RAMB - MAIO 2017

aumgartten

FJR

390

ssoc

ras

2017; 63(5):388-392

their results influenced the Committee’s decision-mak-

ing. At any rate, this limited set of toxicity tests is clear-

ly insufficient to support a clinical trial of an investiga-

tional drug. A sub-chronic/chronic toxicity study (longer

than 28 days) in both rodent and non-rodent species, for

instance, is missing. The fact that phosphoethanolamine

is a natural substance and that syn-phospho pills are

already in use by many cancer patients is not a valid

argument for waiving a thorough preclinical safety as-

sessment of this investigational drug. Drug adverse effects

other than short-term toxicity generally remain unrec-

ognized unless experimental and/or epidemiology ob-

servational studies are conducted.

The guidelines by the International Council on Har-

monisation of Technical Requirements for Registration

of Pharmaceuticals for Human Use (e.g., ICH guidelines

for non-clinical safety studies to conduct clinical trials)

clearly state that: “Nonclinical safety studies [...] should

be adequate to characterise potential adverse effects that

might occur under the conditions of the clinical trial to

be supported.” According to the ICH recommendations

and other guidelines, a nonclinical safety evaluation must

include repeated-dose studies in two species (one non-

-rodent), the duration of which should be at least equiva-

lent to that of the clinical trial to be supported (e.g., to

support a 6-month clinical trial, durations of nonclinical

repeated dose assays must be 6-month or longer). Re-

peated dose studies in two species with adequate duration

to support a clinical study of syn-phospho in cancer pa-

tients were not available, nor were these studies in prog-

ress or even contracted by the MCTI at the time of research

protocol approval and trial onset. Furthermore, a study

by Kano-Sueoka et al.

found that phosphoethanolamine

was a growth factor of rat mammary carcinoma cells in

culture, while results from a study contracted by the

MCTI suggested that syn-phospho may have enhanced

the number of lung metastases in rats implanted with

Walker 256 carcinosarcoma.

It is noteworthy that experimental tests on a possible

anticancer activity of syn-phospho or (pure) phospho-

ethanolamine yielded disappointing results. The studies

by Chierice and coworkers

5-10

and those further contract-

ed by the MCTI

12,13

showed consistently that syn-phospho

has very low cytotoxicity. Syn-phospho was toxic to tumor

and non-tumor cell lines only in the mM (10

-3

M) concen-

tration range while most oncologic drugs used in clinical

practice (e.g., sunitinib, cisplatin, doxorubicin, and more)

are toxic to cancer cell lines at µM (10

-6

M) or even nM

(10

-9

M) concentrations. Moreover, the effects of syn-phos-

pho on rodent xenograft tumor growth were modest and

inconsistent across experiments.

11,13

Chierice et al.

6-8

used

the intraperitoneal (ip) route (an unlikely route of admin-

istration for a human drug) to treat immunocompetent

mice bearing transplanted tumors and thus indirect effects

of ip administered syn-phospho (and its impurities) on

tumor growth mediated by immune-stimulation cannot

be ruled out.

In summary, not only preclinical safety studies are

insufficient (and there exist concerns regarding a possible

stimulation of cancer cell proliferation), but also experi-

mental studies failed to find evidence that syn-phospho

has an antitumor activity. In other words, there is no

reasonable prospect that syn-phospho (or highly pure

phosphoethanolamine) would bring concrete benefits to

cancer patients and, in addition, the nonclinical toxicity

profile is limited and unclear.

A second concern refers to the scientific validity of the

clinical study. To be scientifically valid, a trial must be

soundly designed and robust to demonstrate whether

syn-phospho is an effective and safe oncologic drug. Un-

fortunately, contrasting to FDA clinical trial register system,

Brazil’s platform registry does not allow the public to learn

about the study’s design. It is unclear, for instance, wheth-

er this is a randomized trial. Random assignment and

concealed allocation of trial participants are necessary to

avoid systematic differences between baseline character-

istics of groups that are being compared. Randomization

is particularly complex in oncologic treatment trials. Al-

though not providing details on the inclusion and exclu-

sion criteria, the Brazilian platform registry informs that

patients diagnosed with 11 different general ICD codes

will be eligible. Taking into account that enrolled patients

possibly are at different stages of the disease, that they

underwent different prior therapies and are under differ-

ent concomitant treatments, investigators will face a tre-

mendous challenge in comparing drug effects on two

groups of this highly heterogeneous population of patients.

What are the clinical efficacy endpoints selected for this

trial (overall survival, progression-free survival, time to

progression, time to treatment failure, event-free survival,

and so on)?

Moreover, how did investigators estimate

the sample size needed to provide a statistically and clin-

ically meaningful response to the central research question

(anticancer efficacy and safety of syn-phospho)?

A third concern refers to the social value of this trial.

As mentioned above, preclinical studies failed to demon-

strate the antitumor activity of syn-phospho. In addition,

no documented case report and no medical records cor-

roborated the anecdotal reports saying that patients with

cancer improved after taking syn-phospho pills. It is fair