Clinical trial NCT03082209: A Study of the Safety and Tolerability of ABBV-621 in Participants With Previously-Treated Solid Tumors and Hematologic Malignancies
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Advanced Solid Tumors
Cancer
Hematologic Malignancies
Keywords: Solid Tumors
Hematologic Malignancies
Cancer
non-Hodgkin lymphoma
acute myeloid leukemia (AML)
colorectal cancer (CRC)
Diffuse Large B-Cell Lymphoma (DLBCL)
Lead sponsor: AbbVie
Sponsor class: INDUSTRY
First posted: 2017-03-17
Enrollment: 153
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is an open-label, Phase I, dose-escalation study to determine the maximum tolerated dose (MTD) and/or recommended phase two dose (RPTD), and evaluate the safety, efficacy, and pharmacokinetic (PK) profile of ABBV-621 for participants with previously-treated solid tumors or hematologic malignancies.

Only chemotherapy combination (ABBV-621 + FOLFIRI) enrolling participants with RAS-mutant CRC who have received one prior line of therapy is open for enrollment.


Eligibility criteria: Inclusion Criteria:

* Must have a diagnosis of a solid tumor (except primary brain tumors), acute myeloid leukemia (AML), or non-Hodgkin lymphoma (NHL); NHL may be of any subtype for Dose Escalation but is limited to diffuse large B-cell lymphoma (DLBCL) for those enrolled to the cohort evaluating the combination of ABBV-621 and venetoclax. Participants in the Dose Optimization solid tumor cohorts must have either colorectal cancer with documented KRAS mutations (as determined by local testing), or pancreatic cancer (irrespective of mutational status). Participants in the chemotherapy combination cohorts must have metastatic or advanced unresectable colorectal cancer with documented RAS mutations (as determined by local testing).
* Participant 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.
* Participant in chemotherapy cohorts with CRC must have progressed after or failed to respond to initial systemic therapy.
* Must have measurable disease (by Response Evaluation Criteria In Solid Tumors \[RECIST\] 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.
* Must agree to provide the following samples for biomarker analysis:

  * All participants: archived tumor tissue (if available).
  * Participants in Dose Optimization (excluding AML): pre- and on-treatment fresh tissue biopsies. (Note: fresh tissue biopsies will be optional for participants with solid tumor or NHL in Dose Escalation and will be collected only if consent is provided)
  * All participants with AML: pre- and on-treatment bone marrow aspirates (BMA)
  * Participants in chemotherapy combination cohorts: participants must provide a fresh biopsy if an archival biopsy is not available
* Participant in chemotherapy cohorts with CRC must have confirmed RAS mutation
* Must have an Eastern Cooperative Oncology Group (ECOG) Performance Score of 0 - 2. Participants in chemotherapy combination cohorts must have ECOG Performance Score of 0 - 1.
* Must have adequate hematologic, renal and hepatic function.

Exclusion Criteria:

* Participants with 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 participant identified through cerebrospinal fluid (CSF) analysis, as having active central nervous system (CNS) disease, will be excluded.
* Presence of primary hepatobiliary malignancy, including cholangiocarcinoma or hepatocellular carcinoma, gallbladder carcinoma, cancer of ampulla of Vater.
* 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.
* Participant with a history of cirrhosis or other indication of significant possible hepatic dysfunction. Note: Those with non-alcoholic steatohepatitis (NASH) should be discussed with the AbbVie TA MD before enrollment.
* Participant with a positive diagnosis of hepatitis A, B, or C.
* Dose Optimization combination cohorts only: Prior receipt, at any time, of a BCL-2 inhibitor
* Dose Optimization combination cohorts only: Participant has received strong or moderate CYP3A inhibitors or inducers within 7 days prior to the initiation of study treatment.
* Dose Optimization combination cohorts only: Participant has malabsorption syndrome or other condition that precludes enteral route of administration.
* Dose Optimization combination cohorts only: Participant has promyelocytic leukemia (M3).
* 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.
* 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.
* Chemotherapy combination CRC participants only: Prior receipt of an irinotecan-based chemotherapy.
* Chemotherapy combination CRC participants only: Disease progression within 3-months of initiating first-line therapy.
* Chemotherapy combination CRC participants only: history of Gilbert's syndrome or UG1T1A1 genotypes.
* Chemotherapy combination with bevacizumab participants only: clinically significant conditions that may place the participant at higher risk with anti-angiogenic therapy.

Primary outcomes:
measure: Maximum Tolerated Dose (MTD) and/or Recommended Phase 2 Dose (RP2D) for ABBV-621
timeFrame: Up to 21 days
measure: Area under the serum/plasma concentration time curve (AUC) of ABBV-621
timeFrame: Up to 64 days
measure: Area under the serum/plasma concentration time curve (AUC) of Venetoclax
timeFrame: Up to 64 days
measure: Maximum observed serum concentration (Cmax) of ABBV-621
timeFrame: Up to 64 days
measure: Maximum observed serum concentration (Cmax) of Venetoclax
timeFrame: Up to 64 days
measure: Time to Cmax (Tmax) of ABBV-621
timeFrame: Up to 64 days
measure: Time to Cmax (Tmax) of Venetoclax
timeFrame: Up to 64 days
measure: Terminal phase elimination rate constant (β) for ABBV-621
timeFrame: Up to 64 days
measure: Terminal phase elimination rate constant (β) for Venetoclax
timeFrame: Up to 64 days
measure: Terminal Phase Elimination Half-life (t1/2) of ABBV-621 in Plasma
timeFrame: Up to 64 days
measure: Terminal Phase Elimination Half-life (t1/2) of Venetoclax in Plasma
timeFrame: Up to 64 days
Secondary outcomes:
measure: QTcF Change from Baseline
timeFrame: Up to 64 days
measure: Number of Participants with Dose-limiting Toxicities (DLTs)
timeFrame: Up to 42 days after first day of study drug administration or 14 days after bone marrow biopsy showing < 5% blast count (whichever is later)
Other outcomes:
Locations:
city: New Haven
country: United States
facility: Yale University /ID# 158029
state: Connecticut
city: Chicago
country: United States
facility: The University of Chicago Medical Center /ID# 158030
state: Illinois
city: Harvey
country: United States
facility: Ingalls Memorial Hosp /ID# 171221
state: Illinois
city: Ann Arbor
country: United States
facility: Univ Michigan Med Ctr /ID# 207134
state: Michigan
city: Providence
country: United States
facility: Rhode Island Hospital /ID# 171157
state: Rhode Island
city: Nashville
country: United States
facility: Vanderbilt University Medical Center /ID# 215000
state: Tennessee
city: Houston
country: United States
facility: MD Anderson Cancer Center /ID# 202187
state: Texas
city: Houston
country: United States
facility: Millennium Oncology /ID# 214981
state: Texas
city: San Antonio
country: United States
facility: South Texas Accelerated Research Therapeutics /ID# 160574
state: Texas
city: Milwaukee
country: United States
facility: Medical College of Wisconsin /ID# 171152
state: Wisconsin
city: Kashiwa-shi
country: Japan
facility: National Cancer Center Hospital East /ID# 160596
state: Chiba
city: Yamagata-shi
country: Japan
facility: Yamagata University Hospital /ID# 200681
state: Yamagata
city: Rotterdam
country: Netherlands
facility: Erasmus Medisch Centrum /ID# 160869
state: Zuid-Holland
city: Groningen
country: Netherlands
facility: Universitair Medisch Centrum Groningen /ID# 169748
city: Maastricht
country: Netherlands
facility: Maastricht Universitair Medisch Centrum /ID# 214935
city: Utrecht
country: Netherlands
facility: Universitair Medisch Centrum Utrecht /ID# 169747
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d'Hebron /ID# 170809
city: Madrid
country: Spain
facility: Hospital Universitario Fundacion Jimenez Diaz /ID# 200106
city: Madrid
country: Spain
facility: Hospital Universitario HM Sanchinarro /ID# 165136
Study officials:
affiliation: AbbVie
name: ABBVIE INC.
role: STUDY_DIRECTOR
References:
citation: LoRusso P, Ratain MJ, Doi T, Rasco DW, de Jonge MJA, Moreno V, Carneiro BA, Devriese LA, Petrich A, Modi D, Morgan-Lappe S, Nuthalapati S, Motwani M, Dunbar M, Glasgow J, Medeiros BC, Calvo E. Eftozanermin alfa (ABBV-621) monotherapy in patients with previously treated solid tumors: findings of a phase 1, first-in-human study. Invest New Drugs. 2022 Aug;40(4):762-772. doi: 10.1007/s10637-022-01247-1. Epub 2022 Apr 25.