An Open Label Phase 1, First-In-Human Study of TRAIL Receptor Agonist ABBV-621 in Subjects with Previously-Treated Solid Tumors and Hematologic Malignancies

1.Subject must have a diagnosis of a solid tumor, AML or non-Hodgkin lymphoma
(NHL). Subjects in the dose-optimization cohorts must have either colorectal
cancer with documented KRAS mutations (as determined by local testing), or
pancreatic cancer (irrespective of mutational status). NHL may be of any
subtype for dose escalation but is limited to DLBCL for those enrolled to the
cohort evaluating the combination of ABBV-621 and venetoclax.Subjects in the
chemotherapy combination cohorts must have metastatic or advanced unresectable
colorectal cancer with documented RAS mutation (as determined by local testing).
2. Subject in dose escalation or dose optimization cohort must have received at
least one prior systemic therapy, and must have relapsed or progressed after,
or failed to respond to any/all available effective therapy or therapies. Any
subject with AML must a. have disease that has either persisted or progressed
following allogeneic stem cell transplantation (SCT); b. be ineligible for
allogeneic SCT (for any reason, including age and/or inability to achieve
adequate response); or c. have declined allogeneic SCT. Subject in chemotherapy
cohorts with CRC must have progressed after or failed to respond to initial
systemic therapy consisting of an oxaliplatin and luoropyrimidine-based regimen
without irinotecan (e.g., FOLFOX or CAPOX), CRC subjects enrolled in ABBV-621
and FOLFIRI cohort must have had bevacizumab in the prior line; maintenance
therapy is considered part of first-line therapy. Prior adjuvant therapy is
allowed for CRC.
3. Subject must have measurable disease (by RECIST 1.1 for those with solid
tumors; by Lugano classification for those with NHL), except those with AML,
who must have histologically confirmed relapsed or refractory disease (central
review not required).
4. Subject must consent to provide the following biomarker analyses:
· All subjects: archived tumor tissue (if available)
· Dose optimization subjects(excluding AML): pre and on treatment paired fresh
tissue biopsies. If it is determined that tumor biopsies are not appropriate
for a given subject, the subject may still be enrolled following investigator
consultation with AbbVie. Subjects with DLBCL: Pre and on-treatment paired
fresh biopsies are required from at least six subjects with DLBCL. Note: Pre-
and on-treatment paired fresh tissue biopsies will be optional for subjects
with solid tumor or NHL in Dose Escalation and will be collected so long as
consent is provided.
· All subjects with AML: pre and on-treatment bone marrow aspirates
(BMA)
· For subjects on chemotherapy combination cohorts, subjects must provide a
fresh biopsy if an archival biopsy is not available.
5. Subject in chemotherapy cohorts with CRC must have confirmed RAS mutation
6.Subject must have an Eastern Cooperative Oncology Group (ECOG) Performance
Score of 0 - 2; subjects in chemotherapy combination
cohorts must have ECOG Performance Score of 0-1.
7.Subject must have adequate hematologic, renal and hepatic function

1. Subjects has a history of brain metastases who have not shown clinical and
radiographic stable disease for at least 28 days after definitive therapy. In
addition, any AML patient identified, through CSF analysis, as having active
CNS disease, will be excluded from enrollment.
2. Presence of primary hepatobiliary malignancy, including cholangiocarcinoma
or hepatocellular carcinoma, gallbladder carcinoma, cancer of ampulla of Vater
3. Receipt of any systemic anti-cancer agent, including investigational
anti-cancer products, within 21 days prior to study drug administration or 3
half-lives, whichever is longer
4. Prior receipt, at any time, of TRAIL or TRAIL-like agonist(s) for the
treatment of the malignancy under study.
5. Subjects with history of cirrhosis or other indication of significant
possible hepatic dysfunction
6. Subjects with a positive diagnosis of hepatitis A, B or C
7. Venetoclax + ABBV-621 Combination Therapy Subjects Only: Prior receipt, at
any time, of a BCL-2 inhibitor.
8. Venetoclax + ABBV-621 Combination Therapy Subjects Only: Subject has
received strong or moderate CYP3A inducers within 7 days prior to initiation of
study treatment or strong or medium CYP3A inhibitors within 3 days prior to the
initiation of study treatment.
9. Venetoclax + ABBV-621 Combination Therapy Subjects Only: Subject has
consumed grapefruit, grapefruit products, Seville oranges (including marmalade
containing Seville oranges) or Star fruit within 3 days prior to the initiation
of study treatment.
10. Venetoclax + ABBV-621 Combination Therapy Subjects Only: Subject has a
malabsorption syndrome or other condition that precludes enteral route of
administration.
11. Venetoclax + ABBV-621 Combination Therapy Subjects Only: Subject has
Richter Transformation with or without concurrent chronic lymphocytic leukemia
(subjects with DLBCL transformed from follicular lymphoma or from other
indolent lymphomas are permitted to enroll).
12. Venetoclax + ABBV-621 Combination Therapy Subjects Only: Subject has acute
promyelocytic leukemia (M3).
13. CRC chemotherapy cohort only: Participant with minor surgical procedures,
such as fine needle aspirations or core biopsies, within 7 days prior to first
dose of study drug are excluded.
14. Participants in CRC chemotherapy combination cohort only: cardiomyopathy,
coronary/peripheral artery bypass graft, aneurysm or aneurysm repair,
angioplasty, pulmonary hypertension, cerebrovascular accident or transient
ischemic attack, within 1 year of first dose of study drug.
15. Chemotherapy combination CRC participants only: Disease progression within
3-months of initiating first line therapy.
16. Chemotherapy combination CRC participants only: Prior receipt of an
irinotecan-based chemotherapy.
17. Chemotherapy combination CRC participants only: history of Gilbert's
syndrome or UG1T1A1 genotypes.
18. Chemotherapy Combination CRC Participants Only: Clinically significant
conditions that may place the participant at higher risk with anti-angiogenic
therapy.