Trial design

The platform consists of three parallel treatment arms, each one investigating a novel agent in a group of patients. The platform allows sequential testing of a pipeline of novel agents in each treatment arm. Novel agents will be allocated for inclusion in the trial according to an overarching prioritisation list and a robust systematic scientific assessment performed by an international Trial Steering Committee.

Based on their mechanism of action, there are three treatment arms prioritised for inclusion at the initiation of the platform. These are:

  • Bispecific antibodies (BsAb)
  • Antibody-drug conjugate (ADC) with standard chemotherapy
  • Chimeric antigen receptor (CAR) T-cells

The priority list will be regularly reviewed by the TSC and treatment arms can be amended to reflect any changes required.

The platform’s adaptive Bayesian statistical design will support efficient GO/NoGO decisions in each treatment arm. This approach estimates the likelihood that an agent is clinically effective, maximising the use of all available data in this rare population, and enabling decision-making, even with small numbers of patients. It allows continuous evaluation as the sample size increases and, if the observed trial data demonstrates a high likelihood that the agent is ineffective at any time, then it can be stopped, allowing the next novel agent in the priority list for that treatment arm to be introduced.

Primary Objectives

  • Treatment Arm I: Bispecific Antibody (BsAb):

Estimate the clinical efficacy of BsAb treatment in patients with relapsed/refractory B-NHL in either first (only one prior line of therapy) or subsequent relapse (more than one prior line of therapy).

  • Treatment Arm II: Antibody-drug conjugate (ADC) with standard chemotherapy:

Estimate the clinical efficacy of an ADC treatment with modified R-ICE chemotherapy in patients with relapsed/refractory B-NHL in first (only one prior line of therapy) or subsequent relapse (more than one prior line of therapy), including those achieving an insufficient response (partial response (PR) or progressive disease (PD)) to BsAb therapy to allow them to progress to haematopoietic stem cell transplantation (HSCT).

  • Treatment Arm III: Chimeric antigen receptor (CAR) T-cells: 

Estimate the efficacy of CAR T-cell therapy in patients who have CAR T-cell product available and who have had insufficient response (PR, PD, stable disease (SD)) to prior therapy to progress to HSCT.

Secondary Objectives

  • Assess the safety profile of the novel agent in children, adolescents and young adults
  • Confirm the pharmacokinetics of the novel agent at the recommended trial dose in children, adolescents and young adults, where relevant
  • Any other treatment arm specific objectives (e.g. assess the relevant pharmacodynamic markers for the novel agent).

Statistical considerations and recruitment

The trial will use a Bayesian approach to estimation and decision-making in each treatment arm.

The statistical analysis plan will be a simple beta-binomial conjugate analysis combining the observed trial data with a minimally-informative prior distribution. The posterior probability distribution will be used to:

(i)  estimate the true efficacy rate with 95% credible intervals to indicate the level of uncertainty and

(ii)  determine whether the probability that the true efficacy rate is greater than a clinically relevant critical value is sufficiently high (>0.80) to declare the treatment worthy of consideration (referred to as a GO decision).

Each treatment arm (or sub-group) will initially aim to recruit 15 patients. At regular intervals, an independent Data Monitoring Committee (DMC) will assess the data for futility and efficacy.  At these stopping points, a posterior probability distribution will be used to calculate the predicted probability of success given the current observed data.

Should a treatment arm be deemed worthy of further consideration based on the analysis of 15 patients, then there will be an option to expand recruitment to a larger number of patients to provide evidence to support a marketing authorisation application.

Glo-BNHL trial will aim to recruit 30 patients per year (across all arms) with recruitment for 7 years.