Novel taxanes

Novel formulations of paclitaxel have been introduced in to clinical care, including both ABI-007 (Abraxane), CT-2103 (Xytotax), and Cabazitaxel (Jevtana), which is a novel taxane characterized by decreased propensity for P -glycoprotein–mediated drug resistance.

ABI-007 (Abraxane) is an albumin-bound paclitaxel that is solvent free, reversibly binds paclitaxel, transports it across the endothelial cell, and concentrates in the vicinity of the neoplasm. This agent can be administered without the common predications. Preclinical data have suggested that this agent achieves higher antitumor activity and higher intracellular concentrations of active drug when compared with paclitaxel. ABI-007 was compared with polyethylated castor oil-based standard paclitaxel in patients with metastatic breast cancer. Patients (n = 454) were randomized to either ABI-007 260 mg/m ² or paclitaxel 175 mg/m ² . Significantly higher response rates and longer time to tumor progression were reported with ABI-007 (23.0 vs 16.9 weeks, respectively; hazard ratio [HR] = 0.75; P = .006). Grade 3 sensory neuropathy was more common in the ABI-007 arm than in the standard paclitaxel arm. No hypersensitivity reactions occurred with ABI-007 despite the absence of premedication and shorter administration time. A randomized phase II study compared ABI-007 administered triweekly and weekly with triweekly docetaxel as first-line treatment of metastatic breast cancer. A total of 302 patients were randomized to either 300 mg/m ² of ABI-007 every 3 weeks, 100 mg/m ² weekly for 3 of 4 weeks, 150 mg/m ² weekly for 3 of 4 weeks, or docetaxel 100 mg/m ² every 3 weeks. The investigators reported that ABI-007, regardless of dose, showed a greater overall response rate than docetaxel. This agent has been further explored in other disciplines such as gynecologic malignancies. Coleman and colleagues reported a phase II evaluation of ABI-007 in the treatment of recurrent or persistent platinum-resistant ovarian, fallopian tube, or primary peritoneal cancer. Eligible patients were defined by persistent or progressive disease after primary chemotherapy or recurrence within 6 months of treatment completion. Treatment consisted of ABI-007 100 mg/m ² days 1, 8, and 15 on a 28-day schedule. Of the 47 evaluable patients, the investigators reported 1 complete and 10 partial responses (23%), whereas 17 patients (36%) had stable disease. The median progression-free survival (PFS) was 4.5 months (95% confidence interval [CI]: 2.2–6.7), whereas the overall survival (OS) was 17.4 months (95% CI: 13.2–20.8). Seventeen patients (36%) had PFS greater than 6 months.

CT-2103 (Xyotax) (paclitaxel poliglumex [PPX]), is a conjugate of α-poly- l -glutamic acid and paclitaxel. Like ABI-007, this macromolecular drug conjugate eliminates the need for Cremophor. PPX has been studied in recurrent or persistent ovarian or primary peritoneal cancer. In one phase II study, patients received PPX at 235 mg/m ² every 21 days or 175 mg/m ² . The investigators reported that 16% and 41% of patients had a partial response or experienced stable disease, respectively. The median PFS was 2.8 months (95% CI 1.48–4.8 months) and median OS was 15.4 months. The most frequent grade 3 or 4 toxicities were neutropenia, constitutional symptoms, gastrointestinal symptoms, and neuropathy. This agent is being explored as maintenance therapy in ovarian cancer (clinical trial GOG 212).

In a phase II study conducted by Lin and colleagues, an unexpected incidence of hypersensitivity reactions was noted with CT-2103 in patients with metastatic breast cancer. The investigators reported that CT-2103 had activity in this small study (response rate of 17%); however, neurotoxicity and hypersensitivity reactions were more frequent in this patient population than expected, and led to early termination of the trial. Grade 3 or 4 hypersensitivity reactions were observed in 4 patients; none occurred before cycle 4 of therapy. Given the delayed incidence of hypersensitivity reactions, it was suggested that these reactions were a true drug allergy, distinct from the hypersensitivity reactions seen with standard paclitaxel. Cabazitaxel (Jevtana) is a new taxane characterized by a favorable pharmacokinetic profile and a decreased propensity for P -glycoprotein–mediated drug resistance. In June 2010, it was approved for the management of metastatic hormone-resistant prostate cancer. The approval of cabazitaxel was based primarily on the TROPIC (Treatment of Hormone-Refractory Metastatic Prostate Cancer Previously Treated with a Taxotere-Containing Regimen) trial. De Bono and colleagues reported the results of a phase III trial in patients with metastatic castration-resistant prostate cancer who had received previous hormone therapy, but whose disease had progressed during or after treatment with a docetaxel-containing regimen. Patients received prednisone daily, and were randomly assigned to receive either 12 mg/m ² mitoxantrone or 25 mg/m ² cabazitaxel every 3 weeks. The primary end point was OS. Secondary end points included PFS and safety. The investigators reported that the median survival was 15.1 months (95% CI 14.1–16.3) in the cabazitaxel group and 12.7 months (11.6–13.7) in the mitoxantrone group. The HR for death of men treated with cabazitaxel compared with those taking mitoxantrone was 0.70 (95% CI 0.59–0.83, P< .0001). Median PFS was 2.8 months (95% CI 2.4–3.0) in the cabazitaxel group and 1.4 months (1.4–1.7) in the mitoxantrone group (HR 0.74, 0.64–0.86, P< .0001). The most common clinically significant grade 3 or higher adverse events were neutropenia, febrile neutropenia, and gastrointestinal events. This agent has provided a new avenue for patients with advanced prostate cancer.

Vinca alkaloids

The vinca alkaloids are agents classified as destabilizing agents that cause microtubule polymerization, suppress treadmilling/dynamic instability, inhibit mitosis, and result in apoptosis. Vinca alkaloids have a well-established role both in solid and hematological malignancies. Vincristine is well established as a therapeutic agent in the treatment of leukemias, lymphomas, and sarcomas. Vinblastine is an integral agent in the management of patients with testicular cancer Hodgkin disease and lymphoma, whereas vinorelbine is used in the management of nonsmall cell lung cancer. Although vinorelbine was never approved for the management of patients with breast cancer, there is significant activity as a single agent as well as in combination with trastuzumab. Vindesine is being explored as a potential option in the management of acute lymphocytic leukemia.

Vinflunine

Vinflunine is a novel vinca alkaloid that destabilizes microtubules and decreases microtubule growth rate. Studies have reported a differential affinity for tubulin, a superior in vivo activity when compared with other vinca alkaloids, and a slow rate of resistance. This agent is water soluble, thereby obviating solvent vehicles.

Clinical studies have focused on transitional cell carcinoma of the genitourinary tract, nonsmall cell lung cancer, and mesothelioma. A dosing regimen of vinflunine of 280 to 350 mg/m ² intravenously once every 21 days has been used in most trials. Neutropenia was the prominent toxicity observed in most studies. A phase II trial in breast cancer yielded encouraging results in that 18 of 60 patients experienced an objective response. This agent has also been combined with trastuzumab and has yielded responses: 8 of 17 patients experienced a partial response. The adverse side effects of this agent include neutropenia, fatigue, and constipation.

Combretastatin

Combretastatins were originally isolated Pettit and colleagues from the root bark of the Combretum caffrum tree have been shown to target the microtubule, inhibiting the polymerization of tubulin to microtubules. These agents show potent antineoplastic activity by inhibiting cell progression at mitosis and initiating apoptosis. Combretastatin A4 phosphate (CA4P) is a simple derivative of the natural product that was prepared to increase water solubility. CA4P has also been shown to be a vascular-disrupting agent. CA4P is in clinical trials for treatment of cervical, colorectal, nonsmall cell lung, prostate, ovarian, and thyroid cancers.

Panzem

Matei and colleagues studied the role of 2-methoxyestradiol (Panzem), a metabolite of estradiol that destabilizes microtubules and exerts antiangiogenic properties, in eligible patients with ovarian cancer. The primary end point was ORR. Eighteen patients were enrolled. The most common adverse events were fatigue, nausea, diarrhea, neuropathy, edema, and dyspnea (most being grade 1–2). There were no objective responses, but 7 patients had stable disease. Of those 7 patients, 2 patients had stable disease for greater than 12 months. The rate of clinical benefit was 31%. This agent has also been explored in neuroendocrine tumors and prostate cancer.

Maytansine analogues

Maytansine and its analogues (maytansinoids) are potent microtubule-targeted compounds that bind to tubulin at the vinca-binding site. Similar to vinca alkaloids, maytansine can depolymerize microtubules and arrest cells in mitosis. Maytansine shows greater cytotoxicity in cells than the vinca alkaloids; however, a limiting factor in the use of these agents is their narrow therapeutic window because of neurotoxicity and gastrointestinal effects. An attractive approach involving vectorization of microtubule-binding agents to the tumor cell using a monoclonal antibody has reintroduced these agents into clinical practice. Trials of trastuzumab-DM1 (T-DM1), a maytansinoid conjugated to the human epidermal growth factor receptor 2-specific therapeutic antibody trastuzumab, showed impressive efficacy in heavily pretreated patients with metastatic breast cancer. Phase I and phase II clinical trials of T-DM1 as a single agent and in combination with paclitaxel, docetaxel, and pertuzumab have shown clinical activity and a favorable safety profile in patients with HER2-positive metastatic breast cancer. Two randomized phase III trials of T-DM1 are recruiting patients: EMILIA (Open-Label Study of Trastuzumab Emtansine (T-DM1) vs Capecitabine+Lapatinib in Patients With HER2-Positive Locally Advanced or Metastatic Breast Cancer) is evaluating T-DM1 compared with lapatinib plus capecitabine, and MARIANNE (Study of Trastuzumab Emtansine [T-DM1] Plus Pertuzumab/Pertuzumab Placebo Versus Trastuzumab [Herceptin] Plus a Taxane in Patients With Metastatic Breast Cancer) is evaluating T-DM1 plus placebo versus T-DM1 plus pertuzumab versus trastuzumab plus a taxane.

AK inhibitors

Aurora A and B are serine/threonine kinases essential for the formation of normal mitotic spindles and function of centrosomes. Aurora A has been suggested to be an oncogene, but recent data suggest that although aurora A kinase amplification and overexpression are not sufficient to induce transformation, it creates the environment by which other cellular changes and genetic alterations occur to complete oncoplastic transformation. In addition to their roles in mitosis, aurora A and B are known to interact with other cellular processes important in oncogenesis, including those involving NF-κ-B, p53, and N-myc. They are also frequently overexpressed in human tumors and hence have been identified for further development in cancer treatment. Inhibition of AK has been shown to result in inappropriate chromosomal segregation, believed to be the result of effects on spindle assembly. Depletion of aurora A in vitro causes G2-M arrest, which results in apoptosis. Aurora B kinase plays an important role in mitosis and functions in both chromosome attachment and orientation. It is part of a chromosome passenger complex that includes inner centromere protein, borealin, and surviving.

Alisertib is an orally active AK inhibitor that preferentially inhibits aurora A kinase. It is a potent inhibitor of cell division in vitro and shows growth inhibition in tumor xenografts using both solid malignancy and lymphoma models. In 1 phase I trial, 61 patients were treated in 16 different cohorts evaluating daily dosing (7 days on/14 days off), divided dosing (4 times a day for 7 days followed by 14 days off), and divided dosing with the addition of methylphenidate or modafinil. Most patients treated were men with a median age of 60 years. The most common malignancies were colorectal, lung, genitourinary, and sarcoma. Seventy-nine percent had received 3 or more previous treatment regimens. The major dose-limiting toxicity (DLT) was neurocognitive changes and somnolence, which was grade 3 in 18%. It was otherwise well tolerated up to 60 mg/d in divided doses. Dose escalation was otherwise halted because of somnolence, which persisted despite psychostimulants. No responses were seen, but 9 patients had stable disease for at least 4 cycles. In a second phase I study of 43 patients, dose escalation using intermittent dosing in a 28-day cycle was conducted. The DLTs consisted of somnolence and transaminitis; however, it was deemed that treatment of 10 to 14 days of a 28-day cycle was feasible. MTD was established at 70 mg/d administered in 4 divided doses for 14 days of a 28-day cycle. Again, no clinical responses were observed.

MK-0457 was evaluated in a phase I study evaluating a 5-day continuous infusion schedule (doses 0.5–12 mg/m ² /h were tested). A total of 16 patients participated in this trial and DLT (neutropenia) was observed at the 12 mg/m ² /h dose level. Three of 16 patients had stable disease.

MLN8237 is another AK A inhibitor that is available orally. It underwent phase I testing as a once-daily dose administered 7 of 21 days, with doses ranging from 5 to 150 mg/d tested. The MTD was reached at 150 mg/d and consisted of neutropenia, mucositis, and somnolence. No responses were recorded, although 5 patients achieved disease stability. It continues in clinical trials as a single agent and with chemotherapy.

The selective AK B inhibitor barasetib (AZD1152) was evaluated at 2 different dosing schedules in advanced solid tumors in a European study that recruited 59 patients. MTD was set at 200 mg when used as a 2-hour infusion weekly and at 450 mg when dosed every 2 weeks. The DLT was the same in both schedules and consisted of neutropenia, which occurred in 58% of patients. Although no responses were recorded, 25% achieved stable disease. Another phase I to II study was performed in newly diagnosed or relapsed acute myelogenous leukemia (AML). The MTD determined in the phase I setting was 1200 mg, dosed as a continuous infusion for 7 days of a 21-day cycle. The overall hematologic response rate was 25%, with toxicity consisting of stomatitis as the primary DLT. The response rate was similar to that achieved in a Japanese phase I study in which a 19% response rate was noted in a population with advanced AML, although in this more advanced population the predominant toxicity was neutropenia.

Danusertib (PHA-739,358) is an intravenous pan-AK inhibitor that underwent phase I evaluation in solid tumors using a 24-hour infusion schedule every 14 days. Fifty-six patients were enrolled, with febrile neutropenia established as the DLT. The recommended phase II dose was established at 750 mg/m ² , with granulocyte colony-stimulating factor recommended. Two responses were seen in this phase I study: a patient with lung cancer had an objective response that lasted for 23 weeks and a patient with recurrent ovarian cancer had a 27% reduction in tumor dimensions and a 30% decline in her cancer antigen 125. A second phase I study in Europe evaluated danusertib on a weekly schedule (3 weeks on/1 week off). Fifty-six patients underwent evaluation and, again, neutropenia proved to be dose-limiting. The MTD was established at 330 mg/m ² when infused over 6 hours. Although no responses were recorded, 24% had stable disease and 5 patients remained progression free at 6 months. Danusertib continues in clinical evaluation, particularly in imatinib-resistant chronic myelogenous leukemia (CML) based on the finding that it inhibits the multidrug-resistant T315I mutant of Bcr-Abl, which is responsible for 25% or more of CML resistance to imatinib.

Other agents in this class include AS703569, SNS-314, and AMG-900. Early clinical trials are ongoing, with no results yet published.

PLK inhibitors

PLKs are serine/threonine kinases that are also involved in checkpoint regulation in mitosis. As with the AKs, they are highly upregulated in human malignancies. Depletion of PLKs in cancer cells results in decreased cell proliferation and viability by interruption of the spindle assembly, resulting in prolonged mitotic arrest and eventual apoptosis. A summary of published clinical trials involving this class is discussed.

GSK461364 is a competitive inhibitor of Plk-1. Forty patients were enrolled in a phase I study of this agent that evaluated 2 different schedules: 3 weeks on/1 week off and a semicontinuous 28-day cycle (days 1, 2, 8, 9, 15, and 16). The DLTs were grade 4 neutropenia, grade 3 to 4 thrombocytopenia, and thromboembolic events (which occurred in 20% of patients); MTD was established at 300 mg for weekly dosing and 225 mg for semicontinuous dosing. No responses were recorded. Fifteen percent achieved stable disease, including 4 patients with esophageal cancer. The investigators concluded that sufficient interest was seen, although they recommended prophylactic anticoagulation in subsequent studies.

BI 2536 is a small molecule Plk-1 inhibitor that underwent a phase I evaluation in patients with advanced solid tumors in which 25-mg to 250-mg doses were administered; patients showing clinical benefit were treated with additional courses. The MTD was set at 200 mg, with DLT defined as neutropenia (56% had grade 3–4 severity). No responses were recorded, although 23% treated at or above the MTD had stable disease for at least 3 months. A subsequent open-label phase I evaluation was performed in 70 patients, which tested 2 schedules: 2 weeks on/1 week off as a 1-hour infusion or as a 24-hour continuous infusion on day 1 of a 21-day cycle. The MTD with weekly dosing was established at 100 mg/dose. With the continuous infusion schedule, doses up to 225 mg were tolerated and an MTD was not reached. Both schedules were associated with significant neutropenia: grade 3 to 4 in 36% using weekly dosing and 50% with the 24-hour infusion. No responses were recorded; 32% had stable disease with weekly dosing.

An open-label randomized phase II study of BI 2536 was also conducted in patients with advanced nonsmall cell lung cancer. Ninety-five patients received BI 2536 as an intravenous infusion on day 1 (200 mg) or from days 1 to 3 (50–60 mg) of a 21-day cycle, with interpatient dose escalation allowed based on patient tolerance. There were 4 responses (overall response rate, 4.2%), and median PFS was 2 months. The median OS was 7 months and there were no differences in outcomes associated with drug schedule. Thirty-seven percent of patients had grade 4 neutropenia, and 2 drug-related deaths (sepsis and pulmonary hemorrhage) occurred.

ON 01,910.Na regulates mitotic pathways, including Plk-1. A first-in-man study involving 20 patients evaluated this agent as a 2-hour infusion on days 1, 4, 8, 11, 15, and 18 of a 28-day cycle. The MTD was established at 3120 mg/dose. The predominant toxicities were associated with skeletal and abdominal adverse events, as well as significant tumor pain. One objective response was recorded in a patient with recurrent ovarian cancer. It persisted for up to 24 months. A separate phase I study was performed in 13 patients with high-risk myelodysplastic syndrome. All patients were reported to have a response, including 4 who had a complete marrow response.

KSP inhibitors

Kinesins are enzymes that use ATP to translocate along or destabilize microtubules, and are important for the process of cell division. KSP is a specific kinesin expressed only in dividing cells and thus is critical to the organization of the mitotic spindle. Subsequent inhibition of KSP results in apoptosis because of mitotic arrest.

Ispinesib (SB-715,992) underwent phase II evaluation in 17 patients with metastatic or recurrent malignant melanoma. The dose and schedule used were 18 mg/m ² as a 1-hour infusion on a 3-week cycle. Although no responses were observed, 35% had stable disease for a median of 3 months. Grade 3 adverse events were limited, but consisted of dizziness and blurry vision. Because of lack of activity, it was not recommended for further evaluation in this population.

MK-0371 is a C2-hydroxymethyl dihydropyrrole KSP inhibitor designed to circumvent P -glycoprotein efflux and optimized for antitumor properties by incorporation of fluorine. In phase I testing that involved 35 patients with taxane-refractory cancers, MT-0371 was evaluated using a 24-hour infusion schedule dosed every 21 days. The MTD was established at 17 mg/m ² /d without evidence of myelosuppression. The DLT seen at higher doses consisted of prolonged grade 4 neutropenia. No responses were noted, but stable disease for at least 4 cycles was seen in 16 patients.