Study of Neoadjuvant Enfortumab Vedotin and Pembrolizumab in Cisplatin-eligible Upper Tract Urothelial Cancer

Trial Title: Study of Neoadjuvant Enfortumab Vedotin and Pembrolizumab in Cisplatin-eligible Upper Tract Urothelial Cancer

NCT ID: NCT06356155

Condition: Urothelial Carcinoma

Conditions: Official terms:
Carcinoma, Transitional Cell
Pembrolizumab

Conditions: Keywords:
Neoadjuvant
cisplatin-eligible

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: Drug
Intervention name: Enfortumab vedotin
Description: 1.25 mg/kg IV
Arm group label: Combination Therapy

Other name: PADCEV-EJFV

Intervention type: Drug
Intervention name: Pembrolizumab
Description: 200 mg IV
Arm group label: Combination Therapy

Other name: Keytruda

Summary: This trial is a multi-site, single-arm, phase 2 trial of neoadjuvant combination of enfortumab vedotin and pembrolizumab in cisplatin-eligible patients with high-grade localized/locally advanced cT1-4 N0-1 M0 upper tract urothelial cancer who are deemed eligible for curative-intent surgery (radical nephroureterectomy or distal ureterectomy) followed by adjuvant pembrolizumab.

Criteria for eligibility:
Criteria:
Inclusion Criteria: - Patients must have a diagnosis of high-grade upper tract (renal pelvis and/or ureter) urothelial carcinoma proven by biopsy or cytology 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 - Patients must not have any component of small cell carcinoma. Other variant histologic types are permitted provided the predominant (≥50%) subtype is urothelial carcinoma. - Imaging within 28 days prior to registration, patients with N0 or N1 disease may be included. - Patients must be considered to be a candidate for definitive surgery (nephroureterectomy or distal ureterectomy) with curative intent by the treating urologist. Lymph node dissection is strongly encouraged but its scope and determination will be at the discretion of the treating urologist. Details of the surgery such as bladder cuff removal are left to the discretion of the treating urologist. Robotic or open approaches are allowed. - Patients must be eligible for cisplatin. Cisplatin eligibility is defined as meeting all of the following criteria: Creatinine clearance ≥ 45 mL/min calculated by Cockcroft-Gault equation (using actual body weight) or measured by 24-hour urine collection, Absence of Grade ≥ 2 peripheral neuropathy, Absence of New York Heart Association Class III or higher heart failure. - Prior local endoscopic therapy for upper tract urothelial cancer is permitted if completed at least 6 months prior to the initiation of study treatment and if all toxicities from such therapy have improved to grade 1 or resolved. - Prior uro-oncologic history: History of or active non-invasive carcinoma or carcinoma in situ of the bladder/urethra or upper tract is allowed, Patients may have received prior intravesical chemotherapy or immunotherapy such as BCG, Prior neoadjuvant or adjuvant chemotherapy or antibody-drug conjugate for bladder cancer or invasive contralateral upper tract cancer is allowed but must have been completed ≥ 1 year prior to study registration. - Patients must be age ≥ 18 on the date of registration. - ECOG Performance Status 0-1 - Criteria for patients with hepatitis B or C are listed below. Hepatitis B and C screening tests are not required unless there is a known history of HBV or HCV infection or as mandated by local healthy authority. Hepatitis B positive subjects: Participants who are HBsAg positive are eligible if they have received HBV antiviral therapy for at least 4 weeks and have undetectable HBV viral load prior to enrollment, Participants should remain on anti-viral therapy throughout study intervention and follow local guidelines for HBV anti-viral therapy post completion of study intervention. Participants with history of HCV infection are eligible if HCV viral load is undetectable at screening. Participants must have completed curative anti-viral therapy at least 4 weeks prior to enrollment. - Patients must have adequate organ and bone marrow function as defined in Table 1. Specimens must be collected within 14 business days prior to start of study enrollment: Absolute neutrophil count (ANC)≥1500/µL, Platelets ≥100 000/µL, Hemoglobin≥9.0 g/dL or ≥5.6 mmol/L, Creatinine clearance ≥45 mL/min, Total bilirubin ≤1.5 × ULN OR direct bilirubin ≤ULN for participants with total bilirubin levels >1.5 × ULN or ≤3 ×ULN for patients with Gilbert's disease, AST (SGOT) and ALT (SGPT)≤2.5 × ULN, 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 - Women and men of reproductive potential must agree to use an effective contraceptive method during treatment and for 4 months after the last dose of study drug for women and for 4 months after the last dose of study drug for men. See Section 16.3, Appendix 3. Men must also refrain from donating sperm during this period. - Women of reproductive potential must have a negative pregnancy test within 14 days prior to registration and are not breastfeeding. - Patients must not have any other medical condition(s) that make(s) their participation in the study unadvisable in the opinion of the treating oncologist. - All patients must be informed of the investigational nature of this study. The patient must have the ability to understand and the willingness to sign a written informed consent document. Patients with impaired decision-making capacity who have a legally authorized representative or caregiver and/or family member available will also be considered eligible. Exclusion Criteria: - Prior exposure to immune-mediated therapy, including but not limited to, other anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4), anti-PD1, anti-PD-L1, anti-PD-L2 antibodies, and therapeutic anticancer vaccines. - Prior exposure to monomethyl auristatin E antibody-drug conjugates (MMAE ADC). - Patient is currently on or used immunosuppressive medication within 14 days prior to the first dose of pembrolizumab. The following are exceptions to this criterion: Intranasal, inhaled, intra-auricular, topical steroids, or local steroid injections (e.g. intra-articular injection), Use of chronic immunosuppressive agents at baseline at doses not to exceed more than prednisone 10 mg/day or equivalent, Steroids as premedications for hypersensitivity reactions (e.g. CT scan premedication). - Active or prior documented autoimmune or inflammatory disorders requiring immunosuppressive therapy within 2 years prior to registration. Exceptions are well-controlled hyper/hypothyroidism, celiac disease controlled by diet alone, diabetes mellitus type 1, alopecia, psoriasis, eczema, lichen planus, vitiligo, or similar skin/mucosa conditions. - Evidence of metastasis (N2-3 or M1) on axial imaging at baseline. - History of invasive, node positive, or metastatic bladder cancer OR invasive contralateral upper tract cancer within 2 years prior to registration. - Enrolled in another interventional clinical trial at the time of registration. - Patient has another active malignancy, unless potentially curative treatment has been completed with no evidence of malignancy for 1 year. The time requirement does not apply to participants who underwent successful definitive resection of non-melanoma skin cancers, superficial bladder cancer (described above in inclusion criteria 7), in situ cervical cancer, other in situ cancers, or either clinically insignificant per the investigator (e.g. ≤Gleason 3+4) on surveillance or previously treated prostate cancer without rising PSA and no plan to treat. NOTE: Patients with 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 has one kidney. - Patient is pregnant or lactating. - Has severe hypersensitivity (≥ Grade 3) to enfortumab vedotin, pembrolizumab, and/or any of its excipients. - 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-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines are live attenuated vaccines and are not allowed. - Has an active infection requiring systemic therapy. - Has a history or current evidence of any condition or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator. - Has a known history of Human Immunodeficiency Virus (HIV) infection. - Has a known history of active TB (Bacillus Tuberculosis). - Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. - Has had an allogenic tissue (e.g. hematopoietic stem cell transplant HSCT)/solid organ transplant. - Has any of the following: Prior exposure to MMAE ADCs , Moderate or severe liver dysfunction (does not meet hepatic function laboratory criteria outlined in Table 1), Uncontrolled diabetes mellitus as deemed by Hemoglobin A1c of 8 or greater.

Gender: All

Minimum age: 18 Years

Maximum age: N/A

Healthy volunteers: No

Locations:

Facility:
Name: University of Michigan Comprehensive Cancer Center

Address:
City: Ann Arbor
Zip: 48109
Country: United States

Contact:
Last name: Irene Tsung, M.D.

Phone: 734-936-4385
Email: itsung@umich.edu

Investigator:
Last name: Irene Tsung, MD
Email: Principal Investigator

Start date: October 2024

Completion date: July 2027

Lead sponsor:
Agency: University of Michigan Rogel Cancer Center
Agency class: Other

Source: University of Michigan Rogel Cancer Center

Record processing date: ClinicalTrials.gov processed this data on November 12, 2024

Source: ClinicalTrials.gov page: https://clinicaltrials.gov/ct2/show/NCT06356155