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 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)).

15 Jun 2021·Cancer researchQ1 · MEDICINE

Hexavalent TRAIL Fusion Protein Eftozanermin Alfa Optimally Clusters Apoptosis-Inducing TRAIL Receptors to Induce On-Target Antitumor Activity in Solid Tumors

Q1 · MEDICINE

Article

Author: Solomon, Larry R. ; Cheng, Dong ; Smith, Morey L. ; Xiao, Yu ; Tahir, Stephen K. ; DiGiammarino, Enrico ; Abraham, Vivek C. ; Trela, Bruce ; Widomski, Deborah ; Liu, Zhihong ; Phillips, Darren C. ; Morgan-Lappe, Susan E. ; Lu, Xin ; Rudra-Ganguly, Nandini ; Zhang, Haichao ; Zhou, Li ; Xu, Nan ; Buchanan, Fritz G. ; Xue, John

Abstract:

TRAIL can activate cell surface death receptors, resulting in potent tumor cell death via induction of the extrinsic apoptosis pathway. Eftozanermin alfa (ABBV-621) is a second generation TRAIL receptor agonist engineered as an IgG1-Fc mutant backbone linked to two sets of trimeric native single-chain TRAIL receptor binding domain monomers. This hexavalent agonistic fusion protein binds to the death-inducing DR4 and DR5 receptors with nanomolar affinity to drive on-target biological activity with enhanced caspase-8 aggregation and death-inducing signaling complex formation independent of FcγR-mediated cross-linking, and without clinical signs or pathologic evidence of toxicity in nonrodent species. ABBV-621 induced cell death in approximately 36% (45/126) of solid cancer cell lines in vitro at subnanomolar concentrations. An in vivo patient-derived xenograft (PDX) screen of ABBV-621 activity across 15 different tumor indications resulted in an overall response (OR) of 29% (47/162). Although DR4 (TNFSFR10A) and/or DR5 (TNFSFR10B) expression levels did not predict the level of response to ABBV-621 activity in vivo, KRAS mutations were associated with elevated TNFSFR10A and TNFSFR10B and were enriched in ABBV-621–responsive colorectal carcinoma PDX models. To build upon the OR of ABBV-621 monotherapy in colorectal cancer (45%; 10/22) and pancreatic cancer (35%; 7/20), we subsequently demonstrated that inherent resistance to ABBV-621 treatment could be overcome in combination with chemotherapeutics or with selective inhibitors of BCL-XL. In summary, these data provide a preclinical rationale for the ongoing phase 1 clinical trial (NCT03082209) evaluating the activity of ABBV-621 in patients with cancer.

Significance::

This study describes the activity of a hexavalent TRAIL-receptor agonistic fusion protein in preclinical models of solid tumors that mechanistically distinguishes this molecular entity from other TRAIL-based therapeutics.

01 Sep 2020·Clinical and translational radiation oncology

Enhancing radiation response by a second-generation TRAIL receptor agonist using a new in vitro organoid model system

Article

Author: Zerp, Shuraila F ; Voest, Emile E ; Bibi, Zainab ; Verbrugge, Inge ; Verheij, Marcel

BACKGROUND:

For many cancer types, including colorectal carcinoma (CRC), combined modality treatments have shown to improve outcome, but are frequently associated with significant toxicity, illustrating the need for new therapeutic approaches. Based on preclinical data, TRAIL receptor agonists appeared to be promising agents for cancer therapy especially in combination with DNA damaging regimens. Here, we present the combination of the second-generation TRAIL receptor agonist APG-880 with radiation in a new and clinically relevant 3D model system.

METHODS:

To investigate the effect of APG-880 in combination with radiation we performed short-term cytotoxicity and long-term clonogenic survival assays in established CRC cell lines, and in tumor organoids derived from colon cancer patients.

RESULTS:

APG-880 is a potent inducer of apoptosis in CRC cell lines and in patient-derived CRC organoids. Furthermore, a supra-additive effect on cytotoxicity was found when APG-880 and radiation were combined simultaneously, with combination indices around 0.7. Lastly, in the long-term survival assays, we demonstrated a radiosensitizing effect of APG-880 with dose enhancement factors between 1.3 and 1.5.

CONCLUSIONS:

In a new, clinically relevant CRC-organoid model system we demonstrated a more than additive combined effect between the second-generation TRAIL receptor agonist APG-880 and radiation.

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

10 top R&D records.

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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

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03082209 (EHA2020)	Phase 1	Relapsing acute myeloid leukemia \| Diffuse Large B-Cell Lymphoma	34	Eftozanermin alfa monotherapy	bqtwhjluvh(fskorwiciy) = Serious eftoza-related AEs were reported in 5 pts (AML eftoza-VEN); none occurred in >1 pt. clakghjtxo (qgyidyyqgk )	-	14 May 2020
NCT03082209 (EHA2020)	Phase 1		34	Eftozanermin alfa and Venetoclax combination therapy		-	14 May 2020
NCT03082209 (ASCO2019) Manual	Phase 1	Solid tumor	57	ABBV-621	jyqagysnor(iytghclycc) = Not reached oualwdjgdw (zcqgmdtuhu ) View more	Positive	01 Jun 2019
AACR2017	Phase 1	Solid tumor	-	ABBV-621	cosasfxhbv(pjikzedupr) = qdmgjktujt vrtofsrrmq (dqrkhmtxxz )	-	01 Jul 2017

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