AVID100 in Advanced Epithelial Carcinomas

<p>Uncontrolled, open label, non-randomized, Enrollment in the order of confirmation of eligibility, Escalating doses of study drug in sequential patient cohorts (Phase 1a)</p><p>• Cohort expansion at the MTD or R2PD and in other cohorts based on safety (Phase 1a)</p>

Uncontrolled, open label, non-randomized, Enrollment in the order of confirmation of eligibility, Escalating doses of study drug in sequential patient cohorts (Phase 1a).

Minimum of 1 to 3 patients per dose cohort; approximately 4 dose cohorts to be evaluated to establish the MTD and/or RP2D.
The initial dose of AVID-100 to be evaluated will be 20 mg/m2/dose (with the maximum dose to be administered in this trial not to exceed 220 mg/m2/dose).
An accelerated titration design (1 patient per cohort) will be used for dose-escalation for up to 2 cohorts or until the occurrence of an event that activates a stopping rule.
Thereafter, dose-escalation will follow a standard 3+3 design with a target toxicity level of 33.3% or less as determined by DLTs.

Minimum of 1 to 3 patients per dose cohort; approximately 4 dose cohorts to be evaluated to establish the Maximum tolerated dose.

<p>Inclusion Criteria (Phase 1):</p><ol><li>Patients with a documented (histologically- or cytologically-proven) solid tumor epithelial carcinoma that is locally advanced or metastatic</li><li>Patients with a malignancy that is either refractory to standard therapy, or for which no standard therapy is available</li><li>Patients with a malignancy that is currently not amenable to surgical intervention due to either medical contraindications or non-resectability of the tumor</li><li>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.</li><li>Patients with an ECOG performance status of 0, 1, or 2, and an anticipated life expectancy of &gt; 3 months</li><li>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.</li><li>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.</li></ol><p>Patients to be Excluded (patients must not meet any of the following criteria Phase 1 only)</p><ol><li>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.</li><li>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</li><li>Patients with a malignancy other than that of epithelial origin</li><li><p>Patients with any of the following hematologic abnormalities at baseline:</p><ul><li>Hemoglobin &lt; 9.0 g&#x2F;dL</li><li>Absolute neutrophil count (ANC) &lt; 1,500 per mm3</li><li>Platelet count &lt; 100,000 per mm3</li></ul></li><li><p>Patients with any of the following serum chemistry abnormalities at baseline:</p><ul><li>Total bilirubin &gt; 1.5 × the upper limit of normal (ULN) for the institution</li><li>AST or ALT &gt; 3 × the ULN for the institution (&gt; 5× ULN if due to hepatic involvement by tumor)</li><li>Serum creatinine &gt; 1.5 × ULN</li></ul></li><li><p>Patients with any of the following coagulation parameter abnormalities at baseline:</p><ul><li>PT (INR) &gt; 1.5 × ULN for the institution</li><li>PTT &gt; 1.5 × ULN for the institution</li></ul></li><li><p>Patients with:</p><ul><li>Active thrombosis, or a history of deep vein thrombosis (DVT) or pulmonary embolism (PE) within 4 weeks prior to first study drug administration;</li><li>Active uncontrolled bleeding or a known bleeding diathesis</li></ul></li><li><p>Patients with a significant cardiovascular disease or condition, including:</p><ul><li>Congestive heart failure (CHF) currently requiring therapy</li><li>Need for anti-arrhythmic medical therapy for a ventricular arrhythmia or other uncontrolled arrhythmia (patients with controlled atrial fibrillation (heart rate [HR] &lt; 90) for &gt; 30 days prior to study entry are eligible)</li><li>Severe conduction disturbances (e.g., 3rd degree heart block)</li><li>Angina pectoris requiring therapy</li><li>Left ventricular ejection fraction (LVEF) known to be below the lower limit of normal (LLN) for the center, or &lt; 50% by MUGA or echocardiogram if no LLN is defined by the site</li><li>QTc interval &gt; 480 msec</li><li>Uncontrolled hypertension (per the Investigator&#x27;s discretion)</li><li>Class III or IV cardiovascular disease according to the New York Heart Association&#x27;s (NYHA) Functional Criteria</li><li>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</li></ul></li><li><p>Patients with a significant ocular disease or condition, including:</p><ul><li>History of ocular inflammatory disease</li><li>History of disorders of the cornea</li></ul></li><li><p>Patients with a significant pulmonary disease or condition, including:</p><ul><li>History of chronic obstructive pulmonary disease (COPD)</li><li>History of interstitial lung disease (ILD), pulmonary fibrosis</li><li>History of pulmonary inflammatory disease, pneumonitis, acute respiratory distress syndrome (ARDS)</li><li>History of pneumonia within 6 months prior to the first study drug administration</li></ul></li><li><p>Patients with significant gastrointestinal (GI) abnormalities, including but not limited to:</p><ul><li>History of inflammatory bowel disease</li><li>Diarrhea &gt; Grade 2 within 2 weeks prior to first study drug administration</li></ul></li><li>Patients with non-healing wounds on any part of the body</li><li>Patients with a known or suspected hypersensitivity to any of the excipients of formulated AVID100</li><li>Patients with a known history of human immunodeficiency virus (HIV) or active&#x2F;chronic infection with hepatitis B virus (HBV) or hepatitis C virus (HCV)</li><li>Patients with any other serious&#x2F;active&#x2F;uncontrolled infection, any infection requiring parenteral antibiotics, or unexplained fever &gt;38º C within 2 weeks prior to first study drug administration</li><li>Patients with unresolved &gt; Grade 1 toxicity associated with any prior antineoplastic therapy with the exception of persistent Grade 2 alopecia, decreased hemoglobin, and&#x2F;or peripheral neuropathy</li><li>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</li><li>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&#x27;s safety or interfere with obtaining informed consent, compliance with study procedures, or evaluation of the safety of the study drug</li><li>Patients with a psychiatric disorder or altered mental status that would preclude understanding of the informed consent process and&#x2F;or completion of the necessary study-related evaluations</li><li>Patients with the inability or with foreseeable incapacity, in the opinion of the investigator, to comply with the protocol requirements</li></ol><p>Drugs and Other Treatments to be Excluded</p><ol><li>Any antineoplastic agent for the primary malignancy (standard or investigational), without delayed toxicity, within 4 weeks, 5 plasma half-lives, or twice the duration of the biological effect, whichever is shortest, prior to first study drug administration and during study with the exception of: Nitrosoureas and nitrogen mustard within 6 weeks prior to first study drug administration and during study</li><li>Any other investigational treatments during study.
This includes participation in any medical device or other therapeutic intervention clinical trials.</li><li>Radiotherapy for target lesions within 4 weeks prior to first study drug administration and during study</li><li>Herbal preparations or related over-the-counter (OTC) preparations&#x2F;supplements containing herbal ingredients aimed at treating the underlying malignancy within 2 weeks prior to first study drug administration and during study</li><li>Strong inhibitors and&#x2F;or inducers of cytochrome P450 (CYP) isoenzyme 3A4 within 2 weeks prior to first study drug administration and during study</li><li>Immunosuppressive or systemic hormonal therapy within 2 weeks prior to first study drug administration and during study.</li><li>Prophylactic use of hematopoietic growth factors within 1 week prior to first study drug administration and during Cycle 1 of study; thereafter prophylactic use of growth factors is allowed as clinically indicated</li></ol>

<p>Inclusion Criteria (Phase 1):</p><ol><li>Patients with a documented (histologically- or cytologically-proven) solid tumor epithelial carcinoma that is locally advanced or metastatic</li><li>Patients with a malignancy that is either refractory to standard therapy, or for which no standard therapy is available</li><li>Patients with a malignancy that is currently not amenable to surgical intervention due to either medical contraindications or non-resectability of the tumor</li><li>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.</li></ol><p>Patients to be Excluded (patients must not meet any of the following criteria Phase 1 only)</p><ol><li>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.</li><li>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</li><li>Patients with a malignancy other than that of epithelial origin</li><li>Patients with hematologic abnormalities at baseline</li><li>Patients with a significant cardiovascular disease or condition</li><li>Patients with a significant ocular disease or condition</li><li>Patients with a significant pulmonary disease or condition</li><li>History of pneumonia within 6 months prior to the first study drug administration</li><li>Patients with significant gastrointestinal (GI) abnormalities</li><li>Patients with non-healing wounds on any part of the body</li></ol><p>Drugs and Other Treatments to be Excluded</p><ol><li>Any antineoplastic agent for the primary malignancy (standard or investigational), without delayed toxicity, within 4 weeks, 5 plasma half-lives, or twice the duration of the biological effect, whichever is shortest, prior to first study drug administration and during study with the exception of: Nitrosoureas and nitrogen mustard within 6 weeks prior to first study drug administration and during study</li><li>Any other investigational treatments during study.
This includes participation in any medical device or other therapeutic intervention clinical trials.</li><li>Radiotherapy for target lesions within 4 weeks prior to first study drug administration and during study</li><li>Herbal preparations or related over-the-counter (OTC) preparations&#x2F;supplements containing herbal ingredients aimed at treating the underlying malignancy within 2 weeks prior to first study drug administration and during study</li><li>Strong inhibitors and&#x2F;or inducers of cytochrome P450 (CYP) isoenzyme 3A4 within 2 weeks prior to first study drug administration and during study</li><li>Immunosuppressive or systemic hormonal therapy within 2 weeks prior to first study drug administration and during study.</li><li>Prophylactic use of hematopoietic growth factors within 1 week prior to first study drug administration and during Cycle 1 of study; thereafter prophylactic use of growth factors is allowed as clinically indicated</li></ol>

2017-04-26

2017-04-27

2017-04-27

2017-05-01

<p>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&#x2F;2a, multicenter, open-label, dose-escalation, cohort study of AVID100, an anti-human EGFR monoclonal antibody (mAb) linked to the maytansinoid DM1.</p><p>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.</p><p>Once the MTD and&#x2F;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).</p><p>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.</p>

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.

<p>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.</p><p>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&#x27;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.</p>

<p>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.</p><p>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.</p>