Clinical Trial 22706

• Overview

  Study Title:

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

  Summary:

  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.

  Objective:

  Primary objectives: * To identify the maximum tolerated dose (MTD) and/or optimal dose of disitamab vedotin when administered in combination with tucatinib. * To characterize the safety and tolerability of disitamab vedotin monotherapy regimens in: *HER2-low 2L or 3L advanced BC *HER2+ 3L+ advanced BC *HER2-low 2L advanced GC/GEJC * To characterize the safety and tolerability of disitamab vedotin plus tucatinib in: *HER2-low 2L or 3L advanced BC *HER2+ 3L+ advanced BC *HER2-low 2L advanced GC/GEJC * To assess the antitumor activity of disitamab vedotin monotherapy in: *HER2-low 2L or 3L advanced BC *HER2+ 3L+ advanced BC *HER2-low 2L advanced GC/GEJC * To assess the antitumor activity of disitamab vedotin plus tucatinib in: *HER2-low 2L or 3L advanced BC *HER2+ 3L+ advanced BC *HER2-low 2L advanced GC/GEJC Secondary Objectives: * To assess the antitumor activity of disitamab vedotin monotherapy * To assess the antitumor activity of disitamab vedotin plus tucatinib * To characterize the PK of disitamab vedotin, total antibody, and unconjugated MMAE in monotherapy and plus tucatinib * To characterize the immunogenicity of disitamab vedotin

• Treatments

  Therapies:

  Antibody-Drug Conjugate; Therapy (NOS)

  Medications:

  Disitamab Vedotin (); Tucatinib ()

• Inclusion Criteria

  Key Inclusion Criteria:
  • Age ≥18 years, or considered an adult by local regulations, at time of consent.
  • The subject or the subject’s legally authorized representative must provide documented informed consent.
  • Measurable disease according to RECIST v1.1
  • An ECOG Performance Status score of 0 or 1.
  • Adequate baseline cardiac parameters.
  • Adequate bone marrow, hepatic, renal function based on following baseline laboratory data collected within 7 days of Cycle 1 Day 1.
  • Subject must be willing and able to comply with study procedures, laboratory tests, and other requirements of the study, including recording tucatinib daily dosing on electronic diary (eDiary).
  • 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.
  • All subjects must have experienced disease progression on or after standard of care therapies or be intolerant of standard of care therapies.
  • 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) based on ASCO and College of American Pathologists (CAP) guidelines for assessment of HER2 in BC for interpretation of HER2 expression and amplification (Wolff 2018b).
  • 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+) according to ASCO and CAP guidelines for assessment of HER2 in BC (Wolff 2018b).
  • All subjects must have: a) Received prior trastuzumab, pertuzumab and a taxane if available as local standard of care therapy. b) Have progression on or after, or intolerant to, T-DXd or other topoisomerase I inhibitor therapies. c) No more than 3 prior systemic cytotoxic chemotherapy regimens (including ADCs) for LA/mBC.
  • Histologically or cytologically confirmed diagnosis of gastric or gastroesophageal junction adenocarcinoma.
  • Locally-advanced, unresectable, or metastatic stage.
  • Must have HER2-low expression defined as IHC 1+ or IHC 2+/ISH-negative determined by most recent local assessment based off the ASCO and CAP guidelines for assessment of HER2 in GC for interpretation of HER2 expression and amplification (Bartley 2017).
  • Subjects must be willing and able to provide archival or newly obtained formalin-fixed paraffin-embedded (FFPE) tumor tissue blocks to a sponsor-designated central laboratory (or, alternatively, freshly sectioned slides; see laboratory manual for details).
  • All subjects must have received: a) Prior systemic therapy with platinum, fluorouracil, or taxane for locally advanced unresectable or metastatic disease. b) Progression within 6 months of last dose of (neo)adjuvant cytotoxic chemotherapy is considered as 1 line of systemic therapy for LA/mGC/GEJC. c) Prior anti-PD-(L)1 therapy is allowed. d) No more than 2 prior systemic cytotoxic chemotherapy regimens (including ADC) for LA/mGC/GEJC.
  • Subjects must not have received prior treatment with HER2 directed therapy.
  • Other inclusion criteria may apply.

• Exclusion Criteria

  Key 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.
  • CNS and/or leptomeningeal metastasis.
  • Subjects who have received prior systemic anticancer treatment including investigational agents within 4 weeks (please consult medical monitor for permitting shorter interval for kinase inhibitors or other short half-life anticancer drugs) prior to first dose of study treatment: a) Participants must have recovered from all AEs due to previous therapies to ≤ Grade 1 or baseline (except for alopecia). Participants with ≤ Grade 1 neuropathy may be eligible. b) If the participant had major surgery, the participant must have recovered adequately from the procedure and/or any complications from the surgery prior to starting study intervention.
  • Subjects with acute, chronic, or symptomatic infections, including: a) Ongoing symptomatic 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) Hepatitis B virus (HBV) infection (defined as positive for HBV surface antigen with positive HBV DNA) 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.
  • Subjects with a 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.
  • Uncontrolled cardiac disease including: a) Cardiac failure – New York Heart Association (NYHA) Class III or IV heart failure (see Section 10.9). 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. d) Hypertension – uncontrolled hypertension (systolic blood pressure >180 mmHg and/or diastolic blood pressure >100 mmHg).
  • Subjects who have received prior radiotherapy within 2 weeks of start of study treatment. a) Subject must have recovered adequately from all radiation-related toxicities. A 1-week washout is permitted for palliative radiation (≤2 weeks duration of radiotherapy) to non-CNS disease.
  • Subjects who have received major surgery within 4 weeks prior to Cycle 1 Day 1 (dose escalation phase) or randomization in the optimization or expansion phases must have recovered adequately.
  • Subjects requiring chronic oxygen therapy or have ≥ Grade 3 dyspnea, hypoxia, or other pulmonary disease unrelated to underlying malignancy.
  • Subjects who have received a live or live-attenuated vaccine within 30 days prior to Cycle 1 Day 1 (dose escalation phase) or randomization in the optimization or expansion phases. Administration of killed vaccines is allowed.
  • Subjects who are pregnant, breastfeeding, or planning a pregnancy.
  • Current therapy with other investigational agents.
  • Presence of known chronic liver disease.
  • Other exclusion criteria may apply.

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