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Outcomes and prognostic factors for relapsed or refractory lymphoma patients in phase I clinical trials

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Summary

Background Although safety and prognostic factors for overall survival (OS) have been extensively studied in Phase I clinical trials on patients with solid tumours, data on lymphoma trials are scarce. Here, we investigated safety, outcomes and prognostic factors in relapsed or refractory lymphoma patients included in a series of Phase I trials. Method and patients All consecutive adult patients with recurrent/refractory lymphoma enrolled in 26 Phase I trials at a single cancer centre in France between January 2008 and June 2016 were retrospectively assessed. Results 133 patients (males: 65%) were included in the analysis. The median (range) age was 65 (23–86). Aggressive non-Hodgkin, indolent non-Hodgkin and Hodgkin types accounted for 64%, 25% and 11% of the patients, respectively. The patients had received a median (range) of 3 (1–13) lines of treatment prior to trial entry. The median [95% confidence interval] progression-free survival and OS times were 3.0 [1.8–3.6] and 17.8 [12.7–30.4] months, respectively. High-grade toxicity (grade 3 or higher, according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events classification) was experienced by 56 of the 133 patients (42%) and was related to the investigational drug in 44 of these cases (79%). No toxicity-related deaths occurred. Dose-limiting toxicity (DLT) was encountered in 11 (9%) of the 116 evaluable patients. High-grade toxicity occurred during the DLT period for 34 of the 56 patients (61%) and after the DLT period in the remaining 22 (39%). The main prognostic factors for poor OS were the histological type (i.e. tumour aggressiveness), an elevated serum LDH level, and a low serum albumin level. Early withdrawal from a trial was correlated with the performance status score, the histological type and the serum LDH level. The overall objective response and disease control rates were 24% and 57%, respectively. Conclusion Performance status, LDH, albumin and histological type (tumour aggressiveness) appear to be the most relevant prognostic factors for enrolling Phase I participants with relapsed or refractory lymphoma. 39% of the patients experienced a first high-grade toxic event after the dose-limiting toxicity period, suggesting that the conventional concept of dose-limiting toxicity (designed for chemotherapy) should be redefined in the era of modern cancer therapies.

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Acknowledgements

The authors thank David Fraser (Biotech Communication SARL, Ploudalmézeau, France) for copy-editing assistance.

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Author notes

  1. Jean-Marie Michot and Lina Benajiba contributed equally to this work.

Authors and Affiliations

  1. Gustave Roussy, Département des Innovations Thérapeutiques et Essais Précoces, Université Paris-Saclay, F-94805, Villejuif, France

    Jean-Marie Michot, Lina Benajiba, Capucine Baldini, Clement Bonnet, Christophe Massard, Frederic Bigot, Benjamin Verret, Zoé A. P. Thomas, Andrea Varga, Anas Gazzah, Antoine Hollebecque, Rastilav Balheda, Aurore Jeanson, Sophie Postel-Vinay, Jean-Charles Soria & Vincent Ribrag

  2. Gustave Roussy, Département d’Imagerie Médicale, Université Paris-Saclay, F-94805, Villejuif, France

    Jean-Marie Michot, Lelia Haddag & Vincent Ribrag

  3. Gustave Roussy, Service de Biostatistiques et Epidémiologie, INSERM CESP OncoStat, Université Paris-Saclay, F-94805, Villejuif, France

    Jean-Marie Michot, Laura Faivre, Xavier Paoletti & Vincent Ribrag

  4. Gustave Roussy, Département d’Hématologie, Université Paris-Saclay, F-94805, Villejuif, France

    Jean-Marie Michot, Camille Bigenwald, David Ghez, Julien Lazarovici, Alina Danu & Vincent Ribrag

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  1. Jean-Marie Michot
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Contributions

JMM and LB equally contributed to this work. VR, LB, JCS, LF and JMM designed the study, collected and analyzed data, and wrote the manuscript. LF and XP analyzed data. LH reviewed CT data. CB, AJ, AH, SPV, BV, ZT, FB, CB, CB, AV, RB and AG collected data. SDB, CM, AD, DG, JL collected data and reviewed the manuscript. All authors approved the manuscript.

Corresponding author

Correspondence to Jean-Marie Michot.

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Conflict of interest statement

The authors declare no conflicts of interest with regard to this manuscript.

Funding

The work was funded by the Drug Development Department at the Gustave Roussy (Villejuif, France).

Ethical approval

All study procedures were approved by local independent ethics committee and were performed in accordance with the tenets of the 1964 Declaration of Helsinki and its amendments.

Informed consent

All patients had provided their written consent to inclusion of their data in the present study’s database.

Additional information

Highlights

• In the Phase I population with relapsed or refractory lymphoma, serum LDH, albumin levels and the histological type (tumour aggressiveness) were prognostic factors for overall survival.

• 39% of the patients experienced a first high-grade toxic event after the dose-limiting toxicity period, suggesting that the conventional concept of dose-limiting toxicity (designed for chemotherapy) should be redefined in the era of modern cancer therapies.

• The objective response and disease control rates were respectively 24% and 57% - suggesting that inclusion in an early-stage clinical trial is a valuable new treatment option in hard-to-treat relapsed or refractory lymphoma.

Electronic supplementary material

Figure 6

(supplemental material). Outcomes for patients with recurrent/refractory lymphoma participating in Phase I clinical trials, according to the histological type (aggressive non-Hodgkin lymphoma, indolent non-Hodgkin lymphoma, and Hodgkin lymphoma). ** Aggressive non-Hodgkin types included diffuse large B-cell lymphoma, peripheral T-cell lymphoma not otherwise specified, and mantle cell lymphoma. *** Indolent non-Hodgkin types included follicular lymphoma, lymphocytic lymphoma/B-cell chronic lymphocytic leukemia, Waldenstrom macroglobulinemia, and marginal zone lymphoma. (PPTX 138 kb)

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Michot, JM., Benajiba, L., Faivre, L. et al. Outcomes and prognostic factors for relapsed or refractory lymphoma patients in phase I clinical trials. Invest New Drugs 36, 62–74 (2018). https://doi.org/10.1007/s10637-017-0480-x

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