Abstract
Purpose
Sirolimus is the prototypical mammalian target of rapamycin inhibitor. Sorafenib and sunitinib are small molecule inhibitors of multiple kinases including vascular endothelial receptor kinases (VEGFR). These agents have different mechanisms of action providing a strong rationale for combination.
Experimental Design
Patients with advanced cancer were assigned to receive either sirolimus or the VEGFR inhibitor alone for a 2 week lead-in period followed by combination therapy. The primary endpoint of each trial was to determine whether a drug interaction exists between sirolimus and either sorafenib or sunitinib, as defined by a difference in Cmax for each drug alone compared with its Cmax during combination therapy.
Results
The sorafenib and sunitinib trials enrolled 34 and 23 patients, respectively. There were no clinically significant differences in Cmax for any of the drugs alone compared to the Cmax during combination therapy. Toxicity profiles were similar to those expected for each drug alone. One patient with adrenal cortical cancer had a partial response to sirolimus and sunitnib.
Conclusions
Sirolimus can be safely combined with sorafenib or sunitinib. Our trial design is feasible and informative in screening for potential drug-drug interactions using a relatively small number of patients and limited pharmacokinetic sampling.
Keywords: Combination therapy, Drug interaction, Sirolimus, Sunitinib, Sorafenib
INTRODUCTION
Sirolimus (rapamycin) is a natural macrolide with immunosuppressive properties that is currently approved for the prevention of organ rejection after transplantation. It is the prototypical (and eponymous) inhibitor of mammalian target of rapamycin (mTOR), a key regulator of protein translation. Like other mTOR inhibitors, it has significant anticancer activity in preclinical models.(1–3) A phase I trial of sirolimus in cancer patients reported 6 mg daily as the maximum tolerated dose, while 3 mg daily was well tolerated(4). In addition, sirolimus has documented antitumor activity in patients with malignant perivascular epithelioid cell tumors (5). However, the use of sirolimus analogs specifically developed as anticancer agents has been favored, as there has been no commercial development of sirolimus in oncology, presumably due to the expiration of patents covering its use as an anticancer agent (6, 7).
Sorafenib and sunitinib are small molecule inhibitors of multiple receptor tyrosine kinases (RTKs) that have antiangiogenic properties due to inhibition of vascular endothelial growth factor receptors (VEGFR). Both drugs are approved for the treatment of renal cell carcinoma(8, 9). Sorafenib is also approved for the treatment of advanced hepatocellular carcinoma(10) and sunitinib is approved for the treatment of gastrointestinal stromal tumors(11).
Because VEGFR inhibitors and sirolimus have different mechanisms of action in pathways of cell proliferation and angiogenesis, there is a strong rationale for combining these agents. To facilitate future studies of such combinations, we designed two drug interaction studies to test the clinical and pharmacokinetic feasibility of administering sirolimus with either sorafenib or sunitinib to patients with advanced malignancies.
PATIENTS AND METHODS
Eligibility
Patients were eligible for either trial if they were 18 years of age or older with pathologically confirmed advanced solid tumors and progressive disease after standard therapy. Patients were required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2 and adequate organ and marrow function. For the sunitinib study, patients were excluded if their corrected QT interval was greater than 500 milliseconds.
For the trial of sirolimus and sorafenib, prior treatment with sorafenib or an mTOR inhibitor (including sirolimus) was allowed; prior therapy with both sorafenib and an mTOR inhibitor was not allowed. In the trial of sirolimus and sunitinib, no prior VEGFR or mTOR inhibitors were permitted.
For the sorafenib trial, patients on a stable therapeutic dose of warfarin with an INR less than 3 and no thromboembolic event within 6 months were eligible. For the sunitinib trial, a normal INR and no thrombotic or thromboembolic events for one year were required.
The protocol was reviewed by the institutional review board and all patients provided written informed consent.
Study Design and Treatments
The primary endpoint of each trial was to determine whether a drug interaction exists between sirolimus and either sorafenib or sunitinib, as indicated by a clinically significant change in pharmacokinetic parameters upon co-administration compared to those of either drug alone. Within each trial, patients were sequentially assigned to one of two treatment arms. During the initial two week lead-in period, patients received either sirolimus or a VEGFR inhibitor alone, according to their assigned treatment arm within each trial. Starting on day 15, all patients on both trials received combination therapy. [Table 1 and Figure 1]. The dose of sirolimus in both trials was selected as one-half (sorafenib trial) or two-thirds (sunitinib trial) of the maximally tolerated dose of 6 mg previously reported (4). Pharmacokinetic sampling was performed as described below.
Table 1.
| Sirolimus and Sorafenib trial | Cycle 1, Days 1–14 (Initial 2 week lead-in period) | Cycle 1, Days 15 and onwards |
|---|---|---|
| Sirolimus pharmacokinetics arm | ||
| Sirolimus | 3 mg po daily | 3 mg po daily |
| Sorafenib | ----- | 400 mg po bid |
| Sorafenib pharmacokinetics arm | ||
| Sirolimus | ----- | 3 mg po daily |
| Sorafenib | 400 mg po bid | 400 mg po bid |
| Sirolimus and sunitinib trial | Cycle 1, Days 1–14 (Initial 2 week lead-in period) | Cycle 1, Days 15 and onwards |
| Sirolimus pharmacokinetics arm | ||
| Sirolimus | 4 mg po daily | 4 mg po daily |
| Sunitinib | ----- | 25 mg po daily |
| Sunitinib pharmacokinetics arm | ||
| Sirolimus | ----- | 4 mg po daily |
| Sunitinib | 25 mg po daily | 25 mg po daily |
Figure 1. Study design and PK data collection for each treatment arm.
For each study arm, pharmacokinetic (PK) data for the initial drug were collected during the 2 week-lead in period on day 14. Pharmacokinetic data for the same drug were again collected after introduction of the interacting drug. After cycle 1, all patients on both trials were treated with combination therapy.
After pharmacokinetic and safety data from the initial treatment groups were reviewed, the sirolimus and sorafenib protocol was amended and an additional 14 patients were enrolled on a third treatment arm to test the tolerability of twice daily sirolimus dosing. Patients on this expansion arm received sirolimus 2 mg twice daily along with sorafenib 400 mg twice daily on days 1–28 of each 28 day cycle.
Patients remained on study until radiographic or clinical disease progression, unacceptable toxicity or withdrawal of consent. Full supportive care was provided as indicated. If a patient experienced any grade 3 or greater toxicity per the National Cancer Institute Common Toxicity Criteria version 3.0, both drugs were interrupted until the toxicity resolved to grade one or less. Patients were removed from the study for any dose interruption of greater than 3 weeks.
Assessments
Evaluations before and during treatment consisted of a complete medical history, physical examinations, hematologic and metabolic laboratory profiles and toxicity assessments according to the National Cancer Institute Common Toxicity Criteria version 3.0. Complete and partial responses and progressive disease were defined and assessed according to the Response Evaluation Criteria in Solid Tumors.(12)
Pharmacokinetic Studies
Sorafenib trial
Samples for pharmacokinetic analysis of sorafenib were collected on day 1 at 1, 4 and 8 hours after sorafenib administration and on day 14 at 0.5 and 6 hours after administration. Sirolimus treatment was started on day 15. Samples for sorafenib pharmacokinetics were collected again on day 15 at 3 and 8 hours after both sirolimus and sorafenib administration, and on day 29 at 20 minutes and 5 hours after administration. For patients assigned to receive sirolimus alone for the initial 2 week lead-in period, samples for pharmacokinetic analysis of sirolimus were collected after sirolimus administration on day 1 at 40 minutes, 3 hours and 8 hours and on day 8 at 20 minutes and 5 hours. Sorafenib treatment was started on day 15. Samples for sirolimus pharmacokinetics were collected again on days 15 and 22 at 20 minutes and 5 hours after drug administration.
Sunitinib trial
Samples for pharmacokinetic analysis of sunitinib and its metabolite, SU12662, were collected on day 14 before sunitinib administration, and at 1, 4,6, 8 and 24 hours after administration. Sirolimus treatment was started on day 15. Samples for sunitinib pharmacokinetics were collected again on day 28 at the same time points. For patients assigned to receive sirolimus alone for the initial 2 week lead-in period followed by combination therapy starting on day 15, samples for pharmacokinetic analysis of sirolimus were collected on days 14 and 28 according to the same collection schedule as for sunitinib.
Specimen Collection
All patient samples were collected in tubes labeled with the patient’s full name, the date and the time of sample collection.
After centrifugation and freezing, sorafenib plasma concentrations were determined by Bayer Pharmaceuticals using a high performance liquid chromatographic mass spectrometric method for the determination of sorafenib in human plasma (13).
Sunitinib concentrations were determined after centrifugation, plasma separation and freezing by BASi laboratories using mass spectrometry (MS). SU011248 and SU012662 were extracted from human plasma by liquid/liquid extraction at alkaline pH with ethyl acetate. Before the extraction, a deuterated internal standard of SU011248 was added. The organic layer was collected and evaporated to dryness. The residue was reconstituted with an ammonium formate/acetonitrile mixture and injected into an LC/MS/MS using a Betasil C18 column with an ammonium formate/acetonitrile mobile phase. Calibration standards for sunitinib and its metabolite were used for quality control within each analytical run to form a calibration curve based on mass spectrometer signal responses. A sirolimus interference assessment was done for the sunitinib and SU012662 assays as well. The presence of sirolimus in quality control standard samples does not have a significant effect on the accuracy and precision of sunitinib or SU012662 concentrations determined.
Sirolimus concentrations were measured using a validated method involving centrifugation, addition of internal standard (triamcinolone, 1 μg/ml) and injection into an API-2000 mass spectrometer (Applied Biosystems, Foster City, CA) with an ESI source. Seven calibration standards and three quality control samples (at low, medium and high concentrations) were included in each run. Intra-assay precision (CV=7–11%) and accuracy (range: 90–108%) were determined by performing three measurements of the same seven standards on the same day. Inter-assay precision (CV=7–13%) and accuracy (range: 98–103%) were determined by assays of the same set of standards in triplicate on three days.
Pharmacokinetic Analysis
Pharmacokinetic analyses for the trial of sirolimus and sorafenib were performed using NONMEM (version VI, level 1, ICON, Ellicott City, MD, USA)(14) and PDx-Pop (version 3.0, ICON, Ellicott City, MD, USA) in conjunction with a G95 Fortran compiler. A one-compartment open model with first-order absorption and elimination was used to fit the concentration data. Inter-individual and residual unexplained variability were described by exponential and combined proportional and additive error models, respectively.
Each patient’s individual PK parameters (Ka, CL/F and V/F) were calculated by the population typical value and their inter-individual variability according to equation 1. Next, AUC0–∞ and Cmax were calculated for every patient by their individual parameters.
For the sirolimus and sunitinb trial, AUC0–∞ was estimated by non-compartmental pharmacokinetic analysis using PKSolutions software (version 2.0, Summit Research Services, Montrose, CO). Cmax is the observed maximum concentration.
Statistical Methods
The primary objective was to determine whether there was a drug interaction between sirolimus and either sorafenib or sunitinib. For both trials, changes in steady-state pharmacokinetic parameters of each drug resulting from the initiation of the interacting drug were analyzed separately in each arm.
A signed rank test was used to determine whether the Cmax or AUC of each drug changed significantly after the addition of the interacting drug. Since we were only interested in large effects, we used a sample size of 6 and 8 patients per arm for the sorafenib and sunitinib trials, respectively. This sample size yielded 80% power to detect a 99% change in sirolimus Cmax and a 82% change in sorafenib Cmax assuming within-patient correlation ρ = 0.50 and Cmax variability as previously reported(15). Similar power was assumed for the sunitinib trial.
RESULTS
Patient Characteristics
The baseline demographics and disease characteristics of the patients are presented in Table 2.
Table 2.
| Sirolimus/Sorafenib | Sirolimus/Sunitinib | |
|---|---|---|
| Total Patients (n) | 34 | 23 |
| Age | ||
| Median | 58 | 58 |
| Range | 36–74 | 22–73 |
| Sex | ||
| Male | 50% | 48% |
| Female | 50% | 52% |
| Performance Status | ||
| ECOG 0 | 16 (47%) | 10 (44%) |
| ECOG 1 | 18 (53%) | 12 (52%) |
| ECOG 2 | 0 (0%) | 1 (4%) |
| Cancer Diagnosis | ||
| Hepatocellular carcinoma | 1 | |
| Ovarian | 2 | 2 |
| Sarcoma | 6 | 2 |
| Non small cell lung cancer | 3 | 4 |
| Colorectal | 6 | 3 |
| Parotid gland | 2 | |
| Breast | 2 | 1 |
| Pancreatic | 3 | 4 |
| Fibromatosis | 1 | |
| Urothelial | 1 | 1 |
| Adenoid cystic | 1 | |
| Thyroid | 1 | |
| Gallbladder | 2 | 1 |
| Esophageal | 2 | |
| Renal | 1 | |
| Testicular | 1 | 1 |
| Adrenal | 2 | |
| Neuroblastoma | 1 | |
Pharmacokinetic Data
Table 3 summarizes the population pharmacokinetic parameter estimates for the rapamycin and sorafenib trial.
Table 3.
| Sirolimus and Sorafenib trial | Estimate | %RSE | 95% CI | individual variability (%) | individual variability |
|---|---|---|---|---|---|
| Sirolimus (n = 6) | |||||
| CL/F (L/h) | 18.7 | 11.6 | 14.4–23.0 | 69.2 | |
| V/F (L) | 138 | 15.9 | 95.1–181 | 0* | |
| Ka (h−1) | 2.01 | 18.5 | 1.28–2.74 | 21.9 | |
| σ1 (Proportional, CV%) | ----- | ----- | ----- | ----- | 41 |
| σ2 (Additive, S.D.) | ----- | ----- | ----- | ----- | 0.001 (ng/mL) |
| Sorafenib (n = 6) | |||||
| CL/F1 (L/h) | 5.81 | 15.5 | 4.05–7.57 | 29.6 | |
| V/F1 (L) | 807 | 37.3 | 217–1400 | 103 | |
| Ka (h−1) | 1.07 | 16.5 | 0.723–1.42 | 111 | |
| σ1 (Proportional, CV%) | ----- | ----- | ----- | ----- | 39.4 |
| σ2 (Additive, S.D.) | ----- | ----- | ----- | ----- | 0.001 (ng/mL) |
When variability is too small (<10−6), it is fixed as zero.
RSE, relative standard error; CI, confidence interval; F, bioavailability of sirolimus; F1, bioavailability of sorafenib; CL/F, apparent clearance; V/F, central volume of distribution.
Baseline Cmax and AUC values and relative differences after initiation of combination therapy for both trials are reported in Table 4. There were no clinically significant changes in Cmax or AUC in the sirolimus and sorafenib trial. The median relative change in sirolimus Cmax was 3.9% (p = 0.03), which was not clinically significant even though it was statistically significantly different from 0%. The median relative change in sorafenib Cmax was −40.7% and was not statistically significant (p = 0.60).
Table 4.
| Sirolimus and Sorafenib trial | Median Baseline value (Range) | Median relative difference, Range (%) | P Value using signed rank test |
|---|---|---|---|
| Sirolimus (n=6) | |||
| Cmax (ng/mL) | 17.2 (15.4, 19.1) | 3.9 (1.3, 11.0) | 0.03 |
| AUC (ng*h/mL) | 129.5 (72.0, 340.9) | 43.7 (10.5, 84.7) | 0.03 |
| Sorafenib (n=6) | |||
| Cmax (ng/mL) | 1183.9 (658.1, 2654.5) | −40.7 (−87.0, 351.2) | 0.6 |
| AUC ( ng*h/mL ) | 61680.5 (59568.1, 156617.1) | 6.1 (−17.3, 22.0) | 0.46 |
| Sirolimus and sunitinib trial | Median Baseline value (Range) | Median relative difference, Range (%) | P Value using signed rank test |
| Sirolimus (n=8) | |||
| Cmax (ng/mL) | 24.7 (15.9–81.3) | −29.8 (−77.4, 28.8) | 0.09 |
| AUC ( ng*h/mL ) | 679.6 (121.7, 2034.2) | −47.7 (−75.4, 1394.8) | 0.78 |
| Sunitinib (n=7) | |||
| Cmax (ng/mL) | 43.8 (33.3–59.3) | 19.6 (−23.5, 45.4) | 0.06 |
| AUC ( ng*h/mL ) | 3767.7 (2149.6, 5246.7) | 54.3 (−34.3, 232.8) | 0.04 |
| SU12662 (n=7) | |||
| Cmax (ng/mL) | 11.9 (7.4–27.3) | 35.3 (−15.4, 55.5) | 0.09 |
| AUC ( ng*h/mL ) | 3681.8 (1283.5, 6367.7) | 61.6 (−79.7, 1031.2) | 0.5 |
There were no clinically significant differences in Cmax or AUC in the sirolimus and sunitinib trial. The median changes in Cmax for sirolimus, sunitinib and SU12662 were −29.8%, 19.6%, and 35.3%, respectively (p > 0.05). [Table 4]
Toxicity
Table 5 summarizes the clinically relevant grade 3–5 adverse events for each arm. Combination therapy was well tolerated in both trials and did not result in unexpected toxicities. In the sirolimus and sorafenib trial, one patient died from infection and a second patient died of an arrhythmia. In the sirolimus and sunitinib trial, two patients died due to disease progression while on study. A third patient died of disease progression within 30 days of going off the study. None of the deaths on either of the trials were thought to be therapy related.
Table 5.
| sirolimus/sorafenib (n=20) | sirolimus/sorafenib twice daily (n=14) | sirolimus/sunitinib (n=23) | |
|---|---|---|---|
| Diarrhea | 5 (25%) | ----- | 1 (4%) |
| HFS | 2 (10%) | 3 21(%) | ----- |
| Vomiting | 1 (5%) | 1 (7%) | ----- |
| Hypophosphatemia | 2 (10%) | 7 (50%) | ----- |
| DVT | 1 (5%) | ----- | ----- |
| Atrial Fibrillation* | 1 (5%) | ----- | ----- |
| Leukopenia | ----- | 1 (7%) | 1 (4%) |
| Neutropenia | ----- | ----- | 3 (13%) |
| Lymphopenia | ----- | 1 (7%) | 2 (7%) |
| Thrombocytopenia | ----- | ----- | 2 (7%) |
| Anemia | 1 (5%) | 2 (14%) | 2 (7%) |
| GI Bleed | 1 (5%) | ----- | ----- |
| Infection* | 1 (5%) | ----- | ----- |
| Hypertension | 1 (5%) | ----- | 1 (4%) |
| Pain | 2 (10%) | ----- | ----- |
| Elevated AST | 1 (5%) | 1 (7%) | 1 (4%) |
| Elevated ALT | 1 (5%) | ----- | ----- |
| Elevated bilirubin | ----- | 1 (7%) | ----- |
| Dyspnea | 1 (5%) | ----- | 1 (4%) |
| SVC Syndrome | 1 (5%) | ----- | ----- |
| Weight loss | 1 (5%) | ----- | ----- |
| Rash | 1 (5%) | 3 (21%) | ----- |
| Oral mucositis | ----- | ----- | 1 (4%) |
| Chest pain | ----- | ----- | 1 (4%) |
| SBO | ----- | ----- | 2 (7%) |
| Fatigue | ----- | 1 (7%) | 3 (13%) |
| Hyperglycemia | ----- | ----- | 1 (4%) |
| Hypokalemia | ----- | 1 (7%) | 1 (4%) |
| Hyponatremia | ----- | 1 (7%) | 1 (4%) |
| Kidney injury | ----- | ----- | 1 (4%) |
| Confusion | ----- | ----- | 1 |
| Pulmonary artery thrombus | ----- | 1 (7%) | ----- |
Indicates grade 5 toxicity
For the sirolimus and sorafenib expansion study arm of 14 patients treated with twice daily sirolimus and sorafenib, there were again no unexpected toxicities noted compared to those expected for either drug alone.
Efficacy
In the sirolimus and sorafenib trial, 79 4-week cycles were administered (median 2; range 1–16). There were no responses. Of the 9 patients with stable disease, two patients with sarcoma and one patient with metastatic urothelial carcinoma had prolonged periods of stable disease with 6, 10, and 16 cycles of treatment, respectively.
In the sirolimus and sunitinib trial, 84 4-week cycles were administered (median 2; range 1–14). The best response was a partial response in a patient with adrenal cortical carcinoma who remained on study for 11 cycles. Of the 10 patients with stable disease, one patient with hepatocellular carcinoma received 12 cycles before stopping treatment to pursue an alternative therapy and another patient with non-small cell lung cancer received 14 cycles of treatment before coming off study due to progressive disease
Fourteen additional patients were treated with twice daily sirolimus and sorafenib, including 38 4-week cycles (median 2; range 1–6). There were no responses.
DISCUSSION
We conducted two drug interaction studies of sirolimus in combination with either sorafenib or sunitinib. Combined mTOR and VEGFR pathway inhibition is a feasible and potentially effective treatment option in patients with advanced malignancies. Currently, several trials examining the combination of sorafenib and the mTOR inhibitor everolimus are ongoing in patients with renal cell carcinoma,(16) hepatocellular carcinoma,(17, 18) neuroendocrine tumors,(19) thyroid cancer,(20) and other tumors.(21, 22) Trials of sorafenib and temsirolimus are also ongoing in patients with similar malignancies(23–25) as well as in melanoma(26) and glioblastoma(27) Trials of sunitinib in combination with both everolimus and with temsirolimus are ongoing in patients with renal cell carcinoma.(28, 29)
At the time we designed these studies, we chose to study sirolimus due to its commercial availability, oral formulation, and long safety record. Preclinical evidence for mTOR activity in decreasing tumor proliferation and angiogenesis made sirolimus a strong option to test the feasibility of combining mTOR and VEGFR targeted therapies. Given our limited national and global healthcare resources, the repositioning of drugs previously approved for other indications reduces both drug development costs in oncology and costs to the healthcare system. Taking into consideration these issues of limited resources and the high costs associated with oncology drug development, a feasible future clinical trial would randomize patients with renal cell carcinoma to VEGF inhibition with or without the addition of sirolimus.
We did not expect any major drug interactions in either trial. Although all three drugs are substrates for CYP3A4, none have been demonstrated to be inhibitors of this enzyme. Furthermore, the pharmacokinetics of sunitinib and sorafenib are only modestly affected by inhibitors of CYP3A4 (30, 31). We also considered that there might be an interaction due to effects on ABC or SLC transporters, given the pleiomorphic effects of these agents (32–36).
As expected, we did not observe any clinically significant drug interactions between sirolimus and either sorafenib or sunitinib. However, our trials were powered to detect only large (2-fold, or 100%) pharmacokinetic interactions, and thus we cannot exclude smaller interactions that could still have clinical sequelae.
Patients tolerated both regimens with toxicity profiles similar to those expected from either drug alone. There was notable grade 3 hypophosphatemia in the sirolimus and sunitinib study. Observed toxicities were similar to those seen other early phase trials combining mTOR and VEGF inhibition in patients with metastatic melanoma (37) and renal cell carcinoma (38, 39)as well as a trial in patients with glioblastoma(40), which also included pharmacokinetic data suggesting no significant drug interaction between sorafenib and temsirolimus. In contrast, a phase I trial of sunitinib and temsirolimus in patients with renal cell carcinoma was terminated after two of three patients experienced grade 3 toxicities on the lowest dose level cohort (41).
While other trials have examined the feasibility of combining mTOR and VEGF targeted agents using a traditional 2-drug dose escalation study design, our studies were designed with a more focused approach to detecting potential drug interactions, given the importance of hypothesis driven, drug specific early phase trial design(42). A previously reported phase I dose escalation trial of sirolimus defined 6 mg as the maximum tolerated dose of daily oral sirolimus, with 3 mg being well tolerated (4) while an ongoing study at the University of Chicago was able to administer 90 mg sirolimus weekly without dose limiting toxicity (43). Therefore, we chose a conservative starting dose of 3 or 4 mg of sirolimus in the sorafenib and sunitinib trials, respectively. Furthermore, because the known pharmacology would have predicted no significant drug-drug interaction in either combination, using therapeutic dose levels of sorafenib and sunitinib was thought to be rational and acceptable, while also minimizing sub-therapeutic dosing in any subject. Our two-phase trial design allows for the direct comparison of pharmacokinetic parameters before and after the addition of a second drug using treatment doses of both agents in all patients. In addition, by including a 2-week lead in period, we were able to screen for potential drug interactions after achieving steady state drug concentrations. We recognize that pharmacokinetic drug interactions represent only one of several effectors of treatment response and toxicity. We also note that a more formal drug-drug interactions study would be randomized, and might also include a formal analysis of other endpoints, such as toxicity.
We have demonstrated that our trial design is both feasible and informative in screening for potential drug interactions using a relatively small number of patients and limited pharmacokinetic sampling. Ongoing clinical trials will further clarify the efficacy of combination mTOR and VEGF inhibition in specific tumors, such as renal cell carcinoma.
Acknowledgments
This research was supported by the Pharmacology Core of the University of Chicago Cancer Research Center (NIH P30 CA14599), the Basic Research Training Grant in Medical Oncology (NIH/NCI T32 CA009566) and the Training Grant in Clinical Therapeutics (NIH/NIGMS T32 GM007019).
Footnotes
Portions previously presented at the 44th Annual Meeting of the American Society of Clinical Oncology (ASCO), Chicago, IL, 2008.
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