Disitamab Vedotin with Pembrolizumab vs Chemotherapy in Previously Untreated Urothelial Cancer Expressing HER2

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Seagen Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

15 Jul 2024 → ongoing

Decision date (initial)

2024-10-23

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Seagen Inc

External identifiers

EU CT number

2022-501105-12-00

ClinicalTrials.gov

NCT05911295

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Others, Safety, Therapy, Pharmacodynamic, Efficacy, Pharmacokinetic

To compare the efficacy of disitamab vedotin in combination with pembrolizumab to chemotherapy as first-line treatment in participants with advanced UC that expresses HER2

Secondary objectives 6

1. To compare objective response rate (ORR) between treatment with disitamab vedotin in combination with pembrolizumab versus chemotherapy
2. To compare duration of response (DOR) between treatment with disitamab vedotin in combination with pembrolizumab versus chemotherapy
3. To compare disease control rate (DCR) between treatment with disitamab vedotin in combination with pembrolizumab versus chemotherapy
4. To compare progression-free survival (PFS) by investigator between treatment with disitamab vedotin in combination with pembrolizumab versus chemotherapy
5. To evaluate the safety profile of each treatment regimen
6. To compare the impact of treatment with disitamab vedotin in combination with pembrolizumab versus chemotherapy with respect to quality of life (QoL) and symptoms, including pain, from the participant’s perspective.

Conditions and MedDRA coding

Urothelial Carcinoma

Study design 1 period

Regulatory references

Scientific advice from competent authorities

Food And Drug Administration, European Medicines Agency

Plan to share IPD

Yes

IPD plan description

Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical trials/trial data and results/data requests. URL: https://www.pfizer.com/science/clinical trials/trial data and results/data requests

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

1. Age 18 years and older at the time of consent or considered an adult by local regulations
2. Subjects must have LA/mUC with histopathological confirmation (Stage IIIB-IV per American Joint Committee on Cancer, Cancer Staging Atlas 8th ed.), including UC originating from the renal pelvis, ureters, bladder, or urethra. Mixed-cell type tumors are eligible as long as urothelial (transitional cell histology) carcinoma is the predominant cell type.
3. Subjects must have measurable disease by investigator assessment according to RECIST v1.1. Note: Subjects with prior definitive radiation therapy must have measurable disease per RECIST v1.1 that is outside the radiation field or has demonstrated unequivocal progression since completion of radiation therapy.
4. Subjects must not have received prior systemic therapy for locally advanced or metastatic UC with the following exceptions: a. 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 therapy
5. Subjects must be considered eligible to receive cisplatin- or carboplatin-containing chemotherapy, per the investigator’s evaluation. Subjects meeting any of the following criteria should be considered cisplatin ineligible, and will receive carboplatin: a. CrCl <60 mL/min but ≥30 mL/min within 7 days of randomization (measured by the Cockcroft-Gault formula). Note: Subjects with a CrCl ≥50 mL/min and no other cisplatin ineligibility criteria may be considered cisplatin-eligible based on the investigator’s clinical judgment. b. ECOG performance status of 2 within 7 days of randomization (refer to Inclusion Criterion 8 for additional criteria for ECOG 2 subjects). c. NCI CTCAE Grade 2 or higher hearing loss. Note: If a subject is determined to be cisplatin eligible, gemcitabine and cisplatin are to be administered without exception.
6. Subjects must be willing and able to provide archived formalin-fixed paraffin-embedded tumor tissue blocks (or, alternatively, freshly sectioned slides; see laboratory manual for details) from a muscle-invasive or metastatic UC lesion or a biopsy sample of metastatic UC. This must be obtained prior to study treatment initiation and will be sent to a sponsor designated central laboratory for biomarker analysis. If archival tissue is not available, then a newly obtained baseline biopsy of an accessible tumor lesion is required within 28 days prior to Cycle 1 Day 1. Biopsy must provide adequate tissue for HER2 testing. a. Tumor tissue recommended to be collected within 12 months prior to enrollment, and after completion of the most recent (neo) adjuvant systemic therapy
7. HER2 expression of 1+ or greater on IHC determined by central laboratory
8. An ECOG performance status score of 0, 1, or 2 within 7 days prior to randomization. a. Subjects with ECOG 2 must meet additional criteria: Hb ≥10 g/dL, CrCl ≥50 mL/min, and heart failure severity less than New York Heart Association (NYHA) Class III.
9. Adequate baseline cardiac parameters: a. LVEF ≥50% b. Fridericia’s corrected QT interval (QTcF) <470 ms
10. The following baseline laboratory data, laboratory values collected within 7 days prior to randomization are acceptable: a. Hb ≥9 g/dL without transfusion b. ANC ≥1.5 × 109/L c. Platelet count ≥100 × 109/L d. ALT and AST ≤2.5 × upper limit of normal (ULN) without liver metastases or ≤5 × ULN with liver metastases e. Serum total bilirubin ≤1.5 × ULN or direct bilirubin ≤ ULN for subjects with total bilirubin >1.5 × ULN; serum total bilirubin ≤3 × ULN for subjects with Gilbert's syndrome f. CrCl ≥30 mL/min, as calculated using the Cockcroft-Gault formula g. International normalized ratio (INR) or prothrombin time (PT) ≤1.5 × ULN and activated partial thromboplastin time (aPTT) ≤1.5 × ULN. Subjects receiving anticoagulant therapy are eligible and are required to have INR/PT and aPTT within therapeutic range. Note: In subjects transfused before the study, the transfusion (such as red blood cell, whole blood, or plasma transfusion) must be ≥14 days prior to start of therapy to establish adequate laboratory parameters independent from transfusion support
11. Subjects of childbearing potential (as defined in Section 10.4) under the following conditions: a. Must have a negative serum pregnancy test (minimum sensitivity 25 mIU/mL or equivalent units of beta human chorionic gonadotropin [β-hCG]) result within 72 hours prior to the first dose of study intervention. Subjects with false positive results and documented verification that the subject is not pregnant are eligible for participation. b. Must agree not to try to become pregnant during the study and for at least 2 months after the final dose of disitamab vedotin and 4 months after the final dose of pembrolizumab, and 6 months after the final dose of cisplatin, carboplatin, and gemcitabine. c. Must agree not to breastfeed or donate ova, from the time of informed consent and continuing through 2 months after the final dose of disitamab vedotin and 4 months after the final dose of pembrolizumab, and 6 months after the final dose of cisplatin, carboplatin, and gemcitabine. d. If sexually active in a way that could lead to pregnancy, must consistently use at least 2 acceptable methods of birth control (contraception), at least one of which must be highly effective (as defined in Section 10.4) starting at time of informed consent and continuing through at least 2 months after the final dose of disitamab vedotin and 4 months after the final dose of pembrolizumab, and 6 months after the final dose of cisplatin, carboplatin, and gemcitabine.
12. Subjects who can get someone pregnant (as defined in Section 10.4) under the following conditions: a. Must agree not to donate sperm from the time of informed consent and continuing through at least 4 months after the final dose of disitamab vedotin and 6 months after the final dose of cisplatin, carboplatin, and gemcitabine. b. If sexually active with a person of childbearing potential in a way that could lead to pregnancy, must consistently use at least 2 acceptable methods of birth control (contraception), at least 1 of which must be highly effective (as defined in Section 10.4) from the time of informed consent and continuing through at least 4 months after the final dose of disitamab vedotin and 6 months after the final dose of cisplatin, carboplatin, and gemcitabine. c. If sexually active with a person who is pregnant or breastfeeding, must consistently use a condom (as defined in Section 10.4) from the time of informed consent and continuing through at least 4 months after the final dose of disitamab vedotin and 6 months after the final dose of cisplatin, carboplatin, and gemcitabine.
13. The subject must provide documented informed consent.
14. Subject must be willing and able to comply with the trial procedures and the follow-up schedule.

Exclusion criteria 24

1. Known hypersensitivity to any excipient contained in the drug formulation of disitamab vedotin, cisplatin, carboplatin, gemcitabine, or pembrolizumab
2. History of severe/life threatening irAE with PD-(L)1 inhibitors are excluded. Please consult with medical monitor. a. Grade ≥3 pneumonitis IMAEs, cardiomyopathy, etc. b. Grade 4 diarrhea/colitis IMAEs, hepatitis IMAEs, rash IMAEs c. Grade 3/4 adrenal insufficiency, hypophysitis, uveitis, hypothyroidism
3. CNS and/or leptomeningeal metastasis. a. Subjects with treated CNS metastases (by whole brain radiation therapy, surgery or radiosurgery, etc.) are permitted on study if all of the following are met: b. CNS metastases have been clinically stable for at least 4 weeks and baseline scans show no evidence of new or worsening CNS metastasis. c. Subject is on a stable dose of ≤10 mg/day of prednisone or equivalent for at least 2 weeks
4. History of or active autoimmune disease that has required systemic treatment in the past 2 years (ie, with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). a. Replacement therapy (eg, thyroxine, insulin, physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic disease-modifying treatment and is allowed. b. Subjects with vitiligo, psoriasis, type 1 diabetes mellitus, hypothyroidism, or resolved childhood asthma/atopy are allowed. c. Subjects requiring intermittent use of bronchodilators, inhaled steroids, or local steroid injections are allowed. d. Subjects with hypothyroidism that is stable with hormone replacement or Sjögren's syndrome are allowed.
5. Subjects 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
6. Subjects with prior solid organ or bone marrow transplantation
7. Pleural effusion or ascites with symptoms or requiring symptomatic treatment
8. Subjects with an estimated life expectancy <12 weeks
9. Subjects with ongoing clinically significant toxicity associated with prior treatment that has not resolved to ≤ Grade 1 or returned to baseline, except for Grade 2 alopecia
10. Subject has received prior radiotherapy to a metastatic site without the use of chemotherapy radiosensitization within 3 weeks of the first dose of study intervention, with the exception of palliative radiotherapy to bone lesions, which is allowed if completed 2 weeks before the start of study intervention. Subjects must have recovered from all radiation-related toxicities and must not require corticosteroids. Note: Ongoing hormonal/antihormonal treatment (eg, for breast cancer) is allowed, provided that the subject is eligible per exclusion criteria of prior malignancy
11. Subjects who previously received treatment with an MMAE agent or anti-HER2 therapy
12. Ongoing sensory or motor neuropathy Grade 2 or higher
13. Subjects with acute, chronic, or symptomatic infections, including: a. Ongoing symptomatic severe acute respiratory syndrome-associated coronavirus 2 (SARS-CoV-2) infection except for subjects who have recovered clinically but continue to have a detectable presence of SARS-CoV-2. b. History of human immunodeficiency virus (HIV) infection. Testing is not required unless mandated by local regulations. c. History of hepatitis B virus (HBV) infection (defined as positive for HBV surface antigen) or known active hepatitis C virus (HCV) infection (defined as HCV RNA [qualitative] is detected). Subjects who have been curatively treated for hepatitis C infection are permitted if they have documented sustained virologic response of ≥12 weeks. HBV negative DNA of ≥12 weeks is also allowed. No HBV or HCV testing is required, unless mandated by local regulations or institutional standard
14. Has a diagnosis of immunodeficiency condition/disorder (ie, immunoglobulin A [IgA] deficiency, etc.) or is receiving chronic systemic steroid therapy (dose >10 mg daily of prednisone or equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug
15. Subjects with history of idiopathic pulmonary fibrosis, organizing pneumonia, drug induced pneumonitis, noninfectious pneumonitis, interstitial lung disease, or idiopathic pneumonitis are excluded. Subjects with current pneumonitis or interstitial lung disease are also excluded
16. Subjects with a history of another invasive malignancy within 3 years before the first dose of study intervention, or any evidence of residual disease from a previously diagnosed malignancy. a. Subjects with adequately resected early-stage non-melanoma skin cancer or carcinoma in situ are allowed. b. Subjects with a history of prostate cancer (T2NXMX or lower with Gleason score ≤7) treated with definitive intent (surgically or with radiation therapy), provided that the subject is considered prostate cancer free and the following criteria are met:  Subjects who have undergone an adequate surgical resection must have undetectable prostate specific antigen (PSA) for ≥1 year and at screening.  Subjects who have had radiation must have a PSA doubling time >1 year (based on at least 3 values determined >1 month apart) and a total PSA value that does not meet Phoenix criteria for biochemical recurrence (ie, <2.0 ng/mL above nadir).  Subjects with untreated low-risk prostate cancer (Gleason score ≤6) on active surveillance with PSA doubling time >1 month (based on at least 3 values determined <1 month apart) are also eligible. c. Malignancies that can be cured after treatment (including but not limited to adequately treated thyroid cancer, cervical carcinoma in situ, basal or squamous cell skin cancer, or radical treatment of ductal carcinoma in situ to the breast).
17. Uncontrolled cardiac disease including: a. Cardiac failure – NYHA Class III or IV heart failure (see Section 10.5) b. Cardiac arrhythmia – Grade 2 or higher arrhythmia or heart block c. Cardiac ischemia – unstable angina within the past 12 months, myocardial infarction or cerebral infarction within the past 6 months, etc. Experience of any of the following procedures or conditions in the preceding 6 months: coronary artery bypass graft, angioplasty, vascular stent, any other structural heart disease interventions. d. Hypertension: Subjects with CTCAE Grade 3, defined as systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥100 mmHg despite adequate medical intervention will be excluded. Subjects with hypertension adequately controlled at baseline may be enrolled into the study. e. Unexplained syncope, symptomatic hypotension, or asymptomatic hypotension with systolic blood pressure <90 mmHg
18. Subjects who have received radiotherapy within 2 weeks prior to randomization
19. Subjects who have received major surgery within 4 weeks prior to randomization. Subject must have recovered adequately from complications from the study intervention prior to randomization
20. Subjects requiring chronic oxygen therapy or have Grade ≥3 pulmonary disease unrelated to underlying malignancy
21. Subjects who have received a live or live-attenuated vaccine within 30 days prior to randomization
22. Subjects who are pregnant or breastfeeding women
23. Other serious underlying medical condition, psychiatric or substance abuse disorder that, in the opinion of the investigator, would impair the subject’s ability to receive or tolerate the planned treatment, or comply with the requirements of the study and follow-up
24. Other serious, uncontrolled concomitant diseases that may affect protocol compliance or interpretation of outcomes, including active opportunistic infections or advanced (severe) infections, or uncontrolled diabetes

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. PFS per Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 by blinded independent central review (BICR)
2. Overall survival (OS)

Secondary endpoints 15

1. ORR per RECIST v1.1 by BICR
2. ORR per RECIST v1.1 by investigator assessment
3. DOR per RECIST v1.1 by BICR
4. DOR per RECIST v1.1 by investigator
5. DCR per RECIST v1.1 by BICR
6. DCR per RECIST v1.1 by investigator
7. PFS per RECIST v1.1 by investigator
8. Type, incidence, relatedness, severity, and seriousness of adverse events (AEs)
9. Type, incidence, and severity of laboratory abnormalities
10. Treatment discontinuation rate due to AEs
11. Electrocardiogram abnormalities, including changes in QTc
12. Effect on left ventricular ejection fraction
13. Change from baseline to Week 16 in European Organisation for Research and Treatment of Cancer core QoL questionnaire (EORTC QLQ C30) Global Health Status (GHS)/QoL Score (Items 29+30)
14. Time to Deterioration in EORTC QLQ-C30 GHS/QoL Score (Items 29 + 30)
15. Time to pain progression

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Comparator 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Seagen Inc.

Sponsor organisation

Seagen Inc.

Address

21823 30th Drive Southeast

City

Bothell

Postcode

98021-3907

Country

United States

Scientific contact point

Organisation

Seagen Inc.

Contact name

Clinical Trial Information

Public contact point

Organisation

Seagen Inc.

Contact name

Clinical Trial Information

Third parties 12

Locations

13 EU/EEA countries · 77 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Serious breaches 1 · Art. 52 CTR

Temporary halts 2 · Art. 38 CTR

Corrective measures 1 · Art. 77 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 229 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

11 submissions — initial application plus substantial / non-substantial modifications