John Gutheil

Efficacy and Safety of Trastuzumab as a Single Agent in First-Line Treatment of HER2-Overexpressing Metastatic Breast Cancer

PURPOSE To evaluate the efficacy and safety of first-line, single-agent trastuzumab in women with HER2-overexpressing metastatic breast cancer. PATIENTS AND METHODS One hundred fourteen women with HER2-overexpressing metastatic breast cancer were randomized to receive first-line treatment with trastuzumab 4 mg/kg loading dose, followed by 2 mg/kg weekly, or a higher 8 mg/kg loading dose, followed by 4 mg/kg weekly. RESULTS The objective response rate was 26% (95% confidence interval [CI], 18.2% to 34.4%), with seven complete and 23 partial responses. Response rates in 111 assessable patients with 3+ and 2+ HER2 overexpression by immunohistochemistry (IHC) were 35% (95% CI, 24.4% to 44.7%) and none (95% CI, 0% to 15.5%), respectively. The clinical benefit rates in assessable patients with 3+ and 2+ HER2 overexpression were 48% and 7%, respectively. The response rates in 108 assessable patients with and without HER2 gene amplification by fluorescence in situ hybridization (FISH) analysis were 34% (95% CI, 23.9% to 45.7%) and 7% (95% CI, 0.8% to 22.8%), respectively. Seventeen (57%) of 30 patients with an objective response and 22 (51%) of 43 patients with clinical benefit had not experienced disease progression at follow-up at 12 months or later. The most common treatment-related adverse events were chills (25% of patients), asthenia (23%), fever (22%), pain (18%), and nausea (14%). Cardiac dysfunction occurred in two patients (2%); both had histories of cardiac disease and did not require additional intervention after discontinuation of trastuzumab. There was no clear evidence of a dose-response relationship for response, survival, or adverse events. CONCLUSION Single-agent trastuzumab is active and well tolerated as first-line treatment of women with metastatic breast cancer with HER2 3+ overexpression by IHC or gene amplification by FISH.

Reduced Cardiotoxicity and Preserved Antitumor Efficacy of Liposome-Encapsulated Doxorubicin and Cyclophosphamide Compared With Conventional Doxorubicin and Cyclophosphamide in a Randomized, Multicenter Trial of Metastatic Breast Cancer

PURPOSE To determine whether Myocet (liposome-encapsulated doxorubicin; The Liposome Company, Elan Corporation, Princeton, NJ) in combination with cyclophosphamide significantly reduces doxorubicin cardiotoxicity while providing comparable antitumor efficacy in first-line treatment of metastatic breast cancer (MBC). PATIENTS AND METHODS Two hundred ninety-seven patients with MBC and no prior chemotherapy for metastatic disease were randomized to receive either 60 mg/m(2) of Myocet (M) or conventional doxorubicin (A), in combination with 600 mg/m(2) of cyclophosphamide (C), every 3 weeks until disease progression or unacceptable toxicity. Cardiotoxicity was defined by reductions in left-ventricular ejection fraction, assessed by serial multigated radionuclide angiography scans, or congestive heart failure (CHF). Antitumor efficacy was assessed by objective tumor response rates (World Health Organization criteria), time to progression, and survival. RESULTS Six percent of MC patients versus 21% (including five cases of CHF) of AC patients developed cardiotoxicity (P =.0002). Median cumulative doxorubicin dose at onset was more than 2,220 mg/m(2) for MC versus 480 mg/m(2) for AC (P =.0001, hazard ratio, 5.04). MC patients also experienced less grade 4 neutropenia. Antitumor efficacy of MC versus AC was comparable: objective response rates, 43% versus 43%; median time to progression, 5.1% versus 5.5 months; median time to treatment failure, 4.6 versus 4.4 months; and median survival, 19 versus 16 months. CONCLUSION Myocet improves the therapeutic index of doxorubicin by significantly reducing cardiotoxicity and grade 4 neutropenia and provides comparable antitumor efficacy, when used in combination with cyclophosphamide as first-line therapy for MBC.

Randomized Trial of a Slow-Release Versus a Standard Formulation of Cytarabine for the Intrathecal Treatment of Lymphomatous Meningitis

PURPOSE To evaluate the efficacy and safety of a slow-release formulation of cytarabine (DepoCyt; Chiron Corp, Emeryville, CA, and Skye Pharma, Inc, San Diego, CA) that maintains cytotoxic concentrations of cytarabine (ara-C) in the CSF of most patients for more than 14 days. PATIENTS AND METHODS Twenty-eight patients with lymphoma and a positive CSF cytology were randomized to receive DepoCyt 50 mg once every 2 weeks or free ara-C 50 mg twice a week for 1 month. Patients whose CSF cytology converted to negative and who did not have neurologic progression received an additional 3 months of consolidation therapy and then 4 months of maintenance therapy. All patients received dexamethasone 4 mg orally bid on days 1 through 5 of each 2-week cycle. RESULTS The response rate was 71% for DepoCyt and 15% for ara-C on an intent-to-treat basis (P =.006). All of the patients on the DepoCyt arm but only 53% of those on the ara-C arm were able to complete the planned 1-month induction therapy regimen. Time to neurologic progression and survival trend in favor of DepoCyt (median, 78.5 v 42 days and 99.5 v 63 days, respectively; P >.05). DepoCyt treatment was associated with an improved mean change in Karnofsky performance score at the end of induction (P =.041). The major adverse events on both arms were headache and arachnoiditis, which were often caused by the underlying disease. CONCLUSION DepoCyt injected once every 2 weeks produced a high response rate and a better quality of life as measured by Karnofsky score relative to that produced by free ara-C injected twice a week.

First-Line Herceptin® Monotherapy in Metastatic Breast Cancer

The pivotal phase II and III Herceptin® trials proved the efficacy and safety of second- or third-line single-agent Herceptin and first-line Herceptin in combination with chemotherapy, respectively. In the current trial, 114 patients were randomized to one of two dose groups of first-line Herceptin monotherapy: standard dose of 4 mg/ kg initial dose followed by 2 mg/kg intravenous (i.v.) weekly; or high dose of 8 mg/kg initial dose followed by 4 mg/kg i.v. weekly. The regimen was generally well tolerated. A similar incidence of adverse events was demonstrated in the two dose groups with the possible exception of acute infusion-related events such as fever and chills as well as rash and dyspnea, which appear to be more prevalent in the higher dose group. The overall response rate was 26% and response rates were similar between the two dose groups (24% for the standard Herceptin dose group and 28% for the high Herceptin dose group). Subgroup analysis determined a higher response rate in IHC 3+ patients (35%) and FISH-positive patients (41%). When women with stable disease for ≧6 months were included with responders, the clinical benefit rate in IHC 3+ patients was 47%. Median survival was 24.4 months, which is comparable with the survival rate seen in the pivotal phase III combination trial (25 months). Therefore, single-agent Herceptin is an important new option for the first-line treatment of HER2-positive metastatic breast cancer patients.

First-line, single-agent Herceptin(trastuzumab) in metastatic breast cancer: a preliminary report.

Following confirmation of the appropriate dosage, safety and potential efficacy of Herceptin(trastuzumab) in small-scale phase I and II trials involving patients with refractory disease, a large trial was conducted in 222 patients with breast cancer who had relapsed after one or two chemotherapy regimens for their metastatic disease. The results showed a positive and durable overall response rate (15% according to a response evaluation committee (REC) assessment) using trastuzumab monotherapy (initial dose 4 mg/kg intravenously (i.v.) followed by 2 mg/kg i.v. weekly). In another recently completed phase II trial, 113 patients were randomised to two dose levels (initial dose of 4 mg/kg i.v. dose followed by 2 mg/kg i.v. weekly, or initial dose of 8 mg/kg followed by 4 mg/kg i.v. weekly) of single-agent trastuzumab as first-line therapy for metastatic disease. The preliminary overall response rate was 23% based on investigator assessment, and tolerability was excellent as in previous trials; efficacy was similar in both dose groups, but the side-effects tended to be more frequent in the higher dose group. The preferred dosage is therefore the same as that currently recommended, i.e. an initial dose of 4 mg/kg i.v. followed by 2 mg/kg weekly i.v. until disease progression.

Palifermin Reduces the Incidence of Oral Mucositis in Patients With Metastatic Colorectal Cancer Treated With Fluorouracil-Based Chemotherapy

PURPOSE To characterize the efficacy and safety of palifermin in reducing the incidence of oral mucositis (OM) and diarrhea when administered to patients with metastatic colorectal cancer (CRC) receiving fluorouracil/leucovorin (FU/LV) chemotherapy. PATIENTS AND METHODS Patients (N = 64) were randomly assigned to receive either placebo or palifermin (40 microg/kg for 3 consecutive days) before each of two consecutive cycles of chemotherapy with FU/LV. The incidence of OM and diarrhea, safety, disease progression, and survival were evaluated. RESULTS Thirty-six patients received placebo and 28 patients received palifermin. The incidence of WHO grade 2 or higher OM was lower in patients who received palifermin compared with placebo (29% v 61% in cycle 1; 11% v 47% in cycle 2). FU dose reductions in the second chemotherapy cycle were more frequent in the placebo group (31%) than in the palifermin group (14%). Investigators reported lower mucositis scores and patients reported less severe symptoms with palifermin. There were no statistically significant differences in the incidence or severity of diarrhea or in overall survival between the groups. Overall, palifermin was safe and well tolerated. CONCLUSION Palifermin administered at the indicated dosing regimen (40 microg/kg for 3 consecutive days) before chemotherapy was well tolerated and resulted in a statistically significant and clinically meaningful reduction in the incidence of WHO grade 2 or higher OM in patients with metastatic CRC.

Phase II Trial of Idiotype Vaccination in Previously Treated Patients With Indolent Non-Hodgkin’s Lymphoma Resulting in Durable Clinical Responses

PURPOSE To evaluate idiotype (Id) vaccination as a single agent in previously treated patients with indolent non-Hodgkins lymphoma. PATIENTS AND METHODS Patients underwent biopsy for determination of their lymphoma-specific Id sequence. Recombinant Id protein was manufactured and covalently linked with keyhole limpet hemocyanin (KLH) to generate Id/KLH. Patients received Id/KLH 1 mg on day 1 subcutaneously, with granulocyte-macrophage colony-stimulating factor 250 mug on days 1 to 4, monthly for 6 months. Booster injections were administered until progression. Both clinical and immune responses were evaluated. RESULTS Thirty-two previously treated patients received at least one injection of Id/KLH, and 31 were assessed for efficacy. Responses were observed in four patients (one complete response and three partial responses). Median time to onset of response was 5.9 months (range, 2.3 to 14.1 months). Median duration of response has not been reached but should be at least 19.4 months (range, 10.4 to 27.2+ months). Median time to progression is 13.5 months. The most common adverse events were mild to moderate injection site reactions. Six (67%) of nine patients tested demonstrated a cellular immune response, and four (20%) of 20 patients demonstrated an antibody response against their Id. CONCLUSION This trial demonstrates that Id/KLH alone can induce tumor regression and durable objective responses. Further study of Id/KLH is recommended in other settings where efficacy may be further enhanced as in first-line therapy or after cytoreductive therapy.

An Open Label Trial of Sustained-release Cytarabine (DepoCyt™) for the Intrathecal Treatment of Solid Tumor Neoplastic Meningitis

Drugs currently available for intrathecal administration are cleared rapidly from the CSF. DepoCyt is a slow-release formulation of cytarabine that maintains cytotoxic concentrations of free cytarabine in the CSF for >14 days following a single injection. DepoCyt was administered to 110 patients with a diagnosis of neoplastic meningitis based on either a positive CSF cytology (76) or neurologic and CT or MRI scan findings sufficient to document neoplastic meningitis (34). Patients were treated with DepoCyt 50 mg every 2 weeks for 1 month of induction therapy by either lumbar puncture (LP) or intraventricular (IVT) injection. Patients without neurologic progression were candidates to receive an additional 3 months of consolidation therapy. All patients received dexamethasone 4 mg BID on days 1–5 of each cycle. Median time to neurologic progression was 55 days; median overall survival was 95 days. Among the 76 patients with a positive CSF cytology at baseline, 70 were evaluable for response, and of this group19 (27%) attained the criteria for response (cytologic response in the absence of neurologic progression). The most important adverse events were headache and arachnoiditis. When drug-related, these were largely low grade, transient, and reversible. Drug-related grade 3 headache occurred on 4% of cycles; grade 3 or 4 arachnoiditis occurred on 6% of cycles. No cumulative toxicity was observed. DepoCyt injected once every 2 weeks produced a response-rate comparable to that previously reported for methotrexate given twice a week. The once in every 2-week-dosing interval offers an advantage over conventional schedules (2–3 doses/week) used for other agents available for intrathecal injection.

Intrathecal treatment of neoplastic meningitis due to breast cancer with a slow-release formulation of cytarabine

DepoCyte is a slow-release formulation of cytarabine designed for intrathecal administration. The goal of this multi-centre cohort study was to determine the safety and efficacy of DepoCyte for the intrathecal treatment of neoplastic meningitis due to breast cancer. DepoCyte 50 mg was injected once every 2 weeks for one month of induction therapy; responding patients were treated with an additional 3 months of consolidation therapy. All patients had metastatic breast cancer and a positive CSF cytology or neurologic findings characteristic of neoplastic meningitis. The median number of DepoCyte doses was 3, and 85% of patients completed the planned 1 month induction. Median follow up is currently 19 months. The primary endpoint was response, defined as conversion of the CSF cytology from positive to negative at all sites known to be positive, and the absence of neurologic progression at the time the cytologic conversion was documented. The response rate among the 43 evaluable patients was 28% (CI 95%: 14–41%); the intent-to-treat response rate was 21% (CI 95%: 12–34%). Median time to neurologic progression was 49 days (range 1–515+); median survival was 88 days (range 1–515+), and 1 year survival is projected to be 19%. The major adverse events were headache and arachnoiditis. When drug-related, these were largely of low grade, transient and reversible. Headache occurred on 11% of cycles; 90% were grade 1 or 2. Arachnoiditis occurred on 19% of cycles; 88% were grade 1 or 2. DepoCyte demonstrated activity in neoplastic meningitis due to breast cancer that is comparable to results reported with conventional intrathecal agents. However, this activity was achieved with one fourth as many intrathecal injections as typically required in conventional therapy. The every 2 week dose schedule is a major advantage for both patients and physicians.

Phase I/II study of the hypoxia-activated prodrug PR104 in refractory/relapsed acute myeloid leukemia and acute lymphoblastic leukemia

We previously demonstrated vast expansion of hypoxic areas in the leukemic microenvironment and provided a rationale for using hypoxia-activated prodrugs. PR104 is a phosphate ester that is rapidly hydrolyzed in vivo to the corresponding alcohol PR-104A and further reduced to the amine and hydroxyl-amine nitrogen mustards that induce DNA cross-linking in hypoxic cells under low oxygen concentrations. In this phase I/II study, patients with relapsed/refractory acute myeloid leukemia (n=40) after 1 or 2 prior treatments or acute lymphoblastic leukemia (n=10) after any number of prior treatments received PR104; dose ranged from 1.1 to 4 g/m2. The most common treatment-related grade 3/4 adverse events were myelosuppression (anemia 62%, neutropenia 50%, thrombocytopenia 46%), febrile neutropenia (40%), infection (24%), and enterocolitis (14%). Ten of 31 patients with acute myeloid leukemia (32%) and 2 of 10 patients with acute lymphoblastic leukemia (20%) who received 3 g/m2 or 4 g/m2 had a response (complete response, n=1; complete response without platelet recovery, n=5; morphological leukemia-free state, n=6). The extent of hypoxia was evaluated by the hypoxia tracer pimonidazole administered prior to a bone marrow biopsy and by immunohistochemical assessments of hypoxia-inducible factor alpha and carbonic anhydrase IX. A high fraction of leukemic cells expressed these markers, and PR104 administration resulted in measurable decrease of the proportions of hypoxic cells. These findings indicate that hypoxia is a prevalent feature of the leukemic microenvironment and that targeting hypoxia with hypoxia-activated prodrugs warrants further evaluation in acute leukemia. The trial is registered at clinicaltrials.gov identifier: 01037556.