You are on page 1of 15

NIH Public Access

Author Manuscript
Clin Cancer Res. Author manuscript; available in PMC 2012 April 1.

NIH-PA Author Manuscript

Published in final edited form as:


Clin Cancer Res. 2011 April 1; 17(7): 19561963. doi:10.1158/1078-0432.CCR-10-2061.

Two Drug Interaction Studies of Sirolimus in Combination with


Sorafenib or Sunitinib in Patients with Advanced Malignancies
Tara C. Gangadhar, Ezra E. W. Cohen*, Kehua Wu, Linda Janisch, David Geary, Masha
Kocherginsky, Larry K. House, Jackie Ramirez, Samir D. Undevia, Michael L. Maitland, Gini
F. Fleming, and Mark J. Ratain
Division of Hematology and Oncology, University of Chicago, Chicago, IL

Abstract

NIH-PA Author Manuscript

PurposeSirolimus 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 DesignPatients 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.
ResultsThe 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.
ConclusionsSirolimus 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

NIH-PA Author Manuscript

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.(13) 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

Corresponding author: Ezra E.W. Cohen, Section of Hematology/Oncology, University of Chicago, 5841 South Maryland Avenue,
MC2115, Chicago, IL, 60637, ecohen@medicine.bsd.uchicago.edu.
Portions previously presented at the 44th Annual Meeting of the American Society of Clinical Oncology (ASCO), Chicago, IL, 2008.

Gangadhar et al.

Page 2

development of sirolimus in oncology, presumably due to the expiration of patents covering


its use as an anticancer agent (6,7).

NIH-PA Author Manuscript

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

NIH-PA Author Manuscript

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 02 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

NIH-PA Author Manuscript

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.
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

Clin Cancer Res. Author manuscript; available in PMC 2012 April 1.

Gangadhar et al.

Page 3

this expansion arm received sirolimus 2 mg twice daily along with sorafenib 400 mg twice
daily on days 128 of each 28 day cycle.

NIH-PA Author Manuscript

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

NIH-PA Author Manuscript

Sorafenib trialSamples 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 trialSamples 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.

NIH-PA Author Manuscript

Specimen Collection
All patient samples were collected in tubes labeled with the patients 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

Clin Cancer Res. Author manuscript; available in PMC 2012 April 1.

Gangadhar et al.

Page 4

NIH-PA Author Manuscript

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 g/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=711%) and accuracy (range: 90108%)
were determined by performing three measurements of the same seven standards on the
same day. Inter-assay precision (CV=713%) and accuracy (range: 98103%) were
determined by assays of the same set of standards in triplicate on three days.
Pharmacokinetic Analysis

NIH-PA Author Manuscript

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 onecompartment 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 patients 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.

NIH-PA Author Manuscript

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 = 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.

Clin Cancer Res. Author manuscript; available in PMC 2012 April 1.

Gangadhar et al.

Page 5

Pharmacokinetic Data

NIH-PA Author Manuscript

Table 3 summarizes the population pharmacokinetic parameter estimates for the rapamycin
and sorafenib trial.
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).
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

NIH-PA Author Manuscript

Table 5 summarizes the clinically relevant grade 35 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.
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.

NIH-PA Author Manuscript

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 16). 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(2325) as well as in
Clin Cancer Res. Author manuscript; available in PMC 2012 April 1.

Gangadhar et al.

Page 6

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)

NIH-PA Author Manuscript

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 (3236).

NIH-PA Author Manuscript

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).

NIH-PA Author Manuscript

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

Clin Cancer Res. Author manuscript; available in PMC 2012 April 1.

Gangadhar et al.

Page 7

formal drug-drug interactions study would be randomized, and might also include a formal
analysis of other endpoints, such as toxicity.

NIH-PA Author Manuscript

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).

References

NIH-PA Author Manuscript


NIH-PA Author Manuscript

1. Failli A, Steffan R; American Home Products Corporation (New York, NY) assignee. Silyl ethers of
rapamycin. 1992 June 9, 1992.
2. Liu M, Howes A, Lesperance J, et al. Antitumor activity of rapamycin in a transgenic mouse model
of ErbB2-dependent human breast cancer. Cancer Res. 2005; 65:532536. [PubMed: 15958580]
3. Namba R, Young LJ, Abbey CK, et al. Rapamycin inhibits growth of premalignant and malignant
mammary lesions in a mouse model of ductal carcinoma in situ. Clin Cancer Res. 2006; 12:2613
21. [PubMed: 16638874]
4. Jimeno A, Rudek MA, Kulesza P, et al. Pharmacodynamic-guided modified continuous
reassessment method-based, dose-finding study of rapamycin in adult patients with solid tumors. J
Clin Oncol. 2008; 26:41729. [PubMed: 18757332]
5. Wagner AJ, Malinowska-Kolodziej I, Morgan JA, et al. Clinical activity of mTOR inhibition with
sirolimus in malignant perivascular epithelioid cell tumors: targeting the pathogenic activation of
mTORC1 in tumors. J Clin Oncol. 2010; 28:83540. [PubMed: 20048174]
6. Cohen EE. mTOR: the mammalian target of replication. J Clin Oncol. 2008; 26:3489. [PubMed:
18202406]
7. Hartford CM, Ratain MJ. Rapamycin: something old, something new, sometimes borrowed and now
renewed. Clin Pharmacol Ther. 2007; 82:3818. [PubMed: 17728765]
8. Escudier B, Eisen T, Stadler WM, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N
Engl J Med. 2007; 356:12534. [PubMed: 17215530]
9. Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell
carcinoma. N Engl J Med. 2007; 356:11524. [PubMed: 17215529]
10. Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J
Med. 2008; 359:37890. [PubMed: 18650514]
11. Casali PG, Garrett CR, Blackstein ME, et al. Updated results from a phase III trial of sunitinib in
GIST patients (pts) for whom imatinib (IM) therapy has failed due to resistance or intolerance.
JCO. 2006:24.
12. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment
in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer
Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000;
92:20516. [PubMed: 10655437]
13. Zhao M, Rudek MA, He P, et al. A rapid and sensitive method for determination of sorafenib in
human plasma using a liquid chromatography/tandem mass spectrometry assay. J Chromatogr B
Analyt Technol Biomed Life Sci. 2007; 846:17.
14. Beal, S.; Sheiner, L. NONMEM Users Guide. San Francisco, CA: University of California, San
Francisco; 1989.
15. Awada A, Hendlisz A, Gil T, et al. Phase I safety and pharmacokinetics of BAY 43-9006
administered for 21 days on/7 days off in patients with advanced, refractory solid tumours. Br J
Cancer. 2005; 92:185561. [PubMed: 15870716]

Clin Cancer Res. Author manuscript; available in PMC 2012 April 1.

Gangadhar et al.

Page 8

NIH-PA Author Manuscript


NIH-PA Author Manuscript
NIH-PA Author Manuscript

16. 1. [cited June 25, 2010]; Available from:


http://clinicaltrials.gov/ct2/show/NCT00392821?term=sorafenib+everolimus&rank=4
17. 2. [cited June 25, 2010]; Available from:
http://clinicaltrials.gov/ct2/show/NCT00828594?term=sorafenib+everolimus&rank=3
18. 3. [cited June 25, 2010]; Available from:
http://clinicaltrials.gov/ct2/show/NCT01005199?term=sorafenib+everolimus&rank=9
19. 4. [cited June 25, 2010]; Available from:
http://clinicaltrials.gov/ct2/show/NCT00942682?term=sorafenib+everolimus&rank=7
20. 5. [cited June 25, 2010]; Available from:
<http://clinicaltrials.gov/ct2/show/NCT01141309?term=sorafenib+everolimus&rank=2>
21. 6. [cited June 25, 2010]; Available from:
<http://clinicaltrials.gov/ct2/show/NCT00474929?term=sorafenib+everolimus&rank=8>
22. 7. [cited June 25, 2010]; Available from:
<http://clinicaltrials.gov/ct2/show/NCT00981162?term=sorafenib+everolimus&rank=5>
23. 8. [cited June 25, 2010]; Available from:
<http://clinicaltrials.gov/ct2/show/NCT00474786?term=sorafenib+and+temsirolimus&rank=10>
24. 9. [cited June 25, 2010]; Available from:
http://clinicaltrials.gov/ct2/show/NCT01025453?term=sorafenib+and+temsirolimus&rank=1
25. 10. [cited June 25, 2010]; Available from:
http://clinicaltrials.gov/ct2/show/NCT01008917?term=sorafenib+and+temsirolimus&rank=6
26. 11. [cited June 25, 2010]; Available from:
<http://clinicaltrials.gov/ct2/show/NCT00349206?term=sorafenib+and+temsirolimus&rank=4>
27. 12. [cited June 25, 2010]; Available from:
<http://clinicaltrials.gov/ct2/show/NCT00329719?term=sorafenib+and+temsirolimus&rank=2>
28. 13. [cited June 25, 2010]; Available from:
<http://clinicaltrials.gov/ct2/show/NCT00903175?term=sunitinib+everolimus&rank=2>
29. 14. [cited June 25, 2010]; Available from:
http://clinicaltrials.gov/ct2/show/NCT01122615?term=sunitinib+and+temsirolimus&rank=1
30. Lathia C, Lettieri J, Cihon F, Gallentine M, Radtke M, Sundaresan P. Lack of effect of
ketoconazole-mediated CYP3A inhibition on sorafenib clinical pharmacokinetics. Cancer
Chemother Pharmacol. 2006; 57:68592. [PubMed: 16133532]
31. van Erp N. Cancer Chemother Pharmacol. 2010 in press.
32. Dai CL, Liang YJ, Wang YS, et al. Sensitization of ABCG2-overexpressing cells to conventional
chemotherapeutic agent by sunitinib was associated with inhibiting the function of ABCG2.
Cancer Lett. 2009; 279:7483. [PubMed: 19232821]
33. Gupta A, Dai Y, Vethanayagam RR, et al. Cyclosporin A, tacrolimus and sirolimus are potent
inhibitors of the human breast cancer resistance protein (ABCG2) and reverse resistance to
mitoxantrone and topotecan. Cancer Chemother Pharmacol. 2006; 58:37483. [PubMed:
16404634]
34. Hu S, Chen Z, Franke R, et al. Interaction of the multikinase inhibitors sorafenib and sunitinib with
solute carriers and ATP-binding cassette transporters. Clin Cancer Res. 2009; 15:60629.
[PubMed: 19773380]
35. Pawarode A, Shukla S, Minderman H, et al. Differential effects of the immunosuppressive agents
cyclosporin A, tacrolimus and sirolimus on drug transport by multidrug resistance proteins. Cancer
Chemother Pharmacol. 2007; 60:17988. [PubMed: 17031644]
36. Shukla S, Robey RW, Bates SE, Ambudkar SV. Sunitinib (Sutent, SU11248), a small-molecule
receptor tyrosine kinase inhibitor, blocks function of the ATP-binding cassette (ABC) transporters
P-glycoprotein (ABCB1) and ABCG2. Drug Metab Dispos. 2009; 37:35965. [PubMed:
18971320]
37. Kim K, Davies M, Papadopoulos N, et al. Phase I/II study of the combination of sorafenib and
temsirolimus in patients with metastatic melanoma. JCO. 2009:27.
38. Cen P, Daleiden A, Doshi D, Amato R. A phase I study of everolimus plus sorafenib in patients
with metastatic renal cell carcinoma. JCO. 2009:27.

Clin Cancer Res. Author manuscript; available in PMC 2012 April 1.

Gangadhar et al.

Page 9

NIH-PA Author Manuscript

39. Kroog G, Feldman D, Kondagunta G, et al. Phase I trial of RAD001 (everolimus) plus sunitinib in
patients with metastatic renal cell carcinoma. JCO. 2009:27.
40. Wen P, Cloughesy T, Kuhn J, et al. Phase I/II study of sorafenib and temsirolimus for patients with
recurrent glioblastoma (GBM) (NABTC 05-02). JCO. 2006:27. [PubMed: 16531661]
41. Fischer P, Patel P, Carducci M, et al. Phase I study combining treatment with temsirolimus and
sunitinib malate in patients with advanced renal cell carcinoma. JCO. 2008:26.
42. Hamburg P, Ratain MJ, Lesaffre E, verweij J. Dose Escalation Models for Combination Phase I
Trials in Oncology. European Journal of Cancer. 2010 In press.
43. Ratain MJ, Napoli KL, Knightley K, et al. A phase 1b study of oral rapamycin (sirolimus) in
patients with advanced malignancies. JCO. 2008:25.

NIH-PA Author Manuscript


NIH-PA Author Manuscript
Clin Cancer Res. Author manuscript; available in PMC 2012 April 1.

Gangadhar et al.

Page 10

Figure 1. Study design and PK data collection for each treatment arm

NIH-PA Author Manuscript

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.

NIH-PA Author Manuscript


NIH-PA Author Manuscript
Clin Cancer Res. Author manuscript; available in PMC 2012 April 1.

Gangadhar et al.

Page 11

Table 1

NIH-PA Author Manuscript

Sirolimus and Sorafenib trial

Cycle 1, Days 114 (Initial 2 week lead-in period)

Cycle 1, Days 15 and onwards

Sirolimus

3 mg po daily

3 mg po daily

Sorafenib

-----

400 mg po bid

Sirolimus pharmacokinetics arm

Sorafenib pharmacokinetics arm


Sirolimus

-----

3 mg po daily

Sorafenib

400 mg po bid

400 mg po bid

Cycle 1, Days 114 (Initial 2 week lead-in period)

Cycle 1, Days 15 and onwards

Sirolimus

4 mg po daily

4 mg po daily

Sunitinib

-----

25 mg po daily

Sirolimus and sunitinib trial


Sirolimus pharmacokinetics arm

Sunitinib pharmacokinetics arm


Sirolimus

-----

4 mg po daily

Sunitinib

25 mg po daily

25 mg po daily

NIH-PA Author Manuscript


NIH-PA Author Manuscript
Clin Cancer Res. Author manuscript; available in PMC 2012 April 1.

Gangadhar et al.

Page 12

Table 2

NIH-PA Author Manuscript

Total Patients (n)

Sirolimus/Sorafenib

Sirolimus/Sunitinib

34

23

Age
Median

58

58

Range

3674

2273

Male

50%

48%

Female

50%

52%

ECOG 0

16 (47%)

10 (44%)

ECOG 1

18 (53%)

12 (52%)

ECOG 2

0 (0%)

1 (4%)

Sex

Performance Status

Cancer Diagnosis
Hepatocellular carcinoma

NIH-PA Author Manuscript

Ovarian

Sarcoma

Non small cell lung cancer

Colorectal

Parotid gland

Breast

Pancreatic

Fibromatosis

Urothelial

Adenoid cystic

Thyroid

Gallbladder

Esophageal

Renal

Testicular

NIH-PA Author Manuscript

Adrenal

Neuroblastoma

Clin Cancer Res. Author manuscript; available in PMC 2012 April 1.

138
2.01

V/F (L)

(h1)

-----

2 (Additive, S.D.)

807
1.07

V/F1 (L)

(h1)
---------

1 (Proportional, CV%)

2 (Additive, S.D.)

Ka

5.81

CL/F1 (L/h)

Sorafenib (n = 6)

-----

1 (Proportional, CV%)

Ka

18.7

CL/F (L/h)

Sirolimus (n = 6)

-----

-----

16.5

37.3

15.5

-----

-----

18.5

15.9

11.6

%RSE

-----

-----

0.7231.42

2171400

4.057.57

-----

-----

1.282.74

95.1181

14.423.0

95% CI

-----

-----

111

103

29.6

-----

-----

21.9

0*

69.2

individual variability (%)

0.001 (ng/mL)

39.4

0.001 (ng/mL)

41

individual variability

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.

When variability is too small (<106), it is fixed as zero.

NIH-PA Author Manuscript


Estimate

NIH-PA Author Manuscript

Sirolimus and Sorafenib trial

NIH-PA Author Manuscript

Table 3
Gangadhar et al.
Page 13

Clin Cancer Res. Author manuscript; available in PMC 2012 April 1.

Gangadhar et al.

Page 14

Table 4

NIH-PA Author Manuscript

Sirolimus and Sorafenib trial

Median Baseline value (Range)

Median relative difference, Range (%)

P Value using signed rank


test

17.2 (15.4, 19.1)

3.9 (1.3, 11.0)

0.03

129.5 (72.0, 340.9)

43.7 (10.5, 84.7)

0.03

Sirolimus (n=6)
Cmax (ng/mL)
AUC (ng*h/mL)
Sorafenib (n=6)
Cmax (ng/mL)
AUC ( ng*h/mL )
Sirolimus and sunitinib trial

1183.9 (658.1, 2654.5)

40.7 (87.0, 351.2)

0.6

61680.5 (59568.1, 156617.1)

6.1 (17.3, 22.0)

0.46

Median Baseline value (Range)

Median relative difference, Range (%)

P Value using signed rank


test

24.7 (15.981.3)

29.8 (77.4, 28.8)

0.09

679.6 (121.7, 2034.2)

47.7 (75.4, 1394.8)

0.78

Sirolimus (n=8)
Cmax (ng/mL)
AUC ( ng*h/mL )
Sunitinib (n=7)

NIH-PA Author Manuscript

Cmax (ng/mL)
AUC ( ng*h/mL )

43.8 (33.359.3)

19.6 (23.5, 45.4)

0.06

3767.7 (2149.6, 5246.7)

54.3 (34.3, 232.8)

0.04

11.9 (7.427.3)

35.3 (15.4, 55.5)

0.09

3681.8 (1283.5, 6367.7)

61.6 (79.7, 1031.2)

0.5

SU12662 (n=7)
Cmax (ng/mL)
AUC ( ng*h/mL )

NIH-PA Author Manuscript


Clin Cancer Res. Author manuscript; available in PMC 2012 April 1.

Gangadhar et al.

Page 15

Table 5

NIH-PA Author Manuscript

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

NIH-PA Author Manuscript


NIH-PA Author Manuscript

-----

-----

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%)

-----

-----

-----

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

-----

-----

Pulmonary artery thrombus

-----

1 (7%)

-----

Elevated bilirubin

Indicates grade 5 toxicity

Clin Cancer Res. Author manuscript; available in PMC 2012 April 1.

You might also like