PRISM: A Platform Protocol for the Treatment of Relapsed/Refractory Aggressive Non-Hodgkin Lymphoma

• Published in: Blood 2019-11, Vol.134 (Supplement_1), p.2869-2869
• Main Authors: Roschewski, Mark, Izumi, Raquel, Hamdy, Ahmed, Patel, Manish R., Arkenau, Hendrik-Tobias, de Vos, Sven, Reagan, Patrick M, Zinzani, Pier Luigi, Davies, Andrew, Pagel, John M, Vose, Julie M, Bitman, Bojena, Brock, Graham, Clark, Edwin, Frigault, Melanie M., Ware, Joseph, Yang, Buyue, Wilson, Wyndham, Staudt, Louis, Flinn, Ian W.
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2019-125939

Aggressive B-cell lymphomas are genetically and clinically heterogeneous. Standard clinical trial designs do not efficiently evaluate the safety and efficacy of multiple drug combinations within the context of underlying molecular biology. The rapid identification of oncogenic driver pathways and development of multiple targeted drugs in lymphomas create many potential combinations. To address this need, we developed a Phase 1 master protocol termed PRISM (NCT03527147) to evaluate multiple targeted therapies alone or in combination for the treatment of relapsed/refractory (R/R) aggressive B-cell lymphoma. Each study arm is conducted in a predefined disease subset with the aim of addressing clinical and translational questions within an overarching protocol. All study arms are open label and not randomized. Enrolment of subjects into a given study arm is based on meeting inclusion/exclusion criteria and available slots. Pertinent inclusion criteria for the master protocol are: (a) a diagnosis of R/R non-Hodgkin lymphoma based on established World Health Organization criteria; (b) ≥1 prior line of therapy for the treatment of current histology, no known curative treatment options available, or the subject is ineligible for potential curative options; (c) the presence of radiographically measurable lymphadenopathy or extranodal lymphoid malignancy and; (d) an ECOG performance status ≤2. Exclusion criteria for the master protocol include: (a) a history of prior malignancy, severe or uncontrolled disease or conditions; (b) use of anti-lymphoma therapy within 14 days of the first dose of study drug and; (c) a requirement for ongoing immunosuppressive therapy. Treatment-specific inclusion/exclusion criteria are also provided (see www.clinicaltrials.gov). As PRISM has multiple study arms, subjects can be simultaneously screened for multiple arms. In each arm, a safety review for dose-limiting toxicity (DLT) is performed after 6 subjects have completed the protocol-defined DLT window. Further enrolment will only proceed in that arm if ≤1 subject experiences a DLT (Figure 1). The sample size for each respective arm is determined based on prior clinical/experimental data on anticipated/clinically meaningful activity of each drug combination. This determines a minimally acceptable response and a desirable response. For each arm, a futility analysis occurs after approximately 10 sequentially enrolled subjects. An arm is considered futile if there is