New Anticancer Agents in Clinical Development
New Anticancer Agents in Clinical Development
A better understanding of the biology and biochemistry of the cancer cell has led to the development of various promising new antineoplastic compounds that are now undergoing phase I, II, and III clinical testing. These drugs include topoisomerase I inhibitors, such as camptothecin and its analogs 9-aminocamptothecin, irinotecan, and topotecan; the paclitaxel analog docetaxel; gemcitabine, an antimetabolite structurally related to cytarabine; and fluorouracil prodrugs and other thymidylate synthase (TS) inhibitors. Another exciting approach to cancer treatment is the use of agents that induce a less malignant state by altering cellular phenotype. Such agents include angiogenesis inhibitors, differentiating agents, signal transduction inhibitors, and gene therapy.
The 1990s is an exciting decade for oncologists. Intensive research and development programs during the 1980s and 1990s have resulted in new anticancer agents with unique mechanisms of action and significant clinical activity. Recently, three such agents were approved by the FDA: paclitaxel (Taxol), all-trans-retinoic acid, and vinorelbine (Navelbine). These agents have shown significant clinical activity in patients with refractory tumors, such as non-small-cell lung cancer, platinum-refractory ovarian cancer, and anthracycline-refractory breast cancer.
This article will review other promising compounds currently in clinical development. These drugs, which include topoisomerase I inhibitors, docetaxel (Taxotere), gemcitabine (Gemzar), and thymidylate synthase (TS) inhibitors, have significant preclinical activity and are now undergoing phase I, II, and III clinical testing. The hope is that these novel compounds represent the first of a long line of new agents developed as a result of our better understanding of the biology and biochemistry of the cancer cell.
Topoisomerase I inhibitors are an exciting new class of antineoplastic agents currently undergoing clinical testing. These compounds are structurally related to camptothecin, a natural product isolated from the Chinese plant Camptothecin accuminata .
Topoisomerase I is a cellular enzyme involved in maintaining the topographic structure of DNA during translation, transcription, and mitosis . The double helix structure of DNA creates torsional strain in a cell that must be overcome in order for replication and translation to proceed. DNA topoisomerases control and modify the topological state of DNA by creating a transient break in a single strand (topoisomerase I) or both complementary strands (topoisomerase II) of the DNA backbone . These enzymes are capable of catalyzing many types of interconversions between DNA topological isomers. Examples of interconversions include catenation (interlocking of DNA circles) and decatenation, and knotting (passing one double strand of DNA through another strand) and unknotting .
It is now established that transient breakage of the DNA backbone by topoisomerases is accompanied by the formation of a covalent enzyme-DNA intermediate called the cleavable complex . Inhibition of topoisomerase I by camptothecin and its analogs is accomplished by stabilization of the enzyme-DNA cleavable complex. This occurs after the cleavage step and causes the DNA and topoisomerase to be trapped in the cleavable complex. When camptothecin is removed, the DNA is reannealed (ie, the DNA backbone is resealed), and replication can proceed. Thus, inhibition of topoisomerase I blocks cellular RNA and DNA synthesis. The mechanism by which topoisomerase I inhibitors cause cell death is presently unknown .
During extensive screening of random plant products by the Cancer Chemotherapy National Service Center in the late 1950s, a crude extract of C accuminata was found to have anticancer activity . In 1966, Wall and coworkers  isolated this extract, camptothecin (Figure 1), which demonstrated significant anticancer activity in L1210 leukemia and Walker 256 carcinosarcoma [6,7]. In preclinical studies, hemorrhagic enterocolitis was the major dose-limiting toxicity .
Phase I and II Trials--In the late 1960s and early 1970s, camptothecin sodium underwent phase I and phase II testing. Phase I studies were performed using various dosing schedules: single-dose , daily , weekly , and daily for 5 days . Although 5 of 18 patients demonstrated objective tumor responses to the drug in one phase I trial, phase II studies in patients with melanoma  and adenocarcinoma of the colon  were limited by severe hemorrhagic cystitis and unpredictable myelosuppression. As a result, further clinical development of camptothecin sodium was halted.
Development of Analogs--It wasn't until the 1980s, when inhibition of topoisomerase I was identified as the mechanism of action of camptothecin, that interest in this class of compounds was rekindled. In addition, it was found that the lactone ring (E-ring, which is pH labile) was critical to the activity of camptothecin, and thus the sodium salt used in earlier trials (which mainly comprised the carboxylate [inactive] form) might have been the reason for the lack of antitumor activity observed .
Structure-activity studies  revealed that modification of the A-ring improved water solubility and reduced protein binding. Therefore, analogs of camptothecin with increased water solubility and decreased protein binding were developed, with the anticipation that such modifications would enhance activity while decreasing the hemorrhagic cystitis and unpredictable myelosuppression. Currently, camptothecin and four of its analogs are in clinical development: 9-aminocamptothecin (Figure 1), GI147211, irinotecan (CPT-11), and topotecan.
Oral Camptothecin--Camptothecin is undergoing evaluation as an oral preparation. Giovanella and Natelson reported the preliminary results of a trial with oral camptothecin in which the dose-limiting toxicity was gastrointestinal . In the 52 patients treated, 5 partial responses and 1 complete response were noted.
9-Amino-20(S)-camptothecin (9-AC) has demonstrated significant preclinical activity. In studies conducted at the National Cancer Institute that measured DNA strand breaks and cytotoxicity against HT-29 cell lines, 9-AC was found to be slightly more potent than topotecan and significantly more potent than CPT-11, but slightly less potent than SN-38 (the active metabolite of CPT-11) and camptothecin.
Clinical development of 9-AC has proceeded slowly due to its relative water insolubility. In a phase I study of 9-AC administered as a 72-hour continuous infusion in patients with solid tumors, dose-limiting neutropenia occurred at 59 mcg/m²/h . Other toxicities (all grade 2) included nausea, vomiting, mucositis, and diarrhea. Further dose escalation in combination with granulocyte colony-stimulating factor (G-CSF, filgrastim; Neupogen) is currently under study.
GI147211 is a new water-soluble analog of camptothecin. In human tumor xenograft models HT-29 and SW-48 (colon), PC-3 (prostate), and MX-1 (breast), GI147211 was 1.5 to 1.8 times more active than topotecan in suppressing growth. GI147211 has also been found to be 2.3 to 4.3 times more potent in inhibiting topoisomerase I activity than topotecan .
Based on its preclinical activity, GI147211 has recently undergone clinical testing with two dosing schedules: daily doses for 5 days and a 72-hour continuous infusion every 21 days. Reversible grade 3 and 4 neutropenia and thrombocytopenia have been observed with both schedules . Phase II trials are underway using the daily for 5 days schedule.
The initial preclinical and clinical development of irinotecan (CPT-11) was conducted primarily in Japan. In preclinical testing, irinotecan was found to be active against a broad spectrum of tumor models . However, the decarboxylated metabolite SN-38 (7-ethyl-10-hydroxy-camptothecin; Figure 1) plays a major role in the antitumor activity of irinotecan in vivo .
The maximum tolerated dose (MTD) of irinotecan depends on the dose and schedule, with diarrhea and neutropenia being the major toxicities. Schedules employing a daily dosing schedule have demonstrated more neutropenia, whereas intermittent schedules have been associated with significant diarrhea . The dose intensity on all the schedules has been approximately 100 mg/m²/wk . However, in a recently published study from France , escalation of the irinotecan dose was accomplished by means of aggressive treatment of the diarrhea with antimotility agents. An MTD of 600 mg/m² given over 90 minutes every 3 weeks was reported, with neutropenia being dose-limiting.
Diarrhea--Irinotecan has been associated with two forms of diarrhea. The first type occurs during or just after the infusion and has a cholinergic mecha nism. The use of atropine at the onset of this early diarrhea is an effective treatment.
The second type of diarrhea begins 3 to 5 days after the irinotecan infusion and may be moderate to severe in 20% of patients. Aggressive treatment at the onset with antimotility agents may obviate its severity. If late diarrhea is not treated early, it usually runs a 5- to 7-day course. The mechanism of this type of diarrhea is unknown, but it may be secondary to the biliary excretion of SN-38, the active metabolite of irinotecan .
Other Toxicities--In addition to dose-limiting myelosuppression and diarrhea, other toxicities reported with irinotecan include anemia, transaminasemia, anorexia, alopecia, malaise, flushing, stomatitis, pneumonitis, nausea, and vomiting. These toxicities are mild to moderate in severity and reversible .
Antitumor Activity--Single-agent activity of irinotecan has been evaluated in a number of tumor types, including non-Hodgkin's and Hodgkin's lymphoma, acute leukemia, colon cancer, non-small-cell and small-cell lung cancer, ovarian cancer, cervical cancer, breast cancer, pancreatic cancer, and gastric cancer (
Table 1). The encouraging activity of this agent seen in patients with refractory tumors, such as cervical cancer and colon cancer, has stimulated large phase II trials now being conducted in the United States and abroad.
Irinotecan Combinations--Because of the novel mechanism of action and clinical activity of irinotecan, investigators have explored its use in combination with other cytotoxic agents. In vitro and in vivo testing of camptothecin analogs has demonstrated synergistic activity when combined with topoisomerase II inhibitors, alkylating agents, platinum compounds, and radiation .
Phase I trials of several irinotecan combinations have been initiated. Impressive activity has been demonstrated when irinotecan is combined with cisplatin (Platinol) or etoposide (VePesid) in patients with non-small-cell lung cancer. In untreated patients with non-small-cell lung cancer, response rates to irinotecan-cisplatin have ranged from 43% to 45% [44,45]. These results have prompted further investigation of this combination.