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, statistics, 2007. CA Cancer J Clin. 2007;57:43–66.
Motzer RJ, Bacik J, Murphy BA, Russo P, Mazumdar M.
the observed response rate was consistent with talac- Interferon-alfa as a comparative treatment for clinical trials toferrin’s cytostatic mechanism of action and also of new therapies against advanced renal cell carcinoma.
was consistent with the response rate observed with other cytostatic agents such as sorafenib and bevaci- Escudier B, Eisen T, Stadler WM, et al. Sorafenib in zumab. The results on secondary efficacy endpoints advanced clear-cell renal-cell carcinoma. N Engl J Med.
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including median PFS (6.4 months) and median OS Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, (21.1 months) compare favorably with those reported interferon alfa, or both for advanced renal-cell carcinoma.
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