Ridaforolimus Research Articles

Phase 1 study of combination carboplatin, paclitaxel, and ridaforolimus in patients with solid, endometrial, and ovarian cancers.

TPS3114 Background: mTOR is a member of the PI3K family. Ridaforolimus (RIDA) is a mTOR inhibitor that has demonstrated tolerability as intravenous (IV) and oral formulations. PI3K/AKT/mTOR signall...

Abstract OT2-6-13: A randomized phase 2 study of the triplet combination of ridaforolimus (RIDA), dalotuzumab (DALO) and exemestane (EX) compared to the ridaforolimus, exemestane doublet in high proliferation, estrogen receptor positive (ER+) advanced breast cancer

Abstract Background: The clinical benefit of combination of mTOR inhibition and anti-hormonal therapy has been previously established and represents a new standard of care for patients with hormone receptor positive (HR+) advanced breast cancer (ABC). Preclinical evaluation of the mTOR pathway demonstrates that dual inhibition of IGFR and mTOR may be additive or synergistic and abrogates the feedback activation of AKT due to rapamycin analog mTOR inhibitors. A completed phase 1 study of the combination of the mTOR inhibitor, RIDA and the anti-IGFR antibody, DALO demonstrated preliminary signals of anti-tumor activity. This was further evaluated in a recently completed phase 2 study of RIDA-DALO compared to exemestane in ER+ ABC. Final safety and efficacy results from that phase 2 study will be reported at this meeting (see Baselga et al). Building upon the clinical synergies of mTOR and EX as well as the biologic relationship of the mTOR and IGFR pathways, a clinical study has been initiated to evaluate the triplet combination of RIDA-DALO-EX compared to RIDA-EX. Methods: This is a multicenter, international, randomized phase 2 study of the triplet combination of RIDA (10 mg by mouth daily for 5 out of every 7 days), DALO (10 mg/kg IV weekly), and EX (25 mg QD) compared to RIDA (30 mg by mouth daily for 5 out of every 7 days) and EX (25 mg QD) in high KI67 (≥15%) expressing ER+, ABC. Approximately 84 patients will be randomized 1:1 to either triplet or doublet therapy. Key eligibility criteria include: HR+ and HER-2 negative measurable ABC, prior therapy with a non-steroidal aromatase inhibitor, and KI67 labeling index ≥15%. The primary endpoint of the study is progression free survival (PFS). Key secondary endpoints include evaluation of percent (%) reduction from baseline in the sum of imaging measurements (target lesion diameters or volumes) at 16 weeks between the two arms, and overall response rates. The sample size is event driven with a target of 38 PFS events, which provides approximately 80% power, at 1-sided alpha of 0.1, to detect a HR of 0.5, corresponding to an approximate 100% improvement in median PFS, from 10.6 to 21.2 months. Safety parameters or adverse experiences of special interest include hyperglycemia, stomatitis, mucosal inflammation, pneumonitis and hearing loss. Accrual has been completed with results expected in May 2014. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT2-6-13.

Phase Ia/b study of combination carboplatin, paclitaxel, and ridaforolimus in patients with solid, endometrial, and ovarian cancers.

TPS3114 Background: mTOR is a member of the PI3K family. Ridaforolimus (RIDA) is a mTOR inhibitor that has demonstrated tolerability as intravenous (IV) and oral formulations. PI3K/AKT/mTOR signalling is associated with resistance to taxanes. In cancer (ca) cells, inhibition of mTOR signalling counteracts AKT-mediated resistance to drugs inhibiting tubulin. Paclitaxel and carboplatin (PC) have broad activity including endometrial, ovarian, and many cancers. mTOR inhibition with PC has synergistic and additive effects in solid tumors. A common defect in endometrioid ca is mutation of PTEN, causing activation of the PI3K/AKT/mTOR pathway. RIDA improved PFS over hormonal therapy of metastatic endometrial cancer in a randomized phase II study (Oza AM, et al. J Clin Oncol. 2011;29 [suppl; abstr 5009]). In 35 patients in a phase II study of RIDA, there were 7.7% partial response (PR) and 58% with stable disease with median duration 6.6 months (Mackay H et al. J Clin Oncol. 2011;29 [suppl; abstr 5013]). Ovarian ca ultimately develops a phenotype resistant to taxanes that may be overcome with mTOR inhibition. RIDA may therefore potentiate the response of endometrial, ovarian, and other solid cancers to PC. Methods: Patients (pts) with advanced solid ca and measureable disease and up to 3 prior therapies received P (175mg/m2 IV) and C (AUC 5 to 6 mg/ml/min IV) on day (D)1 of each 3-week cycle. RIDA in escalating cohorts of 10-40 mg is administered orally daily for 5 days per week (D1-5, D 8-12, D 15-19) in phase IA cohorts. Samples for pharmacokinetics of RIDA and P and pharmacodynamics (PD) are collected. More than 1 anticipated DLT of thrombocytopenia or neutropenia in the latter part of the cycle shifts the escalation of RIDA to an alternate schedule (D1-5, D 8-12). Escalation continues in a 3X3 design until 40 mg/day of RIDA or MTD. Seven pts have been enrolled; 5 ovarian, 1 endometrial, 1 urethral ca. The second cohort of an alternate schedule has been filled and evaluation continues. Further characterization of tolerability, efficacy, and PD are planned at the MTD in the phase IB expansion cohorts of 15 ovarian/15 endometrial cancers.

To assess the effect of ridaforolimus on the QTc interval in patients with advanced cancer.

e13088 Background: Ridaforolimus (RIDA) (AP23573; MK-8669), a unique rapamycin analog and potent inhibitor of mTOR signaling, is being developed for treatment of solid tumors. We aimed to assess the effect of a single supratherapeutic dose of 100 mg RIDA on the QTc interval in advanced cancer patients. This dose was used to achieve an exposure similar to that following the clinical dose regimen. Methods: This was a partially blind, placebo-controlled, 2-part study of RIDA in advanced cancer patients. In Part 1, 2 days of ECG were performed for QTc assessment in a fixed sequence. On Day 1, patients received a single oral dose of placebo; on Day 2 they received a single oral dose of RIDA 100 mg. Each dose was followed by 24 h of Holter ECG. Blood samples for RIDA were measured at pre- and up to 24 h postdose on Day 2. In Part 2, patients had continued access to RIDA for potential clinical benefit, with only safety data collected. Results: 23 patients (8 males; 15 females) were enrolled. For Day 1 placebo treatment, 22 patients were included in the QTcF data; for Day 2 RIDA treatment, 20 were included in the QTcF data and 21 in the pharmacokinetic data. RIDA 100 mg did not prolong the QTcF interval. Upper bound of the 90% CI of the placebo-adjusted mean QTcF interval change-from-baseline was <10 ms at every time point through 24 h. The largest placebo-corrected RIDA change from baseline QTcF occurred at 10 h postdose, mean difference 3.89 ms, 90% CI (0.60, 7.17). After placebo or 100 mg RIDA administration, only 1 patient had QTcF values >450 ms (on both placebo and RIDA) and none had values >480 ms. Neither placebo nor treatment patients had a QTcF change-from-baseline >30 ms. Exposures after single dose RIDA 100 mg were a geometric mean whole blood AUC0-24 of 1875 h·ng/mL and Cmax of 186 ng/mL, approximating steady state exposure with the clinical dose regimen of 40 mg po QD x 5 consecutive days/week. However, these values do not achieve supratherapeutic exposure. RIDA was generally well tolerated, with no patients discontinued from Part 1 due to drug-related AEs. Conclusions: A single dose of RIDA (100 mg) does not prolong the QTc interval in advanced cancer patients and achieved exposures that approximated steady state exposures at the maximally tolerated clinical dose and regimen.

The effect of hepatic insufficiency on the pharmacokinetics of ridaforolimus.

e13001 Background: Ridaforolimus (RIDA) (AP23573; MK-8669), a unique rapamycin analog and a potent inhibitor of mTOR signaling, is being developed for the treatment of solid tumors. The study aims were to assess the safety and whole blood pharmacokinetics following single 10 mg doses of RIDA in patients with moderate hepatic insufficiency (Child-Pugh [CP] score of 7-9). Methods: This was an open-label study comparing the pharmacokinetics after administration of a 10 mg single dose of RIDA to patients with moderate hepatic insufficiency (assessed by the CP scale) with healthy matched controls. Nineteen (19) males and females of non-childbearing potential were enrolled: ten (10) patients with moderate hepatic insufficiency (CP score of 7-9) and 9 healthy matched control subjects (race, age [±5 years], gender, BMI [±3.3 units]). Results: A summary of the blood pharmacokinetic parameters of RIDA administered to patients with moderate hepatic insufficiency and to healthy matched control subjects is presented below. RIDA was generally well tolerated and no patients were discontinued due to drug-related AEs. Conclusions: RIDA exposure in patients with moderate hepatic insufficiency was approximately 2-fold higher than in healthy matched controls. Since RIDA is being studied in phase III at the maximally tolerated dose of 40 mg, this finding is likely to be clinically meaningful and caution should be exercised when dosing patients with moderate hepatic insufficiency. Moderate hepatic insufficiency Healthy matched control Moderate hepatic insufficiency/ healthy matched control Pharmacokinetic parameter N# GM 95% CI N GM 95% CI GMR 90% CI AUC0-∞ † (ng/ml·hr) 10 1168 (669, 2,039) 9 589 (315, 1,100) 1.98 (1.06, 3.71) Cmax † (ng/ml) 10 53.9 (25.5, 114.2) 9 41.4 (17.8, 96.0) 1.30 (0.56, 3.03) Tmax ‡ (hr) 10 6.0 (3.0, 8.0) 9 4.0 (4.0, 8.0) Apparent t1/2 § (hr) 10 111.4 28.0 9 75.0 41.0 Abbreviations: GM, geometric mean; GMR, geometric mean ratio; CI, confidence interval. † Geometric mean computed from least squares estimate from an ANCOVA performed on the natural-log transformed values. ‡ Median [Min, Max] reported for Tmax. § Harmonic mean, jack-knife standard deviation (SD) reported for t1/2. # AN 0003 who discontinued had sufficient PK to be included in the primary analysis.

A phase II study of ridaforolimus (RIDA) and dalotuzumab (DALO) in estrogen receptor-positive (ER+) breast cancer.

TPS110 Background: Activation of the PI3K/AKT/mTOR pathway is common in breast cancer. Preclinical studies indicate that the dual inhibition of IGFR and mTOR may be additive or synergistic and abrogates the feedback activation of AKT due to rapamycin analog mTOR inhibitors. A phase I study of the mTOR inhibitor RIDA and the anti-IGFR antibody DALO demonstrated that the combination was feasible and well-tolerated at doses that were nearly those used for the two single agents and with dose limiting toxicity of stomatitis, similar to RIDA as monotherapy. A preliminary signal of anti-tumor activity, including partial responses and prolonged progression free survival, was observed in ER+ breast cancer, especially in high proliferation tumors. This observation is supported by data from tumor profiling and pre-clinical data suggesting that ER+ high proliferation breast cancer may be responsive to the RIDA-DALO combination. Methods: This is a two-part, adaptive design study intended to first test the combination of RIDA-DALO against a standard agent, exemestane, for ER+ positive breast cancer that has progressed after aromatase inhibitors. The trial is a multi-center, international, randomized study with PFS as the primary endpoint. Patients (pts) are stratified into high and low proliferation strata based on baseline Ki67, and the low proliferation stratum is capped to ensure adequate enrollment of high proliferation pts. If Part A shows a PFS benefit for RIDA-DALO, Part B is intended to show the PFS benefit of the combination over the single agents by comparing RIDA-DALO to RIDA and DALO. Part B will be further adapted based on whether the PFS benefit in Part A is observed in all-comers or the high proliferation subset. Tumor tissue is collected for molecular profiling and analysis of intrinsic subtype, with an efficacy analysis based on classification of tumors using the genomic grade index (GGI) as an exploratory objective. This trial design is intended to establish proof of concept that RIDA-DALO can prolong PFS in ER+ breast cancer in all-comers or a high proliferation subset by Ki67, while efficiently addressing the development of two investigational agents in combination and leading to a two-arm phase III design.

A phase I study of the oral mTOR inhibitor ridaforolimus (RIDA) in combination with the IGF-1R antibody dalotozumab (DALO) in patients (pts) with advanced solid tumors.

3008 Background: RIDA is a non-prodrug rapamycin analog mTOR inhibitor, and DALO is a humanized monoclonal antibody targeting the IGF-1R receptor. In preclinical models, dual mTOR/IGF1-R inhibition results in synergistic antitumor activity and inhibits feedback AKT activation due to TORC1 inhibition by rapamycin analogs. Methods: Pts with advanced cancers who failed standard therapy received RIDA at escalating doses of 10-40 mg/day QD×5/week combined with DALO at 10 mg/kg/week or 7.5 mg/kg every other week. RIDA was administered for one week prior to starting DALO to enable PK/PD assessment with and without DALO. PD parameters were assessed from PBMCs, skin biopsies, and tumor biopsies. Two dose levels were expanded to determine the optimal dose for future study. Results: 62 pts have been enrolled. During dose escalation, only one pt experienced a DLT (prolonged G2 stomatitis at dose level 1). RIDA 40 mg plus DALO 10 mg/kg/week (recommended doses for RIDA and DALO as single agents) was declared MTD. In an expansion cohort at the declared MTD, 4 DLTs were observed in 9 DLT-evaluable patients (G3 stomatitis, 3 pts; G3 fatigue, 1 pt) and cumulatively 4 of 15 (27%) pts at the declared MTD had DLTs. A 2nd expansion cohort at the next lower dose level (RIDA 30 mg plus DALO 10 mg/kg/week) is being evaluated, and there was 1 DLT in 17 DLT-evaluable pts so far. The most frequent treatment-related adverse events included stomatitis, fatigue, and hyperglycemia, mostly grade 1-2. Efficacy signals included 3 confirmed PRs (2 breast cancer [BCa], 1 parotid adenocarcinoma), 2 partial metabolic responses (PMRs) on FDG-PET scan (2 BCa), 2 prolonged SD > 6 months (1 BCa and 1 endometrial ca), and 3 pts with ≥50% decline in CA-125 (2 ovarian and 1 endometrial Ca). Of 23 BCa pts enrolled by December 1, 5 pts had efficacy signals (2 PRs, 1 SD for 9 months, and 2 PMRs); all 5 pts were ER+, and 4 had high Ki67 breast tumors. PK/PD assessments are currently underway and will be presented at the meeting. Conclusions: The combination of ridaforolimus and dalotuzumab is tolerable and has promising antitumor activity in heavily pretreated advanced cancer, particularly in ER+/high proliferation breast cancer. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Merck Merck Merck Merck, Novartis