Combined integrated protocol/basket trial design for a first-in-human trial

Ulla Derhaschnig, Jim Gilbert, Ulrich Jäger, Georg Böhmig, Georg Stingl, Bernd Jilma, Ulla Derhaschnig, Jim Gilbert, Ulrich Jäger, Georg Böhmig, Georg Stingl, Bernd Jilma

Abstract

Background: Innovative trial designs are sought to streamline drug development in rare diseases. Basket- and integrated protocol designs are two of these new strategies and have been applied in a handful oncologic trials. We have taken the concept outside the realm of oncology and report about a first-in-human integrated protocol design that facilitates the transition from phase Ia in healthy volunteers to phase Ib in patients with rare complement-mediated disorders driven by the classical pathway.

Results: We have been conducting a prospective, double-blind, randomized, placebo-controlled first-in-human study with TNT009, which is a humanized monoclonal antibody directed against the C1s subunit of human complement component C1. The trial consisted of three subparts, including normal healthy volunteers (part one and two) and a single cohort of patients in part three. Patients suffered from various complement-mediated diseases sharing the same pathophysiological mechanism, i.e. bullous pemphigoid, antibody-mediated rejection of organ transplants, cold agglutinin disease and warm autoimmune hemolytic anemia. Primary objective of the trial has been to evaluate the safety and tolerability of TNT009 in humans.

Conclusions: This trial provides probably the first example that basket trials may not be limited to single genetic aberrations, which is overly restrictive, but our trial design demonstrates that pathway specificity is a viable paradigm for defining baskets. This will hopefully serve as a role model that could benefit other innovative drug development programs targeting rare diseases.

Trial registration: ClinicalTrials.gov NCT02502903.

Keywords: Basket design; Complement pathway; First-in-human trial; Integrated protocol design; Orphan disease.

References

    1. Goldman M, Seigneuret N, Eichler H-G. The Innovative Medicines Initiative: an engine for regulatory science. Nat Rev Drug Discov. 2015;14(1):1–2. doi: 10.1038/nrd4520.
    1. Asterix. . Accessed April 2016.
    1. Inspire. . Accessed April 2016.
    1. Ideas.. Accessed April 2016.
    1. Menis J, Hasan B, Besse B. New clinical research strategies in thoracic oncology: clinical trial design, adaptive, basket and umbrella trials, new end-points and new evaluations of response. Eur Respir Rev. 2014;23(133):367–78. doi: 10.1183/09059180.00004214.
    1. Redig AJ, Janne PA. Basket trials and the evolution of clinical trial design in an era of genomic medicine. J Clin Oncol Off J Am Soc Clin Oncol. 2015;33:975–7. doi: 10.1200/JCO.2014.59.8433.
    1. Mandrekar SJ, Dahlberg SE, Simon R. Improving Clinical Trial Efficiency: Thinking outside the Box. Am Soc Clin Oncol Educ Book. 2015;e141–7.
    1. Shi J, Rose EL, Singh A, Hussain S, Stagliano NE, Parry GC, et al. TNT003, an inhibitor of the serine protease C1s, prevents complement activation induced by cold agglutinins. Blood. 2014;123(26):4015–22. doi: 10.1182/blood-2014-02-556027.
    1. Morgan BP, Harris CL. Complement, a target for therapy in inflammatory and degenerative diseases. Nat Rev Drug Discov. 2015;14(12):857–77. doi: 10.1038/nrd4657.
    1. Loupy A, Lefaucheur C, Vernerey D, Prugger C, van Huyen Duong J-P, Mooney N, van Huyen J-P D, Mooney N, et al. Complement-binding anti-HLA antibodies and kidney-allograft survival. N Engl J Med. 2013;369(13):1215–26. doi: 10.1056/NEJMoa1302506.
    1. Stegall MD, Chedid MF, Cornell LD. The role of complement in antibody-mediated rejection in kidney transplantation. Nat Rev Nephrol. 2012;8(11):670–8. doi: 10.1038/nrneph.2012.212.
    1. Roumier M, Loustau V, Guillaud C, Languille L, Mahevas M, Khellaf M, et al. Characteristics and outcome of warm autoimmune hemolytic anemia in adults: New insights based on a single-center experience with 60 patients. Am J Hematol. 2014;89(9):E150–5. doi: 10.1002/ajh.23767.
    1. Berentsen S. Complement, cold agglutinins, and therapy. Blood. 2014;123(26):4010–2. doi: 10.1182/blood-2014-04-568733.
    1. Daniel BS, Borradori L, Hall RP, 3rd, Murrell DF. Evidence-based management of bullous pemphigoid. Dermatol Clin. 2011;29(4):613–20. doi: 10.1016/j.det.2011.06.003.
    1. U.S. Food and Drug Administration (FDA). Available from: . Accessed April 2016.
    1. Heads of Medicines Agencies (HMA). CQ and A concerning IPD. Available from: . Accessed April 2016.
    1. Chow S-C, Chang M. Adaptive design methods in clinical trials - a review. Orphanet J Rare Dis. 2008;3:11. doi: 10.1186/1750-1172-3-11.
    1. Chow S-C, Corey R. Benefits, challenges and obstacles of adaptive clinical trial designs. Orphanet J Rare Dis. 2011;6:79. doi: 10.1186/1750-1172-6-79.
    1. Dahlberg SE, Shapiro GI, Clark JW, Johnson BE. Evaluation of statistical designs in phase I expansion cohorts: the Dana-Farber/Harvard Cancer Center experience. J Natl Cancer Inst. 2014;106(7). doi:10.1093/jnci/dju163.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe