Patient case: 60-year-old female with gastric cancer; genetic feature: EGFR

Clinical trial: AVID100 in Advanced Epithelial Carcinomas

Summary: Approximately 80 male and female patients with documented solid tumor malignancies of epithelial origin that are locally advanced or metastatic, and either refractory to standard therapy or for whom no standard therapy is available, will be entered into this Phase 1a/2a, multicenter, open-label, dose-escalation, cohort study of AVID100, an anti-human EGFR monoclonal antibody (mAb) linked to the maytansinoid DM1.
  The initial Phase 1a Dose-Escalation portion of the trial (approximately 30 patients) is designed to evaluate the safety and tolerability, as well as identify the DLT(s), MTD, and RP2D of sequential escalating doses of AVID100 (study drug), when administered to patients with tumors reasonably likely to express EGFR; secondary objectives include characterization of the PK profile of total antibody (AVID100 plus MAB100), AVID100, and DM1, as well as preliminary assessment of the antineoplastic activity of AVID100.
  Once the MTD and/or RP2D is identified, 3 expansion cohorts of patients (approximately 50 patients total) with measureable disease and confirmed EGFR-positive tumors (tumor types to be determined) will be accrued during the subsequent Phase 2a Dose-Expansion portion of the trial where the goal will be to further evaluate the safety, tolerability, and antineoplastic activity of AVID100 when administered at the RP2D; a secondary objective is to further characterize the PK profile of total antibody, AVID100, and DM1 (PK evaluation will be less extensive in Phase 2a when compared to Phase 1a).
  An exploratory objective in both the Phase 1a and Phase 2a portions of the trial will be evaluation of the utility of potential biomarkers and response predictors of AVID100 activity in FFPE tumor tissue (optional in Phase 1a patients, required in Phase 2a patients). Patients will be treated and followed on an outpatient basis throughout the trial, unless hospitalization is required for other reasons, or to assure patient safety.

Detailed description: On Day 1 of study, patients will receive study drug administered by 1-hour IV infusion in a fixed 100 mL volume. AVID100 will be administered once every 3 weeks (Q3W) with administration on Day 1 of the first week, followed by a 3-week recovery period. This 3 week (21 day) period will be considered Cycle 1. In Phase 1a, determinations regarding cohort escalation, DLTs, and MTD will be based on the toxicities observed during this initial cycle. Patients must receive their full planned dose of AVID100, plus complete the designated follow-up period, in order to be considered evaluable for tolerability, unless dose reduction, interruption, or discontinuation was the result of a DLT.
  In all patients entered, a minimum of at least Cycle 1 of study will be completed, if tolerated, after which, in the absence of documented disease progression or unacceptable toxicity, a patient may continue to receive additional cycles of study drug Q3W (+ 2 days), at the same dose and infusion duration established for the patient during Cycle 1, and on the same schedule. These additional 3 week cycles may continue, if tolerated and in the absence of documented disease progression, at the Investigator's discretion, provided specified retreatment criteria have been met. Evidence of progressive disease at any point in the study will necessitate withdrawal of the patient from further participation so that alternative management of their malignancy may be considered.

Eligibility: Inclusion Criteria (Phase 1):
  1. Patients with a documented (histologically- or cytologically-proven) solid tumor epithelial carcinoma that is locally advanced or metastatic
  2. Patients with a malignancy that is either refractory to standard therapy, or for which no standard therapy is available
  3. Patients with a malignancy that is currently not amenable to surgical intervention due to either medical contraindications or non-resectability of the tumor
  4. Phase 1a Dose-Escalation Cohorts: Patients with measurable or non-measurable disease according to RECIST, v1.1 criteria. To include patients reasonably likely to express EGFR.
  5. Patients with an ECOG performance status of 0, 1, or 2, and an anticipated life expectancy of > 3 months
  6. Patients, both male and female, who are either not of childbearing potential or who agree to use a medically effective method of contraception during the study and for 3 months after the last dose of study drug.
  7. Patients with the ability to understand and give written informed consent for participation in this trial, including all evaluations and procedures as specified by this protocol. Informed consent must be obtained prior to patient screening, and before any evaluations or procedures specifically related to this study are performed.
  Patients to be Excluded (patients must not meet any of the following criteria Phase 1 only)
  1. Women who are pregnant or lactating. Women of child-bearing potential (WOCBP) and fertile men with WOCBP partner(s), not using and not willing to use a medically effective method of contraception.
  2. Patients with known central nervous system (CNS) or leptomeningeal metastases, or spinal cord compression not controlled by prior surgery or radiotherapy, or patients with symptoms suggesting CNS involvement for which treatment is required
  3. Patients with a malignancy other than that of epithelial origin
  4. Patients with any of the following hematologic abnormalities at baseline:
  -  Hemoglobin < 9.0 g/dL
  -  Absolute neutrophil count (ANC) < 1,500 per mm3
  -  Platelet count < 100,000 per mm3
  5. Patients with any of the following serum chemistry abnormalities at baseline:
  -  Total bilirubin > 1.5 × the upper limit of normal (ULN) for the institution
  -  AST or ALT > 3 × the ULN for the institution (> 5× ULN if due to hepatic involvement by tumor)
  -  Serum creatinine > 1.5 × ULN
  6. Patients with any of the following coagulation parameter abnormalities at baseline:
  -  PT (INR) > 1.5 × ULN for the institution
  -  PTT > 1.5 × ULN for the institution
  7. Patients with:
  -  Active thrombosis, or a history of deep vein thrombosis (DVT) or pulmonary embolism (PE) within 4 weeks prior to first study drug administration;
  -  Active uncontrolled bleeding or a known bleeding diathesis
  8. Patients with a significant cardiovascular disease or condition, including:
  -  Congestive heart failure (CHF) currently requiring therapy
  -  Need for anti-arrhythmic medical therapy for a ventricular arrhythmia or other uncontrolled arrhythmia (patients with controlled atrial fibrillation (heart rate [HR] < 90) for > 30 days prior to study entry are eligible)
  -  Severe conduction disturbances (e.g., 3rd degree heart block)
  -  Angina pectoris requiring therapy
  -  Left ventricular ejection fraction (LVEF) known to be below the lower limit of normal (LLN) for the center, or < 50% by MUGA or echocardiogram if no LLN is defined by the site
  -  QTc interval > 480 msec
  -  Uncontrolled hypertension (per the Investigator's discretion)
  -  Class III or IV cardiovascular disease according to the New York Heart Association's (NYHA) Functional Criteria
  -  History of acute coronary syndromes (including myocardial infarction [MI] and unstable angina), coronary angioplasty, or stenting within 6 months prior to first study drug administration
  9. Patients with a significant ocular disease or condition, including:
  -  History of ocular inflammatory disease
  -  History of disorders of the cornea
  10. Patients with a significant pulmonary disease or condition, including:
  -  History of chronic obstructive pulmonary disease (COPD)
  -  History of interstitial lung disease (ILD), pulmonary fibrosis
  -  History of pulmonary inflammatory disease, pneumonitis, acute respiratory distress syndrome (ARDS)
  -  History of pneumonia within 6 months prior to the first study drug administration
  11. Patients with significant gastrointestinal (GI) abnormalities, including but not limited to:
  -  History of inflammatory bowel disease
  -  Diarrhea > Grade 2 within 2 weeks prior to first study drug administration
  12. Patients with non-healing wounds on any part of the body
  13. Patients with a known or suspected hypersensitivity to any of the excipients of formulated AVID100
  14. Patients with a known history of human immunodeficiency virus (HIV) or active/chronic infection with hepatitis B virus (HBV) or hepatitis C virus (HCV)
  15. Patients with any other serious/active/uncontrolled infection, any infection requiring parenteral antibiotics, or unexplained fever >38º C within 2 weeks prior to first study drug administration
  16. Patients with unresolved > Grade 1 toxicity associated with any prior antineoplastic therapy with the exception of persistent Grade 2 alopecia, decreased hemoglobin, and/or peripheral neuropathy
  17. Patients with inadequate recovery from any prior surgical procedure, or patients having undergone any major surgical procedure within 4 weeks prior to first study drug administration
  18. Patients with any other serious, life-threatening, or unstable pre-existing medical condition (aside from the underlying malignancy) including significant organ system dysfunction, or clinically significant laboratory abnormality (ies), which, in the opinion of the Investigator, would either compromise the patient's safety or interfere with obtaining informed consent, compliance with study procedures, or evaluation of the safety of the study drug
  19. Patients with a psychiatric disorder or altered mental status that would preclude understanding of the informed consent process and/or completion of the necessary study-related evaluations
  20. Patients with the inability or with foreseeable incapacity, in the opinion of the investigator, to comply with the protocol requirements

Relevance to patient case: not relevant