Talabostat Charles Casey Cunningham Mary Crowley Medical Research Center, 1717 Main Street, 60th Floor, Dallas, Texas, 75201, USA
Talabostat mesilate is an orally active, specific inhibitor of dipeptidyl peptidases, including tumor-associated fibroblast activation protein. However, by an independent mechanism, talabostat also stimulates the upregulation of cytokines and chemokines to engender a tumor-specific host immune response, thus giving it a unique dual mechanism of action. In clinical trials, talabostat has demonstrated significant activity, including achieving complete responses in patients with non-small-cell lung cancer and malignant melanoma.
Keywords: CD26/dipeptidyl peptidase IV , fibroblast activation protein , metastatic melanoma , non-Hodgkin ’ s lymphoma , non-small cell lung cancer , talabostat , tumor stroma
Talabostat mesilate (PT-100) is the methanesulfonate salt of L -valinyl- L -boroproline (chemical structure shown in Figure 1 ) [1] . Amino boronic dipeptides are attractive as potential therapeutics because of their high affinity for the catalytic site of several serine proteases [2] . Of these, talabostat is the most extensively developed clinically. Talabostat is orally available and specifically inhibits dipeptidyl peptidases such as fibroblast activation protein (FAP) [3] and dipeptidyl peptidase IV (DPP-IV)/CD26 [4,5] .
2. Mechanism of action
Although developed as an inhibitor of dipeptidyl peptidases, talabostat also causes a variety of immune effects in animal models by increasing the production of cytokine and chemokines in both lymphoid organs and tumor mass, leading to enhancement of tumor-specific T-cell immunity [6] as well as T-cell-independent stimulation of the antitumor activity of neutrophils, macrophages and natural killer cells [7,8] . The precise mechanism by which these effects occur is not fully known, but talabostat does activate caspase-1 in preclinical models, thereby inducing an IL-1 β response in tumor stroma and associated lymph nodes (B Jones, Point Therapeutics, pers. commun.). Therefore, cytokine production would occur predominantly within the tumor tissue itself, thus encouraging a local and tumor-specific response.
Notably, this effect is enhanced by the addition of any of several chemotherapy agents, including cisplatin, gemcitabine, paclitaxel and 5-fluorouracil, as well as the monoclonal antibody rituximab in the case of the lymphoma model. One possibility is that chemotherapy-induced apoptosis leads to exposure of tumor-associated antigens and thus promotes antigen processing. Subsequent treatment with talabostat might then promote the maturation of professional antigen-presenting cells and the stimulation of antigen-specific T cells, including cytolytic T lymphocytes, via the upregulation of cytokine and chemokine production within the tumor and lymphoid tissues.
3. Preclinical studies
In preclinical studies, talabostat demonstrates significant antitumor effects, both as a single agent and in combination with chemotherapy or monoclonal antibodies [6-8] .
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Treatment of mice with talabostat inhibited the growth of a variety of tumors, including WEHI 164 (fibrosarcoma), EL4 (lymphoma) and B16 (melanoma). Long-lived and specific immunity to secondary rechallenge was also established in talabostat-treated mice that rejected their tumors. Examination of mRNA levels indicated that talabostat increased expression in the tumors and draining lymph nodes of cytokines and chemokines that have the ability to promote antitumor responses involving both innate and adaptive immunity.
4. Clinical studies
Talabostat has been studied in a variety of dose-finding studies in both healthy volunteers and patients with malignant disease.
4.1 Phase I studies in healthy volunteers Two placebo-controlled Phase I studies were conducted in healthy male volunteers. Talabostat was studied at single daily doses from 10 to 2400 µ g and at multiple single daily doses from 25 to 1800 µ g [9] . Overall, the drug was well tolerated, with sensation of temperature change being the most common complaint (25/90; 28%). In the single-dose study, tachycardia (12/54; 22%) and dizziness (8/54; 15%) were also noted; the multiple-dose study found headache (19/36; 53%), myalgia (9/36; 25%), nausea (6/36; 17%), vomiting (5/36; 14%), peripheral edema (5/36; 14%), rigors (5/36; 14%) and arthralgia (4/36; 11%).
Talabostat was rapidly absorbed, with a median time to maximum concentration (T max ) of ≤ 2 h. Maximum observed plasma concentration (C max ) values appeared to be dose proportional and increased with higher doses, as shown in Figure 3 . Once peak plasma concentrations were reached, plasma elimination of talabostat was slow. It is thought that talabostat binds irreversibly to plasma proteins and that this binding is responsible for the long half-life. Urinary excretion and renal clearance increase with dose. Plasma levels of talabostat in the multiple-dose study suggested a multi-compartmental distribution.
In the single-dose study, plasma DPP-IV activity was inhibited, in a dose-related fashion ( Figure 4 ), to ∼ 20% of baseline within 1 h and remained ∼ 30% of baseline throughout 24 h post-dose. In the multiple-dose study, doses of ≥ 100 µ g of talabostat produced pronounced inhibition of plasma DPP-IV activity to ≤ 20% of baseline
BOH
OH
N
O
NH2.CH3SO3H
Figure 1. Chemical structure of talabostat.
within 1 h post-dose, and at doses of ≥ 300 µ g, CD26/DPP-IV activity was almost completely inhibited ( > 95%) within 30 min of the first dose on day 1.
In the single-dose study, higher doses of talabostat (1200, 1800 or 2400 µ g) increased plasma IL-6 levels ∼ 10-fold at 8 h after dosing, whereas IL-11 and granulocyte colony stimulating factor (G-CSF) concentrations did not change.
In the multiple-dose study, plasma concentrations of both G-CSF and IL-6 increased as talabostat dosing was increased, with a dose- and time-dependent increase in plasma concentrations of IL-6 between day 1 and 6, with maximum plasma concentration achieved in the 1200- µ g dose level at ∼ 20 pg/ml at 6 h post-dose on day 7.
In additional Phase I trials, food had only a slight effect on the rate of absorption of talabostat, as evidenced by a 20 – 30% reduction in prolonged T max and mean C max in the presence of food. However, food had no effect on the extent of talabostat absorption, as reflected in relative bioavailability, which was in the range of 1.1 – 1.2. Similarly, whereas ingestion of antacids with talabostat decreased mean C max by apparently 30% at lower doses of drug, relative bioavailability remained in the range of 1.0 – 1.1. Following administration of talabostat 400 µg, antacid decreased the extent of absorption slightly as both C max ratio and relative bioavailability were reduced to 0.7.
In summary, these studies demonstrate that talabostat is readily absorbed, even in the presence of food or antacids, and displays predictable pharmacokinetics. It should be noted that a classic maximum tolerated dose was not defined in any of these studies.
4.2 Phase I studies in patients Talabostat was also investigated in several dose-finding studies in patients with malignant melanoma.
4.2.1 Effect of talabostat on neutrophil production in patients receiving myelosuppressive chemotherapy The ability of talabostat to induce G-CSF and thereby increase neutrophil production was evaluated in a Phase I dose-finding study of talabostat in patients receiving myelosuppressive chemotherapy [10] . Total daily talabostat doses of 200, 400, 800 and 1200 µ g (divided twice daily) were administered to patients for 7 days following administration of their second cycle of chemotherapy. Cycle 1 (chemotherapy alone) served as the patient ’ s own control. Of 13 patients receiving talabostat 800 µ g, 5 experienced a ≥ 2-day improvement in ≥ grade 3 neutropenia. A corresponding upregulation in G-CSF, IL-6 and IL-8 was observed in most patients. Overall, talabostat was generally well tolerated and a maximum tolerated dose was not reached. Adverse events reported con-siderably more frequently in patients receiving talabostat in cycle 2 compared with cycle 1 (control) were: edema/peripheral swelling (15/34 [44%] versus 1/34 [3%]); hypotension (including orthostatic) (8/34 [23%] versus 4/34 [12%]); syncope (4/34 [12%] versus 1/34 [3%]); and hypovolemia
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Targeted FAP inhibition Targeted inhibition of DPP VIII and IXleads to immunostimulation
Tumor stromal fibroblasts( FAP expression)
Macrophage( DPP VIII/IX)
FAP-mediatedintravasation intocirculation
Talabostat
FAP breakdownof extracellularmatrix
FAP activationof latentgrowth factors
Induction ofFAP by tumor
Stromalfibroblasts
Innate immunity Acquired immunity
Neutrophils
Chemokines Chemokines
Tumor
Macrophages Natural killercells
CytolyticT lymphocytes
Memorycells
Cytokines andchemokines
Inhibition of DPP VIII/IXby talabostat induces
an IL-1β response(via caspase-1) in thestroma of tumor and
lymph nodes
Tumor
Talabostat
IL-1β
Figure 2. The novel dual mechanism of action of talabostat.DPP: Dipeptidyl peptidase; FAP: Fibroblast activation protein.
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Figure 3. Maximal dose tolerance study in healthy talabostat plasma levels on subjects: days 1 and 7.There were six subjects per group. For talabostat 600 µg, n = 5 as 1 subject was not dosed on day 7. Cmax: Maximal plasma concentration.
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(5/34 [15%] versus 0). Two patients experienced a grade 3 adverse event that was considered to be related to talabostat, orthostatic hypotension (800 µ g/day) and syncope (1200 µ g/day).
4.2.2 Combination study of talabostat and rituximab in indolent non-Hodgkin ’ s lymphoma A Phase I study to evaluate the safety and activity of adding talabostat to a regimen of rituximab in patients with B-cell malignancies who had previously not responded to rituximab was conducted in 20 patients [11] . Rituximab 375 mg/m 2 was administered weekly × 4. Total daily doses of talabostat 400, 600 or 800 µ g b.i.d. were administered for 6 days following each dose of rituximab. In contrast to the results of the healthy volunteer studies, the adverse event most frequently reported (12/20 patients [60%]) was edema, although fatigue (8/20 patients [40%]), dizziness (7/20 patients [35%]) and nausea (7/20 patients [35%]) were also reported frequently. All adverse events were manageable and reversible following interruption or discontinuation of talabostat and/or rituximab. A maximum-tolerated dose was not determined per protocol; however, 300 µ g b.i.d. was considered the best-tolerated dose for additional study in combination with rituximab. Significant indications of clinical activity were also seen with three patients demon-strating a partial response. Elevations in the following cytokines were reported across all doses following talabostat administration: G-CSF (13/15), IL-1 β (10/15), IL-2 (7/15), IL-6 (8/15), IL-8 (8/15), IL-10 (11/15), TNF- α (11/15) and IFN- γ (3/15).
4.3 Phase II studies All of the data discussed in this section are preliminary results, as data from these studies are being verified at present.
4.3.1 Metastatic melanoma Two studies in stage IV melanoma have completed enrollment, and patients are being followed for survival. The first is a single-agent study [12] ; the second is a combination study [13] .
4.3.1.1 Study of talabostat as a single agent This study was an open-label, single-arm, two-stage multicenter trial conducted to evaluate the activity of talabostat alone in patients with stage IV melanoma with no more than one prior bio- or chemotherapy regimen. Talabostat 300 µ g b.i.d. p.o. was administered on days 1 – 14 of each 3-week cycle with dose escalation to 400 µ g b.i.d. allowed in cycle 2 or subsequent cycles, depending on tolerability. A total of 42 patients were enrolled (27 men and 15 women; median age: 51 years). The majority of patients were M1c (visceral metastases) and had received prior biotherapy or chemotherapy for stage IV disease. Of these, 31 patients were evaluable for response (evaluability defined as completion of at least two cycles of treatment with a postbaseline disease assessment). Of 31 evaluable patients, 2 demonstrated a response to treatment (per the Response Evaluation Criteria in Solid Tumors [RECIST]), including 1 patient with a durable complete response. Both responding patients were classified as M1a (skin metastases) and had
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Figure 4. Plasma DPP-IV activity on study day 1 (study CA 168-002; % baseline).Note:1800 µg dose cohort not analyzed.DPP: Dipeptidyl peptidase.
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progressive disease following prior cytokine treatment. The Kaplan–Meier (K–M) estimate for median progression-free survival (PFS) in all patients was 1.5 months. Median overall survival was estimated at 7.1 months. Again, the most frequently reported adverse events were edema, fatigue, hypotension and nausea, with the most com-mon grade 3 adverse event being peripheral edema. Two grade 4 events were reported: acute (pre) renal failure and aspiration pneumonia.
4.3.1.2 Combination study of talabostat/cisplatin This second study was conducted to assess the antitumor activity of the combination of talabostat and cisplatin in patients with stage IV melanoma [14] . The treatment regimen involved 21-day cycles with administration of cisplatin (75 mg/m 2 , i.v., on day 1 of cycles 1 – 4) and talabostat 300- µ g tablets b.i.d. p.o. on days 2 – 15. Dose escalation to talabostat 400 µ g b.i.d. was allowed depending on tolerability. After cycle 4, single-agent talabostat could be continued if the investigator deemed this to be appropriate. Of the 74 patients who entered the study (50 men, 24 women; median age: 58 years), most were classified as M1c. The most frequent adverse events were nausea, fatigue and vomiting and the most frequent grade 3 toxicities were vomiting, thrombocytopenia, fatigue, edema and neutropenia (4.1%). Grade 4 thrombo-cytopenia was reported in two patients and grade 4 hypotension in one patient. A total of 43 patients were evaluable for response. A partial response was reported in six patients. The median K-M estimate of PFS in all patients was 2.8 months. The median K-M estimate for overall survival in the intent-to-treat population was 8.5 months.
4.3.2 Non-small-cell lung cancer This open-label, single-arm, multicenter combination Phase II trial was conducted to evaluate the activity of talabostat and docetaxel in patients with stage IIIB/IV NSCLC who failed a platinum-based therapy [15] . The treatment regimen included docetaxel 75 mg/m 2 (day 1 of each 21-day cycle) with appropriate premedication; talabostat 200 µ g b.i.d. p.o. days 2 – 15; with dose escalation of talabostat to 300 µ g b.i.d. allowed in subsequent cycles depending on tolerability. Single-agent talabostat continued past six cycles at the discretion of the investigator. A total of 55 patients (26 men and 29 women; median age 61 years) were enrolled in the study. Of these, 35 patients had received one prior regimen for advanced NSCLC and 20 received at least two prior regimens. Of the 55 patients enrolled, 42 met evaluability criteria for response; 6 patients had a response per the World Health Organization, including 2 complete responses. K-M estimates for all patients were 4.2 months for median PFS and 8.4 months for survival. The most frequently reported regimen-related adverse events were again edema, fatigue and neutropenia.
4.3.3 Chronic lymphocytic leukemia This combination Phase II study using talabostat and rituximab was conducted to evaluate the efficacy (response rate) of talabostat and rituximab as salvage therapy in patients with advanced chronic lymphocytic leukemia who failed fludarabine and/or rituximab [16] . The study design involved a single-arm, open-label, multicenter study in up to 54 evaluable patients. The treatment regimen (28-day treatment course) included: rituximab 375 mg/m 2 i.v. weekly for 4 weeks (study days 1, 8, 15 and 22); talabostat 300- µ g tablets b.i.d. on study days 2 – 7, 9 – 14, 16 – 21 and 23 – 28; and additional courses permitted depending on tolerability and response. So far, 48 patients have entered this study. The majority of patients are men and the median age is 64.9 years. Most patients were Rai stage III or IV. The majority of patients have been treated previously with a rituximab regimen, and many have also received alemtuzumab. Of the 48 patients enrolled, 42 meet evaluability criteria. Clinical responses have been reported in 8 out of 42 evaluable patients. A total of six of eight responding patients had received prior rituximab and three had also received alemtuzumab. The most frequently reported adverse events (all toxicity grades) are peripheral edema, nausea, fever, dyspnea and fatigue.
4.4 Phase III studies Based on the Phase I and II studies discussed above, two randomized Phase III studies in NSCLC are being conducted at present. These are talabostat with docetaxel and talabostat with pemeterxed.
5. Conclusions
Talabostat is well tolerated, with peripheral edema the most notable toxicity clearly attributable to the drug. The etiology of this edema is unknown, but may be related to an increase in cytokines such as IL-6. Preliminary data from Phase II studies demonstrate clear and promising activity, particularly in NSCLC. This has prompted further evaluation in ongoing Phase III trials.
6. Expert opinion
Tumors possess a remarkable ability to organize their neighboring fibroblasts and endothelial cells into a nuturing domain [17] and so research has started to explore how this process might be disrupted. One target is FAP, a type II membrane protein found on reactive stromal fibroblasts present in epithelial cancers [18] and in granulation tissue during wound healing [3,19,20] , but is generally absent from most normal adult human tissues. The protein is conserved throughout chordate evolution, with homologs in mouse [21,22] and Xenopus laevis [23] , whose expression correlates with tissue remodeling events [20] . Why tumor-associated fibroblasts express FAP is not known, but it is interesting that FAP is induced by TGF- β [24] , which is commonly produced
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by many tumors [25] . Although not involved in the development of malignancy [26] , the protein has gelatinase activity [20] and so was originally proposed to play a role in the ability of malignant cells to disrupt the extracellular matrix, and its inhibition has therapeutic effects [27,28] . In this respect, FAP does promote tumor growth in animal models [27] and so has been a candidate for therapeutic efforts with antibodies [29,30] . Thus talabostat represents the first small molecule that interacts with this intriguing protein to be actually administered to patients.
However, surprisingly, talabostat also enhances the production and release of a number of cytokines and chemokines, including IL-6, G-CSF, TNF- α , IL-10 and IL-8 from bone marrow stromal cells [6] . The proteolytic activity of peptidases such as DPP-IV/CD26 is involved in regulating the activities of polypeptide hormones and chemokines [31] , so their inhibition may alter cytokine levels and increases the chances that immune recognition of tumor associated antigens will occur. The concept of antigen-stimulatory signal proximity has been exploited in clinical studies using autologous and allogeneic tumor cells genetically modified to increase immune recognition [32-37] . However,
talabostat seems to achieve the same effect in vivo and while chemotherapy is being administered.
Perhaps most remarkably, talabostat achieves these biologic effects with an orally administered compound. This gives optimism that greater understanding of the structure and function of biologically important proteins will increasingly lead to better design of small-molecule modifiers that can be easily manufactured and administered.
Acknowledgements
The author wishes to thank JF Tomera, Director of Clinical Development at Point Therapeutics of Boston, Massachusetts for assimilating details contained within the manuscript.
Declaration of interest
C Cunningham has served on the advisory board for Point Therapeutics. This article was independently commissioned and no fee has been received for preparation of the manuscript.
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Affi liation Charles Casey Cunningham MD Mary Crowley Medical Research Center, 1717 Main Street, 60th fl oor, Dallas, Texas, 75201, USATel: + 1 903 839 3999 ; Fax: + 1 903 839 3999 ; E-mail: [email protected]
