Presenter: Mita M.M. Presenter's Affiliation: University of Texas Health and Science Center, San Antonio Type of Session: Scientific
Prior studies have validated mTOR as a target in cancer therapy.
mTOR is a downstream target of the PI3K/Akt pathway and mTOR has effects both downstream and upstream of Akt. Hence mTOR not only responds to Akt signaling but also regulates Akt activity. This relationship is complex and still under investigation.
Various cancer cell lines have been treated with mTOR and there have been variable effect seen, depending on the cell line. This variability in effect is likely due to the complex upstream and downstream effects that mTOR has on the Akt pathway. Mutations in the PI3K/Akt pathway likely affect how well mTOR inhibitors work in a given cell line.
Deforolimus is a non-prodrug rapamycin analogue which is a potent inhibitor of mTOR and is available in an IV and an oral form.
Prior studies have investigated the maximum tolerated dose (MTD) of the IV formulation of Deforolimus (Trial 202, Journal of Clinical Oncology, 2006).
A Phase I (Mita MM, Journal of Clinical Oncology, 2008) study found that the MTD of IV Deforolimus was 75 mg for weekly dosing and was 18.75 mg/ for daily dosing (5 day a week dosing).
A Phase II (Rizzieri DA, Clinical Cancer Research 2008) study of IV Deforolimus demonstrated a 29% clinical benefit rate (CBR; defined as the sum of the partial and complete responders plus those with stable disease for 16 weeks) in sarcomas, a 9% CBR in endometrial cancer and a 10% CBR in hematologic malignancies. All of these patients were treated with 5 day a week dosing.
The present study examines the MTD of oral Deforolimus. There are several benefits to oral dosing. Oral Deforolimus would allow easier dosing for patients, more flexibility with dosing and the potential to treat patients in the maintenance setting.
Materials and Methods
The present study is a single arm, open label, dose escalation study with a standard 3 x 3 design.
Seven regimens all of which were given over a 28 day cycle were investigated.
Inclusion and exclusion criteria were as follows:
Patients had to have advanced/metastatic solid tumors which were refractory to chemotherapy
Age greater than 18 years
ECOG performance status of 0-2
Adequate renal, liver and bone marrow function
No CNS metastasis, no prior mTOR based treatments
At least 4 weeks since the last treatment.
Dose limiting toxicity (DLT) was defined as any grade 3 or 4 toxicity that persistent for three or more days based on common toxicity criteria (CTC).
Anti-tumor effect was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) criteria.
In the present study, patients who had stable disease for at least 4 cycles of 28 day chemotherapy were considered to have a clinical benefit response (CBR).
A total of 147 patients were enrolled in the present study:
Median age: 56 years (range 23-84)
65 of the patients were male
89% had ECOG performance status 0-1, median score was 1 (range 0-2)
113 patients had 2 or more courses of prior chemotherapy (range 0-7)
113 patients had documented progression of disease.
57% of patients had sarcomas, 6.1% had breast cancer, 6.1% had colorectal cancer, and 5% had renal cancer, with the remainder made up of various other cancers.
Ultimately, of the seven treatment regimens, the daily dose of 40 mg, five days a week, was found to be the MTD (24 patients on this arm).
The predominant dose limiting toxicity (DLT) was mucositis (apthous-ulcer like mouth sores) in all seven treatment regimens, and this was reversible with dose reduction or symptomatic therapy.
MTD was increased by a one-week holiday
Toxicity was as follows:
Grade 3-4 (5 day dosing)
5 day dosing
Grade 3-4 (All)
Pharmacodynamics was also studied by assaying for 4E binging protein (4E-BP1) phosphorylation in Peripheral Blood Mononuclear Cell (PBMC) (4E-BP1 is a downstream target of mTOR). Western blot analysis demonstrated that 4E-BP-1 phosphorylation decreased in PBMC as early as four hours after treatment with Deforolimus.
The greatest response to therapy was seen in sarcomas in which there were two partial responses (of 24 patients) in the 40 mg daily arm. CBR was 27% in patients with sarcoma, with a progression-free survival of 30% at 6 months and an overall survival of 30% at 6 months.
The present study was a comprehensive examination of Deforolimus MDT with examinations of the pharmacokinetics and dynamics of the drug.
Ultimately, the 40 mg daily dosing of Deforolimus given 5 days a week (weekly) for 28 days was found to be the MTD.
Deforolimus appears to be safe with a toxicity profile consistent with IV dosing of Deforolimus.
The pharmacokinetics and pharmacodynamics of the oral version of Deforolimus are similar to the IV formulation.
A dose holiday increased the total cumulative dose of Deforolimus that could be given.
The 40 mg/day dose of Deforolimus, given 5 days a week for 28 days, has been selected for the SUCCEED trial, a global phase III trial of patients with metastatic soft tissue and bone sarcomas in the maintenance setting.
mTOR is part of the PI3K/Akt pathway and is downstream from a variety of receptors, including the IGF-R, EGF-R, PDGF-R, VEGF-R, as well as the c-kit pathway. Increased activity of mTOR can be seen with increase in receptor ligand, increase in receptor expression, or mutation in the receptor where there is a gain of function mutation resulting in constitutive activity. Additionally, mutations in PTEN which down-regulates the PI3K/Akt pathway or mutations which activate the PI3K/Akt pathway can also increase mTOR activity.
Prior studies have demonstrated that mTOR inhibitors are effective in renal cell carcinoma and can increase overall survival. There have also been a number of studies presented in abstract form at ASCO which have demonstrated efficacy of mTOR inhibitors in patients with refractory sarcomas. As there are more data becoming available which demonstrates the efficacy of mTOR inhibitors in cancer treatment, more questions have arisen about the optimal inhibitor to use and the dose which should be used. All of the currently used mTOR inhibitors function via the same mechanism, by binding to FKBP-12 and subsequently binding to and inhibiting mTOR. There may not be a huge difference between these compounds as they function in similar ways, but comparative trials of these various agents are needed.
The optimal dosing of these agents also remains to be determined. It is unclear as to whether the MTD of a drug or the optimal biological dose (a dose which appears to have equal efficacy by pharmacokinetic and dynamic studies, but which has less toxicity) should be used. We are able to measure the level of inhibition of downstream targets of mTOR in the blood, but does this reflect the tumoral dose of the drug? Preclinical models suggest that the level of inhibition of downstream targets of mTOR correlates with antitumoral effect but does this correlate in humans as well? At present, most of the studies which have examined these questions have been underpowered, but there has been some data which suggests that higher doses may be of benefit. Therefore until we can define optimal dosing, the MTD should remain the standard for dosing patients on mTOR inhibitors.
Nov 2, 2010 - Most recent oncology randomized controlled trials evaluate drugs that are available "off-protocol therapy" in the United States, and this can adversely impact trial enrollment, according to a study published online Oct. 25 in the Journal of Clinical Oncology.