RC48-G001 is a phase 2, multi-cohort, open-label, multi-center clinical study evaluating the antitumor activity, safety, pharmacokinetics (PK), and immunogenicity of disitamab vedotin monotherapy or disitamab vedotin in combination with pembrolizumab in adult subjects with locally advanced or metastatic urothelial cancer (LA/mUC) that expresses HER2 (HER2 IHC ≥ 1+).
Subjects will be enrolled in Cohorts A or B depending on the level of HER2 expression (investigational IHC assay) and HER2 gene amplification (investigational ISH assay): Cohort A – HER2-positive (IHC 3+, or IHC 2+ and ISH positive) and Cohort B – HER2-low (IHC 2+ and ISH negative, or IHC 1+). A total of approximately 150 subjects will be enrolled in Cohorts A and B, with approximately 75 subjects in each cohort.
Cohort C – approximately 150 subjects will be randomized in a 1:1 ratio (stratified by HER2 status [HER2-positive: IHC 3+, or IHC 2+ and ISH-positive; and HER2-low: IHC 2+ and ISH negative, or IHC 1+]) to either disitamab vedotin combined with pembrolizumab or disitamab vedotin monotherapy.
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Answer a 2-minute questionnaire and speak to a study representative.
A first step as you consider connecting with a Principal Investigator is to answer a 2-minute online questionnaire about your interest and willingness to be contacted. If your answers show the study might be a good fit for you and your patient, you may choose to have your contact information shared with a study clinic that you select for further discussion.
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Your answers to these questions will only be linked to you if your responses indicate that you would like to be connected with a Principal Investigator and you choose to share your contact information with the study clinic. Pfizer study team members and our partners will have access to reports containing aggregated data that will not be directly linked back to you. Only the study staff can determine if your patient meets the study’s eligibility criteria and is able to enroll in the study.
Arms and Interventions
Cohort A
Population and HER2 Status:
Previously treated LA/mUC HER2-positive: IHC 3+, or IHC 2+ and ISH-positive
Open label study treatment, IV every 2 weeks:
Disitamab vedotin (monotherapy)
Cohort C
Population and HER2 Status:
Treatment-naïve LA/mUC HER2 expressing (HER2 IHC ≥1+)
Combination therapy:
Drug: Disitamab vedotin
Given into the vein (IV; intravenous) every 2 weeks.
Drug: Pembrolizumab
Given by IV on Day 1 of each 6-week cycle.
Inclusion criteria
This is not a complete list of inclusion and exclusion criteria. Please connect with a Principal Investigator for further information.
Cohort A
- 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 measureable lesion by investigator assessment based on RECIST version 1.1
- HER2-expression status determined by the central laboratory to be IHC 3+, or IHC 2+ and ISH-positive, in the provided tumor sample.
- Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1.
Cohort C
- Histopathologically-confirmed LA/mUC, including UC originating from the renal pelvis, ureters, bladder, or urethra
- At least one measureable lesion by investigator assessment based on RECIST v1.1.
- Participant is eligible to receive cisplatin -or carboplatin- containing chemotherapy per investigator evaluation
- HER2-expression status determined by the central laboratory to be IHC 3+, or IHC 2+ and ISH-positive, in the provided tumor sample.
- ECOG performance status of 0, 1, or 2
- No prior systemic therapy for LA/mUC
- Neoadjuvant therapy, including PD-(L)1 inhibitors, is acceptable, if disease recurrence/progression occurred more than 12 months after the last dose of systemic therapy.
This is not a complete list of inclusion and exclusion criteria. Please connect with a Principal Investigator for further information.
Cohort A
- 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
Cohort C
- 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 nueropathy > 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 a 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.
Primary outcomes
- 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 and C
Secondary outcomes
- cORR per RECIST v1.1 by investigator assessment (Cohorts A and C)
- Confirmed duration of response (DOR) per RECIST v1.1 by BICR (Cohorts A and C)
- Confirmed DOR per RECIST v1.1 by investigator assessment (Cohorts A and C)
- Progression-free survival (PFS) per RECIST v1.1 by BICR (Cohorts A and C)
- PFS per RECIST v1.1 by investigator assessment (Cohorts A and C)
- Disease control rate (DCR) per RECIST v1.1 by BICR (Cohorts A and C)
- DCR per RECIST v1.1 by investigator (Cohorts A and C)
- Overall survival (OS) (Cohorts A and C)
- Incidence of dose alterations (Cohorts A and C)
- Incidence of laboratory abnormalities (Cohorts A and C)
- Incidence of ECG abnormalities (Cohorts A and C)
- Change from baseline of LVEF (Cohorts A and C)
- PK parameter - AUC (Cohorts A and C)
- PK parameter - Cmax (Cohorts A and C)
- PK parameter - Tmax (cohorts A and C)
- PK parameter - Ctrough (Cohorts A and C)
- Incidence of anti-drug antibodies (ADAs)) against disitamab vedotin (Cohorts A and C)
- Incidence of anti-drug antibodies (ADAs) against pembrolizumab (Cohort C)
- Incidence of neutralizing antibodies (NABs) against disitamab vedotin (Cohorts A and C)
Protocol Amendment 9 (v10.0), RC48G001 HCP Page, 14Aug24