rmp-7 and Glioblastoma

RMP-7, a bradykinin analog, temporarily increases the permeability of the blood-brain tumor barrier to chemotherapy drugs like carboplatin. We conducted a randomized, controlled trial of carboplatin and RMP-7 versus carboplatin and placebo in patients with recurrent malignant glioma. The primary outcome measure was time to tumor progression (TTP). Adults with recurrent glioblastoma multiforme or anaplastic glioma were randomized in a 1:1 ratio to receive carboplatin and either RMP-7 or placebo. Radiation therapy had failed in all patients, and they may have received prior chemotherapy. Carboplatin (dosed to achieve an area under the curve of 5 mg/ml x time for patients who had received prior chemotherapy, or 7 mg/ml x time for those who had not) was given intravenously every 4 weeks, followed by intravenous infusion of either RMP-7 or placebo (300 ng/kg). TTP, tumor response, neuropsychological assessments, functional independence, and quality of life assessments were analyzed every 4 weeks. There were 122 patients enrolled, 62 in the RMP-7 and carboplatin group and 60 in the placebo and carboplatin group. Median TTP was 9.7 weeks (95% CI, 8.3-12.6 weeks) for the RMP-7 and carboplatin group and 8.0 weeks (95% CI, 7.4-12.6 weeks) for the placebo and carboplatin group. Median survival times were 26.9 weeks (95% CI, 21.3-37.6 weeks) for the RMP-7 group and 19.9 weeks (95% CI, 15.0-31.3 weeks) for the placebo group. No differences were noted for time to worsening of neuropsychological assessments, functional independence, or quality of life assessments. The use of RMP-7 had no effect on the pharmacokinetics or toxicity of carboplatin. At the dose and schedule used in this trial, RMP-7 did not improve the efficacy of carboplatin. Recent preclinical pharmacokinetic modeling of RMP-7 suggests that higher doses of RMP-7 may be required to increase carboplatin delivery to tumor.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Bradykinin; Carboplatin; Confidence Intervals; Double-Blind Method; Female; Glioblastoma; Glioma; Humans; Infusions, Intravenous; Male; Middle Aged; Neoplasm Recurrence, Local; Proportional Hazards Models; Survival Rate

In recurrent malignant glioma, early imaging response to two courses of chemotherapy is generally considered to be predictive of good survival. We studied the relationships between initial tumour volume and speed of imaging response to chemotherapy in malignant glioma.. In 43 chemotherapy naïve patients, 26 glioblastoma multiforme (GBM) + 17 anaplastic astrocytoma (AA), median age 45 years, MRI responses to intravenous cereport and carboplatin were assessed at baseline, then at 2 monthly intervals. Patients were classified as fast responders if they had reached a partial response (PR) after two courses, and slow responders if PR was achieved after three or more courses of chemotherapy.. PR occurred in four patients with GBM (15%) and nine patients with AA (53%). Likelihood of response was related to initial tumour enhancing volume in GBM but not in AA. PR occurred in four of five GBM patients (80%) with initial volume < 15,000 mm3 and none of the 21 cases with an initial volume > 15,000 mm3. In patients achieving a PR, there was no association between speed or duration of response and eventual survival. Fast responders with AA were significantly older than slow responders (p = 0.033).. Initial enhancing volume of GBMs may be an important predictor of imaging response. This has implications where response rates of phase II studies are reported and in stratification for phase III trials. Further work is necessary to confirm these findings with other types of chemotherapy and examine the relationship between proliferation markers and speed of response.

Topics: Adult; Age Factors; Aged; Antineoplastic Agents; Astrocytoma; Bradykinin; Brain Neoplasms; Carboplatin; Female; Glioblastoma; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Predictive Value of Tests; Prognosis; Treatment Outcome

Factors predictive of primary brain tumor outcome have been studied extensively, although the prognostic value of radiologic data, such as MR imaging and angiographic characteristics, has not been studied in depth. The purpose of this study was to determine whether radiologic data were prognostic factors among patients with recurrent glioblastoma multiforme and anaplastic astrocytoma treated with selective intra-arterial chemotherapy.. Forty-six patients were enrolled in a Phase II study of intra-arterial chemotherapy with carboplatin and Cereport (Alkermes Inc.; Cambridge, MA), a bradykinin analog that selectively increases permeability of the blood-tumor barrier. MR imaging volumes of enhancing tumor, resection cavity, and T2 signal abnormality were measured with T1-weighted and T2-weighted sequences. Volumes were analyzed individually and in various combinations. Tumor vascularity was graded on angiograms. Outcome was measured by time to tumor progression and survival.. Of 46 patients included in this study, 41 underwent evaluation. Thirty were male and 11 were female; mean age was 48.5 years. Karnofsky scores ranged from 70 to 100. Thirty-two patients had glioblastoma multiforme, whereas nine had anaplastic astrocytoma. Twenty-eight patients had tumor progression and 13 had stable disease. Twenty-three patients died after an average of 205 days; 18 were surviving at an average of 324 days from the start of intra-arterial chemotherapy. In multivariate analysis, time from diagnosis to intra-arterial chemotherapy was predictive both of time to tumor progression and survival. Net tumor volume and vascularity also were significant for survival. Age, Karnofsky performance status, histologic findings, gender, MR imaging area, resection cavity volume, T2 signal abnormality volume, and various combined volumes were not significant.. If confirmed by further studies, radiologic factors such as tumor volume and angiographic vascularity should be considered in design and stratification of future chemotherapy trials.

Topics: Adult; Aged; Antineoplastic Agents; Bradykinin; Brain; Brain Neoplasms; Carboplatin; Cerebral Angiography; Disease Progression; Female; Glioblastoma; Humans; Infusions, Intra-Arterial; Magnetic Resonance Imaging; Male; Middle Aged; Multivariate Analysis; Neoplasm Recurrence, Local; Prognosis; Retrospective Studies; Survival Rate

Cereport (RMP-7) is a novel bradykinin agonist which is being developed as a modulator of the blood-brain barrier (BBB). In order to investigate the pharmacokinetics of carboplatin in combination with Cereport, we performed pharmacological studies in conjunction with early clinical trials.. Pharmacokinetic samples were collected from eight patients in a phase I study (Cereport 100-300 ng/ kg) and ten patients in a phase II study (Cereport 300 ng/kg). Pharmacokinetic parameters for carboplatin were compared with respect to the dose of Cereport and with historical controls.. Cereport combined with carboplatin was well-tolerated, with mild haematological toxicities consistent with the target area under the concentration time curve (AUC) of 7 mg/ml x min. Although the clearance of carboplatin was within the range reported for this drug alone, the addition of Cereport resulted in a higher than expected carboplatin AUC. This effect was related to the dose of Cereport in the phase I study (AUC values 104-133% of target, Spearman rank correlation coefficient = 0.71, P < 0.001). The higher than expected AUC value was confirmed in the phase II study (AUC values 106-189% of target).. Co-administration of Cereport with carboplatin may result in a greater than predicted AUC. The mechanism of this possible interaction remains to be determined, although this did not result in any increased toxicity. Thus, the clinical potential of this combination in the treatment of brain tumours warrants further investigation.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Area Under Curve; Astrocytoma; Blood Proteins; Blood-Brain Barrier; Bradykinin; Brain Neoplasms; Carboplatin; Female; Glioblastoma; Glioma; Half-Life; Humans; Male; Middle Aged; Protein Binding