Minnie Pearl Cancer Research Network Research Articles

Preoperative oxaliplatin (O), docetaxel (D), capecitabine (C), and concurrent radiation therapy (RT) for patients (pts) with localized esophageal cancer: A phase I/II trial of the Minnie Pearl Cancer Research Network

4058 Background: Preoperative chemoradiotherapy improves outcomes for pts with resectable esophageal cancer compared with surgery alone. We previously reported a 41% 3-year progression-free survival (PFS) with preoperative paclitaxel/carboplatin/5FU/RT in a large phase II trial. The present multicenter community trial examined the role of a newer combination regimen. Methods: The primary endpoints were to assess the safety and response rate (RR) of O/D/C/RT in pts with resectable stage I-III cancer of the mid-/distal-esophagus or GE junction. Treatment (tx): O 40 mg/m2 IV and D 20 mg/m2 IV weekly x 5; C 1000 mg/m2 PO BID D1–7, 15–21, 29–35; and RT 45 Gy, 1.8-Gy M-F weekly x 5, starting D1. Pts were resected 4–8 weeks after tx. The phase I portion (n=10) confirmed the safety of O/D/R, and C was added in the phase II portion. Eligibility: measurable disease; ECOG PS 0–1, informed consent. Analysis was by intent to treat. Results: Nineteen pts were enrolled from 9/04 to 10/05 (trial ongoing). Baseline features: median age 60 years (38–77); male/female, 82%/18%; ECOG PS 0/1: 27%/73%; adenocarcinoma/squamous (77%/23%); I (5%), IIA (5%), IIB (33%), III (38%), primary tumor not assessable (19%). All pts completed O/D/C/RT and 14 (74%) were resected. Grade (G) 3/4 non-hematologic toxicity: anorexia (16%), nausea (16%), and fatigue (11%). Other G3/4 non-hematologic toxicities were ≤5%, with no G3/4 esophagitis. No G3/4 hematologic toxicities or tx-related deaths occurred. Complete/partial responses assessed before surgery were seen in 2 pts/11 pts, respectively, for an overall RR of 68% (95% CI 46%-84%). Four pts (21%) had stable disease and 1 pt had progression (1 pt was unevaluable). Pathological complete responses were seen in 8 of 14 evaluable pts (57%). With a median follow-up of 8 months, actuarial 1-year PFS and overall survival (OS) are 66% and 79%, respectively. Median PFS and OS have not been reached. Conclusions: O/D/C/RT is a relatively well-tolerated and active preoperative therapy for pts with resectable esophageal cancer. Additional pts and follow-up are needed to assess this regimen’s benefits. [Table: see text]

Weekly Docetaxel/Estramustine Phosphate in Patients with Increasing Serum Prostate-Specific Antigen Levels After Primary Treatment for Prostate Cancer: A Phase II Trial of the Minnie Pearl Cancer Research Network

Purpose Docetaxel alone or in combination with estramustine prolongs survival in patients with metastatic hormone-refractory prostate cancer. The role of chemotherapy is undefined in the treatment of patients who develop an increasing serum prostate-specific antigen (PSA) level after primary therapy but have no detectable metastases. This phase II study was performed as a preliminary evaluation of the feasibility and efficacy of weekly docetaxel/estramustine in patients with prostate cancer and increasing serum PSA levels. Patients and Methods Between March 2001 and September 2003, 34 patients entered this phase II trial. All patients had biopsy-proven adenocarcinoma of the prostate and had increasing PSA levels but no clinically or radiographically detected metastases after primary therapy. All patients received docetaxel 35 mg/m 2 intravenously on days 1, 8, and 15 and estramustine phosphate 140 mg 3 times daily for 7 doses, beginning the evening before each dose of docetaxel. Treatment courses were repeated at 28-day intervals, and responding patients received a total of 6 courses. Results Thirty-one patients (91%) completed 6 courses of treatment. Thirty-two of 33 evaluable patients (97%) had a decrease in serum PSA level of > 50% during treatment, and 27 patients (82%) had normalization of serum PSA level. The median progression-free survival was 28 months, with 33% of patients progression free at 3 years. This treatment regimen was well tolerated with no myelosuppression-related complications or uncommon grade 3 nonhematologic toxicity. Conclusion Treatment with weekly docetaxel and estramustine is feasible and active in patients with prostate cancer and increasing serum PSA levels. However, the benefit of early treatment versus treatment when clinical metastases are detected requires demonstration in a randomized phase III trial.

Docetaxel and Epirubicin as First-Line Treatment for Patients with Metastatic Breast Cancer: A Minnie Pearl Cancer Research Network Phase II Trial

Background: Taxanes and anthracyclines are the two most active classes of cytotoxic agents in the treatment of patients with metastatic breast cancer. Epirubicin, a doxorubicin analog, has shown modest toxicity advantages when compared to the parent compound. In this Phase II trial, we evaluated the activity and toxicity of a docetaxel/epirubicin combination. Methods: Thirty patients with previously untreated metastatic breast cancer were treated with docetaxel 60 mg/m2 one-hour IV infusion and epirubicin 90 mg/m2 IV bolus; both drugs were repeated at 21-day intervals. Patients were evaluated for response after 2 courses of treatment; responding and stable patients continued treatment for a total of 6 courses. Results: Fifteen patients (50 percent) had objective response to treatment; an additional 20 percent of patients had stable disease of more then 6 months duration. The median and 2-year progression-free survivals were 12 months and 34 percent, respectively. Median and 2-year overall survivals were 18 months and 42 percent, respectively. Myelosuppression was the most common Grade 3/4 toxicity, and 2 patients in this trial (6 percent) had treatment-related mortality associated with severe sepsis. Conclusion: The results of this Phase II trial confirm previous observations regarding the efficacy and toxicity profile of the docetaxel/epirubicin combination. This combination has activity similar to other taxane/anthracycline combinations used in the first-line treatment of metastatic breast cancer.

Rituximab Plus Short-Duration Chemotherapy as First-Line Treatment for Follicular Non-Hodgkin's Lymphoma: A Phase II Trial of the Minnie Pearl Cancer Research Network

Rituximab Plus Short-Duration Chemotherapy as First-Line Treatment for Follicular Non-Hodgkin's Lymphoma: A Phase II Trial of the Minnie Pearl Cancer Research Network

796 ORAL Bevacizumab, erlotinib, and imatinib in the treatment of patients (pts) with advanced renal cell carcinoma (RCC): Update of a Minnie Pearl Cancer Research Network phase I/II trial

Cancer microenvironment is characterized by significantly lower oxygen concentration. This hypoxic condition is known to reduce drug responsiveness to cancer chemotherapy via multiple mechanisms, among which the upregulation of the ATP-binding cassette (ABC) efflux transporters confers resistance to a wide variety of structurally unrelated anticancer drugs. Vatalanib (PTK787/ZK22584) is a multitargeted tyrosine kinase inhibitor for all isoforms of VEGFR, PDGFR and c-Kit, which exhibit potent anticancer activity in vitro and in vivo. We investigated the potentiation effect of vatalanib on the anticancer activity of conventional cytotoxic drugs in colon cancer cell lines under both normoxic and hypoxic conditions. Mechanistically, vatalanib was found to inhibit ABCG2 and ABCB1 efflux activity, presumably by acting as a competitive inhibitor and interfering with their ATPase activity. Under hypoxic growth condition, ABCG2 and ABCB1-overexpressing cells sorted out by FACS technique as side population (SP) were found to be significantly more responsive to SN-38 (ABCG2 and ABCB1 substrate anticancer drug) in the presence of vatalanib. The anchorage independent soft agar colony formation capacity of the SP cells was remarkably reduced upon treatment with a combination of SN-38 and vatalanib, compared to SN-38 alone. However, vatalanib, at concentrations that produced the circumvention of the transporters-mediated resistance, did not appreciably alter ABCG2/ABCB1 mRNA or protein expression levels or the phosphorylation of Akt and extracellular signal-regulated kinase (ERK1/2). Our study thus advocates the further investigation of vatalanib for use in combination chemotherapy to eradicate drug-resistant cancer cells under hypoxia.

Single-Agent Gefitinib in Patients with Untreated Advanced Non–Small-Cell Lung Cancer and Poor Performance Status: A Minnie Pearl Cancer Research Network Phase II Trial

BACKGROUND: Patients with advanced non–small-cell lung cancer (NSCLC) and poor performance status (PS) are often excluded from trials. Gefitinib is a safe oral agent that may benefit these patients. PATIENTS AND METHODS: Seventy-two patients with poor PS and advanced NSCLC were enrolled onto this study of gefitinib 250 mg per day given orally until disease progression, with evaluation at 8 weeks. Eligible patients had no previous chemotherapy, an Eastern Cooperative Oncology Group PS of 2/3, and stage IIIB/IV NSCLC. Quality of life (QOL) and symptom response (SR) scores were calculated using the Functional Assessment of Cancer–Lung questionnaire. Patient characteristics included a median age of 75 years; PS of 2/3; and bronchoalveolar (n = 3), adenocarcinoma (n = 29), squamous cell (n = 21), large-cell (n = 11), and unspecified histology (n = 6). Mean treatment duration was 4 months (range, 3 days to 18 months), and median duration of follow-up was 12 months. Grade 3/4 toxicities included rash and diarrhea. RESULTS: Among 70 patients assessed for response, there were 3 partial responses (4%), 32 patients with stable disease (46%), and 18 with progressive disease (26%). Median progression-free survival (PFS) and overall survival (OS) were 3.7 months and 6.3 months, respectively. Six-month and 1-year PFS and OS rates were 35% and 21% and 50% and 24%, respectively. Eighty-two percent and 48% of patients reported improvements or no change in QOL and SR, respectively. CONCLUSION: Gefitinib demonstrates modest efficacy and is well tolerated as initial therapy in advanced NSCLC for patients with poor PS.

Paclitaxel, carboplatin, and gemcitabine (PCG) versus gemcitabine and vinorelbine (GV) in chemotherapy naïve patients (pts) with advanced non-small cell lung cancer (NSCLC): A phase III trial of the Minnie Pearl Cancer Research Network (MPCRN)

7056 Background: The MPCRN phase III trial comparing the triplet PCG to the non-platinum doublet GV has been completed for pts with advanced NSCLC. Initially, a four-arm randomized trial was done and PCG and GV were associated with the best median survivals (Cancer 2002; 95:1279–85). GV was significantly less toxic than PCG, providing the rationale for extending the randomized comparison of PCG to GV as a phase III trial. Methods: The primary objective of this randomized phase III study was to compare survival of previously untreated pts with advanced NSCLC treated with PCG versus GV. PCG treatment consisted of P 200mg/m2 IV D1, C (AUC=5) IV D1, G 1000mg/m2 IV D1,8 q 21D. GV treatment was G 1000mg/m2 IV D1,8,15 q 28D and V 25mg/m2 IV D1,8,15 q 28D. Pts were re-evaluated q 2 cycles. Pts without evidence of progression or undue toxicity received a maximum of 6 cycles. Eligibility criteria included: stage IIIB/IV NSCLC, no prior chemotherapy, measurable disease, ECOG PS 0–2, adequate organ function, absence of brain metastases, and informed consent. Study was powered (0.80) to demonstrate an increase in expected 1-year survival from 30% with GV to 45% for PCG, requiring a total of 174 pts on each arm. P-values reported are two sided. Results: 349 pts were enrolled. Baseline pt characteristics were similar in the two groups. Objective response rates were similar for both regimens (PCG 25%; GV 26%). There was less grade 3/4 neutropenia, thrombocytopenia, anemia, alopecia, nausea/vomiting, myalgia/arthralgia and neuropathy (grade 2/3/4) with GV. One-year progression-free survival (PFS) and survival for PCG versus GV were 12% versus 15% (p=NS), and 39% versus 43% ((p=NS), respectively. Conclusions: In the first-line treatment of advanced NSCLC, PCG and GV are equivalent in terms of PFS and survival. Doublet non-platinum therapy with GV is associated with much less toxicity. Further study of GV in early stage NSCLC is warranted. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb

Bevacizumab, erlotinib, and imatinib in the treatment of patients (pts) with advanced renal cell carcinoma (RCC): A Minnie Pearl Cancer Research Network phase I/II trial

4542 Background: Most pts with clear cell RCC have loss of Von Hippel Lindau (VHL) protein primarily due to gene mutation, ultimately resulting in overexpression of vascular endothelial growth factor (VEGF), transforming growth factor (TGF-:), epidermal growth factor (EGF), and platelet-derived growth factor (PDGF). In a previous phase II trial, we demonstrated that combined VEGF/EGF receptor inhibition with bevacizumab and erlotinib was an active and well tolerated treatment for pts with metastatic RCC. In this phase I/II trial, we add imatinib, a PDGF receptor antagonist, to the combination of bevacizumab/erlotinib. Methods: Eligibility: metastatic clear cell RCC, 0–2 previous systemic regimens, ECOG PS 0–1, no previous anti-angiogenesis or EGF receptor inhibitor therapy, no active CNS metastases, adequate organ function, no history of thromboembolic disease, informed consent. All pts received bevacizumab 10mg/kg IV q 2 weeks, and erlotinib 150mg po daily. In the phase I portion of the trial, imatinib levels were escalated: 300mg qd (cohort 1), 400mg qd (cohort 2), and 600mg qd (cohort 3). Pts were evaluated for response after 8 weeks; treatment continued until tumor progression. Results: In the phase I portion of the trial, imatinib 400mg qd was identified as the maximum tolerated dose. At this dose level, 2 of 10 patients had reversible dose-limiting toxicity (diarrhea). Other grade 3 toxicity (1 pt each): nausea, vomiting, rash, pruritus, fatigue, arthralgia. Grade 1/2 toxicities included rash (77%), diarrhea (69%), nausea (61%), fatigue (54%), vomiting (31%), and proteinuria (23%). Amongst the 15 pts treated in the phase I portion of the study, 2 pts had partial response and 9 pts had minor response/stable disease after 8 weeks. At present, 25 pts have been entered on the phase II portion of the study, and accrual is expected to be completed within the next 2 months. Conclusions: The combination of bevacizumab 10mg/kg IV q 2 weeks, erlotinib 150mg po qd, and imatinib 400mg po qd is tolerable therapy for pts with metastatic RCC. Preliminary results also indicate activity with this 3-drug regimen. Updated results on the phase II study will be presented. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech Genentech Genentech

Paclitaxel/carboplatin/etoposide (PCE) therapy for advanced poorly differentiated neuroendocrine (PDNE) carcinoma: A Minnie Pearl Cancer Research Network phase II trial

4058 Background: PDNE carcinoma may arise from a variety of primary sites or present as an unknown primary. PDNE tumors have historically been sensitive to platinum/etoposide-based chemotherapy, as opposed to very poor activity in well differentiated neuroendocrine tumors. This phase II trial expands our experience with PCE in the treatment of patients (pts) with PDNE carcinoma. The objectives were to determine the objective response rate and survival. Methods: Eligibility requirements: small cell carcinoma (except small cell lung cancer) or poorly differentiated carcinoma (PDC) with diagnostic IP staining or electron microscopy; unknown or known primary; metastatic or locally advanced tumor; well differentiated carcinoid-type tumors excluded; ECOG PS 0–2; no previous chemotherapy; measurable disease; adequate organ function; informed consent. Pts received P 200mg/m2 IV, day 1; C AUC 6.0 IV, day 1; E 50/100mg po alternating, days 1–10; (repeated q 21 days x 4 courses). Local radiotherapy was subsequently administered to patients with advanced local tumor. Responding/stable pts received P 70mg/m2 IV, 6 of 8 weeks, for 24 weeks. Results: Between 1/99 and 11/04, 66 pts were treated. Pt characteristics: median age 58 years; male/female, 40/26 [small cell (12 pts); PDC (54 pts)]; primary site known/unknown, 27/39; visceral metastases, 51 pts (77%); ≥ 2 metastatic sites, 44 pts (66%). 59 pts were evaluable for response: complete, 9 pts (15%); partial, 24 pts (40%); stable/minor, 21 pts (35%); progression, 5 pts (10%). Median response duration was 9 months. After a median follow-up of 32 months, median survival is 14.8 months, with 1-, 2-, 3-, 4-, and 5-year survivals of 57%, 34%, 23%, 15%, and 15%, respectively. There was no difference (p=0.43 log rank) in survival comparing pts with known to unknown primary (median 15.6 vs. 13.8 and 1-, 2-year survivals 58%, 39% vs. 55%, 30%, respectively). Grade 3/4 toxicity was predominantly myelosuppression. Conclusions: PCE is active against PDNE and produces clinical benefit and prolongation of survival. A minority of pts remain alive, some progression-free, for several years. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb Bristol-Myers Squibb

Concurrent paclitaxel/carboplatin/infusional 5-FU/radiation therapy (RT) with or without subsequent esophageal resection in patients with localized esophageal cancer: A Minnie Pearl Cancer Research Network trial

4018 Background: Optimal treatment for patients (pts) with localized esophageal cancer is unclear. In various reported trials, results with concurrent chemotherapy/RT have been comparable to results with treatment programs containing surgical resection. We previously demonstrated the efficacy of preoperative concurrent paclitaxel/carboplatin/5FU/RT in a large phase II trial (41% 3-yr PFS). In this trial, we attempt to further define the role of surgical resection by randomizing pts to resection vs completion of full dose RT, following the same preop therapy. Methods: Eligibility: untreated esophageal/GE junction squamous or adenocarcinoma; clinical stage I-III; surgical candidate; ECOG PS 0–2; adequate organ function; informed consent. All pts received paclitaxel 200mg/m2 IV and carboplatin AUC 6.0 IV, days 1 & 22; 5-FU 225mg/m2/day, 24-h continuous infusion, days 1–42; radiation therapy 45 Gy (1.8 Gy single daily fractions). After completion of preop treatment, pts were randomized to either surgical resection (4–6 weeks after preop therapy) or continued RT (total dose 64.8 Gy) plus 1 additional course of paclitaxel/carboplatin. Overall survival and PFS were the major endpoints. Results: Between 10/99 and 10/04, 194 pts were treated: median age 60 years; male/female 81%/19%; adenocarcinoma 72%; distal or GE junction location 84%; clinical stage I vs II/III 9%/91%. Following chemotherapy/RT, 89 pts (46%) agreed to randomization, and 57 pts proceeded with the treatment to which they randomized. When all patients are considered, resected pts (N=91) and full dose RT pts (N=50) had similar median PFS (20 vs 15 mo; p=.92), OS (27 vs 24 mo; p=.74), and 3-yr survival (35% vs 31%). Comparisons were similar in the subset of randomized pts. 4 pts (2%) had treatment-related death during induction; 3 pts (3%) had postop death. Conclusions: Attempts to randomize pts to resection vs full dose RT were largely unsuccessful. However, in large parallel groups of pts, these treatments produced similar PFS and OS, suggesting resection may not be a required component of combined modality treatment. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb

Weekly docetaxel and bortezomib in the treatment of patients with advanced hormone refractory prostate cancer (HRPC): A Minnie Pearl Cancer Research Network phase II trial

4735 Background: Docetaxel (75mg/m2 every 3 weeks) is now standard first-line treatment for patients (pts) with HRPC. Bortezomib, a novel proteosome inhibitor, has shown single-agent activity in pts with refractory HRPC. In an effort to improve efficacy of treatment, we evaluated the combination of docetaxel and bortezomib in this multicenter, community-based phase II trial. Methods: Eligibility criteria: metastatic HRPC; no previous chemotherapy; ECOG PS 0–2; measurable metastatic disease or rising PSA levels with osseous metastasis; serum creatinine ≤ 2mg/dl; adequate hepatic and bone marrow function; informed consent. All patients received docetaxel 30mg/m2 IV and bortezomib 1.6mg/m2 IV both given on days 1, 8, 15 of each 28-day cycle. Bortezomib was administered 60 minutes after infusion of docetaxel. Pts were evaluated for response after 8 weeks of treatment; treatment continued in responding patients for 6 cycles. Results: 30 of a planned 50 pts enrolled between 7/03 and 10/04: median age, 70 years; > 1 hormonal therapy, 70%; ECOG 0/1/2, 37%/60%/3%; osseous metastases only, 57%; osseous/soft tissue, 37%; soft tissue only, 7%; prior prostatectomy, 53%; prior localized XRT, 43%. At present, 22 pts have been evaluated for PSA response: PR 5 (23%), stable 12 (54%), progression 5 (23%). 2 of 11 pts with measurable disease (18%) had PR. With median followup of 4 months, 73% of pts remain progression-free. Grade 3/4 toxicities included: fatigue 1 (3%); nausea 1 (3%). 2 pts had grade 2 neuropathy. There were no treatment-related hospitalizations. Conclusions: The regimen of docetaxel followed by bortezomib administered on a weekly basis has activity and acceptable toxicity in patients with metastatic HRPC. Updated efficacy results will be presented. No significant financial relationships to disclose.

Irinotecan (I), carboplatin (C), and imatinib (IM) in the first-line treatment of extensive-stage small cell lung cancer (SCLC): A phase II trial of the Minnie Pearl Cancer Research Network

7049 Background: The tyrosine kinase c-kit has variable expression in SCLC and may be a poor prognostic factor. IM targets c-kit expression, providing rationale for studying its role in combination...

Irinotecan (I), carboplatin (C), and radiotherapy (RT) followed by bevacizumab (B) in the treatment of limited-stage small cell lung cancer (SCLC): A phase II trial of the Minnie Pearl Cancer Research Network

7050 Background: Preclinical studies have demonstrated VEGF expression in SCLC, a target that may predict response to treatment with anti-angiogenic agents such as B. Few trials have incorporated these agents into the treatment of SCLC, providing rationale for studying B in addition to chemoradiotherapy. Methods: The primary endpoints of this multicenter phase II study were to assess the safety and response rate (RR) of I/C/RT followed by B in patients (pts) with limited-stage SCLC. Treatment consisted of: C AUC=5 IV D1, I 50mg/m2 IV D1, 8 Q 21D for 4 cycles, and concurrent RT 1.8 Gy QD to a total of 61.2 Gy, beginning with the 3rd cycle. 3rd and 4th cycles were 28D each. Pts were restaged after 4 cycles. Pts without progression or undue toxicity received B 10 mg/kg IV Q 14D for 10 doses. Eligibility criteria included: measurable disease, ECOG PS 0–1, adequate organ function, <500mg/24 hour proteinuria, informed consent, and absence of active brain metastases, or hemoptysis. Results: Forty-one pts were enrolled between 08/03 and 09/04. The range of follow-up is 2–14 months. Baseline characteristics include: median age 66 years (42–78); male/female, 35%/65%; ECOG PS 0,1,2: 29%/66%/5%. Grade (G)3/4 non-hematologic toxicity included: hypertension (5%), diarrhea (11%), DVT (5%), vomiting (13%), and fatigue (11%). G3/4 hematologic toxicity included: neutropenia (37%), anemia (0%), and thrombocytopenia (16%). There were no treatment-related deaths, however, 2 pts came off study for dyspnea possibly related to treatment. Response data are available for 37 pts. Complete/partial RR were observed in 12 pts (32%)/18 pts (49%), respectively, for an overall RR of 81%. Eleven percent of pts had stable disease, and no pts have had disease progression (3 pts were unevaluable.) Six-month progression-free (PFS) and overall survival (OS) were 92% and 87%, respectively. One-year PFS and OS will be presented at ASCO. Conclusions: I/C/RT followed by B is a safe and well-tolerated regimen with acceptable RR in the treatment of limited-stage SCLC. One-and two-year PFS and OS will be important in estimating the impact of B in the treatment of SCLC. No significant financial relationships to disclose.

Rituximab with short duration chemotherapy followed by 90Y ibritumomab tiuxetan as first-line treatment for patients with follicular lymphoma: Update of a Minnie Pearl Cancer Research Network phase II trial

6577 Background: First-line treatment with chemotherapy/rituximab combinations improves complete remission (CR) rates and lengthens remission duration in patients with follicular NHL. We previously demonstrated a high CR rate with short course chemotherapy plus rituximab (CHOP-R or CVP-R). In this phase II trial, we added 90Y ibritumomab tiuxetan following short course CHOP-R, in an attempt to further improve the CR rate. Methods: Eligibility criteria included: follicular NHL grades 1–3, stages II-IV, ECOG PS 0–2, adequate organ function, no CNS involvement, no HIV infection, informed consent. Patients with cardiac ejection fraction < 45% received CVP-R instead of CHOP-R. All patients received 4 weeks of rituximab (375mg/m2 weekly x 4) followed by 3 courses of CHOP-R (standard doses). After complete restaging, responding patients with bone marrow involvement < 25% received 90Y ibritumomab tiuxetan 5 weeks after the last dose of CHOP-R. Final restaging was performed 12 weeks after 90Y ibritumomab tiuxetan. Results: 42 patients entered the trial between 4/02 and 3/04. Patient characteristics: median age 57 years; stage IV, 60%; low or low-intermediate IPI risk category, 88%. 3 patients (7%) did not complete treatment (toxicity during CHOP-R, 2; HACA+, 1 patient). Following short course CHOP-R, 100% of patients responded (CR 28%, PR 72%). After 90Y ibritumomab tiuxetan, CR rate rose to 67%. After median follow-up of 20 months, actuarial 2-year PFS is 77%. No unexpected toxicity was seen during CHOP-R therapy. Grade 3/4 hematologic toxicity following 90Y ibritumomab tiuxetan included: neutropenia, 64% (grade 4, 16%); thrombocytopenia 47% (grade 4, 0%); platelet transfusions, 19%; neutropenia/fever, 0. No grade 3/4 non-hematologic toxicities occurred. Myelosuppression resolved within 12 weeks in all pts. Conclusions: Short duration CHOP-R followed by 90Y ibritumomab tiuxetan is highly active and well tolerated in patients with follicular NHL. Further follow-up is necessary to assess progression-free and overall survival. No significant financial relationships to disclose.

Adjuvant paclitaxel (P)/carboplatin (C) in stages I, II non-small cell lung cancer (NSCLC): Comparison of two schedules in phase II trials by the Minnie Pearl Cancer Research Network

7123 Background: Adjuvant therapy with P (200mg/m2)/C (AUC=6) every 3 weeks for 4 cycles is associated with a 13% increase of survival in stage IB NSCLC patients (pts) (Late/breaking abstracts from the 2004 ASCO meeting. J Clin Oncol 2004;22;suppl:7019). Other recent phase III trials also support survival benefit of adjuvant chemotherapy in early stage NSCLC. In metastatic NSCLC, weekly P with q 4 week C may be superior to q 3 week P/C. We conducted two sequential phase II adjuvant trials in stages I and II NSCLC from 1996–2003 to evaluate the toxicity and feasibility of two different schedules of P/C (weekly P with q 4 week C, q 3 week P/C). Methods: Eligibility criteria for both trials included: complete surgical resection with clear margins; stages IB, IIA, IIB (T2N1, T3N0); 3–8 weeks from surgery; ECOG PS 0, 1; adequate organ function; informed consent. A total of 181 pts were enrolled in both trials. 69 pts were treated in the first trial (IB 38, IIA/B 31) with P (200mg/m2)/C (AUC=6) repeated every 3 weeks for 3 courses and 112 pts were treated in the second trial (IB 38, IIA/B 74) with weekly P 100mg/m2 days 1, 8, 15, and carboplatin (AUC=6) day 1, repeated every 28 days for 3 cycles. Pts were followed every 2–3 months subsequently. Results: Toxicity of both regimens was mild with no treatment-related deaths. There were only 2 hospitalizations for neutropenia/fever with each schedule, but there was more nadir grade 3 neutropenia detected in the weekly schedule. Other grade 3/4 toxicities were unusual and similar in both schedules. Survival at 4 years for all pts with stages IB and IIA/IIB was 70% and 50%, respectively. There was no difference with comparing P schedules (p=0.87 log rank). 90% of the pts completed the every 3-week P/C (82% full doses) and 85% completed the weekly P/C therapy (75% full doses). Conclusions: Both P/C regimens are feasible and well tolerated. The survival of pts in these two phase II trials with 3 cycles appears similar to the recently reported positive phase III trials of 4 cycles of adjuvant chemotherapy. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb

Fludarabine/rituximab (FR) followed by alemtuzumab as first-line treatment for patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL): A Minnie Pearl Cancer Research Network phase II trial

6556 Background: The addition of rituximab to fludarabine-based chemotherapy has improved the molecular CR rate and extended progression-free survival as first-line treatment for CLL/SLL. Alemtuzumab improves the CR rate in patients (pts) with residual disease following first-line FR combinations. In this multicenter, community-based phase II trial, we evaluate the efficacy and toxicity of FR followed by short course alemtuzumab. Methods: Eligibility criteria: untreated CLL/SLL requiring treatment; stages II-IV; ECOG PS 0–2; platelet count > 50,000/μL; adequate liver and kidney function; informed consent. All pts received fludarabine 25mg/m2 IV days 1–4, repeated every 28 days for 4 courses, and rituximab 375mg/m2 on weeks 1, 2, 3, 4, 5, 9, and 13. 4 weeks after completion of FR, responding pts received alemtuzumab 30mg 3 times weekly for 4 weeks. Final restaging occurred 4 weeks after completion of alemtuzumab. Results: 37 pts enrolled between 2/02 and 11/04: median age 58 years; male/female, 59%/41%; CLL/SLL, 73%/27%; WBC > 50,000/μL, 43% of pts. 5 pts are still receiving treatment. Of the remaining 32 pts, 29 completed FR, and 21 completed alemtuzumab treatment as planned. 3 pts were withdrawn during FR (myelosuppression, 1; MI 1; facial swelling, 1) and 7 during alemtuzumab (infusion reactions, 4; infection, 2; diarrhea, 1). 24 of 29 evaluable pts (83%) had objective response (CR 10, PR 14). After median follow-up of 17 months, actuarial 2-year PFS and OS are 79% and 89%, respectively. Grade 3/4 toxicity during FR: neutropenia, 26%; thrombocytopenia, 6%; infusion reactions, 6%; neutropenia/fever, 8%. Grade 3/4 alemtuzumab-related toxicity: infusion reactions, 38%; opportunistic infections, 27% (fatal in 2 pts); neutropenia, 14%; neutropenia/fever, 7%; thrombocytopenia, 7%. Conclusions: FR followed by alemtuzumab is highly active, moderately toxic first-line treatment for CLL/SLL. Opportunistic infections are common but manageable in most pts. This type of intensive first-line treatment merits additional evaluation in good performance status pts with CLL/SLL. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech

Weekly docetaxel versus weekly docetaxel/gemcitabine as first-line therapy for patients who are elderly or with poor performance status (PS) or with serious comorbidities with advanced non-small cell lung cancer (NSCLC): Interim safety analysis of a Minnie Pearl Cancer Research Network phase III trial

7151 Background: We have previously shown that weekly docetaxel (D) and weekly docetaxel/gemcitabine (D/G) are active well tolerated regimens for advanced NSCLC patients who are elderly or with poo...

Paclitaxel, carboplatin, and oral etoposide as initial treatment for advanced ovarian carcinoma: a Minnie Pearl Cancer Research Network phase II trial

To evaluate the feasibility and toxicity of the combination of paclitaxel, carboplatin, and etoposide in the first-line treatment of patients with stage III or IV adenocarcinoma of the ovary. Patients entering this trial received paclitaxel 200 mg/m(2), 1 h IV infusion, day 1; carboplatin AUC 6.0 IV, day 1; etoposide 50 mg alternating with 100 mg orally, days 1-10. Patients received 6 courses of treatment, administered at 21-day intervals. All patients were assigned a response category using clinical restaging criteria. The primary endpoints for this trial were progression-free and overall survival. Between October 1996 and April 2001, 52 patients were treated. The overall objective response rate for the 48 evaluable patients was 75%, with 46% complete responses. Amongst the 36 patients with suboptimal disease, median progression-free and overall survivals were 12 and 24 months, respectively. After a median follow-up of 64 months, the median progression-free and overall survival has not been reached for the optimal patients; 5-year progression-free survival is 57% for this group. Treatment-related myelosuppression was common, but myelosuppression-related complications were uncommon, as was grade 3/4 non-hematologic toxicity. No episodes of acute myelogenous leukemia have developed. The combination of paclitaxel, carboplatin, and oral etoposide was feasible and effective in this patient population. Unlike previous reports, no episodes of acute leukemia were seen following this treatment. Definitive conclusions regarding the benefit of adding etoposide to a taxane/platinum combination will require a comparative trial.

Carcinoma of Unknown Primary Site: Sequential Treatment with Paclitaxel/Carboplatin/Etoposide and Gemcitabine/Irinotecan: A Minnie Pearl Cancer Research Network Phase II Trial

To evaluate the efficacy and toxicity of the sequential administration of paclitaxel (Taxol; Bristol-Myers Squibb; Princeton, NJ), carboplatin (Paraplatin; Bristol-Myers Squibb), and oral etoposide (VePesid; Bristol-Myers Squibb) followed by gemcitabine (Gemzar; Eli Lilly; Indianapolis, IN) and irinotecan (Campostar; Pfizer Pharmaceuticals; New York, NY) in the first-line treatment of patients with carcinoma of unknown primary site. One hundred thirty-two patients were treated with sequential combination chemotherapy for a maximum of six cycles. All patients had relatively poor prognostic features. Fifty-nine patients had well-differentiated adenocarcinoma, 73 patients had poorly differentiated carcinoma, and 121 patients had performance status scores of 0 or 1. Thirty-three (30%) of 111 assessable patients (95% confidence interval 27%-33%) had objective responses to treatment (26 partial responses, seven complete responses). The combination of gemcitabine and irinotecan was associated with significantly less toxicity than the triple-drug regimen and improved the responses in several patients (10%). The response rates were similar in the two major histologic tumor types, but were lower for patients with liver-dominant tumors (13%) and higher for patients with lymph-node-dominant tumors (50%). The median progression-free survival time, median survival time, and actuarial survival rates at 1 and 2 years were 5.7 months, 9.1 months, 35%, and 16%, respectively. Sequential combination chemotherapy with paclitaxel/carboplatin/oral etoposide and gemcitabine/irinotecan is an active treatment for patients with carcinoma of unknown primary site, but overall toxicities are greater than those seen with other combinations of new drugs and survival appears similar to that observed in 264 other patients treated in our four previous phase II trials. A better understanding of the biology of these heterogeneous tumors will likely lead to improved therapy for these patients.

Gemcitabine and irinotecan in patients with previously treated carcinoma of unknown primary site: A Minnie Pearl Cancer Research Network phase II trial

4167 Background: Three sequential phase II trials done by the Minnie Pearl Cancer Research Network of taxane, platinum, and etoposide combinations for carcinoma of unknown primary site (CUP) have produced median survivals of about 10 months, and 1, 2, 3, 5, and 8-year survivals of 42%, 22%, 18%, 12%, and 10%, respectively. In an effort to improve efficacy, we evaluated second-line treatment with a new combination regimen of gemcitabine and irinotecan. Methods: The primary objective was to evaluate the toxicity and response rate in CUP as second-line therapy. Eligible patients (pts) had adenocarcinoma, poorly differentiated adenocarcinoma, poorly differentiated carcinoma, or poorly differentiated neuroendocrine carcinoma (PDNE); one prior chemotherapy regimen, not including recent irinotecan and/or gemcitabine; absence of brain metastasis; and adequate organ function. Gemcitabine 1000 mg/m2 IV days 1, 8 and irinotecan 100 mg/m2 IV days 1, 8 were given every 21 days. Pts with objective responses or stable tumor after 2 cycles (6 weeks) continued additional 3-week cycles for a recommended 6 cycles. Results: 31 pts were treated and 27 were evaluable for response; median age 50 years (range 24–74); performance status (0=1, 1=28, 2=2); men - 15; women - 16. The response rate was 15% with 3 (11%) partial responses, 1 (4%) complete response. 11 pts had stable disease and 12 progressive disease. Of the 2 pts with PDNE, both had stable disease. The median time-to-progression, median survival, and 1-year survival were 3.5 months, 4 months, and 15%, respectively. Grade 3/4 toxicities included: neutropenia (30%), thromobcytopenia (8%), diarrhea (8%), anemia (9%), neutropenic fever (3%), nausea/vomiting (8%), and fatigue (8%). Conclusions: Gemcitabine/irinotecan is an active and well-tolerated second-line treatment for pts with CUP. A randomized prospective phase III study of gemcitabine/irinotecan compared to paclitaxel/carboplatin/etoposide in the first-line setting is ongoing. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eli Lilly Eli Lilly; Pfizer-Pharmacia