A Phase II trial of weekly bortezomib and dexamethasone in veterans with newly diagnosed multiple myeloma not eligible for or who deferred autologous stem cell transplantation.

Once-weekly administration of bortezomib has reduced bortezomib-induced peripheral neuropathy without affecting response rates, but this has only been demonstrated prospectively in three- and four- drug combinations. We report a phase II trial of alternate dosing and schedule of bortezomib and dexamethasone in newly diagnosed multiple myeloma patients who are not eligible for or refused autologous stem cell transplantation. Bortezomib 1·6 mg/m(2) intravenously was given once-weekly for six cycles, together with dexamethasone 40 mg on the day of and day after bortezomib. Fifty patients were enrolled; 58% did not require any dose modification. The majority of patients had multiple co-morbidities, including cardiovascular (76%) and renal insufficiency (54%), and the median number of medications prior to enrollment was 13. Of all evaluable patients, the overall response rate was 79% and at least 45% had at least a very good partial response. The median time to first response was 1·3 months (range, 0·25-2·4 months). The progression-free and overall survivals were 8 months and 46·5 months, respectively. Twenty-four percent developed worsening neuropathy. We conclude that alternate dosing and scheduling of bortezomib and dexamethasone is both safe and effective for management of newly diagnosed multiple myeloma in frail patients. (ClinicalTrials.gov number, NCT01090921).

Early-stage BRCA2-linked breast cancer diagnosed in the first trimester of pregnancy associated with a hypercoagulable state.

This patient was found to have a BRCA2 gene mutation. She underwent lumpectomy and axillary lymph node dissection without any evidence of lymph node metastasis. Systemic chemotherapy with doxorubicin and cyclophosphamide for four cycles was administered beginning in the second trimester. She was treated with prophylactic LMWH until delivery and then for 6 weeks postpartum. She delivered a healthy baby boy and, after a period of breast-feeding, underwent bilateral mastectomy with immediate reconstruction. She remains well and is expecting her second child. Prophylactic oophorectomy is planned after completion of this pregnancy.

A randomized phase II chemoprevention trial of 13-CIS retinoic acid with or without alpha tocopherol or observation in subjects at high risk for lung cancer.

No chemoprevention strategies have been proven effective for lung cancer. We evaluated the effect of 13-cis retinoic acid (13-cis RA), with or without alpha tocopherol, as a lung cancer chemoprevention agent in a phase II randomized controlled clinical trial of adult subjects at high risk for lung cancer as defined by the presence of sputum atypia, history of smoking, and airflow obstruction, or a prior surgically cured nonsmall cell lung cancer (disease free, >3 years). Subjects were randomly assigned to receive either 13-cis RA, 13-cis RA plus alpha tocopherol (13-cis RA/alpha toco) or observation for 12 months. Outcome measures are derived from histologic evaluation of bronchial biopsy specimens obtained by bronchoscopy at baseline and follow-up. The primary outcome measure is treatment "failure" defined as histologic progression (any increase in the maximum histologic score) or failure to return for follow-up bronchoscopy. Seventy-five subjects were randomized (27/22/26 to observations/13-cis RA/13-cis RA/alpha toco); 59 completed the trial; 55 had both baseline and follow-up bronchoscopy. The risk of treatment failure was 55.6% (15 of 27) and 50% (24 of 48) in the observation and combined (13 cis RA plus 13 cis RA/alpha toco) treatment arms, respectively (odds ratio adjusted for baseline histology, 0.97; 95% confidence interval, 0.36-2.66; P = 0.95). Among subjects with complete histology data, maximum histology score in the observation arm increased by 0.37 units and by 0.03 units in the treated arms (difference adjusted for baseline, -0.18; 95% confidence interval, -1.16 to 0.81; P = 0.72). Similar (nonsignificant) results were observed for treatment effects on endobronchial proliferation as assessed by Ki-67 immunolabeling. Twelve-month treatment with 13-cis RA produced nonsignificant changes in bronchial histology, consistent with results in other trials. Agents advancing to phase III randomized trials should produce greater histologic changes. The addition of alpha tocopherol did not affect toxicity.

A phase II trial of pyrazine diazohydroxide in patients with disseminated malignant melanoma and no prior chemotherapy--Southwest Oncology Group study.

Malignant melanoma is rapidly increasing in the United States. Metastatic disease responds poorly to currently available chemotherapy. Pyrazine diazohydroxide (PZDH) is a new agent inhibiting DNA synthesis that is active in mouse tumor models and human xenografts and lacks cross resistance with multiple standard agents. In this phase II trial, patients with no prior chemotherapy or immunotherapy for metastatic disease and performance status (SWOG) of 0-1, were treated with pyrazine diazohydroxide at a dose of 100 mg/m2/day by i.v. bolus injection over 5-15 minutes for 5 consecutive days every 6 weeks. There were 23 eligible patients entered on this trial with 74% having PS of 0 and 91% having visceral metastases. There were no confirmed anti-tumor responses. The overall response rate is 0% (95% CI 0%-15%). Median overall survival is six months (95% CI 5-8 months). The most common toxicities were hematologic and consisted of lymphopenia, thrombocytopenia, anemia, and leukopenia. Fatigue. and nausea and vomiting were the next most common toxicities. Pyrazine diazohydroxide by this dose and schedule has insufficient activity in the treatment of disseminated malignant melanoma to warrant further investigation.

SWOG-9510: evaluation of topotecan in hormone refractory prostate cancer: a Southwest Oncology Group study.

BACKGROUND: Prostate cancer is the most common malignancy in American men, and as many as 70% of those initially treated for localized disease will ultimately progress and be considered candidates to receive therapy for metastatic cancer [Fuks et al.: Int J Radiat Oncol Bio Phys 21:537-547, 1991; Chodak et al.: N Engl J Med 330:246-248, 1994]. Although most will respond initially to hormone manipulation, essentially all will fail and require additional therapy. No standard chemotherapy approach has been shown to prolong survival significantly, and new agents are desperately needed. Topotecan is a new topoisomerase-1 inhibitor whose early investigation suggested possible activity in hormone-refractory prostate cancer. METHODS: In this phase II trial, patients having failed one or two prior androgen ablative therapies were treated with 21-day continuous intravenous infusions of topotecan at a dose of 0.5 mg/m(2) per day every 28 days. RESULTS: Twenty-six eligible patients were entered on the study. There were no confirmed tumor responses. Median survival was 9 months. The most common toxicities were hematologic, with 8 of 24 assessable patients experiencing grade 4 toxicity. CONCLUSION: Topotecan infusions at this dose are ineffective in the management of hormone-refractory prostate cancer.