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Phase 2 trial of talactoferrin in previously treated patients with metastatic renal cell carcinoma
Phase 2 Trial of Talactoferrin in Previously TreatedPatients With Metastatic Renal Cell Carcinoma
BACKGROUND. Talactoferrin (TLF), a recombinant form of human lactoferrin
(hLF), is an immunomodulatory iron-binding glycoprotein first identified in
breast milk. Its immunomodulatory functions include activation of natural killer
(NK) and lymphokine-activated killer cells and enhancement of polymorphonu-
clear cells and macrophage cytotoxicity. Studies in animal models have shown
promising anticancer activity, and clinical antitumor activity has been observed
in nonsmall cell lung cancer and other tumor types. The purpose of the current
study was to evaluate the activity and safety of TLF in patients with refractory
metastatic renal cell carcinoma (RCC).
1 Department of Genitourinary Oncology, The Uni-
METHODS. Forty-four adult patients with progressive advanced or metastatic RCC
versity of Texas M. D. Anderson Cancer Center,
who had failed prior systemic therapy received oral talactoferrin at a dose of
1.5 g twice daily on a 12-week-on 2-week-off schedule. Patients were evaluated
2 Department of Clinical Research, University of
for progression-free survival at 14 weeks, overall response rate, and progression-
Chicago Medical Center, Chicago, Illinois.
3 Department of Medicine, CCF Taussig Cancer
RESULTS. TLF was well tolerated. No significant hematologic, hepatic, or renal
Center, CCF Lerner College of Medicine, Case
toxicities were reported. The study met its predefined target with a 14-week pro-
Western Reserve University, Cleveland, Ohio.
gression-free survival rate of 59%. The response rate was 4.5%. The mMedian
4 Department of Hematology/Oncology, Veterans
progression-free survival was 6.4 months and the median overall survival was
Affairs Medical Center, Houston, Texas.
CONCLUSIONS. TLF is a well-tolerated new agent that has demonstrated prelimi-
6 Department of Medical Oncology and Therapeu-
nary signs of clinical activity. Given the lack of toxicity, the lack of rapid disease
tics Research, City of Hope National Medical
progression in this cohort, and the preclinical data on immune activation, a ran-
domized study assessing its effects on disease progression in patients with meta-
7 Department of Medical Oncology, Stanford Uni-
static RCC is rational. Cancer 2008;113:72–7. Ó 2008 American Cancer Society.
KEYWORDS: renal cell carcinoma, talactoferrin, clinical antitumor activity, phase
Research funding received from Agennix Inc.
Dr. Bukowski has acted as a consultant andspeaker for and received research support from Pfi-zer, Genentech, Bayer, Onyx, Wyeth, and Novartis.
Renal cell carcinoma (RCC) affects >40,000 patients per year in
the U.S. and is responsible for close to 13,000 deaths.1 Once
Drs. Varadhachary and Malik are employed by
metastatic, RCC is difficult to treat, and median survival is between
Agennix Inc., which owns development rights to
1 and 2 years.2–4 Several different treatment modalities are available
for metastatic RCC, including immunotherapy, mTOR inhibitors,
Dr. Figlin has received research support from
and vascular endothelial growth factor (VEGF) pathway-targeted
therapies.3–7 Although each modality provides some benefit in asubset of patients, complete response is exceedingly rare, and the
Address for reprints: Eric Jonasch, MD, Depart-
majority of patients with metastatic RCC die of their disease. Addi-
ment of Genitourinary Medical Oncology, The Uni-versity of Texas M. D. Anderson Cancer Center,
1515 Holcombe Blvd., Unit 1374, Houston, TX
Talactoferrin is a unique recombinant form of human lactofer-
77030; Fax: (713) 563-9409; E-mail: ejonasch@
rin, an important immunomodulatory protein. Lactoferrin, an 80-
kilodalton (kD) member of the transferrin family of iron-binding
Received January 23, 2008; revision received
glycoproteins,8 is expressed throughout the body and is found in
February 14, 2008; accepted February 19, 2008.
the highest concentrations in breast milk. Lactoferrin is also present
DOI 10.1002/cncr.23519Published online 16 May 2008 in Wiley InterScience (www.interscience.wiley.com).
Talactoferrin in Metastatic RCC/Jonasch et al.
in immune cells and on all body surfaces exposed to
mens of chemotherapy enrolled 100 patients who
the external environment (eg, intestinal mucosal sur-
received talactoferrin or placebo in addition to best
faces). Lactoferrin plays an important role in helping
supportive care. Patients in the talactoferrin arm
to establish the immune system, including the gut-
demonstrated an improvement in OS with trends in
associated lymphoid tissue (GALT), in infants and is
involved in cellular growth and differentiation, anti-
Based on these encouraging preliminary findings,
a phase 2 study in patients with advanced RCC was
conducted and is reported herein. A talactoferrin
Talactoferrin is produced in Aspergillus niger,15 a fila-
dose of 1.5 g administered orally twice daily was cho-
mentous fungus, and is structurally identical to
sen for this and other phase 2 studies. Primary end-
native human lactoferrin in all material respects, dif-
points included 14-week PFS and response rate.
After oral administration, talactoferrin is trans-
ported into the Peyer patches of the GALT, in which
it recruits immature circulating dendritic cells (DCs)
The study was opened at 6 sites and Institutional
bearing tumor antigens to the GALT and induces
Review Board (IRB) approval was obtained at each
their maturation. DC maturation in the presence of
site before the initiation of patient enrollment. Fund-
tumor antigens and lymphoid effector cells induces a
ing for the study was provided by the study sponsor
(Agennix, Houston, Tex). All patients signed informed
response mediated by anticancer natural killer (NK)
consent as per institutional guidelines. Eligible
and NK-T cells,1,2 and CD81 lymphocytes and NK-T
patients had histologically confirmed metastatic or
cells. This results in the activation of lymphocytes in
unresectable RCC with predominantly clear cell his-
tumor-draining lymph nodes (unpublished data), cel-
tology, and had failed at least 1 systemic therapy.
lular infiltration of distant tumors,3 and tumor-cell
Computed tomography (CT) documentation of dis-
death. Talactoferrin is not systemically bioavail-
ease progression within 9 months of the completion
able,4,5 and mounting the initial immune response in
of the most recent therapy was required, and target
the GALT (away from the primary tumor and using a
lesions had to be measurable according to RECIST.
physiologically important pathway) may help mini-
This determination was investigator-based. The Kar-
mize the effect of the cancer’s local immunosuppres-
nofsky performance status had to be >70, total biliru-
bin 1.5 mg/dL, creatinine 2.0 mg/dL, hemoglobin
In phase 1 clinical studies, oral talactoferrin was
10 g/dL, neutrophil count 2000/mm3, lymphocyte
found to be well tolerated without the occurrence of
count 800/mm3, platelet count 100 000/mm3,
dose-limiting toxicities, and a maximum tolerated
aspartate aminotransferase or alanine aminotransfer-
dose could not be defined.16 Seven patients with
ase <2.5 times the institutional upper limit of nor-
advanced or metastatic RCC who were heavily pre-
mal, serum calcium 11.5 mg/dL, international
treated were evaluated in a phase 1b study. All 7
normalized ratio (INR) 1.2, and forced expiratory
patients demonstrated tumor shrinkage or a reduc-
volume in 1 second (FEV1) or forced vital capacity
tion in tumor growth rate, and 4 patients remained
(FVC) 60% of predicted. Patients with brain metas-
progression-free for >6 months, with 3 patients
tases, active ischemic heart disease, symptomatic
receiving talactoferrin for >2 years. One patient had
congestive heart failure, serious active infection,
a durable partial response with 71% tumor shrinkage
by standard Response Evaluation Criteria in Solid
within 4 weeks, and other malignancies diagnosed
within 5 years (apart from nonmelanoma skin can-
Two double-blind, placebo-controlled phase 2
studies have been conducted in patients with non-
Patients received recombinant human lactoferrin
small cell lung cancer (NSCLC), with both studies
(rhLF) at a dose of 1.5 mg orally twice daily for 12
meeting their prespecified endpoints. A 110-patient
consecutive weeks followed by a 2-week break. A
study in previously untreated patients with NSCLC
maximum of 2 additional cycles were permitted. The
evaluated talactoferrin or placebo in combination
first CT scan was obtained at baseline, followed by
with carboplatin and paclitaxel. The talactoferrin arm
scans at Weeks 8, 14, 21, 27, 34, 41, 48, and 55. Radi-
demonstrated an improvement in response rate with
ologic response was assessed by the investigator.
trends toward improvement in progression-free sur-
Patients were followed for OS for 12 months from
vival (PFS) and overall survival (OS).18 A second
the initiation of the study treatment or until the me-
study in patients who had failed 1 or 2 prior regi-
dian OS for the study was determined, whichever
occurred later, but not longer than 18 months after
The study’s coprimary endpoints were to detect
a PFS rate of 40% at 14 weeks or a 12.5% responserate, either of which were considered to be clinically
significant. In a phase 2 trial of bevacizumab in sec-
ond-line RCC patients, the placebo arm had a 4-
month PFS rate of 20%20 and was chosen as the his-
toric reference. A sample size of 40 patients provided
>80% power to detect an increase in the 14-week
PFS from 20% to 40%, with 1-tailed a of 0.05. An
early stopping rule stated that the study would be
terminated if there were no radiologic responses after
the first 20 patients were enrolled, or fewer than 10%
of the first 20 patients were alive and free of disease
Between September 2004 and February 2005, 44
patients were enrolled at 6 sites. All patients were
evaluable for toxicity and response; therefore, all
data are presented in the intent-to-treat population.
Twenty-two patients (50%) had an Eastern Coopera-
* Memorial Sloan-Kettering Cancer Center reference.
tive Oncology Group (ECOG) performance status of 0and the remainder had an ECOG performance statusof 1 (Table 1). By revised Memorial Sloan-KetteringCancer Center criteria for previously treated patients,
27 patients (61%) were low risk and 17 patients
The 14-week PFS was 59% (P < .0001 for comparison
(39%) were intermediate risk. The median age was
with 20%), meeting a prespecified study endpoint.
64 years and 28 patients (64%) were male. Approxi-
The response rate was 4.5%, with 70.5% of patients
mately 80% of the patients were white. Thirteen
demonstrating stable disease for at least 8 weeks
patients (30%) had received 3 prior therapies; 80%
(Table 3). The median PFS was 6.4 months (1-sided
had received cytokines, 61% had received chemo-
95% confidence interval [95% CI] of 4.7). The median
therapy, and 32% had received investigational agents,
OS was 21.1 months (1-sided 95% CI of 19.5) and the
including 7 who received sorafenib, 5 who received
1-year survival rate was 77% (Table 4).
ABX-EGF, 2 who received temsirolimus, and 1 who
The first responder was a 47-year-old woman
received sunitinib. The median time from first diag-
who underwent surgical resection of a T3bN2M0
RCC in 2003 and who demonstrated pulmonary, ret-roperitoneal, and bone metastases shortly after sur-
Twenty-nine patients (66%) completed cycle 1 of
receiving interferon therapy. Treatment with talacto-
therapy and 20 patients (46%) completed 2 cycles.
ferrin was initiated and the patient demonstrated a
Talactoferrin was well tolerated. Forty-two patients
near-complete resolution of her adrenal metastasis
(96%) reported at least 1 adverse event (AE), and 23
and sclerosis of her bone lesion. There was no evi-
(52%) reported at least 1 related AE. Of the related
dence of disease recurrence at the time of last fol-
AEs, the most common were fatigue, flatulence, ab-
low-up, nearly 2 years from the last dose of
dominal pain, and diarrhea, although none were
talactoferrin. The second responder was a 59-year-
>grade 2 in severity (Table 2) (determined according
old man who was diagnosed in January 2004 with
to the Common Toxicity Criteria [CTC] grading sys-
metastatic RCC. He was treated with interleukin-2,
tem). One case of grade 3 dyspnea was considered to
with progression of disease occurring during treat-
be possibly related to the study drug (Table 2). There
ment. Treatment with talactoferrin was initiated
were no drug-related serious AEs reported.
3.5 months after the completion of interleukin-2
Talactoferrin in Metastatic RCC/Jonasch et al.
TABLE 2Adverse Events Possibly, Most Likely, or Definitely Related to Study Drug, Noted in >4% of theStudy Population
Adverse events reported as related to talactoferrin
*Determined according to the Common Toxicity Criteria grading system.
PR indicates partial response; SD, stable disease; PD, progressive disease; PFS, progression-free sur-vival.
toxicity spectrum lie the cytokines. High-dose interleu-kin-2, which was approved in 1992 by the U.S. Food
therapy and the patient developed a partial response
and Drug Administration for the treatment of meta-
static RCC on the basis of a small number of complete
responses, is a highly challenging agent to administer
receiving talactoferrin, 33 patients (75%) received at
and benefits only a few patients who receive it. Once
least 1 subsequent therapy, whereas 11 patients (25%)
again, consistent predictors of treatment response
did not. Eighteen patients received sorafenib, 9 pa-
have by and large eluded investigators, and efforts to
tients received bevacizumab, and 7 patients received
response continue. A further challenge in developingeffective immunotherapy is the absence of laboratoryendpoints that correlate with clinical benefit. Investi-
gators are thus never sure how close they are to
Over the past few decades, immunomodulatory ther-
achieving a meaningful impact on tumor biology.
apy has shown promise in patients with RCC, but
There is a clear unmet need for effective, well-
significant advances using this approach have been
tolerated immunomodulatory agents that can be
frustrated by the idiosyncratic response characteris-
used either as monotherapy or as adjuncts to chemo-
tics and significant toxicities. On 1 end of the toxicity
therapy, immunotherapy, or antivascular therapies.
spectrum, vaccines have demonstrated immunologic
Oral talactoferrin is an immunomodulatory molecule
activity in several trials, but have not been demon-
that has shown promising antitumor activity in pre-
strated to provide definitive patient benefit.21 Pro-
clinical models and in a variety of solid tumors.
blems include finding immunostimulatory protein
Talactoferrin’s postulated DC activation mechanism,
epitopes, establishing optimal delivery platforms,
which combines the 2 halves of standard immu-
and developing reliable immunologic endpoints that
approximate clinical benefit. On the other end of the
through in-migration of immature DCs and activa-
tion of the immune system through DC maturation)
therapy. The larger repertoire of tumor antigens
appears to hold promise in a challenging field. The
available to the DCs activated by talactoferrin could
data from 2 randomized studies in lung cancer
patients indicate early evidence of talactoferrin’s clin-
downstream effector cells responsible for tumor cell
ical efficacy in solid tumors, and provide a context
with which the data in this article can be interpreted.
For RCC, in which to our knowledge classic cyto-
To our knowledge, the current study is the first
toxic chemotherapy has not been effective to date,
phase 2 study assessing the efficacy of oral talacto-
combination with 1 of the newer VEGF pathway-tar-
ferrin in patients with refractory RCC. The patients
geted agents is a practical choice. Data suggest that
enrolled on the study were heavily pretreated. The
the immunologic response in patients with cancer
prespecified effect on 14-week PFS was met, with the
may be decreased by high levels of circulating VEGF,25
59% observed value being statistically significantly
and preclinical studies suggest that the addition of
increased over the historic reference of 20% (P <
talactoferrin to sunitinib resulted in enhanced activity
.0001), and greater than the targeted value of 40%.
(unpublished data). Combination trials with newer
Although the study by Yang et al.20 on which the his-
agents has often been challenging because of overlap-
toric PFS was based used World Health Organization
ping toxicities, but the attractive safety profile of
(WHO) measurement criteria, a comparison of WHO
talactoferrin makes combination trials more feasible.
criteria with RECIST to our knowledge has not
In summary, talactoferrin is a novel agent that is
demonstrated a consistent difference in outcome
well tolerated and has demonstrated evidence of
measures.22–24 Data from contemporary clinical trials
potential clinical activity in RCC. Although patient
were not available when this study was designed. In
selection may contribute to the results noted in the
the randomized trial comparing sorafenib with pla-
current study, randomized trials, including possibly
cebo, after 3 months of treatment, 255 patients re-
evaluating the combination of talactoferrin with a
ceiving sorafenib (57%) achieved a complete or partial
VEGF pathway-targeted agent, are necessary to vali-
response or stable disease compared with 152 patients
receiving placebo (34%).3 A post hoc comparisonusing these data still shows a statistically significantimprovement in the PFS rate when compared withthe current study (P < .001).
Responses were noted in 2 patients, but the
Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. Cancer
response rate endpoint was not met. Nevertheless,
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the observed response rate was consistent with talac-
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toferrin’s cytostatic mechanism of action and also
of new therapies against advanced renal cell carcinoma.
was consistent with the response rate observed with
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Escudier B, Eisen T, Stadler WM, et al. Sorafenib in
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Hudes G, Carducci M, Tomczak P, et al. Temsirolimus,
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McDermott DF, Regan MM, Clark JI, et al. Randomized
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NOVIDADES NA BIBLIOTECA CD-ROM BIBLIOTECA Profissão Mestre, CD Superprofessor. Curitiba : Humana Editorial, [200-]. ASSUNTO: EDUCAÇÃO. CD-ROM TEKOA Koenju. Aldeia Alvorecer. [S.L.] : Associação Consciência Guarani, [200-]. ASSUNTO: MULTIMÍDIA - RAÇA ÍNDIO - GUARANI - MÚSICA. CD FURTADO, Maria Cristina. O Guardião das Florestas. São Paulo : Editora do Brasil, 2
Overview from USA & UK research programs Dr Jack Melling • Director, UK Microbiological Research Authority, Porton Down• Director, Salk Institute Biologics Development Center, Pennsylvania Consultant: • United States Government Accountability Office• US Dept. of Veterans Affairs Research Advisory Committee on GWI• International AIDS Vaccine Initiative Research Investmen