conatumumab (AMG 655) / Amgen - LARVOL DELTA

Inhibition of PRMT5 with JNJ-64619178 sensitizes B-cell non-Hodgkin lymphoma cells to both intrinsic and extrinsic apoptosis (ASH 2025) - P1 | "Various cell lines, including DLBCL (TMD8, Ri-1, OCI-Ly1,OCI-Ly1R, SUDHL4), double-hit lymphoma patient-derived xenograft (DW19), MCL (Mino, Jeko-1), and BL(Raji, BL-70) were utilized to investigate the in vitro anti-cancer properties of JNJ-9178, BH3 mimetics(venetoclax [Ven, BCL-2i], S63845 [S63, MCL-1i], A1331852 [A133, BCL-xLi]) and TRAIL analogs (rhTRAIL[recombinant human TRAIL], Conatumumab [DR5 agonist], and Mapatumumab [DR4 agonist]). We identified PRMT5 as an important regulator of both intrinsic and extrinsic apoptosis. Ourdata suggest that DBP has the potential to optimize the selection of BH3 mimetics to combine with JNJ-9178 to maximize the activity of this drug across certain B-cell NHL subtypes. Additionally, JNJ-9178sensitizes B-cell NHL cell lines to TRAIL-induced cancer cell-selective extrinsic apoptosis."

IO biomarker • B Cell Non-Hodgkin Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • High-grade B-cell lymphoma • Lymphoma • Myelodysplastic Syndrome • Non-Hodgkin’s Lymphoma • Solid Tumor • ANXA5 • BCL2 • TNFRSF10B

CRISPR screens identify the ATPase VCP as a druggable therapeutic vulnerability in cholangiocarcinoma. (PubMed, Proc Natl Acad Sci U S A) - "To address this, we combined CB-5339 with senolytic agents (ABT-263 and conatumumab), which selectively eliminate senescent CCA cells, resulting in enhanced tumor suppression both in vitro and in vivo. Clinical analysis showed that VCP overexpression in CCA patients correlates with poor prognosis. Our study unveils a "one-two punch" strategy, targeting VCP-mediated senescence followed by senolytic clearance, offering a promising therapeutic approach for CCA."

Journal • Biliary Cancer • Cholangiocarcinoma • Oncology • Solid Tumor

QUILT-2.019: A Study of AMG 655 or AMG 479 in Combination With Gemcitabine for Treatment of Metastatic Pancreatic Cancer (clinicaltrials.gov) - P1/2 | N=138 | Completed | Sponsor: NantCell, Inc. | Phase classification: P1b/2 ➔ P1/2

Combination therapy • Metastases • Phase classification • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor

The generation of stable microvessels in ischemia is mediated by endothelial cell derived TRAIL. (PubMed, Sci Adv) - "Proof-of-concept studies showed that Conatumumab, an agonistic TRAIL-R2 antibody, promoted vascular sprouts from explanted patient arteries. Single-cell RNA sequencing revealed heparin-binding EGF-like growth factor in mediating EC-pericyte communications dependent on TRAIL. These studies highlight unique TRAIL-dependent mechanisms mediating neo-angiogenesis and vessel stabilization and the potential of repurposing TRAIL-R2 agonists to stimulate stable and functional microvessel networks to treat ischemia in PAD."

Journal • Cardiovascular • Oncology • Peripheral Arterial Disease • HBEGF • TNFRSF10B

QUILT-3.026: AMG 655 in Combination With AMG 479 in Advanced, Refractory Solid Tumors (clinicaltrials.gov) - P1/2 | N=89 | Terminated | Sponsor: NantCell, Inc. | Phase classification: P1b/2 ➔ P1/2

Combination therapy • Metastases • Phase classification • Colorectal Cancer • Gastrointestinal Cancer • Hepatology • Lung Cancer • Lung Non-Small Cell Squamous Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Pancreatic Cancer • Sarcoma • Solid Tumor

TRAIL-Based Therapies Efficacy in Pediatric Bone Tumors Models Is Modulated by TRAIL Non-Apoptotic Pathway Activation via RIPK1 Recruitment. (PubMed, Cancers (Basel)) - "The DR5 agonist antibody AMG655 (Conatumumab) was selected as an example of TRAIL-based therapy...We proposed two independent strategies to overcome this issue: (1) a proof-of-concept targeting of RIPK1 by shRNA approach and (2) the use of a novel highly-potent TRAIL-receptor agonist; both shifting the balance in favor of apoptosis. These observations are paving the way to resurrect TRAIL-based therapies in pediatric bone tumors to help predict the response to treatment, and propose a relevant adjuvant strategy for future therapeutic development."

Journal • Ewing Sarcoma • Oncology • Osteosarcoma • Pediatrics • Sarcoma • Solid Tumor • RIPK1

Combined and targeted drugs delivery system for colorectal cancer treatment: Conatumumab decorated, reactive oxygen species sensitive irinotecan prodrug and quercetin co-loaded nanostructured lipid carriers. (PubMed, Drug Deliv) - "In vivo studies in a CRC-bearing model corroborated the capability of nanoparticles for the inhibition of cancer, leading to a reduction of tumor growth without systemic toxicity. The conatumumab decorated, ROS sensitive prodrug contained combination nano-system is a promising platform for CRC therapy."

Journal • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

Efficacy of DR5-targeted immunoliposomes in pancreatic cancer models primed with SMO inhibitors (AACR 2018) - "...Tumor priming using NVP-LDE225, an inhibitor of sonic hedgehog (sHH) signaling, can compromise the stromal drug delivery barrier by mediating stromal thinning, and discharge of tumor interstitial pressure (IFP) and decompression of tumor vasculature, resulting in increased perfusion and deposition of drug-containing nanoparticles into tumors...Efficacy was investigated with SSL liposomes containing doxorubicin (SSL-DXR), optionally coupled covalently with Death Receptor 5 monoclonal antibody AMG655 (SSL-DXR-DR5), which binds the pro-apoptotic DR5 receptor and initiates the extrinsic apoptotic pathway. Quantitative fluorescence microscopy showed that sHH inhibitor treatment mediated a temporal window of enhanced permeability/perfusion and deposition of SSL that varied with the amount of desmoplasia in PDX models, which are otherwise highly impermeant to SSL... Efficacy of SSL-DXR-DR5 immunoliposomes was superior to other treatments in two cell l

Clinical • IO Biomarker • Preclinical • Pancreatic Cancer

Efficacy and Safety of Regorafenib in Combination with Chemotherapy as Second-Line Treatment in Patients with Metastatic Colorectal Cancer: A Network Meta-Analysis and Systematic Literature Review. (PubMed, Adv Ther) - "Regorafenib combined with chemotherapy might be a potential alternative to conventional therapeutic options in second-line treatment of patients with metastatic colorectal cancer and could be considered as the best option for treating patients with KRAS and BRAF mutated mCRC. However future RCTs are needed to confirm these results."

Combination therapy • Journal • Retrospective data • Colorectal Cancer • Fatigue • Gastrointestinal Cancer • Hematological Disorders • Neutropenia • Oncology • Solid Tumor • BRAF • KRAS

Open Label Extension Study of Conatumumab and AMG 479 (clinicaltrials.gov) - P2; N=12; Active, not recruiting; Sponsor: Amgen; Trial primary completion date: Apr 2015 ->Dec 2015

Trial primary completion date • Biosimilar • Colorectal Cancer • Hematological Malignancies • Non Small Cell Lung Cancer • Oncology • Sarcoma

Open Label Extension Study of Conatumumab and AMG 479 (clinicaltrials.gov) - P2; N=12; Active, not recruiting; Sponsor: Amgen; Trial completion date: Jul 2018 ➔ Jan 2019; Trial primary completion date: Jul 2018 ➔ Jan 2019

Trial completion date • Trial primary completion date • Biosimilar • Colorectal Cancer • Gastrointestinal Cancer • Hematological Disorders • Hematological Malignancies • Lung Cancer • Lymphoma • Non Small Cell Lung Cancer • Oncology • Sarcoma

A randomized, placebo-controlled phase 2 study of ganitumab (AMG 479) or conatumumab (AMG 655) in combination with gemcitabine in patients with metastatic pancreatic cancer (Ann Oncol) - P2, N=125; NCT00630552; The 6-month survival rates were 57% in the ganitumab arm, 59% in the conatumumab arm, and 50% in the placebo arm; The grade ≥3 AEs in the ganitumab, conatumumab, and placebo arms, respectively, included neutropenia (18/22/13%), thrombocytopenia (15/17/8%), fatigue (13/12/5%), alanine aminotransferase increase (15/5/8%), & hyperglycemia (18/2/3%)

P2 data • Oncology • Pancreatic Cancer

Open label extension study of conatumumab (AMG 655) (clinicaltrials.gov) - P2, N=30; Enrolling by invitation

Oncology

Pharmacological inhibition of B-Raf/MEK/ERK signaling suppresses DR5 expression and impairs cancer cell response to DR5 activation-induced apoptosis (AACR 2014) - Presentation time: Monday, Apr 07, 2014, 1:00 PM - 5:00 PM; Abstract #2288; “...both B-Raf (e.g., PLX4032) and MEK inhibitors (e.g., AZD6244 and PD0325901) effectively inhibited ERK1/2 phosphorylation and reduced DR5 levels in both human thyroid cancer and melanoma cells. Similar to the observed effect of genetic knockdown of the B-Raf gene, pretreatment of cancer cell lines with either B-Raf or MEK inhibitors attenuated or abolished cellular apoptotic response induced by TRAIL or the DR5 agonistic antibody AMG655."

Preclinical • Melanoma • Oncology • Thyroid Cancer

The serum protein transthyretin as a platform for dimerization and tetramerization of antibodies and Fab fragments to enable target clustering. (PubMed, J Biol Chem) - "Transthyretin (TTR) is an abundant homo-tetrameric serum protein and was selected here for engineering higher-valency molecules because its compact size, simple structure, and natural propensity to tetramerize.   To demonstrate this utility, we fused TTR to the C terminus of conatumumab, an antibody that targets tumor necrosis factor-related apoptosis-inducing ligand receptor 2 (TRAIL-R2), as heavy chains to form antibody dimers and Fab heavy chains to form Fab tetramers.  Moreover, we used constant heavy domain 3 (CH3) heterodimerization substitutions to create TTR-mediated conatumumab tetramers.  The conatumumab-TTR fusions displayed substantially enhanced potency in cell-based assays as well as in murine tumor xenograft models.  We conclude that antibody-TTR fusions may provide a powerful platform for multimerizing antibody and Fab fragments to enhance the capabilities of human therapeutics that benefit from target clustering and higher-order..."

Journal • TNFA

DR5-targeted, chemotherapeutic drug-loaded nanoparticles induce apoptosis and tumor regression in pancreatic cancer in vivo models. (PubMed, J Control Release) - "To take advantage of elevated expression of this pathway, we designed drug-loaded NPs with a surface-conjugated αDR5 antibody (AMG 655)...Moreover, the DNA topoisomerase-1 inhibitor camptothecin (CPT) down-regulated FLIP in pancreatic cancer models and enhanced apoptosis induced by αDR5-NPs...Importantly, CPT-loaded αDR5-NPs markedly reduced tumor growth rates in vivo in established pancreatic tumor models, inducing regressions in one model. These proof-of-concept studies indicate that αDR5-NPs loaded with agents that downregulate or inhibit FLIP are promising candidate agents for the treatment of pancreatic cancer."

Journal • Preclinical • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Solid Tumor • CASP8 • FADD • TOP1

Open label extension study of conatumumab and AMG 479 (clinicaltrials.gov) - P2, N=12; Sponsor: Amgen; Recruiting; Completion date: May 2013 -> Dec 2014.

Trial completion date • Non Small Cell Lung Cancer • Oncology

A randomized phase 2 study of paclitaxel and carboplatin with or without conatumumab for first-line treatment of advanced non-small-cell lung cancer (J Thorac Oncol) - P2, N=172; Study ID: 20060295; PMID: 23370314; “Median PFS was 5.4 months (95% confidence interval [CI] 4.1-6.3) in arm 1 (hazard ratio [HR] 0.84 [95% CI 0.57-1.24]; p = 0.41), 4.8 months (95% CI 3.2-6.5) in arm 2 (HR 0.93 [0.64-1.35]; p = 0.57), and 5.5 months (95% CI 4.3-5.7) in arm 3. There was an interaction between tumor histology and the effect of conatumumab on PFS (squamous HR 0.47 [0.23-0.94]; nonsquamous HR 1.08 [0.74-1.57]; interaction p = 0.039).”

P2 data • Non Small Cell Lung Cancer

Open Label Extension Study of Conatumumab and AMG 479 (clinicaltrials.gov) - P2; N=12; Completed; Sponsor: Amgen; Active, not recruiting ➔ Completed

Clinical • Trial completion

Open Label Extension Study of Conatumumab and AMG 479 (clinicaltrials.gov) - P2; N=12; Active, not recruiting; Sponsor: Amgen; Trial completion date: Nov 2019 ➔ Mar 2020; Trial primary completion date: Sep 2019 ➔ Mar 2020

Clinical • Trial completion date • Trial primary completion date