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

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

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 tucatinib works 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.

This clinical trial is to evaluate disitamab vedotin 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-expressing LA/mBC and LA/mGC/GEJC. 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 4 expansion cohorts in subjects with HER2-low LA/mGC/GEJC, HER2+ LA/mGC/GEJC, HER2-low LA/mBC, and HER2+ LA/mBC.

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 and Optimization Phase Inclusion Criteria

• Histologically or cytologically confirmed diagnosis of gastric or gastroesophageal junction adenocarcinoma or breast carcinoma
• Locally-advanced, unresectable, or metastatic stage
• 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 intolerance to endocrine therapy or 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.

  • Participants with HR negative, HER2-low and PD-L1-positive (CPS 10 or greater) tumors must have received pembrolizumab (or other PD-(L)1 inhibitor) with chemotherapy if available as local standard of care therapy and not medically contraindicated.

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 for advanced disease.
  • 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

Cohort D (HER2+ LA/mGC/GEJC) Inclusion Criteria

• Histologically or cytologically confirmed diagnosis of gastric or gastroesophageal junction adenocarcinoma

• 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 plus fluoropyrimidine and platinum containing chemotherapy if no contraindication.
  • Prior T-DXd treatment is allowed
  • Prior PD1 inhibitor therapy is allowed
  • No more than 2 prior systemic cytotoxic chemotherapy regimens (including ADCs) for LA/mGC/GEJC

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