Activity of Pembrolizumab Plus Enfortumab Vedotin in Collecting Duct and Renal Medullary Carcinoma
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- 入组人数
- 23
- 试验地点
- 1
- 主要终点
- ORR in patients treated with Pembrolizumab plus Enfortumab Vedotin
研究概览
简要总结
This is a single-arm, monocentric, phase II trial, enrolling patients with histological diagnosis of collecting duct carcinoma and renal medullary carcinoma with locally advanced or metastatic disease who will be treated with Pembrolizumab plus Enfortumab Vedotin.
Approximately, 23 patients will be enrolled. At screening, pre-existing archival primary and metastatic FFPE tumor specimen will be collected and submitted for central pathology review and translational analysis. All participants will undergo baseline screening imaging for clinical staging. Patients will be treated with Pembrolizumab q21 plus Enfortumab Vedotin 1,8q21 for 3 cycles (3 infusion of Pembrolizumab and 6 infusion of Enfortumab Vedotin) then radiological imaging will be repeated and patients with SD, PR or CR will continue pembrolizumab until disease progression, unacceptable toxicities or completion of treatment (17 cycles). Patients with progressive disease after 3 cycles of study intervention will be treated as per clinical practice.
Patients who will experience progressive disease during pembrolizumab monotherapy treatment could restart Enfortumab Vedotin.
The study will also involve collection of a blood sample taken at the commencement of treatment, at the first cycle, after cycle 3 and at the end of treatment or progression of disease, to be used for research purposes.
详细描述
BACKGROUND Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody (mAb) with high specificity of binding to the programmed cell death 1 (PD 1) receptor, thus inhibiting its interaction with programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 2 (PD-L2). Based on preclinical in vitro data, pembrolizumab has high affinity and potent receptor blocking activity for PD 1. Pembrolizumab has an acceptable preclinical safety profile and is in clinical development as an intravenous (IV) immunotherapy for advanced malignancies. Keytruda® (pembrolizumab) is indicated for the treatment of patients across a number of indications because of its mechanism of action to bind the PD-1 receptor on the T cell. For more details on specific indications refer to the Investigator brochure (IB).
Enfortumab Vedotin (EV) is an ADC comprised of a fully human anti-Nectin-4 IgG1 kappa mAb conjugated to the small molecule microtubule disrupting agent, MMAE, via a protease cleavable maleimidocaproyl vc linker. Conjugation takes place on cysteine residues that comprise the interchain disulfide bonds of the antibody to yield a product with a drug to antibody ratio of approximately 3:8.
EV binds to the V domain of Nectin-4 protein. In the presumed mechanism of action, the drug binds to the Nectin-4 protein on the cell surface and is internalized, causing proteolytic cleavage of the vc linker and intracellular release of MMAE. Free MMAE subsequently disrupts tubulin polymerization and leads to mitotic arrest.
PHARMACEUTICAL AND THERAPEUTIC BACKGROUND
Pembrolizumab. The importance of intact immune surveillance function in controlling outgrowth of neoplastic transformations has been known for decades. Accumulating evidence shows a correlation between tumor-infiltrating lymphocytes in cancer tissue and favorable prognosis in various malignancies. In particular, the presence of CD8+ T-cells and the ratio of CD8+ effector T cells/FoxP3+ regulatory T-cells (T-regs) correlates with improved prognosis and long-term survival in solid malignancies, such as ovarian, colorectal, and pancreatic cancer; hepatocellular carcinoma; malignant melanoma; and renal cell carcinoma. Tumor-infiltrating lymphocytes can be expanded ex vivo and reinfused, inducing durable objective tumor responses in cancers such as melanoma.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male/female participants who are at least 18 years of age on the day of signing informed consent with histologically confirmed diagnosis of metastatic or advanced Collecting Duct Carcinoma or Medullary Renal Cell Carcinoma will be enrolled in this study.
- •The participant (or legally acceptable representative if applicable) provides written informed consent for the trial.
- •Have measurable disease based on RECIST 1.
- •Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
- •Have confirmed histology diagnosis of Collecting Duct Carcinoma or Medullary Renal Cell Carcinoma by central pathology review.
- •Archival tumor tissue sample or newly obtained [core, incisional or excisional] biopsy of a tumor lesion not previously irradiated has been provided. 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
- •Evaluation of ECOG is to be performed within 7 days prior to the first dose of study intervention.
- •Have adequate organ function as defined in the following table (Table 4). Specimens must be collected within 10 days prior to the start of study intervention.
- •Participants who are HBsAg positive are eligible if they have received HBV anti-viral therapy for at least 4 weeks, and have undetectable HBV viral load prior to randomization.
- •Note: Participants should remain on anti-viral therapy throughout study intervention and follow local guidelines for HBV anti-viral therapy post completion of study intervention.
- •Hepatitis B screening tests are not required unless:
- •Known history of HBV infection
- •As mandated by local health authority
- •Participants with a history of HCV infection are eligible if HCV viral load is undetectable at screening.
- •Note: Participants must have completed curative anti-viral therapy at least 4 weeks prior to randomization.
- •Hepatitis C screening tests are not required unless:
- •a) Known history of HCV infection b) As mandated by local health authority
- •HIV-infected participants must have well-controlled HIV on ART, defined as:
- •Participants on ART must have a CD4+ T-cell count ≥350 cells/mm3 at the time of screening
- •Participants on ART must have achieved and maintained virologic suppression defined as confirmed HIV RNA level below 50 or the LLOQ (below the limit of detection) using the locally available assay at the time of screening and for at least 12 weeks before screening
- •It is advised that participants must not have had any AIDS-defining opportunistic infections within the past 12 months.
- •Participants on ART must have been on a stable regimen, without changes in drugs or dose modification, for at least 4 weeks before study entry (Day 1) and agree to continue ART throughout the study
- •The combination ART regimen must not contain any antiretroviral medications that interact with CYP3A4 inhibitors/inducers/substrates (https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers)
排除标准
- •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 2 weeks prior to treatment allocation.
- •Has received prior radiotherapy within 2 weeks of start of study intervention or radiation-related toxicities requiring corticosteroids. Note: Two weeks or fewer of palliative radiotherapy for non-CNS diseases permitted. The last radiotherapy treatment must have been performed at least 7 days before the first dose of study intervention.
- •Has received a live vaccine or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines is allowed.
- •Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration.
- •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.
- •Known additional malignancy that is progressing or has required active treatment within the past 2 years. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ, excluding carcinoma in situ of the bladder, that have undergone potentially curative therapy are not excluded. Participants with low-risk early-stage prostate cancer (T1-T2a, Gleason score ≤6, and PSA <10 ng/mL) either treated with definitive intent or untreated in active surveillance with stable disease 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 except replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid)
- •Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
- •Has an active infection requiring systemic therapy.
- •Has not adequately recovered from major surgery or has ongoing surgical complications.
- •Has a history or current evidence of any condition, therapy, or laboratory abnormality or other circumstance that might confound the results of the study, interfere with the participant's participation for the full duration of the study, such that it 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.
研究组 & 干预措施
Pembrolizumab + Enfortumab Vedotin
Patients will be treated with Pembrolizumab q21 plus Enfortumab Vedotin 1,8q21 for 3 cycles (3 infusion of Pembrolizumab and 6 infusion of Enfortumab Vedotin) then radiological imaging will be repeated and patients with SD, PR or CR will continue pembrolizumab until disease progression, or unacceptable toxicities or completion of treatment (17 cycles). Patients with progressive disease after 3 cycles of study intervention will be treated as per clinical practice.
Patients who will experience progressive disease during pembrolizumab monotherapy treatment could restart Enfortumab Vedotin.
干预措施: Pembrolizumab + Enfortumab Vedotin (Drug)
结局指标
主要结局
ORR in patients treated with Pembrolizumab plus Enfortumab Vedotin
时间窗: 24 Months
The proportion of patients who have a partial or complete response to Pembrolizumab + Enfortumab Vedotin
次要结局
- Progression-free survival (PFS) in patients treated with Pembrolizumab plus Enfortumab Vedotin(24 Months)
- Overall-survival (OS) in patients treated with Pembrolizumab plus Enfortumab Vedotin(48 Months)
- Number of Participants treated with Pembrolizumab + Enfortumab Vedotin who experience AEs/SAEs(24 Months)
研究者
Giuseppe Procopio
Director of GenitoUrinary Oncology
Fondazione IRCCS Istituto Nazionale dei Tumori, Milano