A Study of the Safety and Tolerability of ABBV-621 in Participants With Previously-Treated Solid Tumors and Hematologic Malignancies

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

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.

Study Overview

• Status: Completed
• Conditions: Cancer; Advanced Solid Tumors; Hematologic Malignancies
• Intervention / Treatment: Drug: ABBV-621; Drug: Venetoclax; Drug: FOLFIRI; Drug: Bevacizumab

• Study Type: Interventional
• Enrollment (Actual): 153
• Phase: Phase 1

Contacts and Locations

Study Locations

• Japan
  • Chiba
    • Kashiwa-shi, Chiba, Japan, 277-8577
      • National Cancer Center Hospital East /ID# 160596
  • Yamagata
    • Yamagata-shi, Yamagata, Japan, 990-9585
      • Yamagata University Hospital /ID# 200681
• Netherlands
  • Groningen, Netherlands, 9713 GZ
    • Universitair Medisch Centrum Groningen /ID# 169748
  • Maastricht, Netherlands, 6229 HX
    • Maastricht Universitair Medisch Centrum /ID# 214935
  • Utrecht, Netherlands, 3584 CX
    • Universitair Medisch Centrum Utrecht /ID# 169747
  • Zuid-Holland
    • Rotterdam, Zuid-Holland, Netherlands, 3015 GD
      • Erasmus Medisch Centrum /ID# 160869
• Spain
  • Barcelona, Spain, 08035
    • Hospital Universitario Vall d'Hebron /ID# 170809
  • Madrid, Spain, 28040
    • Hospital Universitario Fundacion Jimenez Diaz /ID# 200106
  • Madrid, Spain, 28050
    • Hospital Universitario HM Sanchinarro /ID# 165136
• United States
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Yale University /ID# 158029
  • Illinois
    • Chicago, Illinois, United States, 60637-1443
      • The University of Chicago Medical Center /ID# 158030
    • Harvey, Illinois, United States, 60426
      • Ingalls Memorial Hosp /ID# 171221
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • Univ Michigan Med Ctr /ID# 207134
  • Rhode Island
    • Providence, Rhode Island, United States, 02903
      • Rhode Island Hospital /ID# 171157
  • Tennessee
    • Nashville, Tennessee, United States, 37232-0011
      • Vanderbilt University Medical Center /ID# 215000
  • Texas
    • Houston, Texas, United States, 77030
      • MD Anderson Cancer Center /ID# 202187
    • Houston, Texas, United States, 77090-1243
      • Millennium Oncology /ID# 214981
    • San Antonio, Texas, United States, 78229
      • South Texas Accelerated Research Therapeutics /ID# 160574
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226-3522
      • Medical College of Wisconsin /ID# 171152

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

8

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dose Escalation; ABBV-621 via intravenous administration at escalating dose levels in participants with solid tumors including Non-Hodgkin Lymphoma (NHL).	Drug: ABBV-621; Intravenous (IV)
Experimental: Dose Optimization for KRAS-mutant CRC; Participants with colorectal cancer (CRC) will be treated with single-agent ABBV-621 to enable selection of the RP2D.	Drug: ABBV-621; Intravenous (IV)
Experimental: Dose Optimization for Pancreatic Cancer; Participants with pancreatic cancer will be treated with single-agent ABBV-621 to enable selection of the recommended Phase 2 dose (RP2D).	Drug: ABBV-621; Intravenous (IV)
Experimental: Dose Optimization: ABBV-621 + Venetoclax for DLBCL; Participants with diffuse large B-cell lymphoma (DLBCL) will be treated with a combination of ABBV-621 and venetoclax.	Drug: ABBV-621; Intravenous (IV); Drug: Venetoclax; tablet, oral; Other Names: ABT-199; GDC-0199
Experimental: Dose Optimization: ABBV-621 Monotherapy for AML; Participants with Acute Myeloid Leukemia (AML) will be treated with ABBV-621 monotherapy.	Drug: ABBV-621; Intravenous (IV)
Experimental: Dose Optimization: ABBV-621 + Venetoclax for AML; Additional participants with AML will be enrolled and will be treated with a combination of ABBV-621 and venetoclax.	Drug: ABBV-621; Intravenous (IV); Drug: Venetoclax; tablet, oral; Other Names: ABT-199; GDC-0199
Experimental: Chemotherapy combination: ABBV-621+FOLFIRI; Participants with RAS-mutant CRC who have received one prior line of therapy will be administered ABBV-621 in combination FOLFIRI.	Drug: ABBV-621; Intravenous (IV); Drug: FOLFIRI; IV infusion
Experimental: Chemotherapy combination: ABBV-621 + FOLFIRI + Bevacizumab; Participants with KRAS-mutant CRC are administered with ABBV-621 in combination with bevacizumab plus FOLFIRI	Drug: ABBV-621; Intravenous (IV); Drug: FOLFIRI; IV infusion; Drug: Bevacizumab; IV infusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Tolerated Dose (MTD) and/or Recommended Phase 2 Dose (RP2D) for ABBV-621	The MTD and/or RP2D of ABBV-621 will be determined during the dose escalation phase of the study of ABBV-621	Up to 21 days
Area under the serum/plasma concentration time curve (AUC) of ABBV-621	Area under the serum/plasma concentration time curve (AUC) of ABBV-621.	Up to 64 days
Area under the serum/plasma concentration time curve (AUC) of Venetoclax	Area under the serum/plasma concentration time curve (AUC) of venetoclax.	Up to 64 days
Maximum observed serum concentration (Cmax) of ABBV-621	Maximum observed serum concentration (Cmax) of ABBV-621.	Up to 64 days
Maximum observed serum concentration (Cmax) of Venetoclax	Maximum observed serum concentration (Cmax) of venetoclax.	Up to 64 days
Time to Cmax (Tmax) of ABBV-621	Time to Cmax (Tmax) of ABBV-621.	Up to 64 days
Time to Cmax (Tmax) of Venetoclax	Time to Cmax (Tmax) of ventoclax.	Up to 64 days
Terminal phase elimination rate constant (β) for ABBV-621	Terminal phase elimination rate constant (β) for ABBV-621.	Up to 64 days
Terminal phase elimination rate constant (β) for Venetoclax	Terminal phase elimination rate constant (β) for venetoclax.	Up to 64 days
Terminal Phase Elimination Half-life (t1/2) of ABBV-621 in Plasma	Terminal phase elimination half-life (t1/2) for ABBV-621.	Up to 64 days
Terminal Phase Elimination Half-life (t1/2) of Venetoclax in Plasma	Terminal phase elimination half-life (t1/2) for venetoclax.	Up to 64 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
QTcF Change from Baseline	QT interval measurement corrected by Fridericia's formula (QTcF) mean change from baseline by dose level	Up to 64 days
Number of Participants with Dose-limiting Toxicities (DLTs)	Dose limiting toxicities for dose escalation purposes will be determined on events that occur during the first 21-day cycle (with protocol specified exceptions for AML participants).	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)

Collaborators and Investigators

• Sponsor: AbbVie

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): March 20, 2017
• Primary Completion (Actual): January 21, 2022
• Study Completion (Actual): January 21, 2022

Study Registration Dates

• First Submitted: March 14, 2017
• First Submitted That Met QC Criteria: March 14, 2017
• First Posted (Actual): March 17, 2017

Study Record Updates

• Last Update Posted (Estimate): December 9, 2022
• Last Update Submitted That Met QC Criteria: December 8, 2022
• Last Verified: December 1, 2022

More Information

Terms related to this study

• Keywords: Cancer; non-Hodgkin lymphoma; Solid Tumors; Hematologic Malignancies; acute myeloid leukemia (AML); colorectal cancer (CRC); Diffuse Large B-Cell Lymphoma (DLBCL)
• Additional Relevant MeSH Terms: Neoplasms by Site; Hematologic Diseases; Neoplasms; Hematologic Neoplasms; Physiological Effects of Drugs; Antineoplastic Agents; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Venetoclax; Bevacizumab
• Other Study ID Numbers: M15-913; 2016-003887-37 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No