Trial Title:
Pembrolizumab and Enfortumab Vedotin With Pembrolizumab Prior to and After Radical Nephroureterectomy for High-Risk Upper Tract Urothelial Cancer
NCT ID:
NCT05775471
Condition:
Renal Pelvis and Ureter Urothelial Carcinoma
Conditions: Official terms:
Carcinoma
Carcinoma, Transitional Cell
Pembrolizumab
Immunoconjugates
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Not yet recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Procedure
Intervention name:
Biopsy
Description:
Undergo tissue biopsy
Arm group label:
Treatment (pembrolizumab, enfortumab vedotin)
Other name:
BIOPSY_TYPE
Other name:
Bx
Intervention type:
Procedure
Intervention name:
Biospecimen Collection
Description:
Undergo blood and urine collection
Arm group label:
Treatment (pembrolizumab, enfortumab vedotin)
Other name:
Biological Sample Collection
Other name:
Biospecimen Collected
Other name:
Specimen Collection
Intervention type:
Drug
Intervention name:
Enfortumab Vedotin
Description:
Given IV
Arm group label:
Treatment (pembrolizumab, enfortumab vedotin)
Other name:
AGS 22ME
Other name:
AGS-22M6E
Other name:
Anti-Nectin 4 ADC ASG-22CE
Other name:
Anti-nectin-4 Monoclonal Antibody-Drug Conjugate AGS-22M6E
Other name:
ASG-22CE
Other name:
Enfortumab Vedotin-ejfv
Other name:
Padcev
Intervention type:
Procedure
Intervention name:
MR Urography
Description:
Undergo MRU
Arm group label:
Treatment (pembrolizumab, enfortumab vedotin)
Other name:
Magnetic Resonance Urography
Intervention type:
Procedure
Intervention name:
Nephroureterectomy
Description:
Undergo nephroureterectomy
Arm group label:
Treatment (pembrolizumab, enfortumab vedotin)
Other name:
Ureteronephrectomy
Intervention type:
Biological
Intervention name:
Pembrolizumab
Description:
Given IV
Arm group label:
Treatment (pembrolizumab, enfortumab vedotin)
Other name:
Keytruda
Other name:
Lambrolizumab
Other name:
MK-3475
Other name:
SCH 900475
Summary:
This phase II clinical trial tests how well pembrolizumab plus enfortumab vedotin prior
to and after radical nephroureterectomy works in treating patients with high-risk upper
tract urothelial cancer. Immunotherapy with monoclonal antibodies, such as pembrolizumab,
may help the body's immune system attack the cancer, and may interfere with the ability
of tumor cells to grow and spread. Enfortumab vedotin (EV) is a monoclonal antibody,
enfortumab, linked to an anticancer drug called vedotin. It works by helping the immune
system to slow or stop the growth of cancer cells. Enfortumab attaches to a protein
called nectin-4 on cancer cells in a targeted way and delivers vedotin to kill them. It
is a type of antibody-drug conjugate. Radical nephroureterectomy (RNU) is the surgical
removal of a kidney and its ureter. Giving pembrolizumab plus enfortumab vedotin before
surgery may make the tumor smaller and may reduce the amount of normal tissue that needs
to be removed and giving pembrolizumab after surgery may kill any remaining cancer cells.
Detailed description:
PRIMARY OBJECTIVES:
I. To assess pathologic objective response rate (ORR; complete response [CR; pT0] and
partial response [PR; < pT2] rate) at the time of radical nephroureterectomy.
II. To assess recurrence-free survival post radical nephroureterectomy.
SECONDARY OBJECTIVE:
I. To describe the side effect profile, tolerability, and surgical complications in
patients receiving neoadjuvant pembrolizumab (pembro)/ enfortumab vedotin (EV) prior to
RNU.
EXPLORATORY OBJECTIVE:
I. Correlative studies will evaluate the predictive potential of imaging and
ureteroscopic response (visualization of tumor, biopsy, and cytology), and urinary,
serum, and tissue biomarkers to pathologic response.
OUTLINE:
Patients receive pembrolizumab intravenously (IV) and enfortumab vedotin IV on study.
Patients undergo radical nephroureterectomy and receive pembrolizumab IV on study
Patients also undergo magnetic resonance urogram (MRU) imaging and undergo blood, urine
and tissue sample collection throughout the study.
Criteria for 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 high-risk upper tract
urothelial carcinoma will be enrolled in this study
- Male participants: A male participant must agree to use a contraception during the
treatment period and for at least 6 months after the last dose of study treatment
and refrain from donating sperm during this period
- Female participants: A female participant is eligible to participate if she is not
pregnant, not breastfeeding, and at least one of the following conditions applies:
- Not a woman of childbearing potential (WOCBP) OR
- A WOCBP who agrees to follow the contraceptive guidance during the treatment
period and for at least 6 months after the last dose of study treatment
- Have provided archival tumor tissue sample or newly obtained core or excisional
biopsy of a tumor lesion not previously irradiated. Formalin-fixed, paraffin
embedded (FFPE) tissue blocks are preferred to slides. Newly obtained biopsies are
preferred to archived tissue
- 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
- Absolute neutrophil count (ANC) >= 1500/uL (Specimens must be collected within 10
days prior to the start of study intervention)
- Platelets >= 100000/uL (Specimens must be collected within 10 days prior to the
start of study intervention)
- Hemoglobin >= 9.0 g/dL or >= 5.6 mmol/L (Specimens must be collected within 10 days
prior to the start of study intervention)
- Creatinine =< 1.5 x upper limit of normal (ULN) OR measured or calculated creatinine
clearance (glomerular filtration rate (GFR) can also be used in place of creatinine
or creatinine clearance [CrCl]) (Specimens must be collected within 10 days prior to
the start of study intervention) >= 30 mL/min for participant with creatinine levels
> 1.5 x institutional ULN
- Total bilirubin =<1.5 ×ULN OR direct bilirubin =< ULN for participants with total
bilirubin levels > 1.5 × ULN (Specimens must be collected within 10 days prior to
the start of study intervention)
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])
and alanine aminotransferase (ALT) (serum glutamic-pyruvic transaminase [SGPT]) =<
2.5 x ULN (=< 5 x ULN for participants with liver metastases) (Specimens must be
collected within 10 days prior to the start of study intervention)
- 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 (Specimens must be collected within 10 days prior to the start
of study intervention)
Exclusion Criteria:
- 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
- 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 [could consider shorter interval for kinase inhibitors or other short
half-life drugs] prior to allocation
- Note: Participants must have recovered from all adverse events (AEs) due to
previous therapies to =< grade 1 or baseline. Participants with =< grade 2
neuropathy may be eligible. Participants with endocrine-related AEs grade =< 2
requiring treatment or hormone replacement may be eligible
- Note: If the participant had major surgery, the participant must have recovered
adequately from the procedure and/or any complications from the surgery prior
to starting study intervention
- 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-central
nervous system (CNS) disease
- Has received a live vaccine within 30 days prior to the first dose of study drug.
Examples of live vaccines include, but are not limited to, the following: measles,
mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus
Calmette-Guerin (BCG), and typhoid vaccine. Seasonal influenza vaccines for
injection are generally killed virus vaccines and are allowed; however, intranasal
influenza vaccines (eg, FluMist registered trademark) are live attenuated vaccines
and are not allowed
- Is currently participating in or has participated in a study of an investigational
agent or has used an investigational device within 4 weeks prior to the first dose
of study intervention
- 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 known additional malignancy that is progressing or has required active
treatment within the past 2 years. Participants with basal cell carcinoma of the
skin, squamous cell carcinoma of the skin, or carcinoma in situ (eg, breast
carcinoma, cervical cancer in situ) that have undergone potentially curative therapy
are not excluded
- Has known active CNS metastases and/or carcinomatous meningitis. Participants with
previously treated brain metastases may participate provided they are radiologically
stable, i.e. without evidence of progression for at least 4 weeks by repeat imaging
(note that the repeat imaging should be performed during study screening),
clinically stable and without requirement of steroid treatment for at least 14 days
prior to first dose of study intervention
- Has severe hypersensitivity (>= grade 3) to pembrolizumab and/or any of its
excipients
- Has active autoimmune disease that has required systemic treatment in the past 2
years (i.e. with use of disease modifying agents, corticosteroids or
immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or
physiologic corticosteroid replacement therapy for adrenal or pituitary
insufficiency, etc.) is not considered a form of systemic treatment and is allowed
- Has a history of (non-infectious) pneumonitis that required steroids or has current
pneumonitis
- Has an active infection requiring systemic therapy
- Has a known history of Human Immunodeficiency Virus (HIV) infection. However,
subjects who are on anti-retroviral therapy, have a viral load < 200
copies/milliliter, and CD4 count > 200/microliter, with a low risk of acquired
immunodeficiency syndrome (AIDS)-related outcomes will be considered for enrollment.
- Note: No HIV testing is required unless mandated by local health authority
- Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg]
reactive) or known active Hepatitis C virus (defined as HCV ribonucleic acid [RNA]
is detected) infection. Subjects who have underwent treatment with stable hepatitis
B (defined as HBV deoxyribonucleic acid [DNA] < 500 IU/mL) are eligible. Patients
with prior curative treatment of Hepatitis C virus are allowed if previously treated
> 2 weeks prior to treatment initiation and HCV RNA undetectable by established
laboratory values. Note: no testing for Hepatitis B and Hepatitis C is required
unless mandated by local health authority
- Has a history or current evidence of any condition, therapy, or laboratory
abnormality that might confound the results of the study, interfere with the
participant's participation for the full duration of the study, or is not in the
best interest of the participant to participate, in the opinion of the treating
investigator
- Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial
- Is pregnant or breastfeeding or expecting to conceive or father children within the
projected duration of the study, starting with the screening visit through 120 days
after the last dose of trial treatment
- Has had an allogenic tissue/solid organ transplant
- Subjects who have previously received enfortumab vedotin or other MMAE-based ADCs
- Subjects with an estimated life expectancy < 12 weeks
- Subjects with known severe (>= grade 3) hypersensitivity to any enfortumab vedotin
excipient contained in the drug formulation of enfortumab vedotin (including
histidine, trehalose dihydrate, and polysorbate 20). Subjects with known severe (>=
grade 3) hypersensitivity to any pembrolizumab excipient contained in the drug
formulations of pembrolizumab
- Subjects with another underlying medical condition that, in the opinion of the
investigator, would impair the ability of the subject to receive or tolerate the
planned treatment and follow-up; any known psychiatric or substance abuse disorders
that would interfere with cooperating with the requirements of the study
- Subjects with active keratitis or corneal ulcerations. Subjects with superficial
punctate keratitis are allowed if the disorder is being adequately treated in the
opinion of the investigator
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
UCLA / Jonsson Comprehensive Cancer Center
Address:
City:
Los Angeles
Zip:
90095
Country:
United States
Contact:
Last name:
Karim Chamie
Phone:
310-794-2858
Email:
kchamie@mednet.ucla.edu
Investigator:
Last name:
Karim Chamie
Email:
Principal Investigator
Start date:
December 1, 2024
Completion date:
December 1, 2028
Lead sponsor:
Agency:
Jonsson Comprehensive Cancer Center
Agency class:
Other
Collaborator:
Agency:
Merck Sharp & Dohme LLC
Agency class:
Industry
Collaborator:
Agency:
Seagen Inc.
Agency class:
Industry
Source:
Jonsson Comprehensive Cancer Center
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05775471
