Report of the 14th International Conference on Malignant ... · From 2010 until today, five new...

ICML Workshop 1

Report of the 14th International Conference on Malignant

Lymphoma (ICML) closed workshop on future design of clinical

trials in lymphomas.

Anastasios Stathis 1, Alexia Iasonos 2, John F. Seymour 3, Catherine Thieblemont 4, Vincent Ribrag 5,

Emanuele Zucca 1 and Anas Younes 2

1. Oncology Institute of Southern Switzerland, Bellinzona, Switzerland; 2. Memorial Sloan Kettering

Cancer Center, New York, USA; 3. Department of Haematology, Peter MacCallum Cancer Centre &

Royal Melbourne Hospital, and University of Melbourne, Victoria, Australia; 4. Hemato-oncology

Department, Assistance Publique-Hôpitaux de Paris (APHP), Hôpital Saint-Louis, Paris, France; 5.

Department of Medicine Oncology, Gustave Roussy Comprehensive Cancer Center, F-94805 Villejuif,

France

Corresponding Author Anas Younes Lymphoma Service, Memorial Sloan Kettering Cancer Center 1275 York Avenue, Box 330 New York, NY 10065, USA Phone: +1 212-639-7715 Fax: +1 646-422-2291 e-mail: [email protected]

Research. on May 31, 2020. © 2018 American Association for Cancerclincancerres.aacrjournals.org Downloaded from

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 13, 2018; DOI: 10.1158/1078-0432.CCR-17-3021

mailto:[email protected]

http://clincancerres.aacrjournals.org/

ICML Workshop 2

Abstract

The 14th ICML held in Lugano in June 2017 was preceded by a closed workshop (organized in

collaboration with the American Association for Cancer Research and the European School of

Oncology) where experts in preclinical and clinical research in lymphomas met to discuss the current

drug development landscape focusing on critical open questions that need to be addressed in the

future in order to permit a more efficient drug development paradigm in lymphoma. Topics discussed

included both preclinical models that can be used to test new drugs and drug combinations, as well as

the optimal design of clinical trials and the endpoints that should be used to facilitate accelerated

progress. This report represents a summary of the workshop.




ICML Workshop 3

Introduction

Advances in preclinical research resulting in a better understanding of the biology of lymphomas and

improvements in antibody technology have supported the discovery and subsequent clinical

evaluation of a high number of new therapeutic compounds. From 2010 until today, five new drugs

(three molecularly targeted agents and two monoclonal antibodies) have gained US Food and Drug

Administration (FDA) approval for different lymphoma subtypes [1-7]. However, despite these recent

approvals, the success rate of new drugs for lymphomas is very low, similar to the low rate of drug

approvals (less than 5% of new agents entering clinical development) that is observed overall in

oncology [8].

Hundreds of clinical trials are actively enrolling patients with lymphoma each year (ClinicalTrials.gov,

https://clinicaltrials.gov/), providing grounds for some optimism that better therapies will be developed

to improve treatment outcomes. Conversely, no standard methodological criteria exist to guide the

conduct of clinical trials in patients with cancer, including lymphoma [9]. While the classical path of

clinical drug development advances from dose-finding phase I, to efficacy-evaluation phase II, and

finally to randomized phase III comparative trials against established standard regimens [10], this

model is being challenged in several situations. Among the five recent drug approvals in lymphomas,

only one drug was approved based on results of a randomized phase III trial [7], all others being

approved based on results of single arm phase II trials that used response rate as their primary

endpoint [1-6].

In an attempt to describe the current drug development landscape in lymphoma and provide a working

path for the future development of guidelines for preclinical and clinical trials methodology, a closed

workshop was held in Lugano, Switzerland, on June 13, 2017, prior to the opening of the 14th ICML.

The purpose of the workshop was to bring together experts in the field of drug development in

lymphomas spanning basic biology, biomarkers, translational research, clinical medicine and

biostatistics. Professors Anas Younes and Emanuele Zucca co-chaired the meeting which first



https://clinicaltrials.gov/


ICML Workshop 4

addressed key topics in preclinical and early clinical evaluation of new compounds, and subsequently

focused on the endpoints and designs of phase II and phase III clinical trials. Here, we provide a

concise summary of the discussions and recommendations of that workshop.

In vitro and in vivo models

Lymphoma cell lines can be used as screening platforms for the discovery and efficacy evaluation of

new therapies. Cell lines grow easily, they are relatively inexpensive, and can be utilized for high-

throughput testing of therapeutic agents [11]. Changes in gene expression following pharmacologic

inhibition of one or more targets can be studied in vitro and may provide the basis for translational

research that can be applied to primary tumor samples in clinical trials [12]. Cell lines can also be used

to test drug combinations including molecularly targeted agents that inhibit elements of the same or of

different molecular pathways [13, 14]. Because in vitro synergy can be observed with many agents in

some cell lines and at some concentrations, prioritization for future development should be based on

unbiased comparison of several doublets across several cell lines.

There are numerous limitations for using cell lines in preclinical testing to model drug sensitivity or

resistance in human clinical trials including potential for cross contamination, loss of heterogeneity,

genomic instability, possibility of modifying the characteristics of the cells, infections with mycoplasma,

difficulty in establishing cell lines from indolent lymphomas, in addition to inability to study the dynamic

interaction between lymphoma cells and the microenvironment [15]. In vivo models using patient

derived xenografts (PDX) may better represent the actual clinical tumor biology, and can complement

cell line experiments. However, PDX also have limitations, including lack of engraftment of many

indolent lymphomas and the requirement of engraftment in immune deficient mice (Table 1). The use

of genetically engineered and humanized mouse models may open new possibilities for the evaluation

of new drugs that interact with the host microenvironment or immune effectors including evaluation of

immunotherapies [16]. The optimal number of unique tumors that should be tested in PDX




ICML Workshop 5

experiments remains undefined, although most recent influential publications produce supportive data

from 1 to 3 experiments.

Phase I trials

Phase I trials represent the first critical step towards the clinical evaluation of a new drug aiming not

only to define a tolerable and active dose, but also to generate the first potential efficacy signals which

are used to prioritize and direct a more expedient subsequent development of active drugs [17]. Over

the last decade several molecularly targeted agents and monoclonal antibodies have entered

evaluation in phase I trials for patients with lymphoma. Several issues were discussed during the

meeting including the optimal methods of dose escalation both for first-in-class single agents and

novel-novel combinations [18], how to best capture late toxicities, the usefulness of molecular

selection of patients treated with molecularly targeted agents and the importance of response rate

seen with a new drug in phase I (Table 2).

Regarding dose escalation methods, the Continual Reassessment Method (CRM) may be used in

phase I trials as it can accelerate dose escalation and eliminate lower dosing levels faster while

preserving patients’ safety [16]. CRM type designs have been shown to be superior in both accuracy,

i.e. finding the correct dose, and efficiency, i.e. finding the right dose with fewer patients compared to

3+3 or designs that use less structured models [19, 20]. Dose escalation trials involving 2 drugs have

used the 3+3 design, when the dose of one drug is fixed and only the dose of the second drug is being

escalated. However, recent trials in targeted therapy and immunotherapy require the dose exploration

of both drugs simultaneously in order to find the optimal dose combination [18]. In such cases, when

dose escalation is planned for both drugs a CRM design for unknown toxicity ordering is more efficient

in exploring all dose combinations with as few patients as possible [21]. Such a design could likely

result in multiple MTDs that can be further evaluated [22]. A significant attention should be paid when

planning combination studies, as there are now several examples of significant toxicities when




ICML Workshop 6

combining new drugs even in chemotherapy-free regimens [23]. Methods of dose escalation in

combination studies may include either cohorts that use alternate increases of both drugs or use of

one drug in its standard single agent dose and increase only the dose of the second drug [18].

Registered drugs or drug combinations may be used at their standard schedule and doses and

increase the dose of the experimental drug only.

While dose escalation is typically based on lack of DLTs during cycle 1, grade 3-4 toxicities are

frequently observed in later cycles, especially with chronically administered drugs (up to 57% of grade

3 and 4 toxicities are late-onset) [24]. The example of late-onset toxicities observed with the

phosphoinositide 3-kinase (PI3K) inhibitor idelalisib [25], which has an impressive activity in indolent

lymphomas, further supports the need for a better definition of a dose that can be chronically

administered to patients. This may require patients’ monitoring for adverse events beyond cycle 1 or

the evaluation of intermittent schedules for chronically administered drugs. Statistical models may help

to estimate the risk of late toxicities or account for the potential of late onset toxicities without delaying

accrual of new patients who can enroll in the trial. However, their performance and safety needs to be

evaluated via simulated trials prior to implementing them in future clinical trials [26]. Finally, specific

clinical characteristics of the different lymphoma subtypes must be taken in consideration when

planning a phase I trial with a new agent, with regards to patient selection and dose escalation. In fact

some toxicities may be different among different lymphoma subtypes leading to different

recommended phase II doses. The development of the BCL-2 inhibitor venetoclax required indeed

different schedules of administration and resulted in 3 different target doses in chronic lymphocytic

leukemia, in some forms of lymphomas with leukemic presentation (e.g. mantle cell lymphoma) and in

other lymphomas due mainly to the occurrence of tumor lysis syndrome in the former two entities [27,

28].

With regards to patients’ selection based on molecular signatures, currently there is lack of information

in patients with lymphoma. Among the currently approved molecularly targeted agents none of them




ICML Workshop 7

was developed based on a molecular selection of patients in any of the clinical stages of development.

On the other hand lymphoma is not a homogeneous disease and the diverse histological subtypes not

only are characterized by different clinical behavior but they are also molecularly heterogeneous. Thus

responses of patients to a specific therapy can be variable [29]. There are now several examples of

molecularly targeted agents that have shown impressive activity in phase I studies in patients with

indolent lymphoma and chronic lymphocytic leukemia including PI3K inhibitors, which have only

limited single-agent activity in solid tumors, bruton tyrosine kinase (BTK) inhibitors and BCL-2

inhibitors that latter two having been specifically designed and developed for patients with lymphoma

and chronic lymphocytic leukemia. However, no predictive biomarkers of response have been

identified for these agents and current trials with new molecularly targeted agents enroll patients

based on the histologic subtype of lymphoma.

The more recent example of the EZH2 inhibitor tazemetostat that resulted in 92% response rate in

patients with follicular lymphoma carrying a mutated EZH2 versus 26% response rate in those with

wild type disease, underlines the need of a better definition of specific patients populations that may

most benefit from a specific treatment with molecularly targeted agents [30]. A major effort should be

made in future phase I trials testing new drugs in lymphomas to collect tumor tissue from all patients

aiming to identify predictive biomarkers of response that could be further evaluated in later stages of

development. The feasibility of new methods of molecular responses, including minimal residual

disease assessment and the use of liquid biopsies should be encouraged in future phase I trials.

Early phase trials increasingly include several dose expansion cohorts with the aim to obtain

preliminary efficacy data in distinct patient or disease populations before moving into a Phase II study

[31]. Response rates in phase I trials may predict single agent activity in subsequent stages of clinical

development. A threshold of 30% response rate has been generally used as a desirable minimum

requirement of single agent activity and among the recently approved drugs in lymphoma, all of them

had response rates above this bar in the respective phase I trials [32-34]. Drugs with lower response




ICML Workshop 8

rates may still guarantee further clinical development if preclinical data provide evidence of

additive/synergistic responses when used in combination.

Phase II and III trials

An important issue discussed during the meeting was the usefulness of phase II studies and if it would

be more appropriate to move forward directly from phase I to III, skipping phase II trials. For single

agent approval, phase II studies are necessary and activity of the agent needs to be demonstrated in

phase II before moving to phase III studies. The overall activity of a drug is frequently reported as

disease control rate (DCR), which combines complete response (CR) + partial response (PR) + stable

disease (SD). However, SD lumps minor tumor reductions and growth in one group. Accordingly, DCR

may be more clinically meaningful when CRs and PRs are combined with minor tumor responses

(MRs) [35]. New drugs with modest single agent activity in a specific disease type (eg. response rate

less than 30%) may be tested in combination with standard regimes in large-scale phase Ib-II studies

to define subset of patients that may most benefit from the new combination (eg. the combination of

venetoclax with R-CHOP) [36].

On the other hand, agents with established single agent activity may be combined with standard

regimens to evaluate safety in phase Ib studies and then move directly to phase III trials. There are

currently at least two examples of phase III trials (AVD chemotherapy+brentuximab vedotin vs ABVD

chemotherapy and ibrutinib+R-CHOP chemotherapy vs R-CHOP chemotherapy) that were preceded

by phase I trials and them moved directly to phase III skipping phase II trials [37, 38]. This approach

could certainly spare time but the risks of underestimating the toxicities of the new combination before

moving to phase III studies is higher in comparison to the standard approach.

Phase II studies are critical in the evaluation of new drugs combinations. Priority should be given to

testing combinations that are based on strong biological rationale. Phase II studies should evaluate




ICML Workshop 9

patients subsets and biomarkers and they should use a high efficacy bar (either in terms of response

rate or time-related end points) to move forward. While genome sequencing data are increasingly

used to select patients for targeted therapy, it is necessary to better standardize the methods that are

used and the bioinformatics as different sequencing platforms may give different results due to sample

preparation, sequencing methods and bioinformatics analysis tools [39]. Phase II “umbrella” and

“basket” studies with multiple treatment arms of disease types are increasingly used aiming at

answering multiple questions in a shorter period of time [40, 41]. As many such trials include patients

with a variety of solid tumors and lymphoma, it is important to harmonize response criteria among

these diseases [40, 42]. Importantly, current basket trials in solid tumors include patients with different

tumor types, such as lung, colon, breast, and other cancers. In lymphoma, where more than 60

different subtypes exist, it will be important to design lymphoma-specific basket trials that can capture

patients with different lymphoma subtypes based on shared genetic biomarkers.

Adaptive designs for randomized phase III clinical trials may increase the efficiency of these trials by

reducing the need for enrolling a large number of patients, and therefore, reducing the time for

completing these studies [43]. Recently, seamless adaptive designs have became more popular, as

they blur the boundaries between phase I, II, and III studies that are traditionally performed

sequentially, and combine all phases in one large trial [44]. Seamless adaptive trials can be more

efficient as they allow flexibility in trial modifications during the conduct of the study, including

increasing sample size, and adding new cohorts to evaluate different dosing schedules and/or to

examine treatment efficacy in biomarker-defined subpopulations [44]. In fact, recent examples of

seamless trials evaluating immune checkpoint inhibitors encompassed an entire drug development

program in a single trial. This trial design is most suitable for drugs with impressive efficacy, as they

can accelerate drug approval bringing these effective patients quickly to benefit patients. Therefore,

agents with weak or modest clinical efficacy may not be suitable candidates for this design.




ICML Workshop 10

The implementation of seamless adaptive designs in lymphomas could be explored in diffuse large B-

cell lymphoma (DLBCL), where classical designs going from phase II to phase III trials have failed to

improve first-line treatment despite hundreds of trials preformed and thousands of patients treated

[45]. The recognition of the molecular heterogeneity of DLBCL based on the cell-of-origin which

distinguishes two main molecular subtypes (germinal centre B-cell-like and activated B-cell-like) and

the identification of different oncogenic pathways that are altered and can be potentially targeted,

could form the basis for a master protocol design testing different combinations of new drugs with the

standard first line R-CHOP treatment. However such a trial would require major efforts and

international collaborations between academia, pharma and regulatory agencies.

The optimal statistical endpoints to use in phase II/III studies, traditional endpoints such as response

rate, progression-free survival (PFS) and overall survival (OS) are being used based on the specific

lymphoma subtype. In diffuse large B-cell lymphoma (DLBCL), PFS at 24 months is proposed as a

surrogate for OS [46]. In addition to these endpoints, new endpoints including minimal residual

disease should be explored in future clinical trials (Table 3) [47, 48].

Unique clinical trials endpoints.

Overall survival (OS) remains the gold standard for measuring success of new therapies. However, to

show improvement in OS survival requires long-term follow up, sometimes exceeding 10 years. To

accelerate the development of new regimens there is a tremendous interest in using surrogate

biomarkers that may predict improvement in OS. This is mainly relevant to clinical trials in patients with

indolent B cell lymphomas, such as follicular lymphoma and marginal zone lymphoma. Early

progression or events have been proposed as new surrogate endpoints to OS in patients with follicular

lymphoma treated with frontline regimens [49, 50] . However, these endpoints have not been

validated prospectively in modern era, where PET imaging is used for staging. Similarly, maintaining

complete remissions for 30 months has also been proposed as a surrogate endpoint for follicular




ICML Workshop 11

lymphoma [51], but this also needs validation in prospective studies. Other surrogate endpoints

include eradication of circulating tumor DNA, which could be applied across lymphoma types.

Conclusions and future directions

The meeting ended with an overview of the conclusions drawn from both presentations and

discussions. There was uniform agreement that we need standardization of clinical trial methodology

in patients with lymphoma. This meeting has represented a first attempt to describe current drug

development in lymphomas and to focus on some open critical questions that will need to be

addressed in the future. It was agreed that a follow-up meeting will take place in order to establish

guidelines of drug development and clinical trial methodology in lymphoid malignancies.




ICML Workshop 12

References

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23. Ujjani CS, Jung SH, Pitcher B et al. Phase 1 trial of rituximab, lenalidomide, and ibrutinib in previously untreated follicular lymphoma: Alliance A051103. Blood 2016; 128: 2510-2516. 24. Postel-Vinay S, Gomez-Roca C, Molife LR et al. Phase I trials of molecularly targeted agents: should we pay more attention to late toxicities? J Clin Oncol 2011; 29: 1728-1735. 25. de Weerdt I, Koopmans SM, Kater AP, van Gelder M. Incidence and management of toxicity associated with ibrutinib and idelalisib: a practical approach. Haematologica 2017; 102: 1629-1639. 26. Iasonos A, Gonen M, Bosl GJ. Scientific Review of Phase I Protocols With Novel Dose-Escalation Designs: How Much Information Is Needed? J Clin Oncol 2015; 33: 2221-2225. 27. Roberts AW, Davids MS, Pagel JM et al. Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia. N Engl J Med 2016; 374: 311-322. 28. Davids MS, Roberts AW, Seymour JF et al. Phase I First-in-Human Study of Venetoclax in Patients With Relapsed or Refractory Non-Hodgkin Lymphoma. J Clin Oncol 2017; 35: 826-833. 29. Intlekofer AM, Younes A. Precision therapy for lymphoma--current state and future directions. Nat Rev Clin Oncol 2014; 11: 585-596. 30. Morschhauser F, Salles G, McKay P et al. Interim Report From a Phase 2 Multicenter Study of Tazemetostat, an EZH2 Inhibitor, in Patients with Relapsed or Refractory B-Cell Non-Hodgkin Lymphomas. Hematological Oncology 2017; 35(S2): 24-25. 31. Iasonos A, O'Quigley J. Design considerations for dose-expansion cohorts in phase I trials. J Clin Oncol 2013; 31: 4014-4021. 32. Younes A, Bartlett NL, Leonard JP et al. Brentuximab vedotin (SGN-35) for relapsed CD30-positive lymphomas. N Engl J Med 2010; 363: 1812-1821. 33. Advani RH, Buggy JJ, Sharman JP et al. Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed/refractory B-cell malignancies. J Clin Oncol 2013; 31: 88-94. 34. Flinn IW, Kahl BS, Leonard JP et al. Idelalisib, a selective inhibitor of phosphatidylinositol 3-kinase-delta, as therapy for previously treated indolent non-Hodgkin lymphoma. Blood 2014; 123: 3406-3413. 35. Younes A, Hilden P, Coiffier B et al. International Working Group consensus response evaluation criteria in lymphoma (RECIL 2017). Ann Oncol 2017; 28: 1436-1447. 36. Zelenetz AD, Salles GA, Mason KD et al. Results of a Phase Ib Study of Venetoclax Plus R- or G-CHOP in Patients with B-Cell Non-Hodgkin Lymphoma. Blood 2016; 128 (22): 3032. 37. Younes A, Thieblemont C, Morschhauser F et al. Combination of ibrutinib with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) for treatment-naive patients with CD20-positive B-cell non-Hodgkin lymphoma: a non-randomised, phase 1b study. Lancet Oncol 2014; 15: 1019-1026. 38. Younes A, Connors JM, Park SI et al. Brentuximab vedotin combined with ABVD or AVD for patients with newly diagnosed Hodgkin's lymphoma: a phase 1, open-label, dose-escalation study. Lancet Oncol 2013; 14: 1348-1356. 39. Alioto TS, Buchhalter I, Derdak S et al. A comprehensive assessment of somatic mutation detection in cancer using whole-genome sequencing. Nat Commun 2015; 6: 10001. 40. Woodcock J, LaVange LM. Master Protocols to Study Multiple Therapies, Multiple Diseases, or Both. N Engl J Med 2017; 377: 62-70. 41. Joffe E, Iasonos A, Younes A. Clinical Trials in the Genomic Era. J Clin Oncol 2017; 35: 1011-1017. 42. Ribrag V. Toward common response evaluation criteria for solid tumors and lymphomas: RECIL and RECIST? Ann Oncol 2017; 28: 1409-1411. 43. Bhatt DL, Mehta C. Adaptive Designs for Clinical Trials. N Engl J Med 2016; 375: 65-74. 44. Prowell TM, Theoret MR, Pazdur R. Seamless Oncology-Drug Development. N Engl J Med 2016; 374: 2001-2003. 45. Goy A. Succeeding in Breaking the R-CHOP Ceiling in DLBCL: Learning From Negative Trials. J Clin Oncol 2017; 35: 3519-3522. 46. Maurer MJ, Habermann TM, Shi Q et al. Utility of Progression-Free Survival at 24 Months (PFS24) to Predict Subsequent Outcome for Patients with Diffuse Large B-Cell Lymphoma (DLBCL) Enrolled on Randomized




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Clinical Trials: Findings from a Surrogate Endpoint in Aggressive Lymphoma (SEAL) Analysis of Individual Patient Data from 5853 Patients. Blood 2016; 128(22): 3027. 47. Roschewski M, Dunleavy K, Pittaluga S et al. Circulating tumour DNA and CT monitoring in patients with untreated diffuse large B-cell lymphoma: a correlative biomarker study. Lancet Oncol 2015; 16: 541-549. 48. Armand P, Oki Y, Neuberg DS et al. Detection of circulating tumour DNA in patients with aggressive B-cell non-Hodgkin lymphoma. Br J Haematol 2013; 163: 123-126. 49. Maurer MJ, Bachy E, Ghesquieres H et al. Early event status informs subsequent outcome in newly diagnosed follicular lymphoma. Am J Hematol 2016; 91: 1096-1101. 50. Casulo C, Byrtek M, Dawson KL et al. Early Relapse of Follicular Lymphoma After Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone Defines Patients at High Risk for Death: An Analysis From the National LymphoCare Study. J Clin Oncol 2015; 33: 2516-2522. 51. Shi Q, Flowers CR, Hiddemann W et al. Thirty-Month Complete Response as a Surrogate End Point in First-Line Follicular Lymphoma Therapy: An Individual Patient-Level Analysis of Multiple Randomized Trials. J Clin Oncol 2017; 35: 552-560.




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Table Legends

Table 1: Common uses and limitations of lymphoma cell lines and patient-derived xenograft

models.

Table 2: Phase I trials for lymphomas

CRM: Continual Reassessment Method; MTAs: molecularly targeted agents

Table 3: Phase II-III trials for lymphomas

DCR: disease control rate; CR: complete response; PR: partial response; DLBCL: diffuse large B-cell

lymphoma; PFS: progression-free survival; OS: overall survival.




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Table 1: Common uses and limitations of lymphoma cell lines and patient-derived xenograft models.

Common uses/advantages Limitations

Lymphoma cell lines

-Screening platforms -High throughput testing of new agents -Changes in gene expression for discovery of biomarkers -Test of drug combinations

-Genomic instability -Possibility of modifying the characteristics of the cells -Inability to study the interactions between lymphoma and microenvironment

Patients-derived xenografts

-May better represent the actual biology -Can complement cell line experiments

-Lack of engraftment for indolent lymphomas -Requirement of engraftment in immune deficient mice




ICML Workshop 17

Table 2: Phase I trials for lymphomas

Recommendations

Methods of dose escalation

-CRM may be used in phase I trials as it can accelerate dose

escalation and eliminate subtherapeutic doses faster

-CRM may also be used in 2 drugs combinations that require

exploration of the dose of both drugs

-Registered drugs in combinations can be used at their standard

dose and increase only the dose of the experimental drug; a 3+3

design can be used in these trials

Patients’ selection -Efforts should be made to define molecular subsets of patients

most likely to benefit from MTAs

Evaluation of late

onset toxicities

-Statistical models may be helpful but they need to be evaluated

via simulated trials before implementing them in future clinical

trials

Response rate -A threshold of 30% response rate in unselected patients is a

desirable minimum requirement of activity of single agent before

moving to phase II trials

-Agents with lower response rate may still guarantee further

development if a biomarker is available or in drug combinations




ICML Workshop 18

Table 3: Phase II-III trials for lymphomas

Objectives Recommendations

Phase II -Evaluate activity

of single agents

before moving to

phase III trials

-Evaluation of new

drugs

combinations

-DCR encompassing CR+PR+minor tumor

responses may be a clinically meaningful endpoint

-Evaluation of patients subsets and biomarkers to

be implemented in future phase II trials

-Priority should be given to testing combinations

that are based on strong preclinical rationale

-A high efficacy bar in terms of responses or time-

to-event endpoints should be used before moving

to phase III trials

-New drugs with modest single agent activity may

be tested in combination with standard regimens

-Phase II trials may be skipped for drugs with

established single agent activity when studying a

combination with established regimes following

safety evaluation in phase Ib studies

-Multi-arm trials testing different agents or one

agent against different lymphoma types may help

to identify a subset of patients that benefit from a

new drug or a new combination

Phase III Efficacy evaluation

of a new drug or

new drugs

combination

against

established

regimen

-Exploratory endpoints such as evaluation of

minimal residual disease should be added to

traditional endpoints

-In DLBCL, PFS at 24 months is proposed as a

surrogate for OS

-Adaptive designs may reduce the time for

completing phase III trials




Published OnlineFirst March 13, 2018.Clin Cancer Res Anastasios Stathis, Alexia Iasonos, John F. Seymour, et al. trials in lymphomas.Lymphoma (ICML) closed workshop on future design of clinical Report of the 14th International Conference on Malignant

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