Mary Varterasian

Multicenter Phase II Study of the Oral MEK Inhibitor, CI-1040, in Patients With Advanced Non-Small-Cell Lung, Breast, Colon, and Pancreatic Cancer

PURPOSE This multicenter, open-label, phase II study was undertaken to assess the antitumor activity and safety of the oral mitogen-activated extracellular signal regulated kinase kinase (MEK) inhibitor, CI-1040, in breast cancer, colon cancer, non-small-cell lung cancer (NSCLC), and pancreatic cancer. PATIENTS AND METHODS Patients with advanced colorectal, NSCLC, breast, or pancreatic cancer received oral CI-1040 continuously at 800 mg bid. All patients had measurable disease at baseline, a performance status of 2 or less, and adequate bone marrow, liver, and renal function. Expression of pERK, pAkt, and Ki-67 was assessed in archived tumor specimens by quantitative immunohistochemistry. RESULTS Sixty-seven patients with breast (n = 14), colon (n = 20), NSCLC (n = 18), and pancreatic (n = 15) cancer received a total of 194 courses of treatment (median, 2.0 courses; range, one to 14 courses). No complete or partial responses were observed. Stable disease (SD) lasting a median of 4.4 months (range, 4 to 18 months) was confirmed in eight patients (one breast, two colon, two pancreas, and three NSCLC patients). Treatment was well tolerated, with 81% of patients experiencing toxicities of grade 2 or less severity. Most common toxicities included diarrhea, nausea, asthenia, and rash. A mild association (P < .055) between baseline pERK expression in archived tumor specimens and SD was observed. CONCLUSION CI-1040 was generally well tolerated but demonstrated insufficient antitumor activity to warrant further development in the four tumors tested. PD 0325901, a second generation MEK inhibitor, has recently entered clinical development and, with significantly improved pharmacologic and pharmaceutical properties compared with CI-1040, it may better test the therapeutic potential of MEK inhibition in cancer.

Phase II Trial of Intravenous CI-1042 in Patients With Metastatic Colorectal Cancer

PURPOSE To evaluate the antitumor activity, safety, immune response, and replication of CI-1042 (ONYX-015), an E1B 55-kd gene-deleted replication-selective adenovirus, administered intravenously to patients with metastatic colorectal cancer PATIENTS AND METHODS Eighteen patients with metastatic colorectal cancer for whom prior chemotherapy failed were enrolled onto an open-label, multicenter, phase II study. CI-1042 was administered intravenously at a dose of 2 x 1012 viral particles every 2 weeks. Patients were evaluated for tumor response and toxicity; in addition, blood samples were taken for adenovirus DNA and neutralizing antibody analysis. RESULTS Common toxicities included flu-like symptoms, nausea, and emesis. All 18 patients eventually were removed from study because of progressive disease. Seven patients were assessed as having stable disease after 2 months of treatment, whereas two patients were considered to have stable disease after 4 months. Detectable circulating CI-1042 DNA was identified in 36% of patients 72 hours after last infusion, which is suggestive of ongoing viral replication. CONCLUSION In this phase II study, intravenous CI-1042 was administered safely to patients with advanced colorectal cancer. Toxicity was manageable, consisting primarily of flu-like symptoms. Stable disease was experienced by seven patients for 11 to 18 weeks.

Phase I study of bryostatin 1 in patients with relapsed non-Hodgkin's lymphoma and chronic lymphocytic leukemia.

PURPOSE To define, in a phase I study in relapsed non-Hodgkins lymphoma (NHL) and chronic lymphocytic leukemia (CLL), the maximum-tolerated dose (MTD), major toxicities, and possible antitumor activity of bryostatin 1, a macrocyclic lactone. PATIENTS AND METHODS Bryostatin 1 was delivered by 72-hour continuous infusion every 2 weeks to patients with relapsed NHL or CLL, at doses that ranged from 12 microg/m2 to 180 microg/m2 per course. Correlative investigations included evaluations of total protein kinase C (PKC) in peripheral blood and lymphoid differentiation in patient tumor tissue. RESULTS Twenty-nine patients were treated, including three patients with CLL and 26 with NHL. Generalized myalgia was the dose-limiting toxicity (DLT) and occurred in two of three patients treated with bryostatin 1 at 180 microg/m2 per course. Myalgias were dose-related and cumulative, and often started in the thighs and calves, improved with activity, were somewhat responsive to analgesics, and often took weeks to resolve once taken off study. Six patients were treated at the MTD of 120 microg/m2 per course. Myalgia, headache, and fatigue were common. Hematologic toxicity was uncommon. Total cumulative doses of bryostatin 1 up to 1,134 microg/m2 have been administered without untoward toxicity. Eleven patients achieved stable disease for 2 to 19 months. An in vitro assay for total PKC evaluation in patient peripheral-blood samples demonstrated activation within the first 2 hours with subsequent downregulation by 24 hours, which was maintained throughout the duration of the 72-hour infusion. CONCLUSION This phase I study defined the MTD and recommended phase II dose of bryostatin 1, when administered over 72 hours every 2 weeks, to be 120 microg/m2 (40 microg/m2/d for 3 days). Generalized myalgia was the DLT. Future studies will define the precise activity of bryostatin 1 in subsets of patients with lymphoproliferative malignancies and its efficacy in combination with other agents.

Tumor Lysis Syndrome in Small Cell Carcinoma and Other Solid Tumors

OBJECTIVE To review the risk factors and clinical findings associated with tumor lysis syndrome (TLS) in patients with small cell carcinomas and other solid tumors. METHODS Reports of TLS in the English-language literature were identified by searching MEDLINE and the bibliographies of relevant case reports, journal articles, and book chapters. All reports identified through these searches, including abstracts from national meetings, were reviewed and included in this analysis. Data regarding clinical and biochemical parameters relevant to the occurrence of TLS were extracted from each report. RESULTS Of the 25 reported solid tumor patients who developed TLS, 7 had small cell carcinoma, 5 breast cancer, and 4 neuroblastoma. TLS was associated with a variety of treatment regimens, including chemotherapy, immunotherapy, hormonal therapy, radiation therapy, and surgery. Common risk factors for TLS in this population included pretreatment renal insufficiency, elevated serum lactate dehydrogenase (LDH), and hyperuricemia. Among the typical biochemical findings of TLS, acute renal insufficiency and hyperuricemia were identified in nearly all patients and hyperkalemia, hyperphosphatemia, hypocalcemia, and increased serum LDH were reported in over 75% of patients. In addition, seven patients, including the current case, presented with profound metabolic acidosis. Nine of 25 patients died during the acute episode of TLS. CONCLUSIONS Although TLS occurs infrequently in patients with solid tumors, the risk factors and biochemical abnormalities associated with this potentially fatal complication of therapy must be recognized to allow for adequate monitoring and early initiation of appropriate therapeutic measures.

Multicenter, Randomized Phase II Trial of Oral CI-1033 for Previously Treated Advanced Ovarian Cancer

PURPOSE To evaluate the antitumor activity and toxicity of two doses of CI-1033 in patients with platinum-refractory or recurrent ovarian cancer, and to determine baseline expression of epidermal growth factor receptor in tumor cells. PATIENTS AND METHODS This phase II, open-label clinical trial evaluated CI-1033 in patients with ovarian cancer who failed prior platinum-based therapy. Two oral doses of CI-1033 were evaluated--a 50-mg and a 200--mg oral dose administered daily for 21 days in a 28-day cycle. Patients were evaluated for tumor response and toxicity; in addition, archival baseline tumor samples were analyzed by immunohistochemistry for erbB1 to erbB4 status. RESULTS One hundred five eligible patients were treated. Baseline demographic characteristics were balanced in this heavily pretreated patient population. The median number of prior chemotherapy regimens received was four. The most commonly encountered drug-related adverse events for both dose arms were gastrointestinal (diarrhea, nausea, stomatitis) toxicity, asthenia, and rash. No responses were observed. Stable disease was confirmed in 34% and 26% of patients in the 200-mg and 50-mg arms, respectively, and 1-year survival rates were 38.5% and 37.7%, respectively. Baseline erbB3 and erbB4 revealed the highest frequencies of expression, while erbB2 was the lowest. CONCLUSION CI-1033 did not show activity in unscreened patients with advanced ovarian cancer. At 50 mg/d, CI-1033 had a more favorable adverse events profile than at 200 mg/d. erbB3 and erbB4 receptors showed the highest expression in tumor samples while erbB2 revealed the least. There appears to be no association between baseline erbB expression and disease stability.

Phase II study of bryostatin 1 in patients with relapsed multiple myeloma.

Bryostatin 1, a macrocyclic lactoneisolated from the marine bryozoan Bugula neritina,is a protein kinase C (PKC) modulator which has shown bothpreclinical and clinical activity inlymphoid malignancies. We conducted aphase II trial of bryostatin 1 administeredat a dose of 120 μg/m2 by 72-hcontinuous infusion every 2 weeks inpatients with relapsed multiple myeloma. Treatment was well tolerated with myalgiasconstituting the primaray toxicity. Therewere no responses in nine evaluablepatients. The preclinical anti-lymphoidactivity is strong enough to supportfurther exploration of bryostatin 1 indifferent schedules and in combinationtherapy for multiple myeloma.

Infusional CHOP Chemotherapy (CVAD) With or Without Chemosensitizers Offers No Advantage Over Standard CHOP Therapy in the Treatment of Lymphoma: A Southwest Oncology Group Study

PURPOSE Two phase II studies were conducted to evaluate infusional cyclophosphamide, doxorubicin, vincristine, and dexamethasone chemotherapy, termed the CVAD regimen, alone (Southwest Oncology Group [SWOG] 9240) and with the chemosensitizers verapamil and quinine (SWOG 9125) to assess effects on response, survival, and toxicity in intermediate- and high-grade advanced-stage non-Hodgkins lymphoma (NHL). The results were compared with the historic group of patients randomized to CHOP chemotherapy on Intergroup (INT) 0067 (SWOG 8516). PATIENTS AND METHODS All patients had biopsy-proven intermediate- or high-grade NHL (lymphoblastic histology excluded), were ambulatory and previously untreated, and had bulky stage II, III, or IV disease. One hundred twelve patients were registered on SWOG 9240 and received cyclophosphamide 750 mg/m(2) by intravenous bolus day 1, doxorubicin 12.5 mg/m(2)/d and vincristine 0.5 mg/d delivered as a continuous 96-hour infusion on days 1 through 4, and dexamethasone 40 mg/d orally on days 1 through 4 (CVAD). Cycles were repeated every 21 days for eight cycles. One hundred patients on SWOG 9125 received the same chemotherapy and the chemosensitizers verapamil 240 mg bid and quinine 40 mg tid. Chemosensitizers were begun 24 hours before chemotherapy and continued for a total of 6 days. RESULTS Eighty-one patients were eligible for each study. The complete response (CR) rates were 39% on SWOG 9125 and 31% on SWOG 9240. With a median follow-up of 5.8 years on SWOG 9125 and 4.5 years on SWOG 9240, the 2-year failure-free survival (FFS) rate was 42% on SWOG 9125 and 41% on SWOG 9240. Two-year overall survival (OS) rate was 64% on SWOG 9125 and 58% on SWOG 9240. These results are comparable to a 44% CR rate, a 2-year FFS of 46%, and 2-year OS of 63% observed in 225 patients treated with CHOP on INT 0067 (SWOG 8516). CONCLUSION CVAD combination chemotherapy alone or with the chemosensitizers verapamil and quinine is not promising therapy with respect to improved response or OS in intermediate- and high-grade advanced-stage NHL.

Trisomy 6 as a Primary Karyotypic Aberration in Hematologic Disorders

We identified seven patients with hematologic disorders and trisomy 6 as the sole karyotypic aberration in bone marrow aspirates or unstimulated peripheral blood. Five patients were male and two were female; all were adults with ages ranging from 22 to 74 years. Three of the seven patients presented with manifestations of peripheral cytopenia. Their bone marrows were hypocellular with slight or no dysplastic changes and without an increase in blasts. One of these patients subsequently developed acute myeloid leukemia (AML-M1). The four remaining patients were initially diagnosed with AML--three consistent with French-American-British classification of M1 and M4 in the fourth patient. These results suggest that trisomy 6 is a nonrandom primary numerical anomaly of myeloid disorders. The association of cytopenia and hypoplastic bone marrow with trisomy 6 may constitute a new, distinctive variant among myelodysplastic syndromes.

Transplantation in patients with multiple myeloma: A multicenter comparative analysis of peripheral blood stem cell and allogeneic transplant

We performed a multicenter comparative analysis of autologous peripheral blood stem cell transplantation (PBSCT) and allogeneic bone marrow transplantation (alloBMT) in multiple myeloma. Forty-eight consecutive patients received either PBSCT (24 patients) or alloBMT (24 patients) at one of three institutions in the study group. Preparatory regimens consisted of melphalan and total body irradiation (TBI) or melphalan alone in the PBSCT group. The alloBMT group received one of four regimens: cyclophosphamide and TBI; cyclophosphamide, VP-16 and 1,3-bis(2-chloroethyl)-1-nitrosourea (CVB); busulfan and cyclophosphamide (BU/CY) and total marrow irradiation (TMI); or melphalan and TBI. Procedure-related mortality was 12.5% for the PBSCT group and 25% for the alloBMT group. With a median follow-up for survivors in the PBSCT and alloBMT groups of 11 months (range, 4-46) and 15 months (range, 2-84 months), respectively, there was no significant difference in median overall survival (33.5 versus 38.6 months, p = 0.7637) or event-free survival (16.7 versus 31 months, p = 0.8450). There was, however, a plateau in survival at 40% in the alloBMT group. No plateau in survival was seen in the PBSCT group. Clinical relapses occurred as late as 39 months posttransplant. Patients have survived up to 28 months postrelapse.

CLINICAL COURSE AND OUTCOME OF PATIENTS WITH HODGKIN'S DISEASE WHO PROGRESS AFTER AUTOLOGOUS TRANSPLANTATION

Twenty-six of fifty-eight patients undergoing autologous bone marrow transplantation (autoBMT) or peripheral stem cell transplantation (PSCT) for Hodgkins disease had progression of lymphoma (Hodgkins or non-Hodgkins) during the course of their follow-up. The majority of progressions, 81% (21/26), occurred within the first year of transplant; 12% (3/26) occurred at three years or more. Three patients developed a non-Hodgkins lymphoma; all B-cell tumors primarily involving the gastrointestinal tract. The majority of patients (23/26) received at least one therapy after progression and 65% (17/26) of patients received multiple therapies. One patient who received a second BMT is alive without evidence of disease at 49 months following the second autologous BMT. The median survival for the entire group is 11 months. Forty-six percent (12/26) of patients survived more than one year and twenty-three percent (6/26) survived more than two years after disease progression. Post-progression survival is significantly related to time to progression.