A Multicenter, Phase 1/1b Open-Label, Dose-Escalation Study of ABBV-399, an Antibody Drug Conjugate, in Subjects with Advanced Solid Tumors

1. Subject must be >= 18 years of age
2. Subject must have advanced NSCLC that is not amenable to surgical resection
or other approved therapeutic options that have demonstrated clinical benefit.
-Subjects who have refused, are considered ineligible for or are intolerant of
standard therapy are eligible
-Based on evidence gathered in this study or from external sources, the Sponsor
in consultation with the Investigators, may decide to limit to specific tumor
histology.
- For Monotherapy dose-escalation - Subject with advanced solid tumors
- For Monotherapy dose-expansion and Combination Arms A + D - Subject must have
tumor with c-Met overexpression, MET exon 14 skip mutation or MET amplification.
3. Subject has an Eastern Cooperative Oncology Group (ECOG) Performance Status
of 0 to 2. For *monotherapy expansion cohort 1.6 Q2W*, subjects have an ECOG
performance status of 0 or 1.
4. Subject must have measurable disease per RECIST version 1.1 (Appendix C)
5. Subject has fresh and/or archived diagnostic formalin-fixed paraffin
embedded (FFPE) tumor tissue available for analysis
6. Subject has adequate bone marrow, renal, and hepatic function
7. A negative serum pregnancy test for all female subjects of childbearing
potential at the screening visit and a negative urine pregnancy test for all
female subjects of childbearing potential at baseline prior to the first dose
of study drug (for details on contraception refer to Section 5.2.1)
8. Subject is capable of understanding and complying with parameters as
outlined in the protocol and able to sign informed consent, approved by an
Institutional Review Board (IRB) prior to the initiation of any screening or
study-specific procedures.
Additional Inclusion Criteria for Subjects Enrolled on the Combination Therapy
Phase
Subjects in the combination therapy arms A and D must meet the above inclusion
criteria and be eligible to receive erlotinib, or nivolumab per locally
approved labeling, or at the discretion of the Investigator in consultation
with the Medical Monitor
-Subjects enrolled in the combination therapy phase Arm E must satisfy the
above inclusion criteria numbers 1 - 4, 6 - 8 and the following:
•Subject must have metastatic/locally advanced nonsquamous NSCLC with
documented EGFR mutations del19 or L858R, with or without T790M mutation, and
none of the EGFR mutations known to be resistant to osimertinib.
•Subject must have received at least 1 but no more than 2 prior regimens, one
of which must have contained osimertinib. Subject must have had disease
progression while on osimertinib. Only 1 prior regimen may have contained
chemotherapy. From amendment 15 and later, and for the purpose of this
eligibility criterion, consecutive EGFR TKIs will count as 1 regimen.
• Subject must have available post-osimertinib progression tumor tissue for
central c-Met immunohistochemistry (IHC) testing. In cases where it is not
possible to obtain a post-osimertinib progression biopsy, archival tissue may
be allowed.

Additional Inclusion Criteria for Subjects Enrolled in the *monotherapy
expansion cohort 1.6 Q2W*
Subjects must satisfy the above inclusion criteria 1-4 , 6-8, and also the
following:
• Subjects must have locally advanced or metastatic, non-squamous, EGFR wild
type (site documented EGFR status), c-Met+ (as assessed by an AbbVie
designated IHC laboratory) NSCLC. Subjects must not have adenosquamous histology
- Subject must submit archival or fresh tumor material for assessment of c-Met
levels during the pre-screening period. Tumor material from the primary tumor
site and/or metastatic sites are allowed. If archival tissue is negative for
c-Met overexpression, fresh biopsy material may be submitted for reassessment
of c-Met expression.
• Subjects must have received no more than 2 lines of prior systemic therapy
(including no more than 1 line of systemic cytotoxic chemotherapy) in the
locally advanced or metastatic setting.
- Multiple lines of TKIs targeting the same TK count as 1 line of therapy for
the purposes of this eligibility criterion.
• Subjects must have progressed on systemic cytotoxic chemotherapy (or are
ineligible for systemic cytotoxic chemotherapy) and an immune checkpoint
inhibitor (as monotherapy or in combination with systemic cytotoxic
chemotherapy, or ineligible for an immune checkpoint inhibitor), and prior
anti-cancer therapies targeting driver gene alterations (if applicable).
• Subjects should not have received prior c-Met-targeted antibody-based
therapies.

•Subject has received radiation therapy to the lung < 6 months prior to the
first dose of ABBV-399.
•Subject has received anticancer therapy including chemotherapy, immunotherapy,
biologic, or any investigational therapy within a period of 21 days, or herbal
therapy within 7 days prior to the first dose of ABBV-399.
-Palliative radiation therapy for bone or skin metastasis for 10 fractions or
less is not subject to a washout period; see below for central nervous system
metastatases (CNS).
-For approved targeted small molecules, a washout period of 5 half-lives is
adequate (no washout period is required for subjects currently on erlotinib or
osimertinib)
•Subject has uncontrolled metastases to the CNS based on head CT or MRI.
Subjects with brain metastases may be eligible at least 2 weeks after
definitive therapy to all known sites of CNS disease provided they are
asymptomatic and either off or on a non-increasing dose (in last 2 weeks) of
systemic steroids and not on anticonvulsants for seizure activity directly
related to progressive CNS metastases.
• Subjects with a history of interstitial lung disease (ILD) or pneumonitis
that required treatment with systemic steroids.
• Subject has evidence of pulmonary fibrosis on screening imaging assessment or
any history of pneumonitis or interstitial lung disease (ILD) within 3 months
of the planned first dose of the study drug.
• Subject has unresolved clinically significant adverse events >= Grade 2 from
prior anticancer therapy except for alopecia or anemia.
•Subject has had major surgery within 21 days prior to the first dose of
ABBV-399.
•Subject has a clinically significant condition(s)
•Subject has history of major immunologic reaction to any IgG containing agent.
•Subject has any medical condition which in the opinion of the Investigator or
Medical Monitor places the subject at an unacceptably high risk for toxicities.
•Subject is a lactating or pregnant female.
•Subjects with known active COVID-19 infection, subjects with signs/symptoms
associated with COVID-19 infection or known exposure to a confirmed case of
COVID-19 infection during 14 days prior to Screening: must be screen failed and
may only rescreen after they have recovered from COVID-19 or they are no longer
considered contagious, per investigator assessment.

Additional Exclusion Criteria for Subjects Enrolled on the Combination Therapy
Phase
•Subjects enrolled on the combination therapy phase must satisfy the above
exclusion criteria and also the following:
-Subjects may not receive ABBV-399 in combination with osimertinib, erlotinib,
or nivolumab if they have any medical condition which in the opinion of the
Investigator places the subject at an unacceptably high risk for toxicities
from the combination.
Subjects may not receive nivolumab if they have * Active autoimmune disease
with exceptions of vitiligo, type I diabetes mellitus, hypothyroidism and
psoriasis
* Used systemic corticosteroids (> 10 mg daily prednisone or equivalent) or
other immunosuppressive medications within 14 days of study drug
administration, with exception of
inhaled, locally injected or topical steroids
* Known immunosuppressive disease, for example human immunodeficiency virus
infection or history of bone marrow transplant or chronic lymphocytic leukemia.
* Prior PD-1 or PD-L1 inhibitor therapy (except as waived by sponsor)