TAK-164 / Takeda, AbbVie - LARVOL DELTA

A phase I, first-in-human study of TAK-164, an antibody-drug conjugate, in patients with advanced gastrointestinal cancers expressing guanylyl cyclase C. (PubMed, Cancer Chemother Pharmacol) - P1 | "TAK-164 appeared to have a manageable safety profile at 0.064 mg/kg. Hepatic toxicity was identified as a potential risk. The RP2D of 0.064 mg/kg was considered insufficient to derive clinical benefit; there are no plans for further clinical development."

Journal • Metastases • P1 data • Colorectal Cancer • Fatigue • Gastrointestinal Cancer • Gastrointestinal Disorder • Hematological Disorders • Hepatology • Liver Failure • Oncology • Solid Tumor

Pharmacokinetics and Pharmacodynamics of TAK-164 Antibody Drug Conjugate Coadministered with Unconjugated Antibody. (PubMed, AAPS J) - "Rather, the cellular potency of DGN549 was matched with the single-cell uptake of TAK-164 making its IC close to its equilibrium binding affinity (K), and as such, coadministration dilutes total DGN549 in cells below the maximum cytotoxic concentration, thereby offsetting an increased number of targeted cells with decreased ability to kill each cell. These results provide new insights on matching payload potency to ADC delivery to help identify when increasing tumor penetration is beneficial for improving ADC efficacy and demonstrate how mechanistic simulations can be leveraged to design clinically effective ADCs."

Journal • PK/PD data • Oncology

[VIRTUAL] A phase 1 study of TAK-164, an anti-guanylyl cyclase C (GCC) antibody-drug conjugate (ADC), in patients (pts) with advanced gastrointestinal (GI) cancers expressing GCC. (ASCO 2021) - P1 | "TAK-164 appeared to have a manageable safety profile up to 0.064 mg/kg in pts with advanced GI cancers; hepatic toxicity was identified as a potential risk . The RP2D was determined as 0.064 mg/kg but was considered insufficient to derive significant clinical benefit."

Clinical • P1 data • Anemia • Colon Cancer • Colorectal Cancer • Fatigue • Gastrointestinal Cancer • Gastrointestinal Disorder • Hematological Disorders • Hepatology • Liver Failure • Oncology

A Study of TAK-164 in Participants With Advanced Gastrointestinal (GI) Cancer Expressing Guanylyl Cyclase C (GCC) (clinicaltrials.gov) - P1; N=31; Terminated; Sponsor: Millennium Pharmaceuticals, Inc.; Completed ➔ Terminated; Insufficient clinical benefit to participants at the selected recommended phase 2 (RP2D) dose in Part A.

Clinical • Trial termination • Colon Cancer • Colorectal Cancer • Esophageal Cancer • Gastric Cancer • Gastrointestinal Cancer • Gastrointestinal Disorder • Neutropenia • Oncology • Pancreatic Cancer • Solid Tumor

Quantifying ADC bystander payload penetration with cellular resolution using pharmacodynamic mapping. (PubMed, Neoplasia) - "Using TAK-164, an anti-GCC ADC undergoing clinical evaluation, we show that the lipophilic DNA-alkylating payload, DGN549, penetrates beyond the cell targeted layer in GCC-positive tumor spheroids and primary human tumor xenograft models. The penetration distance is similar to model predictions, where the lipophilicity results in moderate tissue penetration, thereby balancing improved tissue penetration with sufficient cellular uptake to avoid significant washout. These results aid in mechanistic understanding of the interplay between antigen heterogeneity, bystander effects, and heterogeneous delivery of ADCs in the tumor microenvironment to design clinically effective therapeutics."

Journal • PK/PD data • Oncology • Solid Tumor

Relationship of guanylyl cyclase C (GCC) expression and efficacy of TAK-164, a GCC-targeted antibody-drug conjugate in a panel of 68 subcutaneous HuPrime colorectal cancer PDX models (AACR 2018) - "In the present study, a mixed effects Cox regression analysis, using a continuous or binary stratification of GCC IHC expression, resulted in a statistically significant (p<0.05) increase in TTR in TAK-164treated mice with higher expression levels of GCC.Ongoing analysis aims to better understand additional molecular drivers of TAK-164 treatment that may be useful for patient enrichment strategies in the clinic. TAK-164 is scheduled to enter phase I evaluation in 2018 in GCC-positive colorectal cancer and other GI malignancies."

Clinical • IO Biomarker • Colorectal Cancer • Pancreatic Cancer

Pharmacokinetics and Catabolism of [H]TAK-164, a Guanylyl Cyclase C Targeted Antibody-Drug Conjugate. (PubMed, Drug Metab Dispos) - "This study characterized in vitro and in vivo DNA binding mechanism and released products of TAK-164. The methodologies described here will be highly useful for characterization of payload-related products of ADCs in general."

Journal • PK/PD data • Gastrointestinal Cancer • Gastrointestinal Disorder • Oncology • CTSB

Preclinical Antitumor Activity and Biodistribution of a Novel Anti-GCC Antibody-Drug Conjugate in Patient-Derived Xenografts. (PubMed, Mol Cancer Ther) - P1 | "Collectively, our data suggest that TAK-164 is highly active in multiple GCC positive tumors including those refractory to TAK-264, a GCC-targeted auristatin ADC. A strong relationship between uptake of 89Zr-labeled TAK-164, levels of GCC expression and, most notably, response to TAK-164 therapy in GCC expressing xenografts and PHTX models. These data supported the clinical development of TAK-164 as part of a first-in-human clinical trial (NCT03449030)."

Journal • Colorectal Cancer • Oncology

[VIRTUAL] Immune modulation following combination of TAK-164 with checkpoint inhibitors (AACR-II 2020) - "We performed immunophenotyping studies which revealed broad immunomodulation of lymphoid and myeloid cells by TAK-164 and combination regimens. Collectively these data support further interrogation of immune checkpoint inhibition in combination with TAK-164."

Checkpoint inhibition • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

A Study of TAK-164 in Participants With Advanced Gastrointestinal (GI) Cancer Expressing Guanylyl Cyclase C (GCC) (clinicaltrials.gov) - P1; N=31; Completed; Sponsor: Millennium Pharmaceuticals, Inc.; Active, not recruiting ➔ Completed; Trial completion date: Oct 2021 ➔ Feb 2020; Trial primary completion date: Oct 2021 ➔ Feb 2020

Clinical • Trial completion • Trial completion date • Trial primary completion date • Colorectal Cancer • Esophageal Cancer • Gastric Cancer • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Solid Tumor • Thoracic Cancer

A Study of TAK-164 in Participants With Advanced Gastrointestinal (GI) Cancer Expressing Guanylyl Cyclase C (GCC) (clinicaltrials.gov) - P1; N=31; Active, not recruiting; Sponsor: Millennium Pharmaceuticals, Inc.; Recruiting ➔ Active, not recruiting; N=100 ➔ 31

Clinical • Enrollment change • Enrollment closed

A Study of TAK-164 in Participants With Advanced Gastrointestinal (GI) Cancer Expressing Guanylyl Cyclase C (GCC) (clinicaltrials.gov) - P1; N=100; Recruiting; Sponsor: Millennium Pharmaceuticals, Inc.; Trial completion date: Apr 2021 ➔ Oct 2021

Trial completion date

A Study of TAK-164 in Participants With Advanced Gastrointestinal (GI) Cancer Expressing Guanylyl Cyclase C (GCC) (clinicaltrials.gov) - P1; N=100; Recruiting; Sponsor: Millennium Pharmaceuticals, Inc.; Trial completion date: Apr 2022 ➔ Apr 2021; Trial primary completion date: Apr 2022 ➔ Apr 2021

Clinical • Trial completion date • Trial primary completion date

Synthesis of Highly Potent N-10 Amino-Linked DNA-Alkylating Indolinobenzodiazepine Antibody-Drug Conjugates (ADCs). (PubMed, ACS Med Chem Lett) - "Indolinobenzodiazepine DNA alkylators (IGNs) are the cytotoxic payloads in antibody-drug conjugates (ADCs) currently undergoing Phase I clinical evaluation (IMGN779, IMGN632, and TAK164). Here, we present an alternative strategy for the IGNs, linking through a carbamate at the readily available N-10 amine present in the monoimine containing dimer. As a result, we have designed a series of N-10 linked IGN ADCs with a wide range of in vitro potency and tolerability, which may allow us to better match an IGN with a particular target based on the potential dosing needs."

Journal