CDX-3379 / Celldex, AstraZeneca - LARVOL DELTA

A Study of CDX-3379 and Cetuximab and in Patients With Advanced Head and Neck Squamous Cell Carcinoma (clinicaltrials.gov) - P2 | N=30 | Terminated | Sponsor: Celldex Therapeutics | Completed ➔ Terminated; Sponsor decision based on emerging risk-benefit profile

Combination therapy • Metastases • Trial termination • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

Clinical Trials Propel New Standards of Care for Thyroid Cancer (OncLive) - "Multidisciplinary approaches remain crucial as treatment options rely on expert insights to cover the wide array of thyroid cancer subgroups, according to Alan L. Ho, MD, PhD."

Interview

Antibody Drug Conjugate Targeted Radio-Immunosensitization (ASTRO 2022) - "To synthesize a MMAE-ADC recognizing murine isoforms, we conjugated MMAE to anti-HER3 antibody CDX3379 creating CDX3379-MMAE and labeled it with Cy5 for non-invasive tracking... These studies provide the first demonstration MMAE-ADC radiosensitization produces durable tumor control in a CD8 T cell dependent manner that is potentiated by immune checkpoint inhibition. Our studies have exciting translational implications by providing a foundation for irradiated cancer patients to be concurrently treated with spatially precise ADC radio-immunosensitization."

IO biomarker • Immune Modulation • Immunology • Inflammation • Oncology • CD8

Phase II Trial of CDX-3379 and Cetuximab in Recurrent/Metastatic, HPV-Negative, Cetuximab-Resistant Head and Neck Cancer. (PubMed, Cancers (Basel)) - "Dual ErbB3-EGFR inhibition remains of scientific interest in HPV-negative HNSCC. Should more tolerable combinations be identified, development in an earlier line of therapy and prospective evaluation of the FAT1 hypothesis warrant consideration."

Journal • P2 data • Dermatitis • Dermatology • Head and Neck Cancer • Immunology • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • ERBB3 • FAT1

Molecular and clinical activity of CDX-3379, an anti-ErbB3 monoclonal antibody, in head and neck squamous cell carcinoma: A preoperative "window of opportunity" study (AACR 2018) - "CDX-3379 is associated with molecular and clinical activity in HNSCC. CDX-3379 administration was well-tolerated and induced a significant decrease in pErbB3. In this small study of 2 CDX-3379 doses over 14 days, one pt experienced a marked clinical effect including reduced tumor size and symptomatology and 92% had RECIST stable disease pre-resection."

Clinical • IO Biomarker • Head and Neck Cancer

CDX3379-04:phase II evaluation of CDX-3379 in combination with cetuximab in patients with advanced head and neck squamous cell carcinoma (HNSCC). (ASCO 2019) - P2; " This open-label phase 2 study (NCT03254927) was designed to enroll up to 30 pts with advanced, HPV-, HNSCC, previously treated with cisplatin, anti-PD-1 antibodies, and cetuximab-resistant (progression within 6 months), according to a Simon’s 2-stage design (13 evaluable pts in Stage 1 with ≥1 objective response allows enrollment of 14 more pts in 2nd stage). CDX-3379 in combination with cetuximab is well tolerated with the primary toxicity of diarrhea. Signs of antitumor activity were observed in these cetuximab-resistant HNSCC pts, including an ongoing, durable CR. Complete stage 1 results will be presented."

Clinical • Combination therapy • IO Biomarker • P2 data • PD(L)-1 Biomarker

A phase 2, multicenter, open-label study to evaluate the efficacy and safety of CDX-3379 in combination with cetuximab in patients with advanced head and neck squamous cell carcinoma (HNSCC). (ASCO 2018) - P2; "A patient (pt) with cetuximab-refractory HNSCC experienced a durable complete response to CDX-3379 + cetuximab, while 2 pts with BRAF-mutant non-small cell lung cancer, one dabrafenib-resistant, experienced partial responses to CDX-3379 + vemurafenib (Falchook ASCO 2016). It is hypothesized that CDX-3379 + cetuximab will achieve ORR of 20%, with 80% power and a null hypothesis of ORR 5% and = 0.05 based on a Simons 2-stage design. Three US sites are actively recruiting pts, with additional sites planned."

Clinical • Combination therapy • IO biomarker • P2 data • PD(L)-1 Biomarker • Head and Neck Cancer • Non Small Cell Lung Cancer

A Study of CDX-3379 and Cetuximab and in Patients With Advanced Head and Neck Squamous Cell Carcinoma (clinicaltrials.gov) - P2; N=30; Completed; Sponsor: Celldex Therapeutics; Active, not recruiting ➔ Completed; Trial completion date: Aug 2021 ➔ Dec 2020

Clinical • Combination therapy • Trial completion • Trial completion date • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

Effective reduction of PD-L1 expression by simultaneous blockade of EGFR and HER3 (ErbB3) in head and neck cancer (AACR 2018) - "Background: We previously reported that simultaneous blockade of EGFR and HER3 by antibodies cetuximab and MM-121, respectively, could more potently reduce tumor growth in both squamous cell carcinoma of head and neck (SCCHN) cell lines and patient derived xenograft (PDX) models (Jiang et al, MCT, 13:1826-36, 2014; Wang et al., CCR, 23:677-86, 2016). In addition to its anti-tumor effect, the combination of cetuximab and CDX-3379 significantly reduced PD-L1 expression. The role of this combination in the regulation of tumor immunology and the tumor microenvironment in SCCHN deserves further investigation."

IO Biomarker • PD(L)-1 Biomarker • Head and Neck Cancer

HER3 targeting potentiates growth suppressive effects of the PI3K inhibitor BYL719 in pre-clinical models of head and neck squamous cell carcinoma. (PubMed, Sci Rep) - "BYL719 is a PI3K inhibitor that has demonstrated efficacy in the treatment of head and neck squamous cell carcinoma. Therefore, inhibition of HER3 with KTN3379 enhanced the effects of PI3K inhibition in pre-clinical HNSCC models. These data support co-targeting HER3 and PI3K for the treatment of HSNCC."

Journal • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck

A Study of CDX-3379 and Cetuximab and in Patients With Advanced Head and Neck Squamous Cell Carcinoma (clinicaltrials.gov) - P2; N=30; Active, not recruiting; Sponsor: Celldex Therapeutics; Trial completion date: Oct 2020 ➔ Aug 2021

Clinical • Combination therapy • Trial completion date • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

Molecular and Clinical Activity of CDX-3379, an Anti-ErbB3 Monoclonal Antibody, in Head and Neck Squamous Cell Carcinoma. (PubMed, Clin Cancer Res) - P1, P2 | "This study demonstrates that CDX-3379 can inhibit tumor ErbB3 phosphorylation in HNSCC. CDX-3379 was well tolerated and associated with measurable tumor regression. A phase 2 study (NCT03254927) has been initiated to evaluate CDX-3379 in combination with cetuximab for patients with advanced HNSCC."

Biomarker • Clinical • Journal • Dermatitis • Dermatology • Fatigue • Head and Neck Cancer • Immunology • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck

A Study of CDX-3379 and Cetuximab and in Patients With Advanced Head and Neck Squamous Cell Carcinoma (clinicaltrials.gov) - P2; N=30; Active, not recruiting; Sponsor: Celldex Therapeutics; Recruiting ➔ Active, not recruiting; N=45 ➔ 30; Trial primary completion date: Jul 2020 ➔ Oct 2020

Clinical • Combination therapy • Enrollment change • Enrollment closed • Trial primary completion date • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

[VIRTUAL] Novel multimodal precision immunotherapy by co-targeting the HER3 oncogenic signaling circuitry and PD-1 for head and neck squamous cell carcinoma (AACR-II 2020) - "These include immune check point blockade with pembrolizumab and nivolumab (anti-PD-1), which have recently demonstrated anti-tumor activity in HNSCC, albeit only <20% of the patients show durable responses...Furthermore, a blocking antibody targeting HER3 (CDX-3379) potently inhibited the tumor growth of PIK3CA wild type but not PIK3CA mutant HNSCC cells...Overall, our findings suggest that persistent tyrosine phosphorylation of HER3 underlies aberrant PI3K/mTOR signaling in HNSCC harboring wild type PIK3CA, and that targeting HER3 may exert its anti-tumor effect by both reducing cancer-driving mTOR activity and reversing an immune evasive tumor microenvironment. These findings also support that co-targeting the HER3 signaling circuitry combined with PD-1 blockade may represent a novel multimodal precision therapeutic approach for HNSCC aimed at achieving durable responses and cancer remission."

IO Biomarker • Late-breaking abstract • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CD8 • CSF2 • ERBB3 • IL10 • IL2 • IL6 • IL7 • PD-1 • PIK3CA

Neuregulin Signaling is a Mechanism of Therapeutic Resistance in Head and Neck Squamous Cell Carcinoma. (PubMed, Mol Cancer Ther) - "Inhibition of this autocrine loop with CDX-3379 (an ErbB3 specific antibody) was sufficient to block ErbB3/AKT signaling in cetuximab resistant cells. In summary this work demonstrates that autocrine NRG ligand secretion is a mechanism for therapeutic resistance to cetuximab and radiation therapy. This cross-resistance to both therapeutic modalities identifies NRG as an actionable therapeutic target for improving treatment regimens in HNSCC."

Journal • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

ErbB activation signatures as potential biomarkers for anti-ErbB3 treatment in HNSCC. (PubMed, PLoS One) - "...Here we show that the molecular components required for ErbB3 activation, including its ligand neuregulin-1 (NRG1), are highly prevalent in HNSCC and that HER2, but not EGFR, is the major activating ErbB3 kinase partner. We demonstrate that cetuximab treatment primarily inhibits the ERK signaling pathway and KTN3379, an anti-ErbB3 monoclonal antibody, inhibits the AKT signaling pathway, and that dual ErbB receptor inhibition results in enhanced anti-tumor activity in HNSCC models...Although ErbB3 and EGFR activation are uncoupled at the receptor level, their respective signaling pathways are linked through co-expression of their respective ligands. We propose that NRG1 expression and EGFR activation signatures may enrich for improved efficacy of anti-ErbB3 therapeutic mAb approaches when combined with EGFR-targeting therapies in HNSCC."

Biomarker • Journal • Biosimilar • Head and Neck Cancer

A Phase 1 Study to Evaluate the Safety and Pharmacokinetics of KTN3379 in Adult Subjects With Advanced Tumors (clinicaltrials.gov) - P1; N=50; Recruiting; Sponsor: Kolltan Pharmaceuticals, Inc.; Trial primary completion date: Mar 2015 ➔ Dec 2015

Trial primary completion date • Biosimilar • Breast Cancer • Colorectal Cancer • Gastric Cancer • Head and Neck Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Triple Negative Breast Cancer

A Window of Opportunity Study of KTN3379 in Surgically Resectable Head and Neck Cancer Patients (clinicaltrials.gov) - P1; N=29; Recruiting; Sponsor: Kolltan Pharmaceuticals, Inc.; Trial primary completion date: Jul 2016 ➔ Dec 2016

Trial primary completion date • Biosimilar • Head and Neck Cancer • Oncology

A Window of Opportunity Study of KTN3379 in Surgically Resectable Head and Neck Cancer Patients (clinicaltrials.gov) - P1; N=29; Not yet recruiting; Sponsor: Kolltan Pharmaceuticals, Inc.

New P1 trial • Biosimilar • Head and Neck Cancer • Oncology

Human papillomavirus regulates HER3 expression in head and neck cancer: implications for targeted HER3 therapy in HPV(+) patients. (PubMed) - Clin Cancer Res - "This study uncovers a direct relationship between HPV infection and HER3 in HNSCC, and provides rationale for the clinical evaluation of targeted HER3 therapy for the treatment of HPV(+) patients."

Journal • Biosimilar • Head and Neck Cancer • Immunology • Oncology

Celldex provides corporate update and reports fourth quarter and year end 2019 results (GlobeNewswire, Celldex Therapeutics, Inc.) - "Expansion cohorts are actively recruiting including: CDX-1140 with KEYTRUDA® (pembrolizumab) in patients who have progressed on checkpoint therapy; and, CDX-1140 with CDX-301 in patients with head and neck squamous cell carcinoma (HNSCC). In addition, a combination of CDX-1140 with chemotherapy in first line metastatic pancreatic cancer is planned...Enrollment continues in the Phase 2 study of CDX-3379 in advanced HNSCC in combination with Erbitux® (cetuximab) in Erbitux-resistant patients who have been previously treated with or are ineligible for checkpoint therapy."

Enrollment status • New trial • Head and Neck Cancer • Infectious Disease • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck

A Phase 1 Study to Evaluate the Safety and Pharmacokinetics of KTN3379 in Adult Subjects With Advanced Tumors (clinicaltrials.gov) - P1; N=24; Recruiting; Sponsor: Kolltan Pharmaceuticals, Inc.

Clinical • New P1 trial • P1 data

A Phase 1 Study to Evaluate the Safety and Pharmacokinetics of KTN3379 in Adult Subjects With Advanced Tumors (clinicaltrials.gov) - P1; N=64; Completed; Sponsor: Celldex Therapeutics; Active, not recruiting ➔ Completed

Clinical • P1 data • Trial completion

Study of CDX-3379, a Human Monoclonal Antibody Targeting ERBB3, in Combination With the MEK Inhibitor, Trametinib, in Patients With Advanced Stage NRAS Mutant and BRAF/NRAS Wildtype (WT) Melanoma (clinicaltrials.gov) - P1/2; N=3; Terminated; Sponsor: NYU Langone Health; N=10 ➔ 3; Recruiting ➔ Terminated; Per regulatory coordinator, the sponsor is no longer supporting the study.

Clinical • Combination therapy • Enrollment change • Trial termination • BRAF • NRAS

Celldex provides corporate update and reports third quarter 2019 results (Celldex Press Release) - "'We are very encouraged by the results we have seen to date across the study and have expanded the trial to more broadly explore the clinical activity we observed in head and neck squamous cell carcinoma and to include a combination cohort with KEYTRUDA under a clinical trial collaboration with Merck...We also continue to make excellent progress in our Phase 2 program of our ErbB3 inhibitor, CDX-3379, and reported the potential for a promising biomarker strategy in head and neck squamous cell carcinoma at ASCO this summer.'"

Clinical