Multi-institutional, randomized, double-blind, placebo-controlled trial to assess the efficacy of a mucoadhesive hydrogel (MuGard) in mitigating oral mucositis symptoms in patients being treated with chemoradiation therapy for cancers of the head and neck.

BACKGROUND: The objective of this trial was to determine how a mucoadhesive hydrogel (MuGard), a marketed medical device, would fare when tested with the strictness of a conventional multi-institutional, double-blind, randomized, placebo-controlled study format. METHODS: A total of 120 subjects planned to receive chemoradiation therapy (CRT) for treatment of head and neck cancers were randomized to receive either MuGard or sham control rinse (SC) during CRT. Subjects completed the validated Oral Mucositis Daily Questionnaire. Weight, opiate use, and World Health Organization (WHO) oral mucositis (OM) scores were recorded. Subjects who dosed at least once daily during the first 2.5 weeks of CRT were included in the efficacy analysis. RESULTS: Of 120 subjects enrolled, 78 (SC, N=41; MuGard, N=37) were eligible for efficacy analysis. Both cohorts were similar in demographics, baseline characteristics, primary tumor type, and planned CRT regimen. MuGard effectively mitigated OM symptoms as reflected by area under the curve of daily patient-reported oral soreness (P=.034) and WHO scores on the last day of radiation therapy (P=.038). MuGard was also associated with nonsignificant trends related to therapeutic benefit including opioid use duration, and OM scores (WHO criteria) at CRT week 4. Rinse compliance was identical between cohorts. No significant adverse events were reported, and the adverse event incidence was similar between cohorts. CONCLUSIONS: Testing MuGard, a rinse marketed as a device, in a standard clinical trial format demonstrated its superiority to SC in mitigating OM symptoms, delaying OM progression, and its safety and tolerability.

ProLindac (AP5346): a review of the development of an HPMA DACH platinum Polymer Therapeutic.

ProLindac (AP5346) is DACH (diaminocyclohexane) platinum polymer prodrug currently in phase II clinical development. It uses a 25 kDa polymer delivery vehicle based on hydroxypropylmethacrylamide (HPMA) to target the active form of the approved drug oxaliplatin to tumors. The pH-sensitive linker that binds platinum to the polymer releases platinum more rapidly in low pH environments, as found typically in many tumors. This review summarizes the development of ProLindac to date, including preclinical efficacy studies, the phase I monotherapy clinical study in patients with solid tumors, and the phase I/II monotherapy study in patients with recurrent ovarian cancer. Both preclinical and clinical study data indicate that ProLindac exhibits efficacy at least equal to, and likely superior to oxaliplatin, while demonstrating excellent tolerability. Additional clinical studies of ProLindac used in combination with other chemotherapeutic agents are planned.

Phase I and pharmacokinetic trial of AP5346, a DACH-platinum-polymer conjugate, administered weekly for three out of every 4 weeks to advanced solid tumor patients.

PURPOSE: To determine the maximum tolerated dose (MTD) safety and pharmacokinetics of AP5346, a copolymer-linked 1,2-diaminocyclohexane(DACH)-platinum compound, in advanced solid tumor patients. EXPERIMENTAL DESIGN: AP5346 was administered as a 1-hour IV infusion on days 1, 8, 15 of a 28-day cycle. Seven dose levels (DL) were explored: DL1: 40 mg platinum (Pt)/m2 (1 patient); DL2: 80 (1); DL3: 160 (3); DL4: 320 (3); DL5: 640 (6); DL6: 850 (6); DL7: 1280 (6) mg Pt/m2. Dose-limiting toxicity (DLT) included infusion omission and cycle delay >2 weeks. RESULTS: Twenty-six patients received 41 cycles (median 1/patient, range 1-4). No DLT occurred in DL 1-4; 1 DLT in DL5 (RD; renal insufficiency), two in DL6 (MTD; vomiting; fatigue) and 5 in DL7 (neutropenic infection with diarrhea; neutropenia with vomiting; vomiting with fatigue; renal insufficiency; and fatigue). Two deaths occurred due to renal insufficiency (DL5); in both cases patients had disease in or surrounding genitourinary tract whose contribution could not be accurately discerned. Grade 1-2 creatinine abnormalities occurred in seven patients. Nausea/emesis was frequent (92%), reaching grade 3-4 (23%), but controlled by antiemetics. Grade 2-4 allergic reactions occurred in 4 patients. Cmax and AUC increased linearly with dose for total plasma platinum and ultrafiltrate platinum. Antitumor activity included two partial responses in metastatic melanoma and ovarian cancer, and an additional CA-125 normalization (from 133 IU/l) in a suspected ovarian cancer. CONCLUSIONS: AP5346 administered weekly for 3 weeks out of every four is tolerated up to a dose of 640 mg Pt/m2 on the first cycle when given with antiemetic prophylaxis. The pharmacokinetics of AP5346 indicates a prolonged half-life, and evidence of antitumor activity was observed at this dose level.

Synthesis and characterization of AP5346, a novel polymer-linked diaminocyclohexyl platinum chemotherapeutic agent.

Syntheses of the novel polymer-bound platinum-based chemotherapeutic agent poly(HPMA)-GGG-Ama=Pt=(1R,2R)-DACH, AP5346, and its precursors are reported. The method utilized in preclinical development of AP5346 is described herein. Additionally, an improved synthesis, which has shown that ion exchange resins can be removed, significantly less platinum can be used when the reaction mixture is pH-stated, and the synthesis can be performed at a higher concentration, is reported. These combined improvements result in a more cost-effective, scaleable procedure. Various methods of analysis of the drug substance are also discussed. Specifically, (1)H NMR spectroscopy is used for identity and can also distinguish small molecule impurities to below 0.1%. (195)Pt NMR determines the coordination environment of the platinum and also identity and purity in relation to platinum chelation of the construct. Size exclusion chromatography is used to establish the molecular weight of AP5346 while ICP-AES determines platinum content and platinum release rates in phosphate-buffered saline. The cumulative results of this work have yielded an efficient syntheses of a polymer-based chemotherapeutic agent with subsequent detailed characterization methods.

Preclinical efficacy and pharmacokinetics of AP5346, a novel diaminocyclohexane-platinum tumor-targeting drug delivery system.

PURPOSE: AP5346 is designed to target a diaminocyclohexane platinum (Pt) moiety to tumors through pH-sensitive linkage to a 25 kDa hydroxypropylmethacrylamide polymer. The goal of these studies was to determine the rate of release of Pt as a function of pH, the antitumor activity, and plasma and tumor pharmacokinetics of AP5346 in preclinical models. EXPERIMENTAL DESIGN: Antitumor activity was assessed in mice bearing B16F10 melanoma and M5076 and 2008 ovarian carcinomas. Pt levels in plasma, tumors, and tumor DNA were measured by atomic absorption and inductively coupled plasma mass spectrometry. RESULTS: AP5346 did not release Pt when suspended in 5% dextrose and released only 3.5% of its Pt in 24 hours in buffer at pH 7.4; the rate of release was 7-fold higher at pH 5.4. When given at their respective maximum tolerated doses, the antitumor activity of AP5346 was superior to that of oxaliplatin against both the B16 melanoma and 2008 human ovarian carcinoma. It was more effective than cisplatin in both cisplatin-sensitive and cisplatin-resistant variants of the M5076 tumor. When given at equitoxic doses, the peak plasma concentration was 25-fold higher, and AUC((0-infinity)) was 93 times higher, for AP5346 than for oxaliplatin. AP5346 delivered 16.3-fold more Pt to the tumor and 14.2-fold more Pt to tumor DNA than oxaliplatin based on AUC((1-168)). CONCLUSIONS: AP5346 has a substantially better therapeutic index than oxaliplatin. AP5346 produced a marked increase in the delivery of diaminocyclohexane Pt to the tumor and tumor DNA over and above that attainable with oxaliplatin.