Replies to post #2152 on Ariad Pharmaceuticals Inc fka ARIA

[BTH]

What type of cancers were involved with the trial?

Breast and colon?

[ariadndndough]

Don very nice find agian, nice to see rida has potential also in solid tumors.

the market overall is presenting us a very special gift in aria at these prices. it may take some more time before the market gives them the market cap they truelly deserve but it will happen.

dough

[piggerpig]

Thanks Don,
This was in the footnotes of the abstract:

Phase I Studies of Drug Combinations
Jaap Verweij, Erasmus University Medical Center, Rotterdam, the Netherlands
Mary L. Disis, University of Washington School of Medicine, Seattle, WA
Stephen A. Cannistra, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA
See accompanying article doi: 10.1200/JCO.2009.27.5867
A better understanding of tumor biology has provided a large
number of drug-able targets that are specific to the cancer cell or its
environment. The ability to identify critical targets involved in cancer
cell growth and survival is one of the reasons that we are witnessing a
tremendous increase in the number of promising new drugs in oncology.
This situation has created several challenges to the drug development
process, including the need to study combinations of targeted
agents that would be more effective and less susceptible to drug resistance
compared with single agents. Although it is possible to conceive
of many different drug combinations that might be studied in the
phase I setting, not every combination will be of equal interest. The
large number of new agents, coupled with the complexity and expense
of performing clinical trials,1 makesit imperative to identify features of
phase I combination trials that predict for a high likelihood of success
when such regimens are evaluated in subsequent phase II and III trials.
In this regard, the editors at Journal of Clinical Oncology (JCO) have
placed higher priority on those phase I drug combination trials that
have the characteristics outlined in Table 1. Implicit in these criteria is
the need for investigators to have a compelling mechanistic rationale
for studying a given drug combination, and to provide results that are
interpretable and that will move the field forward.
The study by Perotti et al2 in this issue of JCO illustrates some of
the features that are considered to be important for high-profile phase
I combination trials being considered for publication by JCO. The
rationale for investigating the combination of the mammalian target
of rapamycin (mTOR) inhibitor ridaforolimus and capecitabine was
based on the additive effect of both agents in preclinical models, the
clinical relevance of these two drug classes when used as single agents
in the treatment of cancer, and the expectation that each agent might
have nonoverlapping toxicities that would permit their safe administration
in a phase I setting. In addition, the study included the performance
of pharmacokinetic (PK) correlates to guard against serious
interaction between the two agents that might compromise activity or
enhance toxicity. The investigators also incorporated pharmacodynamic
end points to demonstrate that the appropriate drug targets
were inhibited at clinically achievable doses of each agent. Finally, the
study provided evidence to suggest that this combination is of sufficient
interest to justify continued investigation. Essentially, all of the
major criteria listed in Table 1 were satisfied by this study, as well as the
minor criterion of demonstrating clinical activity.
The rationale behind testing the combination of ridaforolimus
and capecitabine, clearly described by Perotti et al,2 related to the fact
that capecitabine is a prodrug that is activated by the enzyme thymidine
phosphorylase. A by-product of this reaction is 2-deoxy-Dribose,
a molecule with proangiogenic activity.3 Ridaforolimus, by
exerting its effects through a non–cross-resistant pathway, was hypothesized
to counteract the proangiogenic effects of thymidine
phosphorylase and thereby potentiate the antitumor properties of
fluoropyrimidines. Ridaforolimus was given on days 1, 8, and 15, with
capecitabine given on days 1 through 14 of a 4-week cycle.2 Importantly,
and based on the experience with the combination of temsirolimus
and fluorouracil,4 the investigators elected to maximize the dose
of capecitabine, thereby potentially compromising the dose of the
mTORinhibitor. Ideally, the rationale for justifying this type of design
should be explained thoroughly when reporting such studies.
It appears that the investigators were anticipating mucositis with
this combination and, therefore, defined dose-limiting toxicity to
include at least grade 3 functional mucositis and failure to recover to
grade 1 toxicity by day 28. Although this is a novel approach in
defining dose-limiting toxicity that satisfies one of the minor criteria
listed in Table 1, accepting such levels of severe toxicity might lead to
difficulties when adopting this combination for more general use. In
addition, the combination induced frequent and uncomfortable adverse
effects (stomatitis, 69%; dermatitis, 44%; fatigue, 47%; anorexia,
37%; hemifacial spasm, 37%; diarrhea, 22%), even though these toxicities
were reported to be mild. Continuous mild adverse effects of
Table 1. Characteristics of High-Priority Phase I Drug Combination Trials for
Consideration by JCO
Major criteria
Compelling preclinical rationale for the combination, including inhibition
of intersecting pathways
Novel drug classes that have not been previously combined
Performance of pharmacokinetics to determine whether interaction
exists between the two agents
Tolerability for the combination at the maximum-tolerated dose,
associated with inhibition of a pharmacodynamic end point
Convincing evidence that the combination is of sufficient interest to
investigators that it has now entered phase II or III testing
Minor criteria
Studies assessing and validating novel metrics for dose-limiting toxicity
and novel phase I trial designs for drug combinations
Unexpected but convincing clinical activity of the combination beyond
that observed for either agent alone (acknowledging that clinical
response is not a required element of a phase I study)
JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L S
Journal of Clinical Oncology, Vol 28, 2010 © 2010 by American Society of Clinical Oncology 1
The latest version is at http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2010.30.6282
Published Ahead of Print on September 20, 2010 as 10.1200/JCO.2010.30.6282
Copyright 2010 by American Society of Clinical Oncology
Downloaded from jco.ascopubs.org on September 28, 2010. For personal use only. No other uses without permission.
Copyright © 2010 American Society of Clinical Oncology. All rights reserved.
this kind may well limit the ability of patients to tolerate this regimen,
because they may collectively reduce quality of life and may affect
patient willingness to continue treatment. Despite this, the combination
was considered tolerable and was associated with inhibition of
several pharmacodynamic end points at the identified maximumtolerated
dose (including inhibition of 4E binding protein 1 phosphorylation,
a surrogate of mTOR pathway activity).
A PK drug-drug interaction was also partly assessed in this trial.
Although clinically relevant PK interactions were not noted, there
appeared to be acceptable interpatient variability of capecitabine levels,
whereas a greater degree of variability was observed for ridaforolimus.
Importantly, ridaforolimus (just like rapamycin) inhibited
dihydropyrimidine dehydrogenase, suggesting a class effect formTOR
inhibitors on the enzyme. It is interesting to note that at its nadir,
dihydropyrimidine dehydrogenase activity was always above the
threshold level associated with risk of severe fluoropyrimidineassociated
toxicity, which is reassuring, given that the toxicity profile
of this combination is further refined in future studies.
Although Perotti et al2 suggest that this combination is clinically
active, it is impossible to know whether this was related to either of the
single agents alone, or whether a prolonged period of stable disease
was related to the tumor’s natural history in the absence of therapy. In
this respect, phase I combination studies,5 as well as nonrandomized
phase II studies,4,7 are limited in their ability to accurately assess
clinical activity. This is partly because such studies are commonly
performed in populations of patients that are either extensively pretreated
or highly selected because of toxicity-related concerns.8 In
addition, homogeneous groups of patients are typically not treated at
the maximum-tolerated dose of the regimen. Although we list clinical
activity as a criterion in Table 1, it is considered a minor element
because response data in phase I trials are unreliable surrogates for the
ultimate value of the combination. Thus, clinical activity in a phase I
trial will not be considered a sufficient reason for acceptance in the
absence of the major criteria listed in Table 1.
It is likely that the success of targeted therapies will depend on
their rational use in combination with other agents that affect intersecting
pathways of tumor growth, survival, angiogenesis, and drug
resistance. As such, the editors recognize the importance of performing
combination phase I studies using targeted agents, but at the same
time realize that not all combination studies will be informative. The
criteria outlined in Table 1 should serve as a guide to readers as they
assess the relative merits of combination phase I trials, and will be
helpful to prospective authors considering such articles for publication
in JCO.
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Although all authors completed the disclosure declaration, the following
author(s) indicated a financial or other interest that is relevant to the subject
matter under consideration in this article. Certain relationships marked
with a “U” are those for which no compensation was received; those
relationships marked with a “C” were compensated. For a detailed
description of the disclosure categories, or for more information about
ASCO’s conflict of interest policy, please refer to the Author Disclosure
Declaration and the Disclosures of Potential Conflicts of Interest section in
Information for Contributors.
Employment or Leadership Position: None Consultant or Advisory
Role: Mary L. Disis, VentiRx (C) Stock Ownership: None Honoraria:
None Research Funding: Mary L. Disis, GlaxoSmithKline, Hemispherx
Biopharma Expert Testimony: None Other Remuneration: None
AUTHOR CONTRIBUTIONS
Conception and design: Jaap Verweij, Mary L. Disis,
Stephen A. Cannistra
Collection and assembly of data: Jaap Verweij
Data analysis and interpretation: Jaap Verweij, Mary L. Disis,
Stephen A. Cannistra
Manuscript writing: Jaap Verweij, Mary L. Disis, Stephen A. Cannistra
Final approval of manuscript: Jaap Verweij, Mary L. Disis,
Stephen A. Cannistra
REFERENCES
1. Roberts TG Jr, Lynch TJ Jr, Chabner BA: The phase III trial in the era of
targeted therapy: Unraveling the “go or no go” decision. J Clin Oncol 21:3683-
3695, 2003
2. Perotti A, Locatelli A, Sessa C, et al: Phase IB study of the mTOR inhibitor
ridaforolimus (AP23573, MK-8669) with capecitabine. J Clin Oncol doi:10.1200/
JCO.2010.27.5867
3. Brown NS, Bicknell R: Thymidine phosphorylase, 2-deoxy-D-ribose and
angiogenesis. Biochem J 334:1-8, 1998
4. Punt CJ, Boni J, Bruntsch U, et al: Phase I and pharmacokinetic study of
CCI-779, a novel cytostatic cell-cycle inhibitor, in combination with 5-fluoruracil
and leucovorin in patients with advanced solid tumors. Ann Oncol 14:931-937,
2003
5. Hamberg P, Ratain MJ, Lesaffre E, et al: Dose escalation models for
combination phase I trials in oncology. Eur J Cancer (in press)
6. Cannistra SA: Phase II trials in Journal of Clinical Oncology. J Clin Oncol
27:3073-3076, 2009
7. Zia MI, Siu LL, Pond GR, et al: Comparison of outcomes of phase II studies
and subsequent randomized control studies using identical chemotherapeutic
regimens. J Clin Oncol 23:6982-6991, 2005
8. Hamberg P, Verweij J: Phase I drug combination trial design: Walking the
tightrope. J Clin Oncol 27:4441-4443, 2009
DOI: 10.1200/JCO.2010.30.6282; published online ahead of print at
www.jco.org on September