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Biotech / Medical : Cell Therapeutics (CTIC) -- Ignore unavailable to you. Want to Upgrade?

To: Icebrg who wrote (277)	9/30/2004 5:19:32 AM
From: Icebrg	Read Replies (1) \| Respond to of 946

Phase I study of CT2106 (polyglutamate camptothecin) in patients with advanced malignancies Citation: European Journal of Cancer Supplements Volume 2, No.8, September 2004, page 154 C. Takimoto1, S. Syed1, M. McNamara2, J. Doroshow3, S. Pezzulli4, E. Eastham1, A. Bernareggi5, J. Dupont4 1Cancer Therapy and Research Center, San Antonio, USA 2City of Hope Medical Group, Pasadena, USA 3City of Hope Medical Center, Department of Medical Oncology, Duarte, USA 4Memorial Sloan-Kettering Cancer Center, Department of Medicine, New York, USA 5Cell Therapeutics, Inc., Department of Clinical Pharmacology, Seattle, USA Background: CT-2106 is a novel camptothecin (CPT) conjugate in which CPT is bound to a biodegradable water-soluble poly-L-glutamic acid-glycine polymer. CPT-polymer conjugation allows for greater stability of CPT in circulation and enhanced permeability and retention in tumor tissue. CT-2106 has demonstrated anti-tumor activity in several human tumor cell lines in vivo. Methods: To determine the maximum tolerated dose (MTD) and evaluate the pharmacokinetics (PK) of CT-2106, 31 pts were treated with a 10-minute IV infusion every 21 days. Toxicity was assessed according to NCI CTC v2. PK samples (cycles 1 and 2) were analyzed for conjugated and unconjugated CPT levels by validated HPLC/FD methods. Cohorts of pts received conjugated CPT doses of 12, 25, 50, 75, 90, or 105 mg/m2. Results: Dose-limiting toxicities (DLTs) included: grade (g) 3/4 neutropenia, thrombocytopenia, and mucositis. One pt experienced a g4 cholinergic reaction and esophageal spasm; this pt had previously experienced a severe reaction to irinotecan. Other related toxicities were g3 increased ALT and £g2 anemia, anorexia, dysgeusia, peripheral sensory neuropathy, fatigue, nausea, diarrhea, vomiting, abdominal pain, alopecia, rash, decreased hemoglobin, and hematuria. No g3/4 hematuria or diarrhea was observed. Using standard response criteria, 1 pt with metastatic pancreatic cancer had a partial response, 2 pts with NSCLC had stable disease (SD) for >35 weeks, and 2 pts with colon cancer had SD for >9 weeks. Preliminary PK parameters calculated from 18 pts treated at 25, 50, 75, or 105 mg/m2 demonstrated sustained levels of conjugated CPT in systemic circulation, with mean elimination half-life from 16.6 to 50.8 hrs. Cmax and AUC of conjugated CPT increased linearly with dose, suggesting PK linearity. Unconjugated CPT levels suggest that this active form of the compound is generated by a slow, progressive release from the polymer following the distribution of conjugated CPT to tissues. The PK profile of unconjugated CPT is dependent on the disposition profile of the conjugated drug; unconjugated CPT elimination is formation rate limited. Unconjugated CPT half-life ranged from 31.9 to 60.4 hours. Five days after the 1st administration, mean cumulative urinary excretion of conjugated and unconjugated CPT accounted for 27.9% and 5.1% of the administered dose, respectively. A major conjugated CPT species in urine was glu-gly-CPT (6.9% of dose). Accumulation of conjugated or unconjugated CPT was not observed with repeated dose administration. Plasma and urine PK parameters were nearly identical in cycles 1 and 2. The MTD has been established at 75 mg/m2. Conclusion: CT-2106 has been well tolerated with easily manageable toxicities while generating prolonged systemic exposures to free CPT in plasma. Since clinical activity has been observed, phase I/II single-agent and combination trials are planned.

To: Icebrg who wrote (277)	10/13/2004 4:28:05 AM
From: Icebrg	Respond to of 946

Molecular remission with arsenic trioxide in patients with newly diagnosed acute promyelocytic leukemia Haematologica 2004;89:1266-1267 [Arsenic Trioxide seems to be something of a favorite in "third-world" medical research. Possibly because the molecule traditionally has been used as a drug. The low cost of locally produced drug ($0,5 per vial is mentioned here) certainly helps too. India doesn't look like a prospective market for Trisenox]. Biju George, Likram Mathews, Poonkuzhali Balasubramanian, R.V. Shaji, Alok Srivastava, Mammen Chandy Dept of Hematology, Christian Medical College, Vellore, Tamil Nadu, India Correspondence: Dr. Biju George, Department of Hematology, Christian Medical College, Vellore 632004, Tamil Nadu, India. E-mail: biju@cmcvellore.ac.in Abstract Thirty six APML patients achieving hematological remission with As2O3 were serially monitored using RT-PCR. Though only 5.5% achieved molecular remission at induction remission, 94.5% became negative during consolidation. At 20 months follow-up, 85% remain in remission but longer follow up studies are needed to monitor late relapses. Text Arsenic trioxide (As2O3) achieves induction remission in 70-90% of patients with newly diagnosed acute promyelocytic leukemia (APL) with 65-70% long term remission rates1,2 but there is limited data on molecular remission in these patients. We evaluated this aspect in 40 patients and describe our findings here. The study population was formed of 40 patients with t(15;17) APL treated with As2O3 between January 2000 and February 2004. As2O3 was administered in the context of an institutional study protocol after obtaining ethical clearance in the first 5 patients, but since 2001, As2O3 has become standard therapy for patients who cannot afford treatment with ATRA. Intravenous As2O3, prepared in the hospital pharmacy at the cost of $0.5 per vial, was administered at a daily dose of 10 mg (adults) and 0.15 mg/kg/day (children) as per protocol (Figure 1). Full blood counts, coagulation parameters, as well as renal and hepatic function were closely monitored. Electrocardiograms were done if patient was symptomatic. Platelet and fresh frozen plasma transfusions were given to maintain platelet counts >20,000/mm3 or if the patients had a coagulopathy. Bone marrow examination was done to assess remission on normalization of blood counts. The molecular monitoring was carried out by reverse transciption polymerase chain reaction (RT-PCR) to detect PML-RARa transcripts, as described by van Dongen et al.,3 and was done at diagnosis, at hematologic remission, prior to consolidation therapy, twice during maintenance therapy (3 months apart) and subsequently every 6 months. This method, with nested amplification, has a sensitivity of 10-3 to 10-4. There were 23 males and 17 females, including 31 adults and 9 children (mean age 27.8 years; range: 6 - 60) with hypergranular APL. The median white cell count at diagnosis was 2.5x109/L (range: 0.6 to 58.9). Thirty-six patients (90%) achieved hematologic remission (HCR) at a median time of 42.6 days (range: 26 - 60) with 4 early deaths due to intracranial hemorrhage. Molecular remission was achieved in all at a median time of 83.9 days (range: 51-136).(Table 1). Though only 2 (5.5%) patients became PML-RARa transcript negative at HCR, another 25 (69.5%) had became negative at the start of consolidation without further treatment. Seven patients (19.5%) became negative at the end of consolidation while 2 (5.5%) became negative during maintenance therapy. Thirty-four patients (94.5%) were in molecular remission by the end of consolidation. As far as concerns toxicity, 20 patients (50%) had leukocytosis requiring addition of hydroxyurea with temporary discontinuation of As2O3 in 5 patients and prolonged neutropenia in 1 patient. Asymptomatic elevation of liver enzymes was noted in 7 (17.5%) patients. There were no cases of clinical cardiac toxicity. Isoform analysis showed that 29 patients (72.5%) were bcr-1-positive, 2 (5%) were bcr-2-positive and 9 (22.5%) were bcr-3 positive. The rate of HCR was similar in patients with all isoforms though the median time to HCR was significantly shorter in those with bcr-3 than in those with the bcr-1 isoform [31 vs 46.5 days] (p<0.001) with no significant difference was seen in the median time to molecular remission [67.5 days bcr-3, 84.8 days bcr-1] (p = 0.2). Two patients relapsed 6 and 7 months after treatment: one patient achieved a second complete remission on repeat treatment with a combination of As2O3 and ATRA while the second died of intracranial hemorrhage. At a median follow-up of 20.3 months (range: 4-53), thirty-four patients (85%) remain in remission with a leukemia-free survival of 94.5%. As2O3 achieves induction remission rates similar to those produced by treatment with ATRA or a combination of ATRA and As2O3 with similar numbers of patients achieving molecular remission by the end of consolidation therapy.4,5,6 Trials in patients with relapsed APL have also shown 80-90% PCR negativity by the end of consolidation.7,8 Interestingly As2O3 may show anti-leukemic efficacy for many days after the drug has been stopped, as suggested by the 70% of patients who became RT-PCR negative prior to starting consolidation despite being positive at the time of hematologic remission. There does not seem to be a major difference between patients with the bcr-1 or bcr-3 isoform but larger numbers need to be studied. There are, however, no data available on the significance of isoforms in APL patients primarily treated with As2O3. The median follow-up in our patients in our study is too short (20 months) to evaluate late relapses and the long-term significance of the various isoforms. These preliminary data show that all patients achieving hematologic remission on primary treatment with As2O3 also achieve molecular remission. Ninety-five percent of patients are in molecular remission by the end of consolidation with 85% achieving long-term remission. However, follow-up studies are needed to assess the durability of remissions in these patients.