Phase 2 clinical trial to evaluate the efficacy and safety of varnimcabtagene autoleucel for relapsed/refractory adult acute lymphoblastic leukaemia

Adult patients diagnosed with acute lymphoblastic leukaemia (ALL) whose disease does not respond or comes back after initial therapy have a reduced survival. 

Research direction/proposed solution

We propose an innovative therapy, named varnimcabtagene autoleucel (var-cel), consisting on reprogramming the patient’s own white blood cells so they can eliminate the malignant (tumour) cells. The treatment will be prepared in each patient’s academic non-for-profit institution in what has been termed as “point-of-care" manufacturing. 

Relevance

We have already treated 57 adult Spanish patients with ALL without therapeutic options. Almost 90% of them responded to therapy and their median survival was greater than 30 months when these results were last updated (May 2023). These results were well received by the European Medicines Agency (EMA), which designated var-cel as a priority medicine (PRIME designation) for the European Union (EU). 

Research questions

Our goal is to determine whether these positive results can be reproduced in other EU member states and whether it is feasible to establish a network of academic non-for-profit manufacturing facilities across the EU. 

Research design

Following the initial EMA recommendations, we have designed a clinical trial aimed at evaluating the efficacy and safety of var-cel in patients with ALL who reside in 5 different EU member states. All patients will have high-risk disease and will receive var-cel therapy (i.e. this is a single-arm trial with no random allocation of therapy). The primary endpoints of the study are the percentage of patients in whom the disease is no longer detectable and the duration of this response. The number of patients planned for this trial is 58. The final design will incorporate more specific feed-back from EMA and patient representatives. 

Expected outcomes

We expect to certify three new manufacturing facilities in three different EU member states (the other three are already certified). Once this is completed, we expect around 90% of patients included in this trial to respond to var-cel therapy and, more importantly, we expect that 70% of patients responding to therapy will remain in response 6 months later. If these results are achieved, they will compare favourably with other drugs currently available for the treatment of ALL. Moreover, we expect fewer cases (<10%) of severe side effects, including cytokine release syndrome (i.e., persistent fever, hypotension or reduced oxygen in blood) or neurologic disturbances (i.e. disorientation, uncontrolled shaking), compared to other available products. 

Description of steps required to implement result

The first steps are certifying the new manufacturing facilities and finalising the protocol once all essential feed-back is incorporated. As soon as the trial is approved by competent authorities, and opened in all nine participating hospitals, we must complete patient recruitment in 2 years and then follow the patients for a minimum of 18 months. We will then convene all stakeholders to analyse the results and prepare a report for the EMA. We will also communicate the results directly to patients and to the scientific community. 

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