Background
Because mammalian target of rapamycin (mTOR) inhibitors target the downstream effects of the PI3K/AKT/PTEN-related pathways, this class of drugs has broad antiproliferative activity [
1]. Ridaforolimus (deforolimus; AP23573; MK 8669, AP 23573), a potent mTOR inhibitor with an IC
50 in the nanomolar range, appears to be well tolerated in both intravenous and oral formulations as either a single agent or in combination with other chemotherapy agents [
2]. In preclinical studies, ridaforolimus demonstrated antitumor activity against a broad range of human cancer cell lines in vitro and tumor xenograft models in vivo [
3‐
6]. In phase I and II clinical trials, ridaforolimus displayed activity in various cancers, including sarcoma and hematologic malignancies [
7‐
10]. In a phase III trial of patients with advanced sarcoma, single-agent ridaforolimus treatment (40 mg orally, once daily for 5 consecutive days every week) resulted in a statistically significant improvement in progression-free survival compared with placebo [
11]. Ridaforolimus has shown additive or synergistic activity when combined with other single agents, such as paclitaxel, carboplatin, cisplatin, doxorubicin, imatinib, and trastuzumab [
12,
13]. Therefore, combining chemotherapy regimens with an mTOR inhibitor with a different mechanism of action and reasonable toxicity may provide an advantageous clinical approach.
The combination of paclitaxel and carboplatin is one of the most commonly used chemotherapeutic combinations in cancer treatment, including head and neck cancer, advanced-stage non-small cell lung cancer, endometrial cancer, ovarian cancer, and others. Oral ridaforolimus has shown equivalent effectiveness comparable to the intravenous form [
14]. Therefore, the potential benefit of a convenient oral dosing with paclitaxel plus carboplatin warranted investigation. In this phase I study, our aim was to determine the maximal tolerated dose (MTD) and the recommended phase 2 dose and schedule of oral ridaforolimus in combination with paclitaxel and carboplatin in patients with solid tumor cancers and to describe the safety and tolerability of this combination.
Methods
Study eligibility
Patients ≥18 years of age with solid tumor cancers not deemed curable by other therapies and who had measurable disease by Response Evaluation Criteria in Solid Tumor (RECIST) 1.1 or evaluable disease were eligible. Other eligibility criteria included Eastern Cooperative Oncology Group performance status of 0, 1, or 2; a life expectancy of at least 60 days; adequate bone marrow function, renal function, hepatic function, and neurologic function; serum cholesterol ≤350 mg/dL and triglyceride ≤400 mg/dL; and full recovery to baseline from acute toxicities of all prior chemotherapy regimens. Patients may have had up to 3 (0–3) prior cytotoxic chemotherapeutic regimens including prior treatment with carboplatin and paclitaxel (patients who had regimens switched for toxicity rather than progression, used for radiation sensitization only, or hormonal only were not eligible). No chemotherapy, radiotherapy, biologic, hormonal, or investigational drug therapy within 28 days before start of study treatment was permitted. Patients were excluded if they had any upper gastrointestinal illness that would impair swallowing or absorption of oral medication, any intercurrent illness, were known to have human immunodeficiency virus or AIDS, had received prior therapy with an mTOR inhibitor, or had concomitant treatment with inhibitors or inducers of cytochrome P450-3A. The study protocol was approved by the University of South Florida Institutional Review Board. All patients provided written informed consent before study participation.
Study design and treatment
Patients received oral ridaforolimus daily on days 2–5, days 8–12, and days 15–19 during the first cycle of therapy and then 5 days a week (days 1–5, days 8–12, and days 15–19) throughout the remainder of therapy beginning with the second cycle of therapy. Oral ridaforolimus was administered in combination with day 1 intravenous paclitaxel (175 mg/m2) and carboplatin (AUC = 5–6 mg/mL/min) every 3 weeks, except for the first cycle of therapy where day 1 ridaforolimus was skipped to allow for blood samples to be collected day 1 of the first 2 cycles. These were held for potential PK analyses if specific drug and temporally related toxicities were noted. All patients received steroids, antiemetics, and antihistamines before the administration of paclitaxel and carboplatin. All patients were expected to continue study treatment in the absence of disease progression, complete response, unacceptable toxicity, or voluntary choice to withdraw participation. A 3 + 3 dose escalation design was used, with ridaforolimus dose levels of 10, 20, 30, and 40 mg orally in combination with intravenous paclitaxel and carboplatin based on a predefined dose escalation scheme. Carboplatin was dosed at an AUC of 5, with a planned escalation to an AUC of 6 mg/mL/min based on dose level cohort.
The maximal tolerated dose was defined as the highest dose at which no more than 1 of 6 evaluable patients experienced a dose-limiting toxicity (DLT) due to the combination of ridaforolimus, paclitaxel, and carboplatin during the first cycle of treatment. A patient who did not complete the first cycle of treatment for reasons other than a DLT was replaced. DLT was defined as ≥ grade 3 non-hematologic toxicity (specifically, rash, mucositis, pneumonitis) with the exceptions of fatigue, hypersensitivity reaction, nausea, and vomiting; ≥ grade 3 thrombocytopenia requiring platelet transfusion; grade 4 thrombocytopenia or neutropenia >7 days duration; any grade 4 neutropenic fever requiring hospitalization; unresolved toxicity resulting in delay of retreatment >2 weeks; grade 3 or 4 non-surgical hemorrhages; and failure of administration of ridaforolimus for 5 days or more (consecutive or nonconsecutive) due to any toxicity. Growth factor support was not allowed prophylactically for cycle 1 but could be subsequently used based on investigator discretion.
A modification of the schedule that changed ridaforolimus administration to the first 2 weeks (days 1–5, days 8–12) versus all 3 weeks (days 1–5, days 8–12, days 15–18) of a cycle was predefined for 2 DLTs in a cohort that resulted from thrombocytopenia or neutropenia in the latter part of the cycle. The dose of ridaforolimus remained the same as the maximum achieved level in the prior cohort at which the DLTs were experienced. Dose escalation was to continue at each subsequent cohort until a maximum of 40 mg/day (days 1–5, days 8–12) of ridaforolimus was reached. Subsequent treatment cycles would not begin until absolute neutrophil count reached ≥1500 cells/mm3 and platelet count reached ≥75,000/mm3; mucositis, nausea, and vomiting were grade 1 or less; and bilirubin was ≤1.5 x institutional upper limit of normal. All drugs were held during the recovery period. Therapy was delayed for a maximum of 2 weeks until these values were achieved. Patients who failed to recover adequate counts within a 2-week delay were removed from study. Adverse events were graded according to the Common Terminology Criteria for Adverse Events version 4.0.
Efficacy and safety assessments
Patients were evaluated at baseline and before each subsequent treatment cycle to assess Eastern Cooperative Oncology Group performance status, vital signs, and adverse events. Hematologic and clinical chemistry assessments, including cholesterol, triglyceride, and glucose levels, were performed at baseline and at each treatment cycle. Tumor assessment by RECIST v1.1 was performed at baseline and every 2 cycles thereafter. Patients were required to have completed a minimum of 2 cycles of therapy to be evaluable for efficacy.
Discussion
This phase I study of ridaforolimus combined with paclitaxel and carboplatin demonstrated tolerability at the defined maximal tolerated dose using doses of the 3 agents considered active in patients with solid tumor cancers. Treatment with ridaforolimus showed toxicities that were expected from its known profile. Mouth sores, rash, fatigue, stomatitis, and hypertriglyceridemia have been most prevalent in phase I and II clinical trials with ridaforolimus as a single agent, with incident rates ranging from 31% to 48% [
7,
9]. Previous phase I and II studies have explored combinations of ridaforolimus with capecitabine [
15], weekly paclitaxel [
16], bevacizumab [
16,
17], dalotuzumab [
18,
19], and traztuzumab [
20] and have demonstrated tolerability. Doses of up to 40 mg ridaforolimus once daily as a single agent for 5 consecutive days with 2 days rest each week have been shown to be tolerable in patients with metastatic or advanced solid tumors [
14,
20]. When weekly intravenous ridaforolimus was combined with weekly paclitaxel, 2 recommended doses were determined: 37.5 mg ridaforolimus +60 mg/m
2 paclitaxel and 12.5 mg ridaforolimus +80 mg/m
2 paclitaxel [
16]. At these recommended doses, a DLT of mucositis was observed, with grade 3/4 neutropenia shown in 14% to 37.5% of the cohorts. In our study, hematologic adverse events were somewhat more prominent, likely because of the nature of combination with two cytotoxic chemotherapies. Non-hematologic adverse events shown in our study were similar to other trials with single-agent ridaforolimus. We had anticipated that the use of these three agents together would have greater potential for bone marrow suppression, namely neutropenia and thrombocytopenia. Therefore, we had preplanned an alternate dosing schedule that shortened the administration of ridaforolimus to 2 weeks (10 days) instead of 3 weeks (15 days). Indeed, the two DLTs of grade 4 neutropenia were observed at the starting dose level of 10 mg ridaforolimus (days 1–5, days 8–12, and days 15–18) combined with paclitaxel (175 mg/m
2) and carboplatin (AUC = 5 mg/mL/min). An alternate dosing cohort (dose level 1A; days 1–5 and days 8–12) was initiated at the same dose of ridaforolimus as the first cohort. This alternate dosing cohort (2 weeks on and 1 week off) was feasible for repeated cycles. This is similar to the results of the weekly paclitaxel study above in that patients had to switch from intravenous ridaforolimus in the latter part of the cycle (days 8 and 15) to earlier in the cycle (days 1 and 8) [
16]. It appears that this earlier cycle dosing is sometimes necessary to allow sufficient marrow recovery when combined with cytotoxic chemotherapy.
Ridaforolimus has activity in cancer, particularly in disease stabilization in various tumor types. In a phase III trial of 702 patients with advanced metastatic sarcoma who had attained benefit with prior chemotherapy, administration of oral ridaforolimus as maintenance therapy resulted in a statistically significant improvement of 3.1 weeks in progression-free survival compared with placebo (hazard ratio of 0.72; 95% confidence interval, 0.61–0.85;
P = 0.001) [
11]. Various mTOR inhibitors, including everolimus (RA001), temsirolimus (CCI779), and ridaforolimus (AP2357), either as a single agent or combined with other chemotherapeutic or hormonal agents have been evaluated in patients with advanced or recurrent endometrial cancer with promising results [
21‐
26]. Mutations or loss of function in PTEN (phosphatase and tensin homolog) plays a significant role in the pathogenesis of endometrial cancer. Downstream activation of the PI3K/AKT/mTOR signaling pathway triggered by the loss of function of PTEN suggests a therapeutic role of the mTOR inhibition. Paclitaxel plus carboplatin is a widely used regimen for this cancer; therefore, it would be of interest to study this combination with ridaforolimus at our recommended phase II dose and schedule in this disease. We also noted interesting activity in patients with cervical and vaginal cancer in our study. Among 3 patients with cervical cancer (1 with adenocarcinoma, 1 with squamous cell carcinoma) and 1 patient with vaginal cancer (squamous cell carcinoma), there were a total 29 cycles of treatment with 1 stable disease and 3 partial responses.
In a preclinical study, Molinolo et al. demonstrated that mTOR pathway activation was shown in most human papillomavirus-positive head and neck squamous cell carcinoma and cervical cancer squamous cell carcinoma tumor xenografts. mTOR inhibitors (rapamycin and everolimus) effectively decreased mTOR activity in vivo and caused a remarkable decrease in tumor burden (
P < 0.001) [
27]. In a phase II study of temsirolimus in patients with recurrent or metastatic cervical cancer, among 33 evaluable patients, 1 patient (3.0%) had a partial response and 19 patients (57.6%) had stable disease with a duration of 6.5 months [
28]. There are trials in head and neck squamous cell carcinoma with rapamycin therapy and adding everolimus to definitive chemoradiation treatment in patients with locally advanced cervical cancer. Paclitaxel combined with carboplatin is also a regimen used for the treatment of these cancers; therefore, the addition of ridaforolimus to this combination may be considered for further study, perhaps with or without bevacizumab [
29]. In our study, the combination of oral ridaforolimus with intravenous paclitaxel and carboplatin had no unanticipated toxicities with antitumor activity in patients with solid tumor cancers. Given the broad activity and use of paclitaxel and carboplatin in many tumor types, there is potential to explore this triplet therapy in multiple tumors in which mTOR inhibition may be relevant.
Acknowledgements
We thank Rasa Hamilton (Moffitt Cancer Center) for editorial assistance.
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