NCT04879329招募中2 期
A Phase 2 Multi-Cohort, Open-Label, Multi-Center Clinical Study Evaluating the Efficacy and Safety of Disitamab Vedotin (RC48-ADC) Alone or in Combination With Pembrolizumab in Subjects With Locally-Advanced Unresectable or Metastatic Urothelial Carcinoma That Expresses HER2
干预措施
相关药物
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 372
- 试验地点
- 406
- 主要终点
- Confirmed Objective Response Rate (cORR) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (v1.1) by blinded independent central review (BICR) (Cohorts A, B, C, and G)
研究概览
简要总结
This study is being done to see if a drug called disitamab vedotin, alone or with pembrolizumab, works to treat HER2 expressing urothelial cancer. It will also test how safe the drug is for participants.
Participants will have cancer that has spread in the body near where it started (locally advanced) and cannot be removed (unresectable) or has spread through the body (metastatic).
It will also study what side effects happen when participants get the drug. A side effect is anything a drug does to your body besides treating the disease.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 65+ years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Cohorts A and B
- •Histopathologically-confirmed, locally-advanced, unresectable or metastatic urothelial cancer (LA/mUC), including UC originating from the renal pelvis, ureters, bladder, or urethra
- •Participants must have received only 1 or 2 lines of prior systemic treatment for LA/mUC, including 1 line of platinum-containing chemotherapy
- •At least one measurable lesion by investigator assessment based on RECIST version 1.
- •HER2-expression status determined by the central laboratory to be IHC 1+, 2+ or 3+, in the provided tumor sample
- •Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1
- •Histopathologically-confirmed LA/mUC, including UC originating from the renal pelvis, ureters, bladder, or urethra
- •No prior systemic therapy for LA/mUC
- •Neoadjuvant or adjuvant therapy, including PD-(L)1 inhibitors, is acceptable, if disease recurrence/progression occurred more than 12 months after the last dose of systemic therapy
- •At least one measurable lesion by investigator assessment based on RECIST v1.
- •Participant is eligible to receive cisplatin- or carboplatin- containing chemotherapy per investigator evaluation
- •HER2-expression status determined by the central laboratory to be IHC 1+, 2+ or 3+, on the provided tumor tissue sample
- •ECOG performance status of 0, 1, or 2
- •Histopathologically-confirmed LA/mUC, including UC originating from the renal pelvis, ureters, bladder, or urethra
- •Based on a participant's eligibility to receive treatment with standard of care therapies in Japan, participants must have received all of the following lines of therapy for LA/mUC:
- •a. One prior line of platinum-containing chemotherapy.
- •b. Prior therapy with PD-(L)1 inhibitors as (neo)adjuvant therapy, first-line maintenance therapy or as second line treatment.
- •c. Prior enfortumab vedotin therapy.
- •At least one measurable lesion by investigator assessment based on RECIST v1.
- •ECOG performance status of 0 or 1
- •Histopathologically-confirmed LA/mUC, including UC originating from the renal pelvis, ureters, bladder, or urethra
- •No prior systemic therapy for LA/mUC
- •Neoadjuvant or adjuvant therapy, including PD-(L)1 inhibitors, is acceptable, if disease recurrence/progression occurred more than 12 months after the last dose of systemic therapy.
- •At least one measurable lesion by investigator assessment based on RECIST v1.
- •Participant is eligible to receive cisplatin- or carboplatin- containing chemotherapy per investigator evaluation
- •HER2-expression status determined by the central laboratory to be IHC 1+, 2+ or 3+, in the provided tumor sample
- •ECOG performance status of 0 or 1
- •Histopathologically-confirmed, locally-advanced, unresectable or metastatic urothelial cancer (LA/mUC), including UC originating from the renal pelvis, ureters, bladder, or urethra
- •Participants must have received only 1 or 2 lines of prior systemic treatment for LA/mUC, including 1 line of therapy containing enfortumab vedotin as monotherapy or in combination with pembrolizumab
- •The last administration of enfortumab vedotin must be 90 days from the start of study treatment. Intervening therapies are allowed between the final dose of enfortumab vedotin and the start of disitamab vedotin.
- •At least one measurable lesion by investigator assessment based on RECIST version 1.
- •HER2-expression status determined by the central laboratory to be IHC 1+, 2+ or 3+, in the provided tumor sample
- •Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1
排除标准
- •Cohorts A and B
- •Known hypersensitivity to disitamab vedotin or any of their components
- •Prior antitumor treatment (including chemotherapy, radiotherapy, targeted therapy, immunotherapy etc.) within 2 weeks of start of study (defined as Cycle 1 Day 1 for Cohorts A and B)
- •Toxicity from a previous treatment has not returned to Grades 0 or 1 (except for Grade 2 alopecia)
- •Prior MMAE-based ADCs (eg, enfortumab vedotin) or HER2-directed therapy
- •Major surgery that has not fully recovered within 4 weeks prior to dose administration
- •Peripheral sensory or motor neuropathy ≥ Grade 2 at baseline
- •Known hypersensitivity to disitamab vedotin, pembrolizumab, or any of their components
- •Prior antitumor treatment (including chemotherapy, radiotherapy, targeted therapy, immunotherapy etc.) within 2 weeks of start of study defined as Cycle 1 Day 1 for the single-arm part of Cohort C and as randomization date for the randomized part of Cohort C)
- •Toxicity from a previous treatment has not returned to Grades 0 or 1 (except for Grade 2 alopecia)
- •Prior MMAE-based ADCs (eg, enfortumab vedotin) or HER2-directed therapy
- •Major surgery that has not fully recovered within 4 weeks prior to dose administration
- •Peripheral sensory or motor neuropathy ≥ Grade 2 at baseline
- •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 the first dose of study drug
- •Participants who have previously received any prior treatment with an agent directed to another stimulatory or co-inhibitory T cell receptor (including but not limited to CD137 agonists, CAR-T cell therapy, CTLA-4 inhibitors, or OX-40 agonists) are excluded.
- •Known hypersensitivity to disitamab vedotin or any of their components
- •Prior antitumor treatment (including chemotherapy, radiotherapy, targeted therapy, immunotherapy etc.) within 2 weeks of start of study (defined as Cycle 1 Day 1 for Cohort D)
- •Toxicity from a previous treatment has not returned to Grades 0 or 1 (except for Grade 2 alopecia)
- •Prior HER2-directed therapy
- •Any prior history of ≥ Grade 3 non-hematological AEs related to prior therapy
- •Major surgery that has not fully recovered within 4 weeks prior to dose administration
- •Peripheral sensory or motor neuropathy ≥ Grade 1 at baseline
- •Known hypersensitivity to disitamab vedotin, pembrolizumab, or any of their components
- •Prior antitumor treatment (including chemotherapy, radiotherapy, targeted therapy, immunotherapy etc.) within 2 weeks of start of study (defined as Cycle 1 Day 1 for Cohort E)
- •Toxicity from a previous treatment has not returned to Grades 0 or 1 (except for Grade 2 alopecia)
- •Any prior history of ≥ Grade 3 non-hematological AEs related to prior therapy
- •Prior MMAE-based ADCs (eg, enfortumab vedotin) or HER2-directed therapy
- •Major surgery that has not fully recovered within 4 weeks prior to dose administration
- •Peripheral sensory or motor neuropathy ≥ Grade 1 at baseline
- •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 the first dose of study drug
- •Known hypersensitivity to disitamab vedotin or any of their components
- •Prior antitumor treatment (including chemotherapy, radiotherapy, targeted therapy, immunotherapy etc.) within 2 weeks of start of study (defined as Cycle 1 Day 1 for Cohort G)
- •Toxicity from a previous treatment has not returned to Grades 0 or 1 (except for Grade 2 alopecia)
- •Prior HER2-directed therapy
- •Major surgery that has not fully recovered within 4 weeks prior to dose administration
- •Peripheral sensory or motor neuropathy ≥ Grade 2 at baseline
- •There are additional inclusion and exclusion criteria. The study center will determine if criteria for participation are met.
研究组 & 干预措施
Cohort A - DV monotherapy for HER2-positive tumor types
Experimental
Disitamab vedotin monotherapy
干预措施: disitamab vedotin (Drug)
Cohort B - DV monotherapy for HER2-low tumor types
Experimental
Disitamab vedotin monotherapy
干预措施: disitamab vedotin (Drug)
Cohort C - Non-randomized combination therapy
Experimental
Disitamab vedotin + pembrolizumab
干预措施: pembrolizumab (Drug)
Cohort C - Non-randomized combination therapy
Experimental
Disitamab vedotin + pembrolizumab
干预措施: disitamab vedotin (Drug)
Cohort C - Randomized combination therapy
Experimental
Disitamab vedotin + pembrolizumab
干预措施: disitamab vedotin (Drug)
Cohort C - Randomized combination therapy
Experimental
Disitamab vedotin + pembrolizumab
干预措施: pembrolizumab (Drug)
Cohort C - Randomized monotherapy
Experimental
Disitamab vedotin monotherapy
干预措施: disitamab vedotin (Drug)
Cohort G - DV monotherapy
Experimental
Disitamab vedotin
干预措施: disitamab vedotin (Drug)
Cohort D - DV monotherapy (Japan only)
Experimental
Disitamab vedotin monotherapy
干预措施: disitamab vedotin (Drug)
Cohort E - DV combination therapy (Japan only)
Experimental
Disitamab vedotin + pembrolizumab
干预措施: pembrolizumab (Drug)
Cohort E - DV combination therapy (Japan only)
Experimental
Disitamab vedotin + pembrolizumab
干预措施: disitamab vedotin (Drug)
结局指标
主要结局
Confirmed Objective Response Rate (cORR) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (v1.1) by blinded independent central review (BICR) (Cohorts A, B, C, and G)
时间窗: Duration of treatment; approximately 2 years
The proportion of participants with confirmed complete response (CR) or partial response (PR) according to RECIST v1.1
Incidence of adverse events (AEs) (Cohorts D and E)
时间窗: Approximately 2 years
Any untoward medical occurrence in a clinical investigational participant administered a medicinal product and which does not necessarily have a causal relationship with this treatment.
Incidence of dose alterations (Cohorts D and E)
时间窗: Approximately 2 years
Incidence of laboratory abnormalities (Cohorts D and E)
时间窗: Approximately 2 years
To be summarized using descriptive statistics.
Incidence of electrocardiogram (ECG) abnormalities (Cohorts D and E)
时间窗: Approximately 2 years
Change from baseline of left ventricular ejection fraction (LVEF) (Cohorts D and E)
时间窗: Approximately 2 years
Pharmacokinetic (PK) parameter - Area under the curve (AUC) (Cohorts D and E)
时间窗: Through 30-37 days following the last dose of DV; up to approximately 2 years
To be summarized using descriptive statistics.
PK parameter - Maximum concentration (Cmax) (Cohorts D and E)
时间窗: Through 30-37 days following the last dose of DV; up to approximately 2 years
To be summarized using descriptive statistics.
PK parameter - Time to maximum concentration (Tmax) (Cohorts D and E)
时间窗: Through 30-37 days following the last dose of DV; up to approximately 2 years
To be summarized using descriptive statistics.
PK parameter - Trough concentration (Ctrough) (Cohorts D and E)
时间窗: Through 30-37 days following the last dose of DV; up to approximately 2 years
To be summarized using descriptive statistics.
次要结局
- cORR per RECIST v1.1 by investigator assessment (Cohorts A, B, C, and G)(Duration of treatment; approximately 2 years)
- Confirmed Duration of Response (DOR) per RECIST v1.1 by BICR (Cohorts A, B, C, and G)(From start of treatment to completion of response assessment; approximately 2 years)
- Confirmed DOR per RECIST v1.1 by investigator assessment (Cohorts A, B, C, and G)(From start of treatment to completion of response assessment; approximately 2 years)
- Progression-free survival (PFS) per RECIST v1.1 by BICR (Cohorts A, B, C, and G)(From start of treatment to completion of response assessment; approximately 2 years)
- PFS per RECIST v1.1 by investigator assessment (Cohorts A, B, C, and G)(From start of treatment to completion of response assessment; approximately 2 years)
- Disease control rate (DCR) per RECIST v1.1 by BICR (Cohorts A, B, C, and G)(From start of treatment to completion of response assessment; approximately 2 years)
- DCR per RECIST v1.1 by investigator (Cohorts A, B, C, and G)(From start of treatment to completion of response assessment; approximately 2 years)
- Overall survival (OS) (Cohorts A, B, C, and G)(Duration of study; approximately 3 years)
- Incidence of adverse events (AEs) (Cohorts A, B, C, and G)(Approximately 2 years)
- Incidence of dose alterations (Cohorts A, B, C, and G)(Approximately 2 years)
- Incidence of laboratory abnormalities (Cohorts A, B, C, and G)(Approximately 2 years)
- Incidence of ECG abnormalities (Cohorts A, B, C, and G)(Approximately 2 years)
- Change from baseline of LVEF (Cohorts A, B, C, and G)(Approximately 2 years)
- PK parameter - AUC (Cohorts A, B, C, and G)(Through 30-37 days following the last dose of DV; up to approximately 2 years)
- PK parameter - Cmax (Cohorts A, B, C, and G)(Through 30-37 days following the last dose of DV; up to approximately 2 years)
- PK parameter - Tmax (Cohorts A, B, C, and G)(Through 30-37 days following the last dose of DV; up to approximately 2 years)
- PK parameter - Ctrough (Cohorts A, B, C, and G)(Through 30-37 days following the last dose of DV; up to approximately 2 years)
- PK parameter of pembrolizumab - Cmax (Cohort E)(Through 30-37 days following the last dose of DV; up to approximately 2 years)
- Incidence of anti-drug antibodies (ADAs) against disitamab vedotin (All Cohorts)(Through 30-37 days following the last dose of DV; up to approximately 2 years)
- Incidence of anti-drug antibodies (ADAs) against pembrolizumab (Cohorts C and E)(Through 30-37 days following the last dose of DV; up to approximately 2 years)
- Incidence of neutralizing antibodies (NABs) against disitamab vedotin (All Cohorts)(Through 30-37 days following the last dose of DV; up to approximately 2 years)
研究者
Seagen Trial Information Support
Scientific
Seagen Inc.
研究点 (406)
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