Phase I/IIa Trial Evaluating BT1718 Shows Encouraging Progress in Dose Escalation Phase

General images of ESMO 2019 Congress being held in Barcelona, Spain, September 27 - October 1, 2019. Courtesy European Society for Medical Oncology (ESMO). Used with Permission.
General images of ESMO 2019 Congress being held in Barcelona, Spain, September 27 - October 1, 2019. Courtesy European Society for Medical Oncology (ESMO). Used with Permission.

Updated data from a Phase I/IIa trial evaluating BT1718, a Bicycle Toxin Conjugate being developed Bicycle Therapeutics, was presented during a poster session (Abstract 5664) at the European Society of Medical Oncology (ESMO) 2019 Annual Congress held in September 27 – October 1, 2019, in Barcelona, Spain. [1]

BT1718 is a Bicycle Toxin Conjugate designed to targets Membrane Type 1 Matrix Metalloproteinase (MT1-MMP), also known as MMP-14, which has an established role in cell invasion and metastasis and is linked to poor outcomes and is over-expressed in many solid tumors.

The drug’s target, MT1-MMP, involved in tissue remodelling through proteolysis of extracellular matrix components and is highly expressed in tumors with unmet medical need, including triple negative breast cancer (TNBC) and non small cell lung cancer (NSCLC). MY1-MMP is strongly link with cell invasion and metastasis and high tumor-MT1-MMP expression generally correlates with poor outcomes in multiple tumor types.

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The investigational drug has demonstrated promising target-dependent efficacy in preclinical models, including both cell- and patient-derived xenografts that are resistant to treatment with standards of care.

The drug is based on Bicycle Therapeutics’ proprietary bicyclic peptide (Bicycles®) product platform. The technology, similar to that of antibody-drug conjugates or ADCs, includes tripartite molecules that use a Bicycle (fully synthetic short peptides constrained to form two loops which stabilize their structural geometry) to recognize and bind to a specific tumor antigen, a selectively cleavable linker only cleaved by enzymes within the tumor microenvironment and a small molecule payload. The linker and coupling chemistry hold the payload inert until the conjugate is localized in the tumor microenvironment, delivering payloads into solid tumors with extensive tissue penetration, a short duration of systemic exposure and liver-sparing rapid renal elimination. These properties limit the body’s exposure to payload to minimize any damage to normal tissue.

BT1718 is comprised of Bicycle Therapeutics‘ MT1-MMP targeting Bicycle, which, via a hindered disulphide cleavable linker, is conjugated to mertansine, also called DM1 (and in some of its forms ’emtansine’), a thiol-containing maytansinoid.

Pharmacokinetic (PK) assessment of BT1718: A phase 1/2a study of BT1718, a first in class Bicycle Toxin Conjugate (BTC), in patients (pts) with advanced solid tumors
Poster Presentation: Pharmacokinetic (PK) assessment of BT1718: A phase 1/2a study of BT1718, a first in class Bicycle Toxin Conjugate (BTC), in patients (pts) with advanced solid tumors. [Download]
Progress
The results of the trial in an unselected group of patients with advanced solid tumors, conducted in collaboration with Cancer Research UK, shows an encouraging number of patients with stable disease.

“The data presented at the ESMO 2019 congress encouraging progress of the dose escalation portion of the Phase I/IIa trial evaluating BT1718,” said Kevin Lee, Ph.D., Chief Executive Officer of Bicycle Therapeutics.

“We believe these early data underscore the potential of Bicycles as a novel therapeutic modality and plan to provide additional updates from across our pipeline at medical meetings through the rest of this year,” Lee added

Trial design
Patients in the Phase I dose escalation were assessed for anti-tumor activity, safety and pharmacokinetics up to the data cutoff of August 7, 2019. Based on data from patients in cohorts across dose levels tested, many of which are below the predicted therapeutic range, 13 of 24 evaluable patients (54%) had stable disease at the eight-week timepoint, including a patient who experienced a 45% reduction in a target lesion.

With once-weekly dosing, which is the expected schedule for the Phase IIa portion of the study, BT1718 has appeared tolerable, with manageable adverse events. The Phase I once-weekly dose escalation portion of the trial is ongoing, with dosing at levels equivalent to those associated with preclinical responses.

Across all dose levels and schedules tested, the most common treatment-related adverse events (>15%, n=28) were anemia, diarrhea, nausea, vomiting, fatigue, alanine aminotransferase increase, aspartate aminotransferase increase, blood alkaline phosphatase increase, gamma-glutamyltransferase increase, decreased appetite, lethargy and peripheral neuropathy.

Evaluation of pharmacokinetics demonstrated that BT1718 area under the curve (AUC) was approximately dose proportional over the range 0.6-25 mg/m2, and cycle 2 values were consistent with cycle 1. Mean (±SD) plasma clearance (CLp) was 33.6 (±24.5) L/h, with mean (±SD) volume of distribution (Vss) of 12.5 (±7.3) L, resulting in a terminal half-life (t1/2) of 0.2 to 0.5 hours. Two tumor biopsies were obtained from patients dosed at levels above 15 mg/m2 and analysis showed delivery of DM1 to the tumor consistent with preclinical models. These findings suggest rapid tumor penetration by BT1718. Further plasma and tumor DM1 analysis is ongoing to assess the extent of DM1 retention.

“We are on track to achieve the primary objectives of the Phase I portion of the study,” said Udai Banerji, M.D., Ph.D, chief investigator of the study and Deputy Director of the Drug Development Unit at The Institute of Cancer Research, London and The Royal Marsden NHS Foundation Trust.

“BT1718 represents an exciting potential first-in-class drug, which appears tolerable in Phase I evaluation. Importantly, in two patient biopsies, we observed presence of cytotoxic payload to tumors consistent with targeted delivery and in a manner predicted by our preclinical models.”

Very promising
“Based on our experience, these early clinical data are very promising and a testament to our strong partnership with Bicycle Therapeutics. We are pleased to help accelerate potentially groundbreaking new therapeutics such as BT1718 into clinical trials,” said Nigel Blackburn, Ph.D., Cancer Research UK’s Director of Drug Development.

“This is an excellent example of the innovative work our Centre of Drug Development can support and is an important step toward helping more people survive cancer,” Blackburn further noted.

The Phase I/IIa study of BT1718 is being sponsored by Cancer Research UK. The primary objectives of the Phase I dose escalation portion of the trial are to select the recommended Phase II dose (RP2D) by establishing the maximum tolerated dose and maximum administered dose, and to assess the safety and toxicity profile of BT1718 in patients with advanced solid tumors.

Following selection of the once-weekly RP2D, the Phase IIa portion of the study, consisting of up to four cohorts in selected indications in which MT1-MMP is expressed, will be initiated.

Clinical Trials
BT1718 in Patients With Advanced Solid Tumors – NCT03486730

Reference
[1] Cook N, Banerji U, Evans TRJ, Biondo A, Germetaki T, Randhawa M, Godfrey L, Leslie S, Jeffrey P, Rigby M, Bennett G, Blakemore S, Koehler M, Niewiarowski A, Pittman M, Symeonide SN. Pharmacokinetic (PK) assessment of BT1718: A phase 1/2a study of BT1718, a first in class Bicycle Toxin Conjugate (BTC), in patients (pts) with advanced solid tumors. The European Society of Medical Oncology 2019 Annual Congress, Abstract 5764.[Poster]