futuximab/modotuximab (S95026) / Servier - LARVOL DELTA

CL1-95029-001: S095029 as Monotherapy and in Combination With Sym021 in Patients With Advanced Solid Tumor Malignancies Followed by an Expansion Part With Triple Combinations in Patients With Metastatic Gastric or Colorectal Cancers (clinicaltrials.gov) - P1 | N=51 | Active, not recruiting | Sponsor: Institut de Recherches Internationales Servier | Trial completion date: Jun 2025 ➔ Mar 2026

Monotherapy • Trial completion date • Colorectal Cancer • Gastric Cancer • Oncology • Solid Tumor • BRAF • HER-2 • KRAS • NRAS

CL1-95029-001: S095029 as Monotherapy and in Combination With Sym021 in Patients With Advanced Solid Tumor Malignancies Followed by an Expansion Part With Triple Combinations in Patients With Metastatic Gastric or Colorectal Cancers (clinicaltrials.gov) - P1 | N=51 | Active, not recruiting | Sponsor: Institut de Recherches Internationales Servier | Trial completion date: Jan 2025 ➔ Jun 2025

Combination therapy • Metastases • Monotherapy • Trial completion date • Colorectal Cancer • Gastric Cancer • Oncology • Solid Tumor • BRAF • HER-2 • KRAS • NRAS

S095029 as Monotherapy and in Combination With Sym021 in Patients With Advanced Solid Tumor Malignancies Followed by an Expansion Part With Triple Combinations in Patients With Metastatic Gastric or Colorectal Cancers (clinicaltrials.gov) - P1 | N=51 | Active, not recruiting | Sponsor: Institut de Recherches Internationales Servier | Trial completion date: Jul 2024 ➔ Jan 2025

Combination therapy • Metastases • Monotherapy • Trial completion date • Colorectal Cancer • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • BRAF • HER-2 • KRAS • NRAS

Progress in second-line antibody therapies for advanced esophageal squamous cell carcinoma. (PubMed, Expert Opin Biol Ther) - "Nivolumab and pembrolizumab are anti-PD-1 antibodies that improve immunosuppression by binding to programmed death-1 (PD-1), leading to an antitumor effect...Sym004 and amivantamab are antibodies that target the epidermal growth factor receptor and have demonstrated efficacy in the treatment of other tumors in recent phase I studies. Furthermore, clinical trials on antibody-drug conjugates such as enfortumab vedotin and DS-7300 for solid tumors are currently ongoing. The standard first-line treatments for patients with advanced ESCC contain ICIs. Therefore, drugs with different mechanisms of action that can overcome resistance to ICIs are needed as second-line or later-line treatments to improve clinical outcomes in these patients."

Journal • Metastases • Review • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Oncology • Solid Tumor • Squamous Cell Carcinoma • EGFR • PD-L1

S095029 as Monotherapy and in Combination With Sym021 in Patients With Advanced Solid Tumor Malignancies Followed by an Expansion Part With Triple Combinations in Patients With Metastatic Gastric or Colorectal Cancers (clinicaltrials.gov) - P1 | N=51 | Active, not recruiting | Sponsor: Institut de Recherches Internationales Servier | Trial completion date: Feb 2024 ➔ Jul 2024

Combination therapy • Metastases • Monotherapy • Trial completion date • Colorectal Cancer • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • BRAF • HER-2 • KRAS • NRAS

S095029 as Monotherapy and in Combination With Sym021 in Patients With Advanced Solid Tumor Malignancies Followed by an Expansion Part With Triple Combinations in Patients With Metastatic Gastric or Colorectal Cancers (clinicaltrials.gov) - P1 | N=51 | Active, not recruiting | Sponsor: Institut de Recherches Internationales Servier | Recruiting ➔ Active, not recruiting

Enrollment closed • Colorectal Cancer • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • BRAF • HER-2 • KRAS • NRAS

S095029 as Monotherapy and in Combination With Sym021 in Patients With Advanced Solid Tumor Malignancies Followed by an Expansion Part With Triple Combinations in Patients With Metastatic Gastric or Colorectal Cancers (clinicaltrials.gov) - P1 | N=41 | Recruiting | Sponsor: Institut de Recherches Internationales Servier | Phase classification: P1a/1b ➔ P1

Combination therapy • Metastases • Monotherapy • Phase classification • Colorectal Cancer • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • BRAF • HER-2 • KRAS • NRAS

COLSTAR: Phase 3 Study of Futuximab/Modotuximab in Combination With Trifluridine/Tipiracil Versus Trifluridine/Tipiracil Single Agent in Participants With Previously Treated Metastatic Colorectal Cancer (clinicaltrials.gov) - P3 | N=7 | Terminated | Sponsor: Institut de Recherches Internationales Servier | N=500 ➔ 7 | Trial completion date: Oct 2026 ➔ Jun 2023 | Recruiting ➔ Terminated | Trial primary completion date: Oct 2026 ➔ Jun 2023; Decision based on strategic reasons related to limited development options left in metastatic colorectal cancer.

Combination therapy • Enrollment change • Metastases • Trial completion date • Trial primary completion date • Trial termination • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • BRAF • KRAS

S095029 as Monotherapy and in Combination With Sym021 in Patients With Advanced Solid Tumor Malignancies Followed by an Expansion Part With Triple Combinations in Patients With Metastatic Gastric or Colorectal Cancers (clinicaltrials.gov) - P1a/1b | N=39 | Recruiting | Sponsor: Institut de Recherches Internationales Servier | N=129 ➔ 39 | Trial completion date: Jul 2025 ➔ Jan 2024 | Trial primary completion date: May 2023 ➔ Jan 2024

Combination therapy • Enrollment change • Metastases • Monotherapy • Trial completion date • Trial primary completion date • Colorectal Cancer • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • BRAF • HER-2 • KRAS • NRAS

COLSTAR study: Safety data on the first cohort of patients from the safety lead-in part of the study (ESMO-GI 2023) - P3 | "Funding: The study was funded by Institut de Recherches Internationales Servier.Background: Futuximab/modotuximab (Fu/Mo) is a mixture of two monoclonal antibodies that binds to non-overlapping epitopes of the extracellular domain of the anti-epidermal growth factor receptor (EGFR)...Following the results of a phase 2 trial with Fu/Mo in RASwt mCRC, a phase 3 study in combination with trifluridine/tipiracil (TT) was planned with a safety lead-in part to demonstrate the tolerability of the combination. Here we report the results of the first 7 included patients. COLSTAR is a randomized, open-label study comparing Fu/Mo combined with TT to TT monotherapy in RAS/BRAFwt mCRC patients previously treated with chemotherapy (including oxaliplatin, irinotecan, 5-fluorouracil, anti-VEGF and anti-EGFR)... Overall, the combination of Fu/Mo with TT was well tolerated in this cohort of 7 patients and no new safety signals were observed."

Clinical • Colorectal Cancer • Gastrointestinal Cancer • BRAF

Population pharmacokinetics (popPK) of Sym004 to evaluate the effect of intrinsic and extrinsic factors on exposure in metastatic colorectal cancer (mCRC). (ASCO-GI 2019) - P1, P1/2, P2; "The popPK model described the Sym004 PK data well. No covariates were present that changed the Sym004 exposure in a clinically significant manner which would necessitate a dose modification. The model is suitable for simulating the Sym004 PK for PK/PD analyses."

Clinical • PK/PD data

Efficacy and safety of Sym004 in refractory metastatic colorectal cancer with acquired resistance to anti-EGFR therapy: Results of a randomized phase II study (RP2S) (ESMO 2017) - P2; "...254 patients (pts) were entered to an open label, multinational, 3-arm (1:1:1) RP2S comparing 2 regimens (12 mg/kg [A] or 9 mg/kg loading dose followed by 6 mg/kg [9/6; B]) of weekly Sym004 vs investigator choice (IC) of 5-FU, capecitabine, or best supportive care [C]...Although the study was negative in ITT population, treatment with Sym004 was associated with remarkable response when compared with any 4th-line treatment of mCRC. The promising results in the molecularly selected population provide guidance to design a pivotal ctDNA-guided pivotal trial in EGFR inhibitor refractory mCRC."

Biomarker • Clinical • P2 data • Colorectal Cancer

COLSTAR: Randomized, open-label, multicentre, phase III study comparing futuximab/modotuximab plus trifluridine/tipiracil to trifluridine/tipiracil in KRAS/NRAS and BRAF wild type (wt) metastatic colorectal cancer (mCRC) previously treated with both standard and anti-EGFR treatment (ESMO 2022) - P3 | "Main eligibility criteria include KRAS/NRAS (exons 2, 3 and 4) and BRAF wt (V600E mutation) (double negative; DN) assessed by centralized analysis of ctDNA at screening, and previous treatment with at least 2 regimens including fluoropyrimidine, irinotecan, oxaliplatin, at least one anti-VEGF (bevacizumab, aflibercept, ramucirumab, regorafenib) and at least one anti-EGFR mAb (cetuximab or panitumumab) for ≥4 months. The key secondary endpoint is OS in the triple-negative (KRAS/NRAS, BRAF, and EGFR-ECD wt) population (part 2). A group sequential design with 3 interim analyses (IA) will allow to stop the trial prematurely for futility at each IA as well as for efficacy at last IA."

Clinical • P3 data • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • BRAF • KRAS • NRAS • RAS

COLSTAR: Phase 3 Study of Futuximab/Modotuximab in Combination With Trifluridine/Tipiracil Versus Trifluridine/Tipiracil Single Agent in Participants With Previously Treated Metastatic Colorectal Cancer (clinicaltrials.gov) - P3 | N=500 | Recruiting | Sponsor: Institut de Recherches Internationales Servier | Not yet recruiting ➔ Recruiting

Combination therapy • Enrollment open • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • BRAF • KRAS

S095029 as Monotherapy and in Combination With Sym021 in Patients With Advanced Solid Tumor Malignancies Followed by an Expansion Part With Triple Combinations in Patients With Metastatic Gastric or Colorectal Cancers (clinicaltrials.gov) - P1a/1b; N=119; Recruiting; Sponsor: Institut de Recherches Internationales Servier

Clinical • Combination therapy • Monotherapy • New P1 trial • Colorectal Cancer • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • BRAF • HER-2 • KRAS • NRAS

COLSTAR: Phase 3 Study of Futuximab/Modotuximab in Combination With Trifluridine/Tipiracil Versus Trifluridine/Tipiracil Single Agent in Participants With Previously Treated Metastatic Colorectal Cancer (clinicaltrials.gov) - P3 | N=500 | Not yet recruiting | Sponsor: Institut de Recherches Internationales Servier

Combination therapy • New P3 trial • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • BRAF • KRAS

Population pharmacokinetics (popPK) of Sym004 to evaluate the effect of intrinsic and extrinsic factors on exposure in metastatic colorectal cancer (mCRC). (ASCO-GI 2019) - P1, P1/2, P2; "The popPK model described the Sym004 PK data well. No covariates were present that changed the Sym004 exposure in a clinically significant manner which would necessitate a dose modification. The model is suitable for simulating the Sym004 PK for PK/PD analyses."

Clinical • PK/PD data

Circulating tumor DNA profiling to identify patients with metastatic colorectal cancer with improved overall survival following Sym004 treatment. (ASCO 2018) - P2; "The heterogeneous mutation landscape in patients with EGFR-ECD mutations as well as the partially impaired function of Sym004 against mutated receptors argues against the use of Sym004 for treatment of this patient subpopulation. Collectively, our data demonstrate that anti-EGFR refractory mCRC patients with DNmCRC and/or TNmCRC assessed by ctDNA are likely to benefit from Sym004 treatment, supporting a randomized registration trial in this genomically defined patient population."

Clinical • Colorectal Cancer

Sym004 vs Standard of Care in Subjects With Metastatic Colorectal Cancer (clinicaltrials.gov) - P2; N=240; Recruiting; Sponsor: EMD Serono

Clinical • New P2 trial • Preclinical • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • KRAS

Sym004 vs Standard of Care in Subjects With Metastatic Colorectal Cancer (clinicaltrials.gov) - P2; N=254; Active, not recruiting; Sponsor: Symphogen A/S; Trial primary completion date: Jul 2016 ➔ Dec 2016

Clinical • Preclinical • Trial primary completion date • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • KRAS

Sym004 vs Standard of Care in Subjects With Metastatic Colorectal Cancer (clinicaltrials.gov) - P2; N=254; Active, not recruiting; Sponsor: Symphogen A/S; Trial primary completion date: Dec 2016 ➔ May 2017

Clinical • Preclinical • Trial primary completion date • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • KRAS

Sym004 vs Standard of Care in Subjects With Metastatic Colorectal Cancer (clinicaltrials.gov) - P2; N=254; Active, not recruiting; Sponsor: Symphogen A/S; Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed • Preclinical • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • KRAS

Sym004 vs Standard of Care in Subjects With Metastatic Colorectal Cancer (clinicaltrials.gov) - P2; N=254; Completed; Sponsor: Symphogen A/S; Active, not recruiting ➔ Completed; Trial primary completion date: Mar 2017 ➔ Oct 2016

Clinical • Preclinical • Trial completion • Trial primary completion date • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • KRAS

Phase 2 Study of Sym004 for Adult Patients With Recurrent Glioblastoma (clinicaltrials.gov) - P2; N=43; Completed; Sponsor: Annick Desjardins; Active, not recruiting ➔ Completed; Trial completion date: Aug 2021 ➔ Apr 2020

Clinical • Trial completion • Trial completion date • Brain Cancer • Glioblastoma • Glioma • Oncology • Solid Tumor • EGFR

Sym004 in Combination With FOLFIRI in Metastatic Colorectal Cancer Patients (clinicaltrials.gov) - P1b/2a; N=50; Recruiting; Sponsor: Symphogen A/S; Phase classification: P1/2 ➔ P1b/2a

Phase classification • Biosimilar • Colorectal Cancer • Gastrointestinal Cancer • Oncology