Irinotecan (Camptosar, CPT-11), gemcitabine(Drug information on gemcitabine) (Gemzar), and docetaxel(Drug information on docetaxel) (Taxotere) are chemotherapeutic agents with different intracellular targets and complementary, rather than overlapping, mechanisms of action.
The taxanes induce polymerization of tubulin’s alpha and beta subunits, resulting in stabilization of microtubules and disruption of the cell cycle.[1,2] Difluorodeoxycytidine triphosphate (dFdCTP), the predominant intracellular metabolite of gemcitabine, is incorporated as a substrate during DNA synthesis, causing inhibition of DNA elongation and chain termination after the addition of another base or another molecule of dFdCTP. In addition, the diphosphate form of gemcitabine leads to a decrease in the normal intracellular triphosphate pools.[3,4] The active metabolite of irinotecan(Drug information on irinotecan) SN-38 stabilizes the covalent linkage between the topoisomerase I enzyme and the DNA backbone formed during the enzymatic relaxation of DNA torsional strain. This slows DNA religation during the catalytic cycle.
All three agentsirinotecan, gemcitabine, and docetaxelare individually active in a variety of malignancies as first- and second-line treatment. In preclinical studies, interactions between these agents have been demonstrated, with the magnitude of beneficial interaction at least somewhat schedule related. A marked synergistic effect was observed when CAEP cells, a cell line derived from squamous cell carcinoma of the lung, were exposed to docetaxel followed 24 hours later by gemcitabine; less synergy was observed with the reverse sequence. The two sequences also produced moderate synergistic killing of RAL cells, a cell line derived from adenocarcinoma of the lung. In this cell line, enhanced synergism was encountered when a 48-hour washout was used between docetaxel and gemcitabine exposures. A similar sequence, docetaxel given first followed 24 hours later by irinotecan, resulted in synergistic interactions between these two drugs in cancer cell lines.[7,8]
Simultaneous exposure to gemcitabine and irinotecan resulted in antagonism at low concentrations but synergism at concentrations of gemcitabine above 0.1 mM and irinotecan above 3.2 µM in the SCOG small-cell lung cancer cell line. In MCF7 breast cancer cells, synergism occurred at gemcitabine concentrations of 0.1 to 2 mM and irinotecan concentrations of 0.2 to 10 µM. However, antagonism occurred at high concentrations (ie, > 2 mM of gemcitabine and > 20 mM of irinotecan).
Phase I data from our institution showed that gemcitabine administered at 1,000 mg/m2 over 30 minutes followed by irinotecan at 100 mg/m2 over 90 minutes (IrinoGem) could be administered on a day 1 and 8 schedule every 3 weeks. This IrinoGem regimen has recently been studied in a phase II trial for chemotherapy-naive advanced and metastatic pancreatic cancer patients. In that trial, almost 90% full doses of both drugs were delivered on days 1 and 8. The regimen has been well tolerated and active with modest toxicity.
To build on the clinical activity of IrinoGem and take advantage of the available preclinical synergy data, we conducted a phase I trial of the combination of docetaxel, gemcitabine, and irinotecan (the DIG regimen) in patients with solid tumors. The schedule and doses chosen were based on the preclinical synergistic interactions and our prior experience delivering almost full doses of gemcitabine and irinotecan in combination. In this trial, the doses of gemcitabine and irinotecan were initially fixed at 1,000 mg/m2 and 100 mg/m2, respectively. Docetaxel doses were to be escalated until the maximum tolerated dose for the combination was defined.
Two different schedules were studied: docetaxel was either administered on days 1 and 8, followed 24 hours later by gemcitabine and irinotecan on days 2 and 9 (schedule A), or docetaxel was administered on day 8, with gemcitabine and irinotecan on days 1 and 9 (schedule B). As was done in our prior studies with the gemcitabine/irinotecan combination, irinotecan was given immediately following gemcitabine.
The objectives of the study were to determine the maximum tolerated dose of docetaxel that could be administered with fixed doses of gemcitabine and irinotecan, to describe the pattern of dose-limiting toxicity, and to define the recommended phase II doses for each of the tested schedules of this three-drug regimen.
Adult patients with pathologically confirmed solid tumors that were refractory to standard therapy, or for whom no standard therapy of proven efficacy was available, were eligible if they had adequate organ function, performance status of 0 to 2, and resolution of toxic effects from prior therapy. Adequate organ function was defined as granulocyte count of at least 1,500/mL, platelet count of at least 100,000/mL, serum creatinine < 2.1 mg/dL, and serum bilirubin < 2.1 mg/dL. Female patients with child-bearing potential must have had a negative pregnancy test.
Patients were ineligible if they had known bone marrow metastases, a history of congestive heart failure requiring medical therapy (New York Heart Association class III or IV), unstable angina, atrial fibrillation, or myocardial infarction within the 6 months prior to study entry, uncontrolled bacterial, viral, or invasive fungal infection, prior whole pelvic radiation, or a psychiatric condition that would prevent informed consent. Prior chemotherapy with any or all three of the agents under study was allowed. Measurable or evaluable disease was not required. All patients gave written informed consent by signing an informed consent document approved by the Institutional Review Board of the Medical University of South Carolina.
Docetaxel was administered as a 60-minute (later amended to a 30-minute) intravenous infusion on days 1 and 8 (arm A) or day 8 only (arm B). This was followed 24 hours later, on either days 2 and 9 (arm A) or day 9 (arm B) of each 3-week treatment cycle by a 30-minute intravenous infusion of gemcitabine at 1,000 mg/m2 immediately followed by irinotecan at 100 mg/m2 over 90 minutes. On arm B, the day 1 doses of gemcitabine and irinotecan were given without docetaxel pretreatment. The dose levels tested in this phase I trial are shown in Table 1. Cohorts of at least three patients were evaluated at each dose level. No dose escalation was permitted within individual patients.
Patients were removed from protocol if they demonstrated progressive disease or allergic reaction with diffuse rash or anaphylaxis, or if treatment termination was deemed in the best medical interests of the patient. Patients experiencing a dose-limiting toxicity, but also demonstrating clinical or radiographic response or stable disease with subjective benefit, could continue treatment at the next lower dose level.
All patients received prophylactic antiemetic therapy chosen by their treating physician. Antiemetics generally included an HT3 blocker not only before docetaxel, but also before gemcitabine and irinotecan. Oral dexamethasone(Drug information on dexamethasone) at 8 mg was taken the night before and bid on the same day as docetaxel for a total of three doses (dexamethasone at 20 mg IV was given 30 minutes before the infusion of docetaxel if the patient had not taken the dexamethasone the night before).
Gemcitabine at 1,000 mg/m2 was prepared in 250 mL of normal saline and given over 30 minutes by IV infusion on days 2 and 9 (arm A) or days 1 and 9 (arm B) of each treatment cycle. Immediately following completion of each dose of gemcitabine, irinotecan at 100 mg/m2, prepared in 500 mL of normal saline or 5% dextrose(Drug information on dextrose) in water (D5W) solution, was administered over 90 minutes by IV infusion. Docetaxel at the cohort-specific dose was prepared in 100 mL of normal saline or D5W, and given over 60 minutes (later amended to 30 minutes) by IV infusion on days 1 and 8 (arm A) of each treatment cycle, or only on day 8 if the arm B dose escalation was being employed. The treatment cycles were repeated every 3 weeks.
Prophylactic atropine(Drug information on atropine) was not routinely given. In patients who developed cholinergic diarrhea during the infusion of irinotecan, 0.5 mg of atropine was administered IV. These and any other patients who reported diarrhea within the first 8 hours after completing irinotecan were given prophylactic atropine just before all subsequent doses of irinotecan. Patients were instructed to begin taking oral loperamide(Drug information on loperamide) (Imodium) at the earliest signs of diarrhea and/or abdominal cramping that occurred more than 8 hours after receiving irinotecan. Loperamide was prescribed as 4 mg orally at the onset of cramps and/or diarrhea, and then 2 mg every 2 hours around the clock until the patient was diarrhea-free for at least 12 hours. During the night, patients were advised to take 4 mg of loperamide every 4 hours instead of 2 mg every 2 hours.
Growth factors were not permitted during the first cycle of therapy, unless profound neutropenia and severe or life-threatening infection were present. Patients received full supportive care (ie, transfusions of blood products, antibiotics, antidiarrheals, analgesics, etc, as appropriate).