD4 T cell count of ≥350 are eligible to enroll in this study
with the approval of the study PI.
- Subjects with uncontrolled diabetes. Uncontrolled diabetes is defined as hemoglobin
A1c (HbA1c) ≥8% or HbA1c 7% to <8% with associated diabetes symptoms (polyuria or
polydipsia) that are not otherwise explained.
- Has a history of autoimmune disease, including but not limited to myasthenia gravis,
myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis,
inflammatory bowel disease, Wegener's granulomatosis, vascular thrombosis associated
with antiphospholipid syndrome, Sjogren's syndrome, Guillain-Barre syndrome, multiple
sclerosis, systemic vasculitis, or glomerulonephritis.
- Patients with history of autoimmune related hypothyroidism on stable dose of
thyroid replacement hormone may be eligible for this study
- Patients with controlled Type I diabetes mellitus on a stable dose of insulin may
be eligible for this study
- Has a history of idiopathic pulmonary fibrosis, pneumonitis/interstitial lung disease
that requires steroids or has current pneumonitis/interstitial lung disease (including
drug induced), organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic
organizing pneumonia, etc.), or evidence of active pneumonitis on screening chest
computed tomography (CT) scan
- 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
antibody
- Patients with past HBV infection or resolved HBV infection (defined as the
presence of hepatitis B core antibody [HBc Ab] and absence of HBsAg) are
eligible. HBV DNA must be obtained in these patients prior to Cycle 1, Day 1 and
confirmed to be negative.
- Patients positive for hepatitis C virus (HCV) antibody are eligible only if
polymerase chain reaction is negative for HCV RNA.
- Active tuberculosis or BCG infection
- Severe infections within 4 weeks prior to Cycle 1, Day 1, including but not limited to
hospitalization for complications of infection, bacteremia, or severe pneumonia
- Signs or symptoms of infection within 2 weeks prior to Cycle 1, Day 1. Abnormal
urinalysis does not constitute signs/symptoms of infection unless urine culture
obtained at screening grows ≥ 100,000 colonies of bacteria.
- Therapeutic oral or IV antibiotics within 2 weeks prior to Cycle 1, Day 1
- Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary
tract infection or to prevent chronic obstructive pulmonary disease exacerbation)
are eligible.
- Patients receiving antibiotics for active infection are not eligible
- Prior allogeneic stem cell or solid organ transplant
- AEs from prior anticancer therapy that have not resolved to Grade ≤ 1 except for
alopecia
- Patients with a history of or active bone marrow disorders expected to interfere with
study therapy (e.g. acute leukemias, accelerated/blast-phase chronic myelogenous
leukemia, chronic lymphocytic leukemia, Burkitt lymphoma, plasma cell leukemia, or
non-secretory myeloma)
- Known clinically significant liver disease, including active viral, alcoholic, or
other hepatitis; cirrhosis; and inherited liver disease
- Any other diseases, metabolic dysfunction, physical examination finding, or clinical
laboratory finding giving reasonable suspicion of a disease or condition that
contraindicates the use of an investigational drug or that may affect the
interpretation of the results or render the patient at high risk from treatment
complications
- Patients with active keratitis or history of corneal ulcers are excluded
- Patients with eczema, psoriasis, lichen simplex chronicus of vitiligo with
dermatologic manifestations only (e.g., patients with psoriatic arthritis would be
excluded) are permitted provided that they meet the following conditions:
- Rash must cover less than 10% of body surface area (BSA)
- Disease is well controlled at baseline and only requiring low potency topical
steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%, flucinolone
0.01%, desonide 0.05%, aclometasone dipropionate 0.05%)
- No acute exacerbations of underlying condition within the last 12 months (not
requiring psoralen plus ultraviolet A radiation [PUVA], methotrexate, retinoids,
biologic agents, oral calcineurin inhibitors; high potency or oral steroids)
- Malignancies other than the disease under study within 5 years prior to Cycle 1, Day
1, with the exception of those with a negligible risk of metastasis or death and with
expected curative outcome (such as adequately treated carcinoma in situ of the cervix,
basal or squamous cell skin cancer, localized prostate cancer treated surgically with
curative intent, or ductal carcinoma in situ treated surgically with curative intent)
or undergoing active surveillance per standard-ofcare management (e.g. prostate cancer
with Gleason score ≤ 7, and prostate-specific antigen [PSA] ≤ 10 mg/mL, etc).
Gender
All
Ages
18 Years - N/A
Accepts Healthy Volunteers
No
Contacts
David Aggen, MD, PhD, 646-422-4679, [email protected]
Location Countries
United States
Location Countries
United States
Administrative Informations
NCT ID
NCT05239624
Organization ID
21-316
Responsible Party
Sponsor
Study Sponsor
Memorial Sloan Kettering Cancer Center
Collaborators
Astellas Pharma US, Inc.
Study Sponsor
David Aggen, MD, PhD, Principal Investigator, Memorial Sloan Kettering Cancer Center
Verification Date
February 2023