Irinotecan (Camptosar, CPT-11),
gemcitabine (Gemzar), and 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 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
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
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
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 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 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 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 (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).
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