Phase 2 Basket Study of Disitamab Vedotin in Adults with Previously Treated, Locally-Advanced Unresectable or Metastatic HER2-Expressing Solid Tumors

Trial ID: 2023-504445-31-00
Protocol: C5731005 / SGNDV-005
Sponsor: Seagen Inc.

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Diseases & Conditions

Endometrial cancer Ovarian cancer Non-small cell lung cancer Head and neck cancer

Objectives

The primary objective of this study is to evaluate the **antitumor activity** of disitamab vedotin in participants with previously treated, locally-advanced unresectable or metastatic HER2-expressing solid tumors. This is clinically relevant as it aims to determine the efficacy of disitamab vedotin in targeting and reducing tumor growth in patients who have limited treatment options due to the advanced stage of their disease.

Secondary objectives include:

To evaluate the **safety and tolerability** profile of disitamab vedotin, which is crucial for understanding the potential adverse effects and overall patient tolerance to the treatment.
To assess the **antitumor activity** of disitamab vedotin per investigator assessment by other clinically relevant measures, providing additional insights into its effectiveness.
To evaluate the **pharmacokinetics (PK)** of disitamab vedotin, which will help in understanding the drug's absorption, distribution, metabolism, and excretion.
To evaluate the **immunogenicity** of disitamab vedotin, which is important for assessing the potential for immune response against the drug.

Participants

The clinical trial involves a total of **132 participants** diagnosed with various types of cancer, including **carcinoma of the head and neck**, **non-small-cell lung carcinoma**, **ovarian neoplasms**, and **endometrial neoplasms**. The study population comprises both male and female subjects, with an age range corresponding to categories 3 and 4, indicating adult and elderly participants. The trial includes individuals with previously treated, locally-advanced unresectable or metastatic HER2 expressing solid tumors. Participants were selected based on specific inclusion criteria, such as having measurable disease per RECIST v1.1 criteria and an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1. The trial population includes a vulnerable population, and lifestyle factors such as diet and physical activity were not specified. The selection process ensured that participants had prior exposure to certain therapies, including platinum-based treatments and, where applicable, anti-PD(L)1 therapy. HER2 expression levels were determined by local IHC testing, and participants were required to provide formalin-fixed, paraffin-embedded tumor tissue blocks or freshly sectioned slides for analysis.

Plans and Procedures

The clinical trial is designed to evaluate the **antitumor activity** of **disitamab vedotin** in adult participants with previously treated, locally-advanced unresectable or metastatic solid tumors that express HER2. This is a Phase 2, randomized, double-blind, controlled study. The trial is expected to commence recruitment on August 1, 2024, and conclude by June 17, 2028. Participants will be involved in the study for a duration that aligns with the trial's endpoints and their individual response to treatment, with the possibility of early termination based on specific conditions such as adverse events or disease progression.

The study will include several key visits: an initial screening visit to confirm eligibility based on inclusion criteria such as HER2 expression and measurable disease per RECIST v1.1 criteria, followed by regular follow-up visits to monitor treatment response and safety. The end-of-study visit will assess the overall outcomes and any long-term effects of the treatment. Participants will receive **disitamab vedotin** via infusion, with a maximum daily dose of 1.5 mg/kg and a total dose not exceeding 150 mg. The primary endpoint is the confirmed objective response rate, while secondary endpoints include the incidence and severity of adverse events, disease control rate, duration of response, progression-free survival, and overall survival.

Inclusion criteria specify that participants must have a pathologically documented carcinoma of the head and neck, non-small-cell lung cancer, ovarian neoplasms, or endometrial neoplasms, with prior treatment history as outlined for each cohort. Exclusion criteria are not specified in the provided data. Participants must provide formalin-fixed, paraffin-embedded tumor tissue blocks and have an Eastern Cooperative Oncology Group performance status score of 0 or 1. The study will monitor the pharmacokinetics of **disitamab vedotin** and the incidence of antidrug antibodies. Conditions for early termination include significant adverse events, lack of efficacy, or withdrawal of consent.

Treatment

The clinical trial involves the administration of **Disitamab Vedotin**, an experimental medication formulated as a **powder for solution for infusion**. This investigational drug is a recombinant humanized anti-HER2 monoclonal antibody-MMAE conjugate, developed by Seattle Genetics Inc. The active substance, **disitamab vedotin**, is classified as a protein of other origin. The medication is administered via infusion, with a maximum daily dose of 1.5 mg/kg and a total maximum dose of 150 mg. The treatment period is extensive, with a maximum duration set at 9999999 time units, indicating a long-term administration plan. The study does not involve a pediatric formulation, and the drug is not classified as an orphan drug.

Efficacy

The efficacy of Disitamab Vedotin in the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is the confirmed objective response rate (ORR) as per the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1), which will be evaluated by the investigator. Secondary endpoints include the type, incidence, severity, seriousness, and relatedness of adverse events (AEs), including AEs of special interest (AESIs), as well as the type, incidence, and severity of laboratory abnormalities and significant changes from baseline. Additional secondary endpoints are the frequency of treatment interruptions, dose reductions, and treatment discontinuations due to AEs, confirmed disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS), all assessed per RECIST v1.1 by the investigator. Pharmacokinetic parameters of Disitamab Vedotin, total antibody (TAb), and unconjugated MMAE will also be evaluated, along with the incidence of antidrug antibodies (ADA) against Disitamab Vedotin.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Cohort 1: HNC •Must have pathologically-documented carcinoma of the head and neck with primary tumor site arising from the oral cavity, salivary gland, oropharynx, hypopharynx, and larynx; tumors arising from the nasopharynx are excluded. •Unresectable locally recurrent or metastatic stage disease •Prior therapies: -Participants must have disease progression after treatment with a platinum-based therapy or other first line treatment regimen
Cohort 2: NSCLC •Pathologically documented NSCLC •Unresectable locally-advanced or metastatic stage disease •Prior therapies: -Must have progressed during or after a platinum-based therapy or, within 6 months of platinum-based adjuvant, neoadjuvant, or concomitant chemoradiotherapy for early or locally-advanced stage disease -Must have received prior anti-PD(L)1 therapy, unless contraindicated - Participants with known AGAs must have received appropriate targeted therapy, where available -No more than 2 prior lines of cytotoxic chemotherapy for advanced disease
Cohort 3: Ovarian Cancer •Pathologically documented epithelial cancers of ovarian, fallopian tube, or peritoneal origin •Unresectable locally-advanced or metastatic stage disease •Prior therapies -Must have platinum resistant disease (6 months or less between the completion of platinum-based treatment and identification of recurrence) -Must not have received more than 4 lines of prior cytotoxic chemotherapies for advanced disease -May have received prior anti-PD(L)1 therapy
Cohort 4: Endometrial Cancer •Must have pathologically documented adenocarcinoma of the endometrium •Must have unresectable locally-advanced or metastatic stage disease. •Prior therapies: -Must have relapsed/progressed after at least one prior platinum-based chemotherapy for recurrent, metastatic or primary unresectable disease -Must not have received more than 3 lines of prior cytotoxic chemotherapies for advanced disease -May have received prior anti-PD(L)1 therapy
HER2 expression of 1+, 2+, or 3+, as determined by local IHC testing on a fresh or archival tumor tissue. Note: Subjects with HER2 mutations are eligible.
Measurable disease per RECIST v1.1 criteria as assessed by the investigator.
Able to provide formalin-fixed, paraffin-embedded (FFPE) tumor tissue blocks (or freshly sectioned slides).
Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1.

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Exclusion Criteria

Prior treatment with an MMAE-containing agent
Known hypersensitivity to any excipient contained in the drug formulation of disitamab vedotin
History of another invasive malignancy within 2 years before the first dose of study intervention, or any evidence of residual disease from a previously diagnosed malignancy
Active untreated CNS or leptomeningeal metastasis