A Study of Disitamab Vedotin Alone or With Other Anticancer Drugs in Solid Tumors

Study Overview
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Brief Summary
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This clinical trial is studying solid tumor cancers. A solid tumor is one that starts in part of your body like your lungs or liver instead of your blood. Once they've grown bigger in one spot or spread to other parts of the body, they're harder to treat. This is called advanced or metastatic cancer. Participants in this study must have breast cancer or gastric cancer. Participants must have tumors that have HER2 on them. This allows the cancer to grow more quickly or spread faster. There are few treatment options for patients with advanced or metastatic solid tumors that express HER2. This clinical trial uses an experimental drug called disitamab vedotin (DV). Disitamab vedotin is a type of antibody drug conjugate or ADC. ADCs are designed to stick to cancer cells and kill them. This clinical trial uses a drug called tucatinib, which has been approved to treat cancer in the United States and some other countries. This drug is sold under the brand name TUKYSA®. This study will test how safe and how well DV, with or without tucatinib, is for participants with solid tumors. This study will also test what side effects happen when participants take these drugs. A side effect is anything a drug does to the body besides treating the disease.

Detailed Description
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This clinical trial is to evaluate disitamab vedotin alone and in combination with tucatinib in subjects with LA/metastatic breast cancer or gastric cancer/GEJC that express HER2. The study has a dose escalation phase evaluating disitamab vedotin plus tucatinib followed by a dose optimization phase. The 2 dose levels identified in the dose escalation phase will be assessed in the optimization phase for both safety and efficacy in HER2-low LA/mBC subjects. Once the safety and efficacy profile of disitamab vedotin plus tucatinib has been established and a disitamab vedotin dose with the optimum benefit/risk ratio has been determined the disitamab vedotin plus tucatinib combination therapy will be evaluated in an expansion phase with 2 expansion cohorts in subjects with HER2 low mGC/GEJC and HER2 + LA/mBC.

Official Title
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A Phase 1b/2 Open-Label Study of Disitamab Vedotin Monotherapy or in Combination With Other Anticancer Therapies in Solid Tumors

Conditions
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Breast Neoplasms, Gastroesophageal Junction Adenocarcinoma, HER2 Low Breast Neoplasms, HER2 Positive Breast Neoplasms, Stomach Neoplasms, Triple Negative Breast Neoplasms

Intervention / Treatment
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* Drug: disitamab vedotin
* Drug: tucatinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: General Inclusion Criteria Measurable disease according to RECIST v1.1 Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1 Dose Escalation Phase Inclusion Criteria Histologically or cytologically confirmed diagnosis of gastric or gastroesophageal junction adenocarcinoma or breast carcinoma Locally-advanced, unresectable, or metastatic stage HER2 status IHC 1+ or higher by most recent local assessment. Must have experienced disease progression on or after standard of care therapies or be intolerant of standard of care therapies. Cohort A (HER2-Low Breast Cancer) Inclusion Criteria Histologically or cytologically confirmed diagnosis of breast carcinoma Locally-advanced, unresectable, or metastatic stage HER2-low status determined by most recent local assessment (IHC 1+ or IHC 2+/ISH-negative) Prior therapies requirements No more than 3 prior systemic cytotoxic chemotherapy regimens (including ADCs) for LA/mBC. Participants with known BRCA mutation must have received a PARP-inhibitor where available and not medically contraindicated Have progression on or after, or intolerant to, T-DXd, sacituzumab govitecan, or other topoisomerase I inhibitor therapies, if available as local standard of care therapy Participants with HR+ tumors must have endocrine therapy refractory disease: Progressed on ≥2 lines of endocrine therapy for LA/mBC AND had received a CDK4/6 inhibitor in the adjuvant or metastatic setting OR Progressed on 1 line of endocrine therapy for LA/mBC AND had a relapse while on adjuvant endocrine therapy after definitive surgery for primary tumor AND had received a CDK4/6 inhibitor in the adjuvant or advanced setting Participants with HR negative, HER2-low and PD-L1-positive (CPS 10 or greater) tumors must have received pembrolizumab with chemotherapy if available as local standard of care therapy. Cohort B (HER2+ Breast Cancer) Inclusion Criteria Histologically or cytologically confirmed diagnosis breast carcinoma Locally-advanced, unresectable, or metastatic stage HER2+ status determined by most recent local assessment (IHC 3+ or IHC 2+/ISH+) Participants must have: Received prior trastuzumab, pertuzumab and a taxane if available as local standard of care therapy. Have progression on or after, or intolerant to, T-DXd or other topoisomerase I inhibitor therapies No more than 3 prior systemic cytotoxic chemotherapy regimens (including ADCs) for LA/mBC Cohort C (HER2-Low Gastric or Gastroesophageal Junction Adenocarcinoma) Inclusion Criteria Histologically or cytologically confirmed diagnosis of gastric or gastroesophageal junction adenocarcinoma Locally-advanced, unresectable, or metastatic stage HER2-low expression defined as IHC 1+ or IHC 2+/ISH-negative determined by most recent local assessment Willing and able to provide archival or newly obtained formalin-fixed paraffin-embedded (FFPE) tumor tissue blocks Participants must have received: Prior systemic therapy with platinum, fluorouracil, or taxane for locally advanced unresectable or metastatic disease Progression within 6 months of last dose of (neo)adjuvant cytotoxic chemotherapy is considered as 1 line of systemic therapy for LA/mGC/GEJC Prior anti-PD-(L)1 therapy is allowed No more than 2 prior systemic cytotoxic chemotherapy regimens (including ADC) for LA/mGC/GEJC Must not have received prior treatment with HER2 directed therapy Exclusion Criteria: Known hypersensitivity to any excipient contained in the drug formulation of disitamab vedotin or tucatinib Prior therapy with ADCs with MMAE payload Prior therapy with tucatinib Active CNS and/or leptomeningeal metastasis. Participants who have received prior systemic anticancer treatment including investigational agents within 4 weeks prior to first dose of study treatment History of other invasive malignancy within 3 years before the first dose of study intervention, or any evidence of residual disease from a previously diagnosed malignancy. Unable to swallow oral tablets or capsules or any significant GI disease which would preclude the adequate oral absorption of medications

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Escalation - Previously treated advanced GC/GEJC or breast cancer<br>disitamab vedotin + tucatinib | Drug: disitamab vedotin<br>* Given into the vein (IV; intravenous)<br>* Other names: RC48, RC48-ADC;Drug: tucatinib<br>* 300mg given twice daily by mouth (orally)<br>* Other names: TUKYSA, ONT-380, ARRY-380;|
| Experimental: Cohort A monotherapy - HER2-low 2L or 3L breast cancer<br>disitamab vedotin monotherapy | Drug: disitamab vedotin<br>* Given into the vein (IV; intravenous)<br>* Other names: RC48, RC48-ADC;|
| Experimental: Cohort A - HER2-low 2L or 3L breast cancer<br>disitamab vedotin + tucatinib | Drug: disitamab vedotin<br>* Given into the vein (IV; intravenous)<br>* Other names: RC48, RC48-ADC;Drug: tucatinib<br>* 300mg given twice daily by mouth (orally)<br>* Other names: TUKYSA, ONT-380, ARRY-380;|
| Experimental: Cohort B monotherapy - HER2+ 3L or higher breast cancer<br>disitamab vedotin monotherapy | Drug: disitamab vedotin<br>* Given into the vein (IV; intravenous)<br>* Other names: RC48, RC48-ADC;|
| Experimental: Cohort B - HER2+ 3L or higher breast cancer<br>disitamab vedotin + tucatinib | Drug: disitamab vedotin<br>* Given into the vein (IV; intravenous)<br>* Other names: RC48, RC48-ADC;Drug: tucatinib<br>* 300mg given twice daily by mouth (orally)<br>* Other names: TUKYSA, ONT-380, ARRY-380;|
| Experimental: Cohort C monotherapy - HER2-low 2L GC/GEJC<br>disitamab vedotin monotherapy | Drug: disitamab vedotin<br>* Given into the vein (IV; intravenous)<br>* Other names: RC48, RC48-ADC;|
| Experimental: Cohort C - HER2-low 2L GC/GEJC<br>disitamab vedotin + tucatinib | Drug: disitamab vedotin<br>* Given into the vein (IV; intravenous)<br>* Other names: RC48, RC48-ADC;Drug: tucatinib<br>* 300mg given twice daily by mouth (orally)<br>* Other names: TUKYSA, ONT-380, ARRY-380;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with dose limiting toxicities DLTs) in dose escalation phase |  | Up to 28 days | 
| Number of participants with adverse events (AEs) | Any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention | Through 30 days after the last study treatment; approximately 5 years | 
| Number of participants with laboratory abnormalities |  | Through 30-37 days after the last study treatment: approximately 5 years | 
| Number of participants with dose alterations |  | Through 30-37 days after the last study treatment: approximately 5 years | 
| Objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) by investigator assessment | The proportion of participants with confirmed response (CR) or partial response (PR) according to RECIST v1.1. | Approximately 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of response (DOR) per RECIST v1.1 by investigator assessment | The time from start of the first documentation of objective tumor response of CR or PR (that is subsequently confirmed) to the first documentation of progressive disease (PD) per RECIST v1.1, or to death due to any cause | Approximately 5 years | 
| Disease control rate (DCR) per RECIST v1.1 by investigator assessment | The proportion of participants with stable disease (SD) or confirmed CR or PR according to RECIST v1.1. | Approximately 5 years | 
| Progression free survival (PFS) per RECIST v1.1 by investigator assessment | The time from randomization (or Cycle 1 Day 1 for participants in dose escalation phase) to the first documentation of disease progression per RECIST v1.1 or death due to any cause. | Approximately 5 years | 
| Overall survival (OS) | The time from randomization (or Cycle 1 Day 1 for participants in dose escalation phase) to the date of death due to any cause. | Approximately 5 years | 
| Pharmacokinetic (PK) parameter - Maximum concentration (Cmax) |  | Through 30-37 days after the last study treatment; approximately 5 years | 
| PK parameter - Area under the concentration-time curve to the time of the last quantifiable concentration (AUClast) |  | Approximately 1 month | 
| Incidence of anti-drug antibodies (ADAs) against disitamab vedotin |  | Through 30-37 days after the last study treatment; approximately 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Breast Cancer, Gastric Cancer, GC, GEJ, HER2-Low Breast Cancer, HER2-Positive Breast Cancer, Seattle Genetics