Kobayashi K, Vogelzang N J, O'Brien S M, Schilsky R L, Vokes E E, Ratain M J
Department of Medicine, University of Chicago Cancer Research Center, Illinois.
Cancer. 1994 Jul 1;74(1):168-73. doi: 10.1002/1097-0142(19940701)74:1<168::aid-cncr2820740127>3.0.co;2-t.
Cladribine (2-CdA, 2-chlorodeoxyadenosine), a chlorinated adenosine analog, is active in the treatment of hairy cell leukemia and other hematologic malignancies, but its use in treating solid tumors is still under investigation, as is the optimal schedule for administering this drug. The authors conducted a dose-finding study to define the maximal tolerated dose and toxicities of this agent when given to patients with refractory solid tumors having normal renal, hepatic, and bone marrow function.
Cladribine was given as a 1-hour intermittent infusion, repeated daily for 5 days, with a cycle length of 28 days. The initial dose was 4 mg/m2, with escalating doses by cohort. Three dosage levels (4, 6, and 8 mg/m2/day) were explored, and patients were observed to determine toxicity. The end points of the study were the definition of the maximally tolerated dose (MTD), toxicity profile, and establishment of a recommended Phase II dose (RPTD) for cladribine.
Eighteen patients were treated; the majority were patients with non-small cell lung cancer and colorectal cancer. The median Cycle-1 leukocyte nadirs for the 4, 6, and 8 mg/m2/day dosage levels were 3100, 2300, and 950 cells/microliters (range 800-3500), respectively, and the and 950 cells/microliters (range 800-3500), respectively, and the mean nadir absolute neutrophil counts were 1500, 936, and 482 cells/microliters (range 130-2241), respectively. Minimal thrombocytopenia was seen, and no evidence for cumulative myelosuppression was observed. Two patients were hospitalized for neutropenic fevers, both of whom received the 6 mg/m2/day dose. One patient who received the 4 mg/m2/day dose had a transient episode of blindness that occurred during the infusion on Day 3 of Cycle 3. Thorough evaluation of this problem did not reveal an etiology, and it did not recur with further administration of cladribine. No other significant nonhematologic toxicity has been noted. No responses were observed.
At the MTD (8 mg/m2/day), the dose-limiting toxicity of this agent is myelosuppression. The RPTD for further testing of this schedule is 6 mg/m2 daily x 5 days.
克拉屈滨（2 - CdA，2 - 氯脱氧腺苷），一种氯化腺苷类似物，在毛细胞白血病和其他血液系统恶性肿瘤的治疗中具有活性，但它在实体瘤治疗中的应用仍在研究中，该药物的最佳给药方案也是如此。作者进行了一项剂量探索研究，以确定在给予肾功能、肝功能和骨髓功能正常的难治性实体瘤患者时，该药物的最大耐受剂量和毒性。
克拉屈滨以1小时间歇输注的方式给药，每日重复给药5天，周期长度为28天。初始剂量为4mg/m²，按队列逐步增加剂量。探索了三个剂量水平（4、6和8mg/m²/天），并观察患者以确定毒性。研究的终点是确定最大耐受剂量（MTD）、毒性特征，并确定克拉屈滨的推荐II期剂量（RPTD）。
18名患者接受了治疗；大多数为非小细胞肺癌和结直肠癌患者。4、6和8mg/m²/天剂量水平的第1周期白细胞最低点中位数分别为3100、2300和950个细胞/微升（范围800 - 3500），平均最低点绝对中性粒细胞计数分别为1500、936和482个细胞/微升（范围130 - 2241）。观察到轻微的血小板减少，未观察到累积骨髓抑制的证据。两名患者因中性粒细胞减少性发热住院，两人均接受6mg/m²/天的剂量。一名接受4mg/m²/天剂量的患者在第3周期第3天输注期间出现短暂失明。对该问题的全面评估未发现病因，再次给予克拉屈滨时未复发。未观察到其他明显的非血液学毒性。未观察到反应。
在最大耐受剂量（8mg/m²/天）时，该药物的剂量限制性毒性是骨髓抑制。该给药方案进一步试验的推荐II期剂量为6mg/m²每日×5天。
