Cumulative Hematologic Toxicity Research Articles

Comparison of Condensed to Standard Schedule of High Dose Cytarabine Consolidation for Acute Myeloid Leukemia in First Complete Remission

Background Traditionally, acute myeloid leukemia (AML) consolidation therapy for patients less than 60 years old with low to intermediate risk disease has been treated with high dose cytarabine (HDAC) cycles given on days 1, 3, and 5 (HDAC-135). However, more recent publications have assessed alternative dosing, namely administering HDAC on days 1, 2, and 3 (HDAC-123). National Comprehensive Cancer Network (NCCN) Guidelines for AML discuss this alternative dosing for HDAC and do not recommend one over another. A prospective study found that there was no cumulative hematologic toxicity and no change in survival when comparing HDAC-123 to HDAC-135 5. As a result, Northside Hospital began using HDAC-123 in patients less than 60 years old for AML consolidation therapy. The purpose of this study was to assess the safety, efficacy, and health care resource consumption associated with HDAC-135 versus the condensed HDAC-123 regimen at Northside Hospital. Methods This single-center, retrospective study included patients with AML between 18 and 60 years old who received at least one cycle of HDAC-123 or HDAC-135 at Northside Hospital Atlanta's outpatient clinic from January 1, 2018 to January 1, 2023. The primary outcome was time to hematologic recovery of white blood cell (WBC), absolute neutrophil count (ANC), and platelets. Secondary endpoints were the amount of transfusions needed, incidence of documented infections, rate of hospital admission, and length of hospital stay. Results A total of 51 patients were included. Twenty one patients received a cumulative total of 39 cycles of HDAC-123 and 30 patients received a cumulative total of 57 cycles of HDAC-135. Overall, baseline characteristics were similar between groups although hemoglobin and hematocrit were significantly lower in the HDAC-123 group. In the HDAC-123 group compared to the HDAC-135 group, the median day of WBC recovery was 15 and 24 days, respectively (p < 0.001). The median day of ANC recovery was 16 and 28 days, respectively (p < 0.001). The median day of platelet recovery was 16 and 20 days, respectively (p < 0.001). Conclusion The results of this retrospective review support the findings of other studies. HDAC-123 demonstrated a significantly reduced time to WBC, ANC, and platelet recovery compared to HDAC-135. HDAC-123 was also was associated with lower rates of microbiologically documented infections but did require more RBC transfusions. HDAC-123 may be preferred over HDAC-135 for consolidation therapy in patients less than 60 years old.

CTNI-41. PHASE II AND PHASE 0 RESULTS OF ABTC 1801: A MULTI-ARM CLINICAL TRIAL OF THE PARP INHIBITOR PAMIPARIB WITH VERY LOW DOSE METRONOMIC TEMOZOLOMIDE IN RECURRENT IDH MUTANT GLIOMAS

Abstract BACKGROUND Preclinical studies have demonstrated that IDH1-mutant (IDHmt) gliomas harbor a BRCAness phenotype with a defect in homologous recombination that confers PARP inhibitor sensitivity. METHODS The phase II component of ABTC 1801 examined the efficacy of the combination of pamiparib (BeiGene BGB-290) with low dose metronomic temozolomide in recurrent IDHmt grade 2 and 3 gliomas. In this two-stage design, Arm A enrolled patients who had failed two lines and Arm B a single line of alkylator therapy. Pamiparib and temozolomide doses based on phase I results was 60 mg BID and 20 mg daily. Primary endpoint was objective response rate (ORR). RESULTS 39 patients (Arm A 15, Arm B 24) enrolled in the phase II. Median age was 45 (range: 25-69), 56% male, and median KPS 90. 72% of tumors were MGMT methylated. There were no confirmed responses in Arm A and one in Arm B; neither arm met the threshold for additional accrual. One-third of subjects discontinued treatment for reasons other than progressive disease. Estimated median PFS was 5.8 months in Arm A and 11.3 months in Arm B. Seven subjects (Arm A 3, Arm B 4) developed DLT during treatment. Grade 3+ toxicity was principally hematologic; 9 patients had grade 3 anemia, 7 grade 3 and 3 grade 4 neutropenia, and 3 grade 3 thrombocytopenia. In enhancing and non-enhancing tumors from 8 surgical arm patients, median unbound drug tumor/plasma ratios were 0.98 and 0.92, respectively; and median unbound pamiparib tumor concentrations were 209 and 188 nmol/L (or nmol/kg), respectively, which were >20-fold the in vitro IC50 for PARP inhibition. CONCLUSIONS While pamiparib appeared to achieve sufficient pharmacologically active concentrations in both enhancing and non-enhancing tumors, combination with temozolomide did not produce a meaningful ORR in IDHmt recurrent gliomas. Cumulative hematologic toxicity was substantial.

High Response and Prolonged Treatment-Free Remission after a Short-Course of Modified Intensive Chemotherapy and Venetoclax in Elderly AML: An Updated Analysis of the Caveat Trial

Background Venetoclax (VEN) plus azacitidine has an established role in the management of older patients (pts) with AML (DiNardo, NEJM 2020). To explore the feasibility of intensive chemotherapy combined with VEN in older pts with newly diagnosed AML, we conducted the CAVEAT trial (Chua et al, JCO 2020). We now present an updated analysis of this trial (with >3 years median follow-up), reporting on the optimal dose of VEN with chemotherapy, with and without posaconazole (POSA), the deliverability of consolidation therapy, characteristics of treatment failure and observation of substantial treatment-free remission in subsets of pts using this time-limited, short-course regimen. Methods The CAVEAT study enrolled pts aged ≥65 years with de novo or secondary/therapy-related AML (sAML) considered suitable for intensive chemotherapy. Five VEN dose escalation cohorts (50-100-200-400-600 mg) were explored initially. Two additional cohorts examined the safety of adjusted dosing of VEN (50 or 100 mg) during anti-fungal prophylaxis with the strong CYP3A4 inhibitor POSA. For induction, VEN was administered over 14 days, commencing with a 7-day pre-chemo dose ramp-up, followed by a 7-day overlap with 5+2 chemotherapy (cytarabine 100mg/m2/d IVI d1-5 and idarubicin 12mg/m2 IV d2-3). Consolidation (CONS) with 2+1 chemotherapy (below), followed by up to 7 cycles of VEN monotherapy maintenance was planned. Results Data cut-off: 31MAR2022. A total of 69 pts are included in this analysis (first pt 17JUL2016, last pt 15MAY2020). Median age was 71 years (range 63-80). Poor risk features included sAML (42%), adverse karyotype (28%) and prior HMA (23%). From the dose escalation phase, the VEN 600 mg cohort was well tolerated (30-day mortality 6%). Induction with VEN-POSA (n=18) was also well tolerated (30-day mortality 0%) with 3 DLTs observed: 2 hematologic (1 in each cohort) and 1 due to pulmonary infiltrates occurring on d2 induction (suspected to be allopurinol hypersensitivity). No clinical TLS was observed. Although hematologic recovery was satisfactory after VEN-POSA induction, recovery was considerably longer in the VEN (100mg)-POSA cohort after CONS1 compared to VEN (50mg)-POSA for both neutrophils (median 64 vs 44d to 0.5 x109/L) and platelets (median not reached vs 26d to 50 x109/L). Therefore, if POSA is used concurrently, VEN 50 mg is recommended. Alternatively, if VEN 600 mg is used, POSA should commence only after completion of VEN. In the VEN 600 mg cohort, significant delays in hematological recovery were also observed after multiple rounds of attenuated CONS (VEN d1-14, bolus doses of cytarabine 100 mg/m2 d1-2, idarubicin 12 mg/m2 on d1), limiting deliverability (median CONS cycles 1; range 1-3). By intention-to-treat, the overall response (CR/CRi) rate was 73%. CR/CRi was 90% in de novo AML (vs 51% in sAML), 84% in intermediate karyotype (vs 69% in adverse), 76% and 83% in NPM1 and IDH2 mutant AML, respectively. With a median follow-up of 37 months (m), the median overall survival (OS) was 15.4m. Median OS was 31.3m in de novo AML (40% alive at 36m) and 30.3m in intermediate karyotype AML (38% alive at 36m). In the VEN 600 mg cohort, median OS was 24.1m (36% alive at 36m). As CAVEAT delivered just one intensive cycle of therapy, followed by limited post remission therapy (median time on therapy 7.7m), we next assessed the duration of treatment-free remission (TFR) among responders. Among pts achieving CR/CRi, 20/51 (39%) experienced TFR (Fig 1). The median TFR was 22.1m (range 4.6-48.3m). At data cut-off, 12 (24%) have ongoing TFR. Notably, 15/20 (75%) with TFR had an NPM1 or IDH2 mutation at diagnosis. 11 out of 14 evaluable pts with NPM1 mutation had mutation clearance by RT-qPCR, including 3 with NPM1 negative disease at time of failure (1 refractory, 2 relapse). Two pts with persistently mutated NPM1 at relapse had a concomitant FLT3-ITD or KIT mutation. The mutation landscape at relapse is shown (Fig 1) Conclusion VEN combined with modified intensive chemotherapy achieved high response rates in older pts with newly diagnosed AML. With long-term follow-up, the time-limited CAVEAT schedule enabled pts, especially with mutated NPM1 or IDH2, to experience a durable treatment-free remission. Cumulative hematological toxicity is limiting, prompting us to now explore non-anthracycline CONS (low dose cytarabine 20mg/m2 SC d1-10 + VEN 400mg d1-7, for up to 4 cycles), followed by VEN monotherapy (400mg D1-14 q28d cycle x7). Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Germline BRCA1/2 mutations and severe haematological toxicities in patients with breast cancer treated with neoadjuvant chemotherapy

BackgroundBRCA1 and BRCA2 play a central role in DNA repair. Therefore, patients harbouring germline (g) BRCA1/2 mutations (m) treated with chemotherapy might be at higher risk of haematological toxicities. MethodsPatients from German Breast Group (GBG) and Arbeitsgemeinschaft Gynäkologische Onkologie-breast group studies with early triple-negative breast cancer (TNBC) and known gBRCA1/2m status treated with anthracycline-taxane-based neoadjuvant chemotherapy were analysed. Primary objective was the rate of neutropenia grade (G)III–IV in cycle 1 (C1). Secondary objectives included effects on overall and other haematological toxicities GIII-IV in C1, cumulative haematological toxicity across all cycles, relative total dose intensity, and granulocyte-colony stimulating factor prophylaxis. Haematological toxicities under taxanes, carboplatin, and cyclophosphamide were explored. ResultsTwo hundred nine of 1171 (17.8%) evaluated patients had gBRCA1/2m. In C1, 37.4% gBRCA1/2m versus 35.7% wild-type patients had neutropenia GIII-IV (P = 0.683). For C1, gBRCA1/2m predicted neither for neutropenia GIII-IV (odds ratio [OR]: 1.26, 95% confidence intervals [CI]: 0.87–1.82, P = 0.226) nor for other haematological toxicities GIII-IV (OR: 0.91, 95% CI: 0.64–1.31, P = 0.625) in multivariable regression models. Analyses of cumulative toxicities across all cycles yielded similar results except thrombocytopaenia GIII-IV, which was increased in gBRCA1m patients. In patients treated with taxanes, the rate of haematological toxicities GIII-IV was higher in gBRCA1/2m compared with wild-type (59.5% versus 43.1%; p < 0.001). No difference was seen under cyclophosphamide or platinum-containing chemotherapies. ConclusionsgBRCA1/2m was not associated with higher risk of overall severe haematological toxicities in the first cycle or cumulatively across all cycles under standard chemotherapy for TNBC. Under taxane, patients with gBRCA1/2m might have a higher risk of haematological toxicities GIII-IV, requiring further research.

Three Weekly Versus Weekly Cisplatin Concurrent Radiotherapy in Patients with Post-operation Cervical Cancer: A Retrospective Analysis

To evaluate completion rate and acute treatment-related toxicity of concurrent chemoradiotherapy with cisplatin 40 mg/m2 for one day per week compared to cisplatin 20 mg/m2 for consecutive five days every three weeks in postoperative radiotherapy for cervical cancer. This retrospective study included 59 patients, with postoperative pathology suggesting cervical malignant tumors, FIGO stage IB-IIA, undergoing radiotherapy and concurrent chemotherapy between January 2013 and December 2017. All patients were divided into two groups, weekly group and triweekly group. Patients of weekly group received weekly cisplatin at a dose of 40 mg/m2 for at least 4 to 5 cycles and patients of triweekly group received 20 mg/m2 cisplatin for five days every three weeks for at least 1 or 2 cycles. All patients received concurrent chemotherapy at the beginning of radiotherapy. Main outcome measures included clinical completion rate and acute treatment-related toxicity. The proportion of patients who completed 4 or 5 cycles chemotherapy in weekly group was 66.7%(20/30), and that completed 1 or 2 cycles chemotherapy in triweekly group was 100%(29/29, P＜0.05). Grade 1-2 acute hematological toxicities were similar in the two groups, as follows: grade 1-2 leukopenia (66.7% vs. 51.7%, p＞0.05), grade 1-2 thrombocytopenia (10% and 13.7%, p＞0.05), and grade 1-2 anemia (43.3% and 20.6%, p＞0.05). Most patients in weekly group have no significant gastrointestinal toxicity, while, in triweekly group, 65.5% patients have grade 1-2 nausea or vomiting( p＜0.05), with no grade 3-4 gastrointestinal toxicity. Only 3.3% of weekly group were found having grade 1 hepatotoxicity, and only 3.4% of triweekly group were found having grade 1 nephrotoxicity. No treatment related deaths were encountered. This retrospective study appears to show concurrent chemoradiotherapy with triweekly 20mg/m2 cisplatin for consecutive five days in post-operation cervical cancer gives better completion rate with similar Grade 1-2 acute hematological toxicities, hepatotoxicity, and nephrotoxicity. In addition, the main reason that part of patients in triweekly group did not complete the whole chemotherapy courses was hematological toxicities after the first cycle chemotherapy. Nevertheless, the cumulative hematological toxicity of weekly cisplatin 40 mg/m2 was not lower than that of three weekly 20 mg/m2 because of the high frequency of chemotherapy. Due to the reduction of the frequency of chemotherapy, the time of hospitalization and the simplification of hospitalization procedures, the better compliance, and quality of life of three weekly patients are in line with the situation of the shortage of medical resources in China. We will continue to follow up these patients to assess late treatment related toxicity and long term treatment outcomes.

The Btk Inhibitor, PCI-32765, Induces Durable Responses with Minimal Toxicity In Patients with Relapsed/Refractory B-Cell Malignancies: Results From a Phase I Study

AbstractAbstract 964 Introduction:Bruton's tyrosine kinase (Btk) is a downstream mediator of B-cell receptor signaling. PCI-32765 is a potent, selective, irreversible and orally bioavailable small molecule inhibitor of Btk. We have previously reported initial efficacy and safety data with this agent in various B-cell malignancies (ASCO 2010 abstract # 8012). We now report updated efficacy and safety of PCI-32765 in patients (pts) with long-term dosing. Pts and Methods:Pts on the Phase 1 study were treated with escalating doses over 6 cohorts. Cohort 1 was dosed at 1.25 mg/kg/day with subsequent dose escalation (2.5, 5.0, 8.3, 8.3 continuous dosing, and 12.5 mg/kg/day) based on safety evaluation. Pts were analyzed according to histology, pretreatment clinical and laboratory characteristics, PCI-32765 dose levels, overall response (OR), and response duration. Results:Responses and time on study (≥ 6 months) are summarized in Table 1. Of 47 pts enrolled in the Phase 1 study, 20 pts (43%) achieved an OR including 3 complete remissions (CR) and 17 partial remissions (PR). Fourteen of 47 pts have been on study ≥ 6 months; of these 8 pts demonstrated a PR or better and 6 pts maintained stable disease (SD). Responses were observed irrespective of pretreatment risk factors such as performance status, lactate dehydrogenase (LDH) levels, or disease burden. Durable responses were seen at all dose levels and across various histologic subtypes (Table 1) and currently 9 of 14 pts with treatment ≥ 6 months are still on study. Study-drug related Grade ≥ 3 toxicities were reported in 9/47 pts (19%). Five of 47 pts discontinued study drug due to adverse events: neutropenia (Grade 3) lasting > 7 days, hypersensitivity reaction (Grade 3), small bowel obstruction (Grade 3), anemia (Grade 2), and exacerbation of chronic obstructive pulmonary disease (Grade 3). No evidence of cumulative hematologic toxicity or long-term safety signals have been observed. No treatment-related deaths have been reported. Conclusion:PCI-32765 is a novel oral Btk inhibitor that induces durable objective responses in various relapsed or refractory B-cell malignancies. The favorable safety profile and lack of cumulative hematologic toxicities support further studies of both monotherapy and combination treatment with PCI-32765. Disclosures:Fowler:Pharmacyclics: Consultancy, Research Funding. Off Label Use: This phase I trial describes the results of a first in human Phase I trial. This drug is not FDA approved for the treatment of malignancy. Sharman:Pharmacyclics, Inc: Honoraria, PI grant. Smith:pharmacyclics: Research Funding. Boyd:pharmacyclics: Research Funding. Grant:pharmacyclics: Research Funding. Kolibaba:pharmacyclics: Research Funding. Furman:Pharmacyclics, Inc: Research Funding. Buggy:pharmacyclics: Employment. Loury:Pharmacyclics: Employment, Equity Ownership. Hamdy:pharmacyclics: Employment. Advani:Pharmacyclics, Inc: Honoraria, PI grant.

Phase I clinical and pharmacokinetic study of trabectedin and carboplatin in patients with advanced solid tumors

This study intended to determine the maximum tolerated dose (MTD) and the recommended phase II dose (RD) of trabectedin combined with carboplatin in patients with advanced solid tumors. Carboplatin-pretreated patients received carboplatin AUC 4 (Group 1), whereas carboplatin-naïve patients received carboplatin AUC 5 (Group 2) as a 1-h i.v. infusion followed by trabectedin at dose range from 0.5-1.2 mg/m(2) in the schedule of 3-h/every-3-weeks. Pharmacokinetic (PK) sampling was performed in the first 2 cycles. Forty-four patients were treated and evaluable for safety and dose-limiting toxicities (DLTs). In Group 1, at trabectedin 1.0 mg/m(2), cumulative hematological toxicity was found in all patients and 1/10 patients had DLTs. The RD was considered trabectedin 0.8 mg/m(2) combined with carboplatin AUC 4. Although no DLT occurred at this dose level, frequent dose delays (28.6%) and the 4-week cycle re-scheduling (66.7%) were required. In Group 2, DLTs occurred at trabectedin 0.8 mg/m(2) (3/8 patients), 1.0 mg/m(2) (3/10 patients) and 1.2 mg/m(2) (2/2 patients) with cumulative hematological toxicity associated with an important number of transfusions. In this group, neither the MTD nor the RD were established. Promising antitumor activity was found for this carboplatin/trabectedin combination; especially in patients with advanced ovarian cancer and soft tissue sarcoma. No significant PK drug-drug interaction occurred. This study established a trabectedin dose of 0.8 mg/m(2) combined with carboplatin AUC 4 and given every 4 weeks as the most feasible schedule in carboplatin-pretreated patients. Dose and cycle recommendations for carboplatin-naïve patients warrant further evaluation.

Bortezomib, dexamethasone, cyclophosphamide and lenalidomide combination for newly diagnosed multiple myeloma: phase 1 results from the multicenter EVOLUTION study

This phase 1 study (Clinicaltrials.gov: NCT00507442) was conducted to determine the maximum tolerated dose (MTD) of cyclophosphamide in combination with bortezomib, dexamethasone and lenalidomide (VDCR) and to assess the safety and efficacy of this combination in untreated multiple myeloma patients. Cohorts of three to six patients received a cyclophosphamide dosage of 100, 200, 300, 400 or 500 mg/m(2) (on days 1 and 8) plus bortezomib 1.3 mg/m(2) (on days 1, 4, 8 and 11), dexamethasone 40 mg (on days 1, 8 and 15) and lenalidomide 15 mg (on days 1-14), for eight 21-day induction cycles, followed by four 42-day maintenance cycles (bortezomib 1.3 mg/m(2), on days 1, 8, 15 and 22). The MTD was the cyclophosphamide dose below which more than one of six patients experienced a dose-limiting toxicity (DLT). Twenty-five patients were treated. Two DLTs were seen, of grade 4 febrile neutropenia (cyclophosphamide 400 mg/m(2)) and grade 4 herpes zoster despite anti-viral prophylaxis (cyclophosphamide 500 mg/m(2)). No cumulative hematological toxicity or thromboembolic episodes were reported. The overall response rate was 96%, including 20% stringent complete response (CR), 40% CR/near-complete response and 68% >or=very good partial response. VDCR is well tolerated and highly active in this population. No MTD was reached; the recommended phase 2 cyclophosphamide dose in VDCR is 500 mg/m(2), which was the highest dose tested.

Brief Chemoimmunotherapy Rituximab (R)-FND ± R Maintenance as First Line Treatment in Elderly Patients with Advanced Follicular Lymphoma (FL): Preliminary Analysis of a Prospective Randomized IIL Trial

Introduction: we investigated efficacy and safety of a brief chemo-immunotherapy R-FND with R consolidation followed by randomization between R maintenance or observation in a study specifically devised for elderly.Material and methods: From January 2004 to December 2007, 235 pts (age 60–75) with untreated advanced stage FL were enrolled into 33 IIL centres and written informed consent was obtained. Treatment plan was: 4 courses of R-FND (375 mg/m2 Rituximab on day 0, 25 mg/m2 fludarabine on dd 1–3, 10 mg/m2 mitoxantrone on day 1, 10 mg dexamethasone on dd 1–3) every 28 days followed by 4 weekly R consolidation; responding pts (CR+CRu+PR) were randomized between R maintenance (375 mg/m2 every 2 months for 4 doses) or observation. Qualitative and quantitative PCR monitoring for IgH/Bcl-2 rearrangement was performed on bone marrow (BM) at diagnosis, after R-FND and R consolidation and during maintenance/observation. Preliminary analysis was performed on 158 pts enrolled in the first 3 years of study up to 31, December 2006.Results: Median age was 65; stage III/IV 19/68%; 57% had BM involvement, 20% B symptoms and 19% LDH >normal; according to FLIPI 11% were at low risk, 32% at intermediate and 57% at high risk. PCR analysis was done in 148 pts at diagnosis: 80 (54%) were Bcl-2 positive. Relevant concomitant illness was observed in 4% of pts, mainly hypertension and chronic pulmonary obstructive disease. Overall response, CR rate and PCR negativity associated with CR after R–FND and R consolidation are shown in the following table. R consolidation converted in CR 28 (45%) of 62 PRs after R-FND.A high CR rate was achieved also in poor prognosis pts (CR according to FLIPI: Low 63%, Intermediate 75%, High 63%). One hundred and thirty-one pts were randomized between maintenance or observation. Twenty-seven patients were not randomized because of: 12 stable/progressive disease, 9 adverse events, 2 concomitant neoplasia, 2 lost at follow-up, 1 non-compliant and 1 withdrawal of consent not due to toxicity. PCR quantitative analysis is still ongoing; preliminary results in the first 40 pts showed a rapid decrease of Bcl-2 rearrangement below the threshold value in 36 pts after R-FND and in 39 pts after R consolidation. The most frequent CTC grade 3–4 toxicity was neutropenia in 26% of 745 courses, with only 11 serious infections; there was no evidence of cumulative haematological toxicity during treatment. R related reactions were seen in 11% of the courses with R discontinuation in only 2 pts. So far 152 pts are alive, 5 died of lymphoma and 1 of hepatic failure in HBV reactivation.Conclusions: A brief chemo-immunotherapy R-FND + R consolidation is safe and effective in elderly pts with untreated FL with high CR rate also in high risk pts. Brief chemo-immunotherapy R-FND led to a rapid reduction of Bcl-2 rearrangement in the majority of pts. Correlation between quantitative PCR and clinical response and outcome will be presented. The results of the whole study will provide insights on the role of R maintenance after brief chemo-immunotherapy in such cohort of pts.NORRCRQualitative PCR- associated with CR (66 pts evaluable for clinical and molecular response)Baseline158---R-FND x 4158142 (90%)80 (51%)27 (41%)R consolidation136131 (83%)105 (67%)43 (65%)

A phase II study of fixed dose rate gemcitabine in patients with relapsed mullerian tumors

Gemcitabine (2',2'-difluorodeoxycytidine) is a novel purine analog with clinical activity against ovarian cancer. Accumulation of gemcitabine triphosphate (dFdCTP) increases in a linear fashion with prolonged infusions of gemcitabine, and there is a strong relationship between intracellular accumulation of dFdCTP and DNA damage. Women with ovarian, fallopian tube, or primary peritoneal carcinoma and documented recurrent disease were eligible for the study. Patients could not have received more than four prior lines of chemotherapy and had to have measurable or evaluable disease. Gemcitabine 800 mg/m2 administered by intravenous infusion at 10 mg/m2/min (fixed dose rate [FDR]) on days 1 and 8 of a 21-day schedule. Twenty-eight patients with a median age 60 (range, 40-77) years were treated. Although 43% were Eastern Cooperative Oncology Group 0, 50% had liver metastases. Eighty-eight cycles of therapy were delivered (median 2 [range, 1-6]). Five of the first ten patients treated at 800 mg/m2 could not receive day 8 FDR-gemcitabine because of neutropenia, and the starting dose was reduced to 700 mg/m2. Even at this dose there was cumulative hematologic toxicity resulting in dose reductions. Vomiting, mucositis, diarrhea, allergy, rash, fever, and alopecia were mild. In 28 patients, there was only one partial response (4%, 95% CI 0-18%) and median time to progression was 1.7 (interquartile range, 1.2-3.9) months. FDR-gemcitabine 700 mg/m2 administered by intravenous infusion at an FDR of 10 mg/m2/min had minimal activity against heavily pretreated recurrent tumors of müllerian origin. The optimal dose and schedule of gemcitabine is yet to be defined in this population.

Hematologic Safety and Tolerability of Topotecan in Recurrent Ovarian Cancer and Small Cell Lung Cancer: An Integrated Analysis

The purpose was to conduct an integrated analysis of the cumulative hematologic toxicity of topotecan in patients with relapsed ovarian cancer and small cell lung cancer (SCLC). Data were pooled from eight phase II and phase III clinical studies performed in patients with relapsed stage III/IV ovarian cancer or extensive SCLC treated with topotecan at a dose of 1.5 mg/m(2) per day on days 1-5 of a 21-day course. Quantitative hematologic toxicities were assessed using the National Cancer Institute Common Toxicity Criteria. A total of 4,124 courses of therapy was administered to the 879 patients in the pooled population. Grade 4 neutropenia was experienced by 78% of patients. The lowest nadirs for neutrophils and platelets generally occurred after the first course of therapy, followed by improvement or stabilization in subsequent courses. Neutropenia was noncumulative. During the first course, significant risk factors were identified: renal impairment and advanced age (grade 3/4 thrombocytopenia and grade 4 neutropenia) and prior radiotherapy; performance status score > or =2; SCLC; and exposure to both cisplatin (Platinol; Bristol-Myers Squibb, Princeton, NJ, http://www.bms.com) and carboplatin (Paraplatin; Bristol-Myers Squibb) (grade 3/4 thrombocytopenia only). The most frequent interventions for hematologic toxicities were RBC transfusions, treatment delays, G-CSF support, and dose reductions. Analysis of neutrophil and platelet nadirs and dosing for each course of therapy showed no apparent evidence of cumulative neutropenia or thrombocytopenia. The risk of grade 3 or 4 anemia was higher during the first four courses of therapy and may need to be more aggressively managed with erythropoietin therapy.

A Phase I Trial Defining the Maximum Tolerated Systemic Exposure of Topotecan in Combination with Carboplatin and Etoposide in Extensive Stage Small Cell Lung Cancer

Purpose. Topotecan is active in relapsed small cell lung cancer; thus, its addition to the standard carboplatin-etoposide regimen may improve outcomes in extensive-stage small cell lung cancer (ES-SCLC) patients. Significant interpatient variability in the topotecan systemic exposure results when it is dosed based on body surface area (mg/m2). The purpose of this Phase I trial was to determine the maximally tolerated systemic exposure (MTSE) of topotecan in combination with carboplatin and etoposide. Methods. Thirty-four chemotherapy-naïve ES-SCLC patients received topotecan in combination with carboplatin AUC 5 mg/mL*min and oral etoposide 100 mg/m2/day. Topotecan was administered as a 30-minute infusion either on Days 1–5 or Days 1–3 and the dosage was individualized to attain a topotecan lactone AUC range (ng/mL*hr) in successive patient cohorts from 7 to 23; 24 to 36; 37 to 53; 54 to 66. Results. The majority (67 percent) of the measured topotecan AUCs were within target range. Overall, 8 of 34 patients experienced Cycle 1 dose-limiting toxicity (DLT), either neutropenia or thrombocytopenia. Carboplatin administration prior to topotecan resulted in 2 of 6 patients having Cycle 1 DLT. When the administration sequence was changed (topotecan, carboplatin, etoposide), Cycle 1 hematologic toxicity decreased; however, the maximum topotecan lactone AUC of 24–36 ng/mL*hr (median dose 0.82 mg/m2) had significant cumulative hematologic toxicity. The number of topotecan doses were reduced from 5 to 3, which resulted in a maximum topotecan lactone AUC of 37 to 53 ng/mL*hr with only 1 of 6 patients having Cycle 1 DLT. Overall response rate was 71 percent with median survival of 10.8 months. Conclusion. It is feasible to target topotecan lactone AUC in adult ES-SCLC patients. However, this triplet regimen resulted in considerable hematologic toxicity and has a median survival comparable to carboplatin-etoposide. Alternative, less toxic regimens should be investigated for improving survival in ES-SCLC.

Bortezomib in Combination with Dexamethasone for Relapsed Multiple Myeloma.

Single agent bortezomib treatment at the dosage and schedule published by Richardson (2003) stabilizes disease in nearly 60% of patients with relapsed, refractory multiple myeloma (MM). However, only 35% of patients achieve an objective (≥ minor) response (MR). Dexamethasone adds to clinical anti-myeloma activity of bortezomib by inducing 18% responses in patients with either stable or progressive disease on bortezomib alone. In an attempt to improve disease response, we evaluated a primary bortezomib/dexamethasone combination in patients with multiple myeloma in ≥ 2nd untreated or refractory relapse. Eligible patients were 18–80 years old, had an ECOG performance status of 0 – 2 and adequate renal, hepatic, pulmonary and cardiac function. Pre-existing peripheral neuropathy ≥ grade 2 or neuropathic pain of any grade were exclusion criteria. However, we made no restrictions in terms of pretreatment blood counts. Fifteen consecutive patients with relapsed multiple myeloma (9/15 with ≥ 2nd untreated and 6/15 with refractory relapse; 71% with a chromosome 13 deletion) were scheduled to receive bortezomib 1.3 mg/m² IV days 1, 4, 8, 11 q 3 weeks for up to 8 cycles in combination with dexamethasone 20 mg PO once daily on the day of bortezomib injection and the day thereafter. Treatment was withheld for nonhematologic adverse events (AE) ≥ grade 3 and reinitiated at a 25% lower dose after resolution. Treatment was not stopped for myelosuppression of any grade if interim response evaluations precluded myeloma progression as the cause of cytopenia. One patient (7%) achieved a complete response, 10 (67%) a partial response, and 1 (7%) a MR resulting in an overall response rate (≥ MR) of 80% (9/9 with ≥ 2nd untreated and 3/6 with refractory relapse; EBMT/IBMTR/ABMTR criteria). Responses occurred after a median of 3 weeks and were independent of conventional prognostic parameters. Importantly, 8/10 patients with a chromosome 13 deletion achieved a ≥ PR. Adverse events, mainly myelosuppression (34% grade 3/4 neutropenia; 47% grade 3/4 thrombocytopenia), neuropathy (grade 2/3/4 20%/7%/0%) and fatigue (grade 2/3/4 20%/13%/20%), were manageable. There was no case of neutropenic infection or thrombocytopenic bleeding. Two patients suffered herpes zoster. The percentage of transfusion dependent patients decreased from 44% during the 1st treatment cycle to 23% and 11% after the 2nd and 3rd treatment cycles, respectively. Even non-responders did not experience cumulative hematologic toxicity. After a median follow-up of 5 months, median event free and overall survival were not reached. Five out of 15 patients were non-responders (n=1) or had experienced disease progression (n=4). Notably, 2 patients with sustained paraprotein and bone marrow remission (confirmed by biopsy) had extramedullary disease progression, pointing to a bone marrow restricted response to bortezomib in MM. This study indicates that bortezomib can be given safely even in patients with poor bone marrow reserve, who would not have been candidates for the SUMMIT trial. Though the remission rate was high, remissions often were not durable. This fact underlines the need for consolidating treatment and evaluation of bortezomib combinations with other anti-myeloma agents.

A phase II study of fixed dose-rate gemcitabine in patients with relapsed Müllerian tumors

5151 Background: Gemcitabine (2',2'-difluorodeoxycytidine) is a novel purine analog with clinical activity against ovarian cancer. Accumulation of gemcitabine triphosphate (dFdCTP) increases in a linear fashion with prolonged infusions of gemcitabine and there is a strong relationship between intracellular accumulation of dFdCTP and DNA damage. Methods: Women with ovarian, fallopian tube or primary peritoneal carcinoma and documented recurrent disease were eligible for the study. Patients could not have received more than 4 prior lines of chemotherapy and had to have measurable or evaluable disease. Gemcitabine 800 mg/m2 was administered by i.v. infusion at 10 mg/m2/min (Fixed dose-rate (FDR)) on days 1 and 8 of a 21 day schedule. Results: Twenty-eight patients with a median age 60 (range, 40–77) years were treated. Although 43% were ECOG 0, 50% had liver metastases. Eighty-eight cycles of therapy were delivered (Median 2(Range, 1–6)). Five of the first 10 patients treated at 800 mg/m2 could not receive day 8 FDR-gemcitabine because of neutropenia and the starting dose was reduced to 700 mg/m2. Even at this dose there was cumulative hematologic toxicity resulting in dose reductions. Vomiting, mucositis, diarrhea, allergy, rash, fever and alopecia were mild. In 28 patients there was only one partial response (4%, 95% CI 0 –18%) and median time to progression was 1.7 (Interquartile range, 1.2 –3.9) months. Conclusions: FDR-Gemcitabine 700 mg/m2 administered by i.v. infusion at a fixed dose-rate of 10 mg/m2/min had minimal activity against recurrent tumors of Müllerian origin. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eli Lilly Co. Eli Lilly Co.

A phase II study of fixed dose-rate gemcitabine in patients with relapsed Müllerian tumors

5151 Background: Gemcitabine (2',2'-difluorodeoxycytidine) is a novel purine analog with clinical activity against ovarian cancer. Accumulation of gemcitabine triphosphate (dFdCTP) increases in a linear fashion with prolonged infusions of gemcitabine and there is a strong relationship between intracellular accumulation of dFdCTP and DNA damage. Methods: Women with ovarian, fallopian tube or primary peritoneal carcinoma and documented recurrent disease were eligible for the study. Patients could not have received more than 4 prior lines of chemotherapy and had to have measurable or evaluable disease. Gemcitabine 800 mg/m2 was administered by i.v. infusion at 10 mg/m2/min (Fixed dose-rate (FDR)) on days 1 and 8 of a 21 day schedule. Results: Twenty-eight patients with a median age 60 (range, 40–77) years were treated. Although 43% were ECOG 0, 50% had liver metastases. Eighty-eight cycles of therapy were delivered (Median 2(Range, 1–6)). Five of the first 10 patients treated at 800 mg/m2 could not receive day 8 FDR-gemcitabine because of neutropenia and the starting dose was reduced to 700 mg/m2. Even at this dose there was cumulative hematologic toxicity resulting in dose reductions. Vomiting, mucositis, diarrhea, allergy, rash, fever and alopecia were mild. In 28 patients there was only one partial response (4%, 95% CI 0 –18%) and median time to progression was 1.7 (Interquartile range, 1.2 –3.9) months. Conclusions: FDR-Gemcitabine 700 mg/m2 administered by i.v. infusion at a fixed dose-rate of 10 mg/m2/min had minimal activity against recurrent tumors of Müllerian origin. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eli Lilly Co. Eli Lilly Co.

Phase I Trial of Gemcitabine and Paclitaxel in Advanced Solid Tumors

Purpose. Gemcitabine and paclitaxel are chemotherapeutic agents with clinical antitumor activity in a broad range of malignant solid tumors. Because of preclinical synergy, unique mechanisms of action and resistance, and nonoverlapping toxicities, gemcitabine and paclitaxel combinations are attractive for testing in clinical trials. Prior weekly gemcitabine and paclitaxel regimens administered on a 28-day cycle have been limited by cumulative hematological toxicity on day 15, thus reducing the planned gemcitabine dose intensity. We therefore conducted a phase I trial of a 21-day schedule of weekly gemcitabine and paclitaxel to determine the tolerability, maximum tolerated dose (MTD), and preliminary estimates of efficacy of this regimen. Patients and Methods. Forty-one patients with advanced malignant solid tumors were accrued. Gemcitabine was given at a fixed dose of 1000 mg/m2 while paclitaxel was administered at an initial dose of 60 mg/m2, then escalated by 15 mg/m2 increments over seven dose levels to a prospectively planned maximum dose of 150 mg/m2. Both agents were infused intravenously on days one and eight every 21 days. At least three patients were enrolled per dose level. No intrapatient dose escalation was allowed. Results. All patients were assessable for toxicity and 31 were assessable for response. The regimen was generally well-tolerated. Dose-limiting thrombocytopenia was observed in one patient at a paclitaxel dose of 135 mg/m2/week (dose level 6). After expansion of this dose level by 14 additional patients, no further dose-limiting toxicities were observed although one patient at dose level seven died of neutropenic sepsis after completing three cycles. There were eight partial responders for an overall response proportion of 26% (95% CI: 11, 41). Twelve patients (39%) had stable disease. Conclusion. This 21-day schedule of gemcitabine and paclitaxel is safe, well-tolerated, and active. The recommended phase II dose is gemcitabine 1000 mg/m2 and paclitaxel 150 mg/m2 on days one and eight every 21 days. The antitumor activity observed with this regimen warrants further investigation.

Multicenter phase II trial of temozolomide in patients with glioblastoma multiforme at first relapse

Recurrent glioblastoma multiforme (GBM) is resistant to most therapeutic endeavors, with low response rates and survival rarely exceeding six months. There are no clearly established chemotherapeutic regimens and the aim of treatment is palliation with improvement in the quality of life. We report an open-label, uncontrolled, multicenter phase II trial of temozolomide in 138 patients (intent-to-treat [ITT] population) with glioblastoma multiforme at first relapse and a Karnofsky performance status (KPS) > or = 70. One hundred twenty-eight patients were histologically confirmed with GBM or gliosarcoma (GS) by independent central review. Chemotherapy-naïve patients were treated with temozolomide 200 mg/m2/day orally for the first five days of a 28-day cycle. Patients previously treated with nitrosourea-containing adjuvant chemotherapy received 150 mg/m2/day for the first five days of a 28-day cycle. In the absence of grade 3 or 4 toxicity, patients on the 150 mg/m2 dose schedule were eligible for a 200 mg/m2 dose on the next cycle. The primary endpoint was six-month progression-free survival assessed with strict radiological and clinical criteria. Secondary endpoints included radiological response and Health-related Quality of Life (HQL). Progression-free survival at six months was 18% (95% confidence interval (CI): 11%-26%) for the eligible-histology population. Median progression-free survival and median overall survival were 2.1 months and 5.4 months, respectively. The six-month survival rate was 46%. The objective response rate (complete response and partial response) determined by independent central review of gadolinium-enhanced magnetic resonance imaging (MRI) scans was 8% for both the ITT and eligible-histology populations, with an additional 43% and 45% of patients, respectively, having stable disease (SD). Objectively assessed response and maintenance of a progression-free status were both associated with HQL benefits (characterized by improvements over baseline in HQL domains). Temozolomide had an acceptable safety profile, with only 9% of therapy cycles requiring a dose reduction due to thrombocytopenia. There was no evidence of cumulative hematologic toxicity. Temozolomide demonstrated modest clinical efficacy, with an acceptable safety profile and measurable improvement in quality of life in patients with recurrent GBM. The use of this drug should be explored further in an adjuvant setting and in combination with other agents.

Combined high-dose platinum and etoposide in previously untreated ovarian cancer patients with residual disease

Only a limited number of patients with advanced ovarian cancer obtain a long-term disease-free interval. The purpose of this study is to find new active drugs and/or regimens. Carboplatin 200 mg m-2 day 1, cisplatin 50 mg m-2 days 2 and 3, and etoposide 70 mg m-2 i.v. days 1-5 every 4 weeks for six cycles were given to 43 previously untreated ovarian cancer patients with residual disease after primary laparotomy. The median observation time was 75 months (range, 63-87 months). Forty-two patients were evaluable for response and the overall pathological response rate was 57% (pathologic complete response (PCR) plus pathological partial response (PPR)), with 26% being PCRs (11/42; 95% confidence interval, 0.14-0.42). The main hematologic toxicity was thrombocytopenia grade 3-4 which occurred in 95% of the cycles. Dose-limiting leucocytopenia only occurred in 21%. Non-hematologic toxicity caused dose-reduction in 33% of the patients, with nephrotoxicity being the main reason (24%). The purpose of the study was to give a high total dose of platinum in combination with etoposide. However, this was not feasible due to excessive cumulative hematologic toxicity and nephrotoxicity. As the activity of the combination was no better than that obtained with other, less toxic regimens, the combination cannot be recommended.

Chemotherapy combined with zidovudine and GM-CSF in human immunodeficiency virus-related non-Hodgkin's lymphoma

The treatment of patients with non-Hodgkin's lymphoma related to the human immunodeficiency virus (HIV-NHL) is complicated by the underlying acquired immunodeficiency syndrome (AIDS). Patients without adverse prognostic factors (no AIDS prior to lymphoma, CD4+ lymphocyte counts greater than 100 x 10(6)/l and good performance status) can be cured of lymphoma and experience long-term survival. Our previous study with the intensive chemotherapy LNH84 regimen yielded a 63% complete response (CR) rate but median survival was only nine months, half of the patients died of AIDS and the other half of their lymphoma. We report here the results of a phase II study combining the same chemotherapy with zidovudine and GM-CSF. Our goal was to improve the treatment outcome over that of our previous study; GM-CSF was expected to decrease the hematological toxicity of chemotherapy and thus permit a dose intensity increase, while zidovudine was supposed to slow down the evolution of AIDS. A phase II non-randomized prospective clinical trial in 7 centres. Thirty-two consecutive adult patients presenting HIV-NHL and performance status of less than three without active opportunistic infection underwent three cycles of doxorubicin 75 mg/m2, cyclophosphamide 1,200 mg/m2, vindesine 2 mg/m2 for two days, bleomycin 10 mg for two days and prednisolone 60 mg/m2 for five days (ACVB). Chemotherapy was associated with zidovudine (5 mg/kg/d) and GM-CSF (5 mu g/kg/d). The induction phase was followed by a four-month consolidation phase. CR and PR > 75% were observed in 56% of patients; 25% of the patients died during the induction phase. These results were analogous to those of the previous study (63% and 14%, respectively). Neither hematological tolerance nor dose intensity were improved. With a mean follow-up of 23.5 months, median survival was 6.7 months. The rate of non-NHL AIDS-related death during CR was not reduced (22% in our study vs. 16% in our previous one). GM-CSF failed to reduce significantly the cumulative hematological toxicity of chemotherapy and zidovudine. New antiviral agents without hematological toxicity would perhaps be useful in this setting.

923 Phase I study of taxol administered weekly in patients with persistent ovarian cancer

We commenced a Phase I study of Taxol administered weekly in pts with persistent ovarian cancer to assess feasibility, toxicity and schedule dependency. Cumulative hematologic toxicity has been uncommon with this schedule. In vitro studies with Taxol have suggested that fractionated brief infusion schedules would be more effective than standard 24 H infusion every 21 days. All pts had received prior platinum-based chemotherapy in addition to at least one regimen with Taxol. Pts with a history of grade 3–4 neuropathy were ineligible. Methods Taxol dose levels of 40, 50, 60, 80 and 100 mg/m2 per week were studied. Treatment was administered in the ambulatory clinic with standard Taxol pre-medication. Results 18 pts enrolled, 17 evaluable for toxicity. Overall response in 3/14 (21.4%) pts evaluable, 2 pts with stable disease. Total of 170 Taxol cycles delivered, median 8 per pt (1–18). 166/170 cycles delivered on schedule. Mean WBC nadir following Taxol cycles was 3.8 (0.8–10.4) × 109/L. No cumulative hematologic toxicity has been noted. No alopecia noted. 11 pts entered study with neuropathy, 7 with grade I, 4 with grade II. No grade III neuropathy noted. In spite of Taxol 100 mg/m2/weekly, we have thus far failed to demonstrate dose-limiting toxicity. Dose escalation continues. Conclusions 1) Weekly administration of Taxol on this dose and schedule is feasible. 2) This schedule does not result in cumulative myelosuppression. We commenced a Phase I study of Taxol administered weekly in pts with persistent ovarian cancer to assess feasibility, toxicity and schedule dependency. Cumulative hematologic toxicity has been uncommon with this schedule. In vitro studies with Taxol have suggested that fractionated brief infusion schedules would be more effective than standard 24 H infusion every 21 days. All pts had received prior platinum-based chemotherapy in addition to at least one regimen with Taxol. Pts with a history of grade 3–4 neuropathy were ineligible. Taxol dose levels of 40, 50, 60, 80 and 100 mg/m2 per week were studied. Treatment was administered in the ambulatory clinic with standard Taxol pre-medication. 18 pts enrolled, 17 evaluable for toxicity. Overall response in 3/14 (21.4%) pts evaluable, 2 pts with stable disease. Total of 170 Taxol cycles delivered, median 8 per pt (1–18). 166/170 cycles delivered on schedule. Mean WBC nadir following Taxol cycles was 3.8 (0.8–10.4) × 109/L. No cumulative hematologic toxicity has been noted. No alopecia noted. 11 pts entered study with neuropathy, 7 with grade I, 4 with grade II. No grade III neuropathy noted. In spite of Taxol 100 mg/m2/weekly, we have thus far failed to demonstrate dose-limiting toxicity. Dose escalation continues. 1) Weekly administration of Taxol on this dose and schedule is feasible. 2) This schedule does not result in cumulative myelosuppression.