solid tumor

Dose Escalation Stage: The primary objectives of this portion are to evaluate the safety and pharmacokinetic (PK) profile of ABBV-221 and determine the maximum tolerated dose over a single treatment Cycle (MTD). The secondary objectives are to evaluate the effect of ABBV-221 on QT prolongation, preliminary assessment of activity of ABBV-221 in a specific subject population, and preliminary retrospective assessment of clinical activity and EGFR expression. Regimen Optimization Stage: The primary objectives of this portion are to determine a recommended Phase 2 Dosage Regimen (RPTD) for ABBV-221, which includes the cycle dose and other dosing parameters to be used during each cycle from treatment initiation through maintenance treatment cycles. In addition the safety and pharmacokinetic profile at the RPTD will be assessed. Expanded Safety Cohort: The primary objectives of this portion are to further assess the safety and pharmacokinetic (PK) profile of ABBV-221 at the RPTD. The secondary objectives are to further evaluate the effect of ABBV-221 on QT prolongation, preliminary assessment of activity of ABBV-221 in a specific subject population, and preliminary retrospective assessment of clinical activity and EGFR expression at the RPTD.

ABBV-221

ABBV-221

Injection

0.3 mg/kg

The preliminary efficacy endpoints include analysis of objective response rate (ORR)
(determined using RECIST version 1.1), time to progression (TTP), overall survival (OS),
duration of overall response, and ECOG performance status.

Noncompartmental methods will be used determine the values for the following
pharmacokinetic parameters of ABBV-221, Total AM1-ABT-806, and unconjugated
MMAE:
● Maximum observed plasma concentration (Cmax) and the time to Cmax (peak
time, Tmax),
● Terminal phase elimination rate constant and the area under the plasma
concentration-time curve (AUC) from time 0 to the time of the last measurable
concentration (AUCt) and from time 0 to infinite time (AUC∞),
● Confirmed positive ADA results will be reported in titer units.

1. Subject must be ≥ 18 years of age.
2. Subject has a solid tumor of a type associated with elevated levels of EGFR (e.g., head and neck squamous cell carcinoma, non-small cell lung cancer [NSCLC], triple negative breast cancer, colorectal carcinoma, and GBM).
3. Subject must have disease that has progressed on prior treatment and is not amenable to surgical resection or other approved therapeutic options with curative intent.
4. Subject cannot tolerate or must not be eligible for other approved therapeutic options with known survival advantage.
5. Subject has an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 2.
6. Dose Escalation/Regimen Optimization Only:
•For doses below 1.0 mg/kg, an archived tumor tissue sample for retrospective analyses is optional.
•For doses at 1.0 mg/kg or above, an archived tumor tissue sample for retrospective analyses is required.
Expanded Safety Cohort Only:
•All subjects must have an archived tumor tissue sample for retrospective analyses.
7. Subject has adequate bone marrow, renal, hepatic and cardiac function as follows:
•Bone marrow: Absolute neutrophil count (ANC) ≥ 1,500/mm3, Platelets ≥ 100,000/mm3;
Hemoglobin ≥ 9.0 g/dL
•Renal function: Serum creatinine ≤ 1.5 times the upper limit of the institution's normal range
•Hepatic function: Bilirubin, aspartate aminotransferase (AST), and alanine aminotransferase
(ALT) ≤ 1.5 times the upper limit of the institution's normal range. Subjects with liver metastasis may have an AST and ALT of ≤ 5.0 times the upper limit of the institution's normal range.
•BNP ≤ the upper limit of normal and left ventricular ejection fraction (LVEF) > 40%. (A subject with a screening BNP above the upper limit of normal may still be eligible if tests of cardiac function [ECG, Echocardiogram, and/or MUGA scan] are normal, the subject has no significant cardiac history, and is asymptomatic. In such cases, the subject may only be considered eligible for participation at the discretion of the investigator, in consultation with the AbbVie Medical Monitor.)
8. Women of childbearing potential and men must agree to use adequate contraception (one of the following listed below) prior to study entry, for the duration of study participation, and for a period of 3 months following completion of therapy. Childbearing is defined as either a female who is able to birth a child or a male who is able to father a child. Women of childbearing potential must have a negative serum pregnancy test within 7 days prior to initiation of ABBV-221. Female subjects considered not of childbearing potential must have documentation of being surgically sterile or post-menopausal for at least 1 year.
•Total abstinence from sexual intercourse beginning at least one complete menstrual cycle prior to study drug administration
•A vasectomized male subject or a vasectomized partner of a female subject
•Hormonal contraceptives (oral, parenteral or transdermal) for at least 3 months prior to study drug administration
•Intrauterine devices (female)
If female, subject must either be postmenopausal defines as:
•Age ≥ 55 years with no menses for 12 or more months without an alternative medical cause.
•Age < 55 years with no menses for 12 or more months without an alternative medical cause
AND an FSH level > 40 IU/L.
OR
•Permanently surgical sterile (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).
9. Subjects must voluntarily sign and date each informed consent, approved by an Institutional Review Board (IRB)/Independent Ethics Committee (IEC), prior to the initiation of any screening or study-specific procedures.
Additional Inclusion Criteria for the Expanded Safety Cohort
10. Subject must have measurable disease per RECIST version 1.1.
11. Subjects must have histologically or cytologically confirmed, metastatic NSCLC. These subjects must have progressed after receiving prior platinum-containing chemotherapy regimen for metastatic disease.

1. Subject has received anticancer therapy including chemotherapy, immunotherapy, radiotherapy, biologic, or any investigational therapy within a period of 21 days prior to the first dose of ABBV-221.
2. Subject has received a prior EGFR-directed monoclonal antibody within a period of 4 weeks prior to the first dose of ABBV-221 on Cycle 1 Day 1.
3. Subject has unresolved, clinically significant toxicities from prior anticancer therapy, defined as any Common Terminology Criteria for Adverse Events (CTCAE) > Grade 1.
4. Subject has had major surgery within 21 days prior to the first dose of ABBV-221.
5. Subject has a clinically significant uncontrolled condition(s) including but not limited to the
following:
•Active uncontrolled infection
•Symptomatic congestive heart failure
•Grade ≥ 2 peripheral neuropathy
•Unstable angina pectoris or cardiac arrhythmia
•Psychiatric illness/social situation that would limit compliance with the study
6. Subject has history of major immunologic reaction (Grade 3 or 4) to any Immunoglobulin G (IgG) containing agent.
7. Subject has any medical condition which in the opinion of the investigator places the subject at an unacceptably high risk for toxicities.
8. Subject is a lactating or pregnant female.
9. Dose Escalation Only: Subject has received medication that includes strong CYP3A4 inhibitors or inducers within 5 days prior to the first dose of study drug.
For Subjects with Glioblastoma Multiforme Only:
10. Subject must have evaluable disease by MRI within 14 days prior to start of study drug.
Corticosteroid dose must be stable or decreasing for at least 5 days prior to the scan. If steroids are added or the steroid dose is increased between the date of screening MRI and the start of treatment, a new baseline MRI is required.
Additional Exclusion Criteria for the Expanded Safety Cohort
11. Subject has been previously exposed to an EGFR antibody.
12. Subject has a malignant tumor in addition to NSCLC that requires treatment and/or could interfere with the ability of the subject to be followed until he or she has met the primary and secondary endpoints.
13. Subject has uncontrolled metastases to the central nervous system (CNS). Computerized tomography (CT) scans are not required to rule out brain or meningeal metastases unless there is clinical suspicion of CNS disease. Subjects with brain metastases are eligible provided they have shown clinical and radiographic stable disease for at least 28 days after definitive therapy.