Phase I study of safety and tolerability of sunitinib in combination with sirolimus in patients with refractory solid malignancies and determination of VEGF (VEGF-A) and soluble VEGF-R2 (sVEGFR2) in plasma.
Sirolimus, an oral mTOR inhibitor, may complement the anti-angiogenic and anti-tumor activity of sunitinib, an oral small molecule inhibitor of multiple receptor tyrosine kinases, by vertical disruption of vascular epithelial growth factor receptor (VEGFR) signaling, by reducing the compensatory production of VEGF in sunitinib-treated patients and also by directly inhibiting tumor cell proliferation. We conducted this phase 1 study to investigate the maximum tolerated dose (MTD) for this combination of sunitinib and sirolimus in humans.



Sunitinib was given at 50 mg daily × 28 every 6 weeks. The first cohort received sunitinib alone for cycle 1 (50 mg daily for 2 weeks followed by 2 weeks off) and received sunitinib at standard dose 50 mg daily for 4 weeks followed by 2 weeks off in combination with sirolimus 4 mg weekly; this dose and schedule were further investigated in second cohort. The third cohort received decreased dose of sunitinib at 37.5 mg daily for 4 weeks followed by 2 weeks off in combination with sirolimus at 4 mg weekly. Sirolimus dose was escalated to 8 mg weekly in fourth cohort.



Eighteen patients with ECOG PS of 0 or 1 were enrolled, median age 57 years (range 24-76), M:F ratio: 11:7. Median number of prior treatments is 2 (range 0-5); six patients had no prior systemic therapy. Half of patients from the first two cohorts required dose reduction or early discontinuation of treatment; therefore, sunitinib dose was decreased to 37.5 mg daily in third and fourth cohort. In third and fourth cohort, one-third of patients required dose modification during cycle 1 or cycle 2. Multiple patients had significant toxicities including fatigue and hand-foot syndrome. One patient developed interstitial pneumonitis, and one patient died suddenly on day 8 due to progressive disease. There were six patients who tolerated four or more cycles. Among these six patients, two patients with renal cell carcinoma (RCC) achieved partial response; one subsequently underwent surgical resection of residual renal mass and lymph node dissection and achieved complete response afterward. One with metastatic melanoma also achieved complete response after metastatectomy. There was no apparent pharmacokinetic interaction between sunitinib and sirolimus. 4 mg weekly sirolimus did not reduce the sunitinib-induced circulating VEGF production but stimulated more VEGF production through some unknown compensatory mechanism.



Toxicity precluded dose escalation of weekly sirolimus in combination with a standard sunitinib dose/schedule. These results suggest caution when combining targeted agents lacking specificity for tumor signaling or vasculature.
Department of Internal Medicine, VA Connecticut Healthcare System, VA Cancer Center, West Haven, CT, 06516, USA.|Division of Medical Oncology, Yale Cancer Center, New Haven, CT, 06511, USA.
Jia
J
Li
Division of Medical Oncology, Yale Cancer Center, New Haven, CT, 06511, USA.
Harriet
H
Kluger
Laboratory Medicine, Yale School of Medicine, New Haven, CT, 06511, USA.
Lesley
L
Devine
Division of Hematology and Oncology, University of Pittsburgh Medical Center Cancer Center, Pittsburgh, PA, 15232, USA.
James J
JJ
Lee
Division of Solid Tumor Oncology, Department of Medical Oncology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA, 19107, USA.
William Kevin
WK
Kelly
Division of Medical Oncology, Yale Cancer Center, New Haven, CT, 06511, USA.
Linda
L
Rink
Division of Hematology/Oncology, Department of Medicine, Tufts Medical Center Cancer Center, Boston, MA, 02111, USA. wsaif@tuftsmedicalcenter.org.
Muhammad Wasif
MW
Saif
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology; D011758:Pyrroles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D020123:Sirolimus / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D000077210:Sunitinib; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D042461:Vascular Endothelial Growth Factor A / Q000097:blood*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000097:blood*; D055815:Young Adult
D007211:Indoles; D011758:Pyrroles; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C546842:MTOR protein, human; C000588866:KDR protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2; D058570:TOR Serine-Threonine Kinases; D000077210:Sunitinib; D020123:Sirolimus
Phase 1; Sirolimus; Sunitinib