Manpreet K. Chadha

Effect of 25-Hydroxyvitamin D Status on Serological Response to Influenza Vaccine in Prostate Cancer Patients

Epidemiologic data suggest that there is an association between vitamin D deficiency and influenza infection. We conducted a prospective influenza vaccination study to determine the influence of vitamin D status on serological response to influenza vaccine in prostate cancer (CaP) patients.

Phase 2 trial of weekly intravenous 1,25 dihydroxy cholecalciferol (Calcitriol) in combination with dexamethasone for castration-resistant prostate cancer

Preclinical data indicate that there is substantial antitumor activity and synergy between calcitriol and dexamethasone. On the basis of these data, the authors conducted a phase 2 trial of intravenous (iv) calcitriol at a dose of 74 μg weekly (based on a recent phase 1 trial) and dexamethasone in patients with castration‐resistant prostate cancer (CRPC).

Vitamin D deficiency and insufficiency among patients with prostate cancer

To assess the frequency of vitamin D deficiency among men with prostate cancer, as considerable epidemiological, in vitro, in vivo and clinical data support an association between vitamin D deficiency and prostate cancer outcome.

Concurrent oxaliplatin, 5-fluorouracil, and radiotherapy in the treatment of locally advanced esophageal carcinoma

Purpose:The combination of oxaliplatin, 5-fluorouracil, and leucovorin with concurrent radiotherapy was demonstrated to be a safe regimen for locally advanced esophageal carcinoma in a prior phase I study. We now report the efficacy data for 42 patients treated with this regimen. Methods:Each chemotherapy cycle lasted 29 days and consisted of 5-fluorouracil, 180 mg/m2 protracted-infusion from days 1 to 29, and oxaliplatin, 85 mg/m2 on days 1, 15, and 29. The first cycle was administered concurrently with radiation. The radiation field included regional lymph nodes as well as the primary tumor or tumor bed to a dose of 50.4 Gy in 28 fractions. After concurrent chemoradiotherapy, 1 to 2 additional cycles of chemotherapy were administered. If esophagectomy was indicated, it occurred 4 weeks after completion of concurrent chemoradiotherapy. In the adjuvant group, concurrent chemoradiotherapy was initiated 4 weeks after surgery. Results:Median age was 61 years (range 38–78 years); 30 (71%) of the patients were male. Thirty-three patients had adenocarcinoma, and 9 had squamous cell carcinoma. Concurrent chemoradiotherapy was administered preoperatively (group 1) in 24 patients, definitively (group 2) in 13 patients, and as adjuvant treatment (group 3) in 5 patients. In group 1, 16 patients were down-staged including 1 patient with minimal residual disease and 5 with a complete pathologic response; 4 patients were not down-staged, and 4 did not undergo esophagectomy (2 progressed, 1 died of unrelated causes, and 1 refused). In group 2, 1 patient had a complete clinical response, 4 others were down-staged, 2 had stable disease, and 6 progressed. Four patients in group 3 progressed. Median survival was 28 months for group 1, 12 months for group 2, and not reached at 14 months for group 3. There was one grade 4 toxicity (anaphylaxis) in group 2. Grade 3 toxicities were reported for 5 patients in group 1 and 1 patient in group 2. They consisted of hypotension (n = 1), fatigue (n = 2), diarrhea (n = 2), neuropathy (n = 1), mucositis (n = 1), pneumonitis (n = 1), dehydration (n = 1), emesis (n = 1), and weight loss (n = 1). Conclusions:Our study supports the incorporation of oxaliplatin into a multimodal concurrent chemoradiotherapy protocol for locally advanced esophageal cancer.

Phase II study of fulvestrant (Faslodex) in castration resistant prostate cancer.

Preclinical evidence supports the role of estrogen receptor signaling in prostate cancer. In this trial we investigated the tolerability and efficacy of fulvestrant, a pure estrogen receptor antagonist, in the treatment of castration resistant prostate cancer (CRPC).

Acute promyelocytic leukemia after mitoxantrone therapy for multiple sclerosis

Mitoxantrone is a DNA-topoisomerase 2 inhibitor used as a single agent for treatment of relapsing-remitting or progressive multiple sclerosis (MS). We present here two patients treated with mitoxantrone for MS who subsequently developed acute promyelocytic leukemia (APL). These constitute, to our knowledge, the eighth and ninth reports of APL in patients treated with mitoxantrone for MS. Topoisomerase 2 inhibitors are associated with therapy-related acute myeloid leukemia (t-AML) with 11q23 abnormalities, but therapy-related APL (t-APL) is less common, and documentation of nine cases of t-APL after mitoxantrone therapy for MS suggests a specific association.

A dramatic, objective antiandrogen withdrawal response: case report and review of the literature

Antiandrogen withdrawal response is an increasingly recognized entity in patients with metastatic prostate cancer. To our knowledge, there have been no reports describing a durable radiologic improvement along with prostate-specific antigen (PSA) with discontinuation of the antiandrogen agent bicalutamide. We report a case in which a dramatic decline of serum PSA levels associated with a dramatic improvement in radiologic disease was achieved with bicalutamide discontinuation.

A phase I QTc study of tivozanib in patients with advanced solid tumors.

445 Background: Tivozanib is a potent and selective tyrosine kinase inhibitor of vascular endothelial growth factor receptors-1, -2, and -3 that is currently being tested in a Phase III study in patients with renal cell carcinoma and Phase I/II studies of other solid tumors. Preclinical and retrospective electrocardiogram (ECG) analyses suggest no effect of tivozanib on QTc, although this has not been prospectively assessed according to ICH E14 Cardiac Assessment of New Drugs Guidelines. This open-label, non-randomized, single-arm study prospectively investigated the effect of tivozanib on the QTcF interval and its morphology on the ECG and ECG-pharmacokinetic (PK) relationship in patients with advanced solid tumors. METHODS Patients with advanced solid tumors, an ECOG score ≤1 and life expectancy ≥3 months were eligible. Patients received 1.5 mg of tivozanib orally, once daily for 21 days. Serial blood samples and time-matched, triplicate, 12-lead ECGs were collected on: Day 1 20-30 minutes pre-dose (no blood sample collected), immediately pre-dose, and at 2.5, 4, 5, 6, 8, and 10 hours post dose; Day 2 pre-dose evaluation was taken approximately 24 hours post Day 1 dose; Day 8 (±1 day) pre-dose, and at 2.5, 5, and 8 hours post dose; Day 21 pre-dose and at 2.5, 4, 5, 6, 8, and 10 hours post dose; and Day 22 at approximately 24 hours post Day 21 dose. Additional safety parameters were evaluated by assessing clinical laboratory tests, physical examinations, vital signs, and recording of adverse events. RESULTS Fifty patients with advanced solid tumors (males, 17; median age, 63 years; 94% white) who received ≥ 1 dose of tivozanib were evaluable. Preliminary data showed that there were no clinically significant changes in QTcF from baseline. Further analysis will be completed, and final safety and ECG-PK modeling will be presented. CONCLUSIONS Preliminary data suggest that tivozanib 1.5 mg/d over a 21-day period does not cause clinically significant QT/QTc prolongation over baseline, suggesting that its safety and PK profile is similar to that observed in previous studies, including ECG evaluation in a monkey telemetry study.

Clinical Trial Designs for Approval of New Anticancer Agents

There is an imperative need for development of newer cancer therapeutics and their rapid availability for cancer patients. Better clinical trial designs may help cancer therapeutics become available for treatment sooner. This chapter focuses on our present knowledge about clinical trial design, discussions of successful trial designs, as well as proposals for novel strategies. An exhaustive review of methods used to select agents which are currently in use is included and followed by a summary table of all of the new agents considered by the Food and Drug Administration’s Oncologic Drug Advisory Committee, including the type of trial performed, approved versus disapproved, and the primary endpoint used for approval. Novel clinical trial design suggestions have been included. We hope the present effort helps readers understand various clinical trial designs and get them enthusiastic about exploring new designs.

Serum 25(OH) vitamin D3 response to vitamin D3 supplementation in men with prostate cancer: Results of a randomized phase II trial.

e13060 Background: There is substantial evidence that low serum 25(OH) vitamin D3 [25D3] levels are associated with higher cancer incidence, mortality and other medical morbidities (e.g., heart disease, stroke, venous thrombosis, infection, and autoimmunity). Considerable data document that >60% of normal individuals and patients with prostate, colorectal and breast cancer have serum 25D3 levels below the lower limit of normal (32ng/ml). The relationship between these low levels and cancer outcome is controversial and the response of cancer patients to vitamin D3 (cholecalciferol) [VD3] supplementation has not been studied carefully. This study evaluated the response and safety of 4 different daily replacement doses of VD3 in men with prostate cancer. METHODS 137 patients with prostate cancer who had either localized or advanced disease, were randomized to assure that 120 patients completed 6 months of VD3 replacement at doses of either 4,000, 6,000, 8,000, or 10,000 IU daily. 117 patients have been completely analyzed. 25D3 plasma levels, serum and urine calcium levels, parathyroid hormone (PTH) plasma levels and signs of toxicity were assessed at 1, 3, and 6 montths. RESULTS Toxicity and adverse events were negligible and not clearly related to VD3; no clinically significant changes in serum or 24hr urine calcium occurred. 25D3 levels achieved were proportional to VD3 dose. There were no changes in PTH level related to VD3 dose, serum level of 25D3 or duration of supplementation. CONCLUSIONS Each of the 4 doses of VD3 supplementation was well tolerated. At 3 months, >80% of patients achieved normal 25D3 serum concentrations. Further studies to explore factors associated with response to VD3 supplementation are being carried out. VD3 dose of 4,000 IU or 6,000 IU daily is very safe and appropriate for future study of the role of supplementation in men with prostate cancer. [Table: see text].