PKCa LY900003 ISIS 3521 Affinitac

Another target of AS-ODN is PKC-a. PKC-a belongs to a class of serine-threonine kinases whose involvement in oncogenesis is suggested by the fact that they are the major intracellular receptors for tumor-inducing phorbol esters. The results of a phase I study suggested that an AS-ODN directed against PKC-a (ISIS 3521) may be effective in the treatment of low-grade lymphoma (11).

In a phase I trial, ISIS 3521 was delivered over a period of 21 d by continuous iv infusion followed by a 7-d rest period (39). Doses were increased from 0.5 to 3.0 mg/kg/d. Twenty-one patients with incurable malignancies were treated in five patient cohorts. The maximum tolerated dose was 2.0 mg/kg/d, equivalent to pharmacologically active doses against human xenografts in mice. The dose-limiting toxicities were thrombocytopenia and fatigue at a dose of 3.0 mg/kg/d. Evidence of tumor response lasting up to 11 mo was observed in three of four patients with ovarian cancer. Another phase I study analyzed the combination of ISIS 3521 with 5-fluorouracil and leukovorin (5-FU/LV) in patients with advanced cancer. ISIS 3521 was tolerable when given with 5-FU/ LV. Partial remission was seen in 2 of 14 patientsp; however, it is uncertain whether clinical activity is a result of enhanced drug interaction (40).

A phase I/II trial of ISIS 3521 with carboplatin and paclitaxel in NSCLC has been reported. The phase I portion, which also included other malignant tumors, showed no dose-limiting toxicity at the highest dose level, consisting of 2.0 mg/ kg/d, d 1-14 by continuous iv infusion of carboplatin (area under the curve 6, d 4) and paclitaxel (175 mg/m2, d 4). There was no evidence of pharmacokinetic interactions between ISIS 3521 and either chemotherapy agent. In the expanded phase, patients received carboplatin, paclitaxel, and ISIS 3521 as above every 21 d. Toxicity consisted of grade 3 to 4 neutropenia (30 patients) and thrombocytopenia (13 patients), but no episodes of grade 3 to 4 neuropathy. Among 48 evaluable patients, 42% had a partial or complete response, and 17% progressed during treatment. The median overall survival was 19 mo with a 1-yr survival rate of 75% and a median time to progression of 6.6 mo (41). Typical survival of patients with NSCLC with similar disease receiving carboplatin and paclitaxel alone is approx 8 mo.

Thus, in this trial the combination of ISIS 3521, carboplatin, and paclitaxel was well tolerated and showed promising activity in NSCLC. Based on these results, a 600-patient, randomized phase III clinical trial of ISIS 3521 in combination with chemotherapy for NSCLC was initiated and has already completed enrollment; no data are currently available.

Another phase II study examined the safety and efficacy of ISIS 3521/ LY900003 combined with docetaxel in patients with stage IIIB/IV, previously treated NSCLC. Response rates are available for 36 patients. The best responses were as follows: partial response in 5 patients (14%); 2 of whom failed prior paclitaxel; stable disease in 15 patients (42%); progressive disease in 16 patients (44%). Grade 3/4 hematological toxicities were neutropenia in 11 patients and thrombocytopenia in 9 patients. The most common other adverse events included grade 3/4 fatigue (three patients), infections (six patients), and neutropenic fever (five patients) (42).

Another phase I/II trial initially evaluated the safety of 2 mg/kg/d ISIS 3521/ LY900003, administered by continous iv infusion on d 0-14 plus 80 mg/m2of cisplatin on d 0 and 1.000 mg/m2 of gemcitabine on d 0 and 7. The combination was well tolerated, with grade 3 to 4 neutropenia and thrombocytopenia in 57 and 43% of cycles, respectively, in seven patients with advanced cancer. No pharmacokinetic interactions were observed. In the phase II portion, data are available for 43 advanced, previously untreated NSCLC patients. Grade 3 to 4 toxicities were as follows: thrombocytopenia (38 patients), neutropenia (19 patients), anemia, (6 patients), fatigue (11 patients), dehydration (7 patients), sepsis (3 patients). There was no grade 3 to 4 neuropathy or azotemia. Thirty-one patients were evaluable for response: complete response was seen in 1 patient (3%), partial response in 11 patients (35%), stable disease in 17 patients (55%), and progressive disease in 2 patients (7%) (43).

ISIS 3521 failed to show significant activity in a phase II trial in patients with metastatic breast cancer (ECOG trial 3197). No objective responses were observed in the study population of 15 patients. Patients were treated with 2 mg/kg/d for 21 d every 28 d administered as continuous iv infusion. Median time to progression was 1.2 mo. Grade 3 to 4 toxicities included thrombocytopenia and infection (44).

Alavi et al. (45) tested the efficacy, toxicity, and pharmacology of ISIS 3521 delivered as a 21-d continuous iv infusion in patients with recurrent high-grade astrocytomas. Toxicities were mild and reversible. There was no evidence of a clinical benefit. Median time to progression was 35 d after entering this protocol, and median survival was 93 d.

In a phase II multicenter trial, 29 patients with advanced relapsed or refractory low-grade or follicular NHL received 2 mg/kg/d of ISIS 3521/LY900003 by 21-d continous iv infusion repeated every 4 wk. Grade 3 to 4 thrombocy-

topenia occurred in seven patients (six with grade 3, one with grade 4), requiring a dose reduction in two. Two patients had grade 3 fatigue, requiring a dose reduction in one. One patient undergoing a dose reduction experienced signs of acute tumor lysis. Another patient developed self-limited toxic hepatitis. One patient had a mixed response. This patient had a 73% reduction in measurable disease, received radiation to three sc nodules, and continues with an excellent response after 8 mo of ongoing treatment. Other best responses included 16 patients with stable disease and 4 patients with progressive disease. Thus, ISIS 3521 treatment is well tolerated in patients with NHL. The observed modest activity is comparable with that observed with other AS-ODNs in NHL (46).

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