Phase I trial of pomalidomide given for patients with advanced solid tumors.

PURPOSE: To determine the safety, the maximal tolerated dose, and to assess for any clinical activity of pomalidomide given to patients with advanced solid tumors. PATIENTS AND METHODS: Patients with incurable solid tumors were enrolled. Two different dosing schedules were explored. In Cohort A patients were given pomalidomide once daily for 21 days followed by a 7 day rest. For Cohort B additional patients were recruited to receive pomalidomide given once daily for 28 consecutive days. Dose-limiting toxicity was defined as ≥grade 3 non-hematological toxicity that occurs during cycle 1 and that does not resolve to ≤grade 1 by day 35. Subjects must have received optimal symptomatic treatment for ≥grade 3 nausea, vomiting, or diarrhea to be considered a DLT. Grade 4 transaminitis was considered to be a DLT while grade 3 transaminitis must be present >7 days to be a DLT. Grade 3 febrile neutropenia was considered a DLT. Grade 4 neutropenia, without a fever, was a DLT if the neutropenia did not improve to ≤grade 1 by day 35 of cycle one. Platelet count ≤25,000/mm(3) must improve to ≥75,000/mm(3) by day 35 of cycle one in order not to be considered a DLT. If a patient did not complete one cycle of therapy, for reasons other than a DLT, a replacement subject was added to the same cohort level. RESULTS: A total of 40 patients were enrolled. In Cohort A, three patients received pomalidomide at 5 mg daily without any significant toxicity. Two patients in the 10 mg cohort experienced dose-limiting toxicities of two episodes of grade 3 dyspnea and one grade 4 neutropenia. Six patients were then enrolled at the 7 mg daily of pomalidomide, and no dose-limiting events were observed. In Cohort B, 29 patients were enrolled and the maximal tolerated dose was 4 mg once daily. Stable disease in a variety of tumors was observed. CONCLUSIONS: Pomalidomide was well tolerated and the recommended phase II dosing schedules are 7 mg daily given for 21 days followed by a 7-day rest or pomalidomide 4 mg given on an uninterrupted daily schedule.

Dose-modified oral chemotherapy in the treatment of AIDS-related non-Hodgkin's lymphoma in East Africa.

PURPOSE Africa is burdened by the AIDS epidemic and attendant increase in HIV/AIDS-related malignancies. Pragmatic approaches to therapeutic intervention could be of great value. Dose-modified oral chemotherapy for AIDS-related non-Hodgkin's lymphoma is one such approach. PATIENTS AND METHODS The oral regimen consisted of lomustine 50 mg/m(2) on day 1 (cycle 1 only), etoposide 100 mg/m(2) on days 1 to 3, and cyclophosphamide/procarbazine 50 mg/m(2) each on days 22 to 26 at 6-week intervals (one cycle) for two total cycles in HIV-infected patients with biopsy-proven non-Hodgkin's lymphoma. Results Forty-nine patients (21 in Uganda and 28 in Kenya) were treated. The majority of patients were female (59%) and had a poor performance status (63%); 69% of patients had advanced-stage disease; and 18 patients (37%) had access to antiretroviral therapy. In total, 79.5 cycles of therapy were administered. The regimen was well tolerated, had modest effects (decline) on CD4(+) lymphocyte counts (P = .077), and had negligible effects on HIV-1 viral replication. Four febrile neutropenia episodes and three treatment-related deaths (6% mortality rate) occurred. The overall objective response rate was 78% (95% CI, 62% to 88%); median follow-up time was 8.2 months (range, 0.1 to 71 months); median event-free and overall survival times were 7.9 months (95% CI, 3.3 to 13.0 months) and 12.3 months (95% CI, 4.9 to 32.4 months), respectively; and 33% of patients survived 5 years. CONCLUSION Dose-modified oral chemotherapy is efficacious, has comparable outcome to that in the United States in the pre-highly active antiretroviral therapy setting, has an acceptable safety profile, and is pragmatic in sub-Saharan Africa. The international collaboration has been highly successful, and subsequent projects should focus on strategies to optimize combination antiretroviral therapy and chemotherapy and follow-up tissue correlative studies.

Phase I trial of docetaxel and thalidomide: a regimen based on metronomic therapeutic principles.

PURPOSE: Pre-clinical models have demonstrated the benefit of metronomic schedules of cytotoxic chemotherapy combined with anti-angiogenic compounds. This trial was undertaken to determine the toxicity of a low dose regimen using docetaxel and thalidomide. PATIENTS AND METHODS: Patients with advanced solid tumors were enrolled. Thalidomide 100mg twice daily was given with escalating doses of docetaxel from 10 to 30 mg/m(2)/week. One cycle consisted of 12 consecutive weeks of therapy. The maximal tolerated dose (MTD) was defined as the dose of thalidomide along with docetaxel that caused < or =grade 1 non-hematologic or < or =grade 2 hematologic toxicity for cycle one. RESULTS: Twenty-six patients were enrolled. Dose-limiting toxicities (DLTs) were bradycardia, fatigue, fever, hyperbilirubinemia, leukopenia, myocardial infarction, and neutropenia. Prolonged freedom from disease progression was observed in 44.4% of the evaluable patients. CONCLUSIONS: This anti-angiogenic regimen was well tolerated and demonstrated clinical benefit. The recommended phase II dosing schedule is thalidomide 100 mg twice daily with docetaxel 25 mg/m(2)/week.

Inflammatory pseudotumor of the middle ear masquerading as Bell's palsy.

We describe the case of a 28-year-old woman who presented with an acute dense left facial paralysis. Magnetic resonance imaging demonstrated enhancement of the labyrinthine portion of the facial nerve, and Bell's palsy was the presumed initial diagnosis. After 2 months without recovery despite receiving steroid and antiviral therapy, the patient underwent further workup. Computed tomographic scan demonstrated a mass lesion adjacent to the tympanic portion of the facial nerve, and electromyography showed active denervation and prominent fibrillation potentials. Surgical excision of the tumor was performed with decompression and sparing of the facial nerve. Histologically, the tumor proved to be an inflammatory pseudotumor (IPT). At the 3-year follow-up, the patient had an improvement in her facial nerve function, progressing to a House-Brackman grade III. An IPT can masquerade as Bell's palsy with sudden complete facial paralysis. Failure to obtain even slight recovery in Bell's palsy should prompt further workup, including appropriate imaging, to assess for a mass lesion. Confusion of an IPT with a nerve-based tumor on frozen section and imaging could lead to inappropriate resection and cable grafting of the facial nerve. Therefore, the relationship between an IPT and facial nerve paralysis is vital and must be recognized for treatment and to maximize postoperative facial nerve function.

Phase II trial of thalidomide as maintenance therapy for extensive stage small cell lung cancer after response to chemotherapy.

BACKGROUND: Extensive-stage small cell lung cancer (SCLC) is a highly aggressive malignancy for which little therapeutic progress has been made over the past 20 years. SCLC is a highly angiogenic tumor and targeting angiogenesis is being investigated. The putative mechanism of action of thalidomide is through inhibition of new blood vessel formation. This trial was designed to evaluate thalidomide in ES-SCLC. PATIENTS AND METHODS: Patients who had received first-line chemotherapy without disease progression were eligible. Patients received thalidomide 200 mg daily as maintenance therapy starting 3-6 weeks after completion of chemotherapy. RESULTS: Thirty patients were enrolled. Toxicity was minimal with grade 1 neuropathy in 27% of patients and only one case of grade 3 neuropathy. Median survival from time of initiation of induction chemotherapy was 12.8 months (95% CI: 10.1-15.8 months) and 1-year survival of 51.7% (95% CI: 32.5-67.9%). Median duration on thalidomide was 79 days. CONCLUSION: Thalidomide 200mg daily is well tolerated when given as maintenance therapy for ES-SCLC after induction chemotherapy. Further evaluation of anti-angiogenic agents in SCLC is warranted.

Randomized phase II trial of different schedules of administration of rebeccamycin analogue as second line therapy in non-small cell lung cancer.

Rebeccamcyin analogue (RA) is an antitumor antibiotic that results in DNA intercalation and topoisomerase I and II inhibition. Phase I trials of the daily x 5 schedule and once every 3 week schedule have been completed. Antitumor activity was observed during the phase I trials. The purpose of this study is to primarily determine the response rate of 2 different schedules of administration of RA in patients with advanced non-small cell lung cancer (NSCLC) who had progressed on one prior chemotherapy regimen. Secondary endpoints were median and 1-year survival rates. A two-stage Simon design was employed for both arms of the study. Patients were randomly assigned to either of two RA treatment schedules of 500 mg/m(2) as a 1 hr infusion repeated every 3 weeks (Arm A) or 140 mg/m(2)/day x 5 days repeated every 3 weeks (Arm B). Forty-two patients were randomized. No confirmed objective responses were seen. Stable disease was seen in 52% of patients on arm A and 37% on arm B. Median survival and 1 year survival rates were 5.6 months and 33.3% for arm A, 9.7 months and 42.1% for arm B respectively. Cox regression model demonstrated increased risk of death in patients younger than the age of 61 and for patients treated on arm A. RA failed to demonstrate a significant response rate in this disease setting, although the proportion of patients with stable disease and 1-year survival were encouraging and similar to other published studies of approved single agents for second-line therapy of NSCLC.