A Phase 1b, Open-Label Study of Eftozanermin Alfa (ABBV-621) in Combination With Bortezomib and Dexamethasone in Subjects With Relapsed or Refractory Multiple Myeloma

Multiple myeloma (MM) is a rare cancer caused by abnormal survival of plasma cells (blood cells). Most trial participants with MM relapse (cancer has come back) or become non- responsive to treatment and remission gets shorter after each line of treatment. This is a study to determine recommended Phase 2 dose and change in disease symptoms of eftozanermin alfa in combination with bortezomib and dexamethasone to assess how efficient the treatment is in adult participants with relapsed/refractory (R/R) MM.
Eftozanermin alfa (ABBV-621) is an investigational drug being developed for the treatment of R/R Multiple Myeloma (MM). Study doctors put the participants in 1 of the 2 groups, called treatment arms. Each group receives a different treatment. Participants in one arm will receive different doses of eftozanermin alfa in combination with bortezomib and dexamethasone to determine phase 2 dose (RP2D). Participants in the other arm will receive eftozanermin alfa at RP2D in combination with bortezomib and dexamethasone. Around 40 adult participants with relapsed/refractory multiple myeloma will be enrolled at approximately 20 sites across the world.
Participants will receive eftozanermin alfa as an infusion into the vein in combination with bortezomib as an infusion into the vein or an injection under the skin and oral dexamethasone tablets for 12 cycles. Each cycle is 21 days for cycles 1-8 and 35 days for cycles 9-12.
There may be higher treatment burden for participants in this trial compared to their standard of care. Participants will attend regular visits during the study at a hospital or clinic. The effect of the treatment will be checked by medical assessments, blood tests, checking for side effects.

Start Date05 Nov 2020

Sponsor / Collaborator

AbbVie, Inc.

NCT03082209 / CompletedPhase 1

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.

Start Date20 Mar 2017

Sponsor / Collaborator

AbbVie, Inc.

100 Clinical Results associated with Eftozanermin alfa

100 Translational Medicine associated with Eftozanermin alfa

100 Patents (Medical) associated with Eftozanermin alfa

Literatures (Medical) associated with Eftozanermin alfa

01 Apr 2024·Cancer chemotherapy and pharmacology

Pharmacokinetics and immunogenicity of eftozanermin alfa in subjects with previously-treated solid tumors or hematologic malignancies: results from a phase 1 first-in-human study

Article

Author: Doi, Toshihiko ; Menon, Rajeev M ; de Jonge, Maja ; Rasco, Drew ; Boehm, Nils ; Guan, Xiaowen ; Siddani, Satya R ; Medeiros, Bruno C ; Biesdorf, Carla ; Polepally, Akshanth R ; Hoffman, David

PURPOSE:

Eftozanermin alfa is a second-generation tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor agonist that enhances death receptor 4/5 clustering on tumor cells to induce apoptosis. We report the pharmacokinetics and immunogenicity of eftozanermin alfa administered intravenously to 153 adults with previously-treated solid tumors or hematologic malignancies from the first-in-human, open-label, dose-escalation and dose-optimization study.

METHODS:

Dose escalation evaluated eftozanermin alfa monotherapy 2.5-15 mg/kg on Day 1 or Days 1/8 of a 21-day cycle. Dose optimization evaluated eftozanermin alfa monotherapy or combination therapy with either oral venetoclax 400-800 mg daily (eftozanermin alfa 1.25-7.5 mg/kg Days 1/8/15 of a 21-day cycle) or chemotherapy (eftozanermin alfa 3.75 or 7.5 mg/kg Days 1/8/15/22 of a 28-day cycle and FOLFIRI regimen [leucovorin, 5-fluorouracil, and irinotecan] with/without bevacizumab on Days 1/15 of a 28-day cycle).

RESULTS:

Systemic exposures (maximum observed concentration [C_max] and area under the concentration-time curve [AUC]) of eftozanermin alfa were approximately dose-proportional across the entire dose escalation range with minimal to no accumulation in Cycle 3 versus Cycle 1 exposures. Comparable exposures and harmonic mean half-lives (35.1 h [solid tumors], 31.3 h [hematologic malignancies]) were observed between malignancy types. Exposures (dose-normalized C_max and AUC) in Japanese subjects were similar to non-Japanese subjects. Furthermore, eftozanermin alfa/venetoclax combination therapy did not have an impact on the exposures of either agent. Treatment-emergent anti-drug antibodies were observed in 9.4% (13/138) of subjects.

CONCLUSIONS:

The study results, including a pharmacokinetic profile consistent with weekly dosing and low incidence of immunogenicity, support further investigation of eftozanermin alfa.

TRIAL REGISTRATION ID:

NCT03082209.

27 Apr 2023·Blood

Activity of eftozanermin alfa plus venetoclax in preclinical models and patients with acute myeloid leukemia

Article

Author: Jongen-Lavrencic, Mojca ; Motwani, Monica ; Smith, Morey ; Sharon, David ; Phillips, Darren C. ; Buchanan, Fritz G. ; Uziel, Tamar ; Medeiros, Bruno C. ; Modi, Dimple A. ; Biesdorf, Carla ; Carneiro, Benedito A. ; Shreenivas, Aditya ; Cheng, Dong ; Morillo, Daniel ; Gort, Eelke ; Tahir, Stephen K. ; Yuda, Junichiro ; Calvo, Emiliano ; Morgan-Lappe, Susan ; Ishizawa, Kenichi

Abstract:

Activation of apoptosis in malignant cells is an established strategy for controlling cancer and is potentially curative. To assess the impact of concurrently inducing the extrinsic and intrinsic apoptosis-signaling pathways in acute myeloid leukemia (AML), we evaluated activity of the TRAIL receptor agonistic fusion protein eftozanermin alfa (eftoza; ABBV-621) in combination with the B-cell lymphoma protein-2 selective inhibitor venetoclax in preclinical models and human patients. Simultaneously stimulating intrinsic and extrinsic apoptosis-signaling pathways with venetoclax and eftoza, respectively, enhanced their activities in AML cell lines and patient-derived ex vivo/in vivo models. Eftoza activity alone or plus venetoclax required death receptor 4/5 (DR4/DR5) expression on the plasma membrane but was independent of TP53 or FLT3-ITD status. The safety/tolerability of eftoza as monotherapy and in combination with venetoclax was demonstrated in patients with relapsed/refractory AML in a phase 1 clinical trial. Treatment-related adverse events were reported in 2 of 4 (50%) patients treated with eftoza monotherapy and 18 of 23 (78%) treated with eftoza plus venetoclax. An overall response rate of 30% (7/23; 4 complete responses [CRs], 2 CRs with incomplete hematologic recovery, and 1 morphologic leukemia-free state) was reported in patients who received treatment with eftoza plus venetoclax and 67% (4/6) in patients with myoblasts positive for DR4/DR5 expression; no tumor responses were observed with eftoza monotherapy. These data indicate that combination therapy with eftoza plus venetoclax to simultaneously activate the extrinsic and intrinsic apoptosis-signaling pathways may improve clinical benefit compared with venetoclax monotherapy in relapsed/refractory AML with an acceptable toxicity profile. This trial was registered at www.clinicaltrials.gov as #NCT03082209.

01 Aug 2022·Investigational new drugs

Eftozanermin alfa (ABBV-621) monotherapy in patients with previously treated solid tumors: findings of a phase 1, first-in-human study

Article

Author: de Jonge, Maja J A ; Medeiros, Bruno C ; Motwani, Monica ; Ratain, Mark J ; Moreno, Victor ; Dunbar, Martin ; Petrich, Adam ; LoRusso, Patricia ; Devriese, Lot A ; Calvo, Emiliano ; Morgan-Lappe, Susan ; Carneiro, Benedito A ; Modi, Dimple ; Rasco, Drew W ; Doi, Toshihiko ; Glasgow, Jaimee ; Nuthalapati, Silpa

Abstract:

Eftozanermin alfa (eftoza), a second-generation tumor necrosis factor-related apoptosis-inducing ligand receptor (TRAIL-R) agonist, induces apoptosis in tumor cells by activation of death receptors 4/5. This phase 1 dose-escalation/dose-optimization study evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary activity of eftoza in patients with advanced solid tumors. Patients received eftoza 2.5–15 mg/kg intravenously on day 1 or day 1/day 8 every 21 days in the dose-escalation phase, and 1.25–7.5 mg/kg once-weekly (QW) in the dose-optimization phase. Dose-limiting toxicities (DLTs) were evaluated during the first treatment cycle to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Pharmacodynamic effects were evaluated in circulation and tumor tissue. A total of 105 patients were enrolled in the study (dose-escalation cohort, n = 57; dose-optimization cohort, n = 48 patients [n = 24, colorectal cancer (CRC); n = 24, pancreatic cancer (PaCA)]). In the dose-escalation cohort, seven patients experienced DLTs. MTD and RP2D were not determined. Most common treatment-related adverse events were increased alanine aminotransferase and aspartate aminotransferase levels, nausea, and fatigue. The one treatment-related death occurred due to respiratory failure. In the dose-optimization cohort, three patients (CRC, n = 2; PaCA, n = 1) had a partial response. Target engagement with regard to receptor saturation, and downstream apoptotic pathway activation in circulation and tumor were observed. Eftoza had acceptable safety, evidence of pharmacodynamic effects, and preliminary anticancer activity. The 7.5-mg/kg QW regimen was selected for future studies on the basis of safety findings, pharmacodynamic effects, and biomarker modulations. (Trial registration number: NCT03082209 (registered: March 17, 2017)).

News (Medical) associated with Eftozanermin alfa

09 Feb 2023

·endpts.com

Updated: AbbVie leaves some oncology programs out of 2023 pipeline highlights

In an investor update Thursday morning, AbbVie left eight programs out of its pipeline highlights it shared with investors, as compared to what exists on the R&D page of its website, last refreshed in December. A Phase III study of Rinvoq in Takayasu arteritis , a rare group of disorders in which blood vessels become inflamed, was not included. The JAK inhibitor is approved for indications like rheumatoid arthritis and carries with it a black box warning. There’s also the removal of late-stage veliparib in breast and ovarian cancers after multiple failures for the PARP inhibitor were announced years ago . A company spokesperson noted the programs remain ongoing. “The updates listed in the slide from this morning highlight our key programs of interest for the investment community and is not a comprehensive snapshot of our entire pipeline,” the spokesperson wrote in an email. Further down the pipeline, AbbVie was quiet on Phase II assets ABBV-4083 in filarial diseases and its Allergan-snagged AGN-231868 in dry eye. A different Allergan asset continues in dry eye, according to the Chicago-area pharma giant’s pipeline update Thursday. Down in Phase I, AbbVie left out four oncology drug candidates. The company reneged on solid and hematologic tumor assets ABBV-155 and ABBV-621 , an IV-infused drug candidate also known as eftozanermin alfa . Small cell lung cancer asset ABBV-011 no longer shows up on the pipeline, and the same goes for ABBV-368 in solid tumors. AbbVie previously nixed a Phase Ib study of ABBV-368 in combination with Idera’s (Aceragen as of last month) tilsotolimod. In its update, AbbVie reminded investors of its four regulatory submissions: Rinvoq for Crohn’s disease; the Genmab-partnered CD3xCD20 bispecific epcoritamab for relapsed/refractory diffuse large B-cell lymphoma; ABBV-951 for advanced Parkinson’s disease and Qulipta for chronic migraine prevention . Editor’s note: This article has been updated to include comment and additional context from an AbbVie spokesperson that the programs remain ongoing.

Phase 1Phase 3Phase 2Drug ApprovalClinical Trial Termination

100 Deals associated with Eftozanermin alfa

External Link

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R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Plasma cell myeloma refractory	Phase 1	US	AbbVie, Inc.	05 Nov 2020
Plasma cell myeloma refractory	Phase 1	JP	AbbVie, Inc.	05 Nov 2020
Plasma cell myeloma refractory	Phase 1	FR	AbbVie, Inc.	05 Nov 2020
Plasma cell myeloma refractory	Phase 1	DE	AbbVie, Inc.	05 Nov 2020
Plasma cell myeloma refractory	Phase 1	IT	AbbVie, Inc.	05 Nov 2020
Plasma cell myeloma refractory	Phase 1	ES	AbbVie, Inc.	05 Nov 2020
Advanced Malignant Solid Neoplasm	Phase 1	US	AbbVie, Inc.	20 Mar 2017
Advanced Malignant Solid Neoplasm	Phase 1	JP	AbbVie, Inc.	20 Mar 2017
Advanced Malignant Solid Neoplasm	Phase 1	NL	AbbVie, Inc.	20 Mar 2017
Advanced Malignant Solid Neoplasm	Phase 1	ES	AbbVie, Inc.	20 Mar 2017

Clinical Result

Indication

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Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03082209 (phase 1 first-in-human study, Pubmed \| Cancer Chemother Pharmacol)	Phase 1	Solid tumor \| Hematologic Neoplasms	153	Eftozanermin alfa monotherapy	srrnjlnfks(nsqzvfvqtt) = zphvpmrcbo hqzyzlnwwy (mbgraiylyc ) View more	Positive	01 Apr 2024
				Eftozanermin alfa + Venetoclax	srrnjlnfks(nsqzvfvqtt) = llnrncgpag hqzyzlnwwy (mbgraiylyc ) View more
NCT03082209 (EHA2020)	Phase 1	Relapsing acute myeloid leukemia \| Diffuse Large B-Cell Lymphoma	34	Eftozanermin alfa monotherapy	hwonzneadn(llovsyothg) = Serious eftoza-related AEs were reported in 5 pts (AML eftoza-VEN); none occurred in >1 pt. pcrranunqm (zllkcjaigd )	-	14 May 2020
				Eftozanermin alfa and Venetoclax combination therapy
NCT03082209 (ASCO2019) Manual	Phase 1	Solid tumor	57	ABBV-621	siwodpypyo(rqcskooxea) = Not reached ntjsgiseiv (gyypybijxa ) View more	Positive	01 Jun 2019
AACR2017	Phase 1	Solid tumor	-	ABBV-621	egtieexkwe(iiukolkvnq) = evosemgpgr csdnaxqjvy (koqdgplwui )	-	01 Jul 2017

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