abstract: Patient Selection for Oncology Phase I Trials: A Multi-Institutional Study of Prognostic Factors [Phase I and Clinical Pharmacology]

Patient Selection for Oncology Phase I Trials: A Multi-Institutional Study of Prognostic Factors [Phase I and Clinical Pharmacology]:

Purpose
The appropriate selection of patients for early clinical trials presents a major challenge. Previous analyses focusing on this problem were limited by small size and by interpractice heterogeneity. This study aims to define prognostic factors to guide risk-benefit assessments by using a large patient database from multiple phase I trials.

Patients and Methods
Data were collected from 2,182 eligible patients treated in phase I trials between 2005 and 2007 in 14 European institutions. We derived and validated independent prognostic factors for 90-day mortality by using multivariate logistic regression analysis.

Results
The 90-day mortality was 16.5% with a drug-related death rate of 0.4%. Trial discontinuation within 3 weeks occurred in 14% of patients primarily because of disease progression. Eight different prognostic variables for 90-day mortality were validated: performance status (PS), albumin, lactate dehydrogenase, alkaline phosphatase, number of metastatic sites, clinical tumor growth rate, lymphocytes, and WBC. Two different models of prognostic scores for 90-day mortality were generated by using these factors, including or excluding PS; both achieved specificities of more than 85% and sensitivities of approximately 50% when using a score cutoff of 5 or higher. These models were not superior to the previously published Royal Marsden Hospital score in their ability to predict 90-day mortality.

Conclusion
Patient selection using any of these prognostic scores will reduce non–drug-related 90-day mortality among patients enrolled in phase I trials by 50%. However, this can be achieved only by an overall reduction in recruitment to phase I studies of 20%, more than half of whom would in fact have survived beyond 90 days.

open access: Progression-free Survival Decreases with Each Subsequent Therapy in Patients Presenting for Phase I Clinical Trials (study included various cancers including ovarian cancer) note: patient warning before reading

Blogger's Note: patient warning - this is not a 'good news' paper so caution advised

Table I 
Patient Diagnoses, Gender, Median Age at Diagnosis and Median Number of Therapies  (Blogger's Note: total patients = 142; ovarian cancer patients = 11)

Patient Characteristics

"We reviewed the patient records of 165 unique patients that were evaluated for participation in six phase I trials. Due to a lack of specific start/stop dates, 25 patients had at least one treatment censored for analysis; with one of these patients not having PFS that could be calculated for this study. Seventeen of these twenty-five patients were diagnosed as having less than stage IV disease, with the majority of censored treatments (radiation, surgery, or neoadjuvant or adjuvant chemotherapy) occurring in the non-advanced/metastatic setting. One hundred forty-four patients met criteria for receiving at least one prior non-investigational systemic therapy for advanced/metastatic cancer prior to coming for a phase I treatment evaluation. There were 77 men and 65 women; median age at cancer diagnosis was 55.3 years (range, 9.4 - 81.6 years). The most common types were: colorectal cancer (n=20 (13.9%)), other gastrointestinal cancer (n=17 (11.8%)), adenocarcinoma of the prostate (n=17 (11.8%)), non-small cell lung cancer (NSCLC) (n=13 (9.0%)), breast cancer (n=12 (8.3%)), ovarian cancer (n=11 (7.6%)), and adenocarcinoma of the pancreas (n=9 (6.3%)) (Table I). Patients had a median of three chemotherapy or hormonal treatments (mean, 3.32 treatments; range, 1 - 11 treatments).
Two of the 144 patients did not receive a second systemic therapy prior to evaluation at our center, so PFS could be calculated for the remaining 142 patients. The PFS from tx_n to tx_n+3 was significantly decreased (p = 0.001850) (Figure 1). Few advanced cancers have more than four lines of FDA-approved or consensus guidelines recommendations for systemic therapy, thus we examined the time to progression of the first five treatments (p = 2.938e-07) (Figure 2)."

Phase I Study of the Vascular-Disrupting Agent OXi4503

Phase I Study of the Vascular-Disrupting Agent OXi4503:

Purpose:
Preclinical studies show that OXi4503 (combretastatin A1 diphosphate, CA1P) is more potent than other clinically evaluated vascular-disrupting agents.

Experimental Design:
Escalating doses of OXi4503 were given intravenously over 10 minutes on days 1, 8, and 15 every 28 days to patients with advanced solid tumors.

Results:
Doses were escalated in single-patient cohorts from 0.06 to 1.92 mg/m², then expanded cohorts to 15.4 mg/m² in 43 patients. Common adverse drug reactions were hypertension, tumor pain, anemia, lymphopenia, and easily controllable nausea/vomiting and fatigue. Five patients experienced different drug-related dose-limiting toxicities, atrial fibrillation, increased troponin, blurred vision, diplopia, and tumor lysis. Prophylactic amlodipine failed to prevent adverse events. Pharmacokinetics showed dose-dependent linear increases in peak plasma concentrations and area under the curve value of OXi4503. One partial response was seen in a heavily pretreated patient with ovarian cancer. Dynamic contrast-enhanced MRI confirmed a dose effect and showed significant antivascular effects in 10 of 13 patients treated at doses of 11 mg/m² or higher.

Conclusions:
The maximum tolerated dose was 8.5 mg/m² but escalation to 14 mg/m² was possible with only temporary reversible cerebrovascular toxicity by excluding hypertensive patients. As a tumor response was seen at 14 mg/m² and maximum tumor perfusion reductions were seen at doses of 11 mg/m² or higher, the recommended phase II dose is from 11 to 14 mg/m². Clin Cancer Res; 18(5); 1415–25. ©2012 AACR.

Amlodipine (Brand name: Norvasc)

www.nlm.nih.gov

Amlodipine is used alone or in combination with other medications to treat high blood pressure and chest pain (angina). Amlodipine is in a class of medications called calcium channel blockers. It lowers blood pressure by relaxing the blood vessels so the heart does not have to pump as hard. It controls chest pain ...

Side effects - How to take - Precautions - Dietary Instructions - Missed a dose

(from asco 2011) video: Dr Steven Joffe – Dana-Farber Cancer Institute, Boston - Ethics of early-phase clinical trials on ecancer tv. Cancer journal: online cancer news, clinical oncology research, cancer information and latest cancer studies - open access cancer journal: ecancermedicalscience

Ethics of early-phase clinical trials

Dr Joffe talks to ecancer tv at ASCO 2011 about the arguments around patient recruitment and expectation management in early-phase clinical trials.