Dose-limiting Neurotoxicity Research Articles

Comparative activity of the enantiomers of fenfluramine and norfenfluramine in rodent seizure models, and relationship with their concentrations in plasma and brain.

To investigate the comparative antiseizure activity of the individual enantiomers of fenfluramine and its major active primary metabolite norfenfluramine in rodent seizure models, and its relationship with the pharmacokinetics of these compounds in plasma and brain. The antiseizure potency of d,l-fenfluramine (racemic fenfluramine) was compared with the respective potencies of its individual enantiomers and the individual enantiomers of norfenfluramine using the maximal electroshock (MES) test in rats and mice, and the 6-Hz 44 mA test in mice. Minimal motor impairment was assessed simultaneously. The time course of seizure protection in rats was compared with the concentration profiles of d-fenfluramine, l-fenfluramine, and their primary active metabolites in plasma and brain. All compounds tested were active against MES-induced seizures in rats and mice after acute (single-dose) administration, but no activity against 6-Hz seizures was found even at doses up to 30 mg/kg. Estimates of median effective doses (ED50 ) in the rat-MES test were obtained for all compounds except for d-norfenfluramine, which caused dose-limiting neurotoxicity. Racemic fenfluramine had approximately the same antiseizure potency as its individual enantiomers. Both d- and l-fenfluramine were absorbed and distributed rapidly to the brain, suggesting that seizure protection at early time points (≤2 h) was related mainly to the parent compound. Concentrations of all enantiomers in brain tissue were >15-fold higher than those in plasma. Although there are differences in antiseizure activity and pharmacokinetics among the enantiomers of fenfluramine and norfenfluramine, all compounds tested are effective in protecting against MES-induced seizures in rodents. In light of the evidence linking the d-enantiomers to cardiovascular and metabolic adverse effects, these data suggest that l-fenfluramine and l-norfenfluramine are potentially attractive candidates for a chiral switch approach leading to development of a novel, enantiomerically-pure antiseizure medication.

Ethnic-specific predictors of neurotoxicity among patients with pediatric acute lymphoblastic leukemia after high-dose methotrexate.

High-dose methotrexate (HD-MTX; 5000mg/m2 ) is an important component of curative therapy in many treatment regimens for high-risk pediatric acute lymphoblastic leukemia (ALL). However, methotrexate therapy can result in dose-limiting neurotoxicity, which may disproportionately affect Latino children. This study evaluated risk factors for neurotoxicity after HD-MTX in an ethnically diverse population of patients with ALL. The authors retrospectively reviewed the medical records of patients who were diagnosed with ALL and treated with HD-MTX at Texas Children's Cancer Center (2010-2017). Methotrexate neurotoxicity was defined as a neurologic episode (e.g., seizures or stroke-like symptoms) occurring within 21days of HD-MTX that resulted in methotrexate treatment modifications. Mixed effects multivariable logistic regression was used to estimate the odds ratio (OR) and corresponding 95% confidence interval (CI) for the association between clinical factors and neurotoxicity. Overall, 351 patients (58.1% Latino) who received 1183 HD-MTX infusions were evaluated. Thirty-five patients (10%) experienced neurotoxicity, 71% of whom were Latino. After adjusting for clinical risk factors, the authors observed that serum creatinine elevations ≥50% of baseline were associated with a three-fold increased odds (OR, 3.32; 95% CI, 0.98-11.21; p=.05) for neurotoxicity compared with creatinine elevation <25%. Notably, predictors of neurotoxicity differed by ethnicity. Specifically, Latino children experienced a nearly six-fold increase in neurotoxicity odds (OR, 5.80; 95% CI, 1.39-24.17; p=.02) with serum creatinine elevation ≥50% compared with creatinine elevation <25%. The current findings indicate that serum creatinine elevations ≥50% may be associated with an increased risk for neurotoxicity among Latino children with ALL and may identify potential candidates for therapeutic or supportive care interventions.

Improved efficacy and safety of low-dose oxaliplatin/pegylated liposomal doxorubicin/S-1 regimen in advanced gastric cancer: a cohort study.

Dose-limiting neurotoxicity is the major side effect caused by oxaliplatin treatment. Optimization of oxaliplatin-containing chemotherapeutic regimens may potentially benefit advanced gastric cancer (AGC) patients. We tried to reduce the dose of oxaliplatin and add a drug to compensate for the efficacy. This cohort study evaluated the efficacy and side effects of low-dose oxaliplatin combined with pegylated liposomal doxorubicin and S-1 (D-SOX) as first-line treatment for AGC. 64 AGC patients treated in our hospital between January 2015 and December 2018 were included in this study. Among them, 29 cases received standard S-1 and oxaliplatin (SOX) regimen, and 35 cases received D-SOX. Progression-free survival (PFS), overall survival (OS), response rate (RR), and safety were analyzed. The median PFS was 7.0 months [95% confidence interval (CI): 5.77 to 8.23 months] in the SOX group and 9.3 months (95% CI: 8.145 to 10.45 months) in the D-SOX group (P=0.021). The median OS was 12.5 months (95% CI: 7.00 to 17.97 months) in the SOX group and 18.7 months (95% CI: 14.485 to 22.9 months) in the D-SOX group (P=0.027). The incidence of treatment-related grade III-IV adverse events (AEs) was less than 10%. The RRs to these 2 regimens were similar (P=0.609). The incidence of neurotoxicity was significantly reduced in the D-SOX group (62.8% vs. 82.7%). Low-dose oxaliplatin combined with S-1 and pegylated liposomal doxorubicin (PLD) regimen improved OS and PFS, while exhibiting better toxicity profile as compared with standard SOX regimen for AGC.

Cisplatin induced neurotoxicity is mediated by Sarm1 and calpain activation

Cisplatin is a commonly used chemotherapy agent with significant dose-limiting neurotoxicity resulting in peripheral neuropathy. Although it is postulated that formation of DNA-platinum adducts is responsible for both its cytotoxicity in cancer cells and side effects in neurons, downstream mechanisms that lead to distal axonal degeneration are unknown. Here we show that activation of calpains is required for both neurotoxicity and formation of DNA-platinum adduct formation in neurons but not in cancer cells. Furthermore, we show that neurotoxicity of cisplatin requires activation of Sarm1, a key regulator of Wallerian degeneration, as mice lacking the Sarm1 gene do not develop peripheral neuropathy as evaluated by both behavioral or pathological measures. These findings indicate that Sarm1 and/or specific calpain inhibitors could be developed to prevent cisplatin induced peripheral neuropathy.

Metformin reduces c-Fos and ATF3 expression in the dorsal root ganglia and protects against oxaliplatin-induced peripheral sensory neuropathy in mice

Oxaliplatin is a third-generation platinum drug commonly used as the first line treatment of metastatic colorectal cancer. Oxaliplatin-based anticancer regimens course with dose-limiting neurotoxicity. The pharmacological strategies used to manage such side effect are not totally effective. Metformin is an anti-diabetic drug that is described to negatively modulate painful diabetic neuropathy. Then, this study aimed to assess the effect of metformin in the oxaliplatin-induced peripheral sensory neuropathy in mice. For that purpose, Swiss male mice were injected with oxaliplatin (1, 2 or 4 mg/kg, i.v., twice a week with a total of nine injections) alone or in combination with daily administration of metformin (250 mg/kg, p.o.). Thermal and mechanical nociceptive tests were performed once a week for five weeks. Then, the animals were euthanized on day 35 post-first injection of oxaliplatin and the dorsal root ganglia were harvested for the assessment of c-Fos and ATF3 expressions. Oxaliplatin caused a nociceptive response accompanied by the increased expression of c-Fos and ATF3 in the dorsal root ganglia and spinal cord. In addition, the oxaliplatin-associated nociception was significantly attenuated by metformin (P < 0.05), which also reduced the expression of c-Fos and ATF3 (P < 0.05). Therefore, metformin protected from the peripheral sensory neuropathy induced by oxaliplatin, which was confirmed by the reduction of c-Fos and ATF3 expression, two known neuronal activation and damage markers, respectively.

(207) Oxaliplatin Depolarizes Isolectin B4-Negative Dorsal Root Ganglion Neurons to Initiate Neuropathic Pain in Mouse

Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting neurotoxicity caused by chemotherapy drugs. CIPN is frequently associated with neuropathic pain that significantly impairs the quality of life and work capability of cancer patients. Use of oxaliplatin for colorectal cancer is associated with a characteristic cold-sensitive pain in addition to mechanical allodynia. The objectives of this work were to study 1) effects of oxaliplatin on membrane excitability in Isoletcin B4-positive and –negative (IB4+ and IB4-) subpopulations of dorsal root ganglion (DRG), and 2) targeting oxaliplatin-induced membrane hyperexcitability to relief neuropathic pain. The effects of oxaliplatin on membrane excitability were examined by whole-cell patch clamping in small sized DRG neurons dissociated from adult C57BL/6 mice in vitro. Pain and motor behaviors were tested in mice treated with oxaliplatin. Cold, heat, mechanical sensitivity, and motor function were assessed by acetone spray, Hargreaves, Von-Frey, and Rotarod tests, respectively. In vitro experiments found that oxaliplatin selectively caused membrane depolarization in IB4-, but not IB4+ neurons. Oxaliplatin also reduced threshold for action potentials (APs), and increased firing numbers of APs in IB4- neurons. The oxaliplatin-induced membrane depolarization and hyperexcitability was completely reversed by retigabine, an FDA approved anti-epileptic drug and a KCNQ/M channel opener. In vivo, oxaliplatin induced cold and mechanical hypersensitivity while it did not change heat sensitivity or motor function. Co-treatment of retigabine inhibited oxaliplatin-induced cold and mechanical hypersensitivity without changing heat sensitivity or motor function. These results suggest that oxaliplatin initiates neuropathic pain through depolarizing IB4- neurons and targeting membrane depolarization can prevent oxaliplatin-induce neuropathic pain.

Novel first-in-class small molecule targeting APE1/Ref-1 to prevent and treat chemotherapy-induced peripheral neuropathy (CIPN).

229 Background: Chemotherapy-induced peripheral neuropathy (CIPN) is an acute and chronic debilitating side effect of a number of chemotherapeutic agents lacking FDA-approved interventions or strategies resulting in dose-limiting neurotoxicity. CIPN can persist following discontinuation of the drug with up to 40% of patients having continued CIPN five years after treatment ends. Thus, CIPN directly affects cancer survivorship, quality of life, and may limit future treatment options if cancer recurs. Although the cellular mechanisms mediating CIPN remain to be determined, several lines of evidence support the notion that DNA damage caused by anticancer therapies could contribute to the neuropathy. Methods: Using an experimental model of isolated sensory neurons in culture, we established a causal relationship between cancer-therapy-induced neurotoxicity and DNA damage and repair. Results: Genetically reducing the activity of APE1 increased the neurotoxicity produced by platin treatment, whereas augmenting the activity of APE1 lessened neurotoxicity. Furthermore, using a targeted small-molecule, APX3330, which increases DNA repair of APE1 in neurons, it lessened neurotoxicity using a variety of endpoints ex vivo; e.g. DNA damage, CGRP release. We will present data using animal models of CIPN demonstrating a protective effect of APX3330 using either cis- or oxaliplatin without diminishing the anti-tumor effect of the platins. A Phase 1 clinical trial for safety/RF2D for APX3330 has completed (NCT03375086). Conclusions: Effective prevention and management of CIPN hinges on understanding its pathophysiology. While multiple causal mechanisms may be at work, we believe that the induction of oxidative DNA damage in sensory neurons is a major cause of CIPN. Thus, enhancement of oxidative DNA damage repair by APX3330 results in reduction of CIPN.

Dynapenia could predict chemotherapy-induced dose-limiting neurotoxicity in digestive cancer patients

BackgroundFIGHTDIGO study showed the feasibility and acceptability of handgrip strength (HGS) measure in routine in 201 consecutive patients with digestive cancer treated with ambulatory chemotherapy. The present study focuses on the second aim of FIGHTDIGO study: the relationships between pre-therapeutic dynapenia and chemotherapy-induced Dose-Limiting Toxicities (DLT).MethodsIn this ancillary prospective study, DLT were analyzed in a sub-group of 45 chemotherapy-naive patients. Two bilateral consecutive measures of HGS were performed with a Jamar dynamometer before the first cycle of chemotherapy. Dynapenia was defined as HGS < 30 kg (men) and < 20 kg (women). DLT and/or Dose-Limiting Neurotoxicity (DLN) were defined as any toxicity leading to dose reduction, treatment delays or permanent treatment discontinuation.ResultsTwo-thirds of chemotherapies were potentially neurotoxic (n = 31 [68.7%]) and 22 patients (48.9%) received FOLFOX (5FU, leucovorin plus oxaliplatin) regimen chemotherapy. Eleven patients (24.4%) had pre-therapeutic dynapenia. The median number of chemotherapy cycles was 10 with a median follow-up of 167 days. Twenty-two patients experienced DLT (48.9%). There was no significant association between pre-therapeutic dynapenia and DLT (p = 0.62). Nineteen patients (42.2%) experienced DLN. In multivariate analysis, dynapenia and tumoral location (stomach, biliary tract or small intestine) were independent risk factors for DLN (HR = 3.5 [1.3; 9.8]; p = 0.02 and HR = 3.6 [1.3; 10.0]; p = 0.01, respectively).ConclusionsDigestive cancer patients with pre-therapeutic dynapenia seemed to experience more DLN. HGS routine measurement may be a way to screen patients with frailty marker (dynapenia) who would require chemotherapy dose adjustment and adapted physical activity programs.Trial registrationNCT02797197 June 13, 2016 retrospectively registered.

Tanshinones from Salvia miltiorrhiza Bunge revert chemotherapy-induced neuropathic pain and reduce glioblastoma cells malignancy.

Medicinal plants and herbal extracts from traditional Chinese medicine are used increasingly commonly worldwide for their benefits to health and quality of life as dietary supplements or as ingredients in functional foods. Among them, Salvia miltiorrhiza Bunge (a natural strong remedy for the treatment of a variety of conditions) is traditionally used for centuries in Asian countries as antioxidant, anticancer, and anti-inflammatory agent. In this context, several evidences support the hypothesis that some tanshinones (in particular tanshinone IIA and cryptotanshinone) extracted from the roots (Danshen) of Salvia miltiorrhiza exert neuroprotective and analgesic activities. Oxaliplatin (OXA), a platinum-based drug used for the treatment of solid tumors, induces neuropathic pain which hampers the chemotherapy success. While several attempts were made to prevent oxaliplatin-induced painful neuropathy, a growing number of evidences look to natural sources as an effective remedy to counterbalance the OXA-mediated side effects. The aim of the present study was to investigate the pain-relieving profile of Danshen and its active constituents tanshinone IIA (TIIA) and cryptotanshinone (CRY) in animal models of neuropathic pain induced by OXA, anticancer drug characterized by a dose-limiting neurotoxicity. Contextually, the neuroprotective and anticancer activities of the selected compounds were tested in different cells lines. A single administration per os of CRY (30 mg mg/kg) significantly, in a dose dependent manner, attenuated chemotherapy-induced pain. A 7 days repeated administrations highlighted the effectiveness and potency of both CRY and TIIA (10 mg/kg). On the other hand, Danshen showed a painkiller profile against oxaliplatin-induced neuropathy. Contextually, Danshen and its active constituents showed remarkable and selective inhibitory activities on glioblastoma cells lines LN-229 (IC50: 50.0 ± 4.0, 48.2 ± 4.9 and 51.9 ± 2.3 μM respectively for Danshen standardized extract, TIIA and CRY) next to healthy but high proliferative cell lines enterocytes (IC50:> 250 μM for TIIA and CRY) and keratinocytes (IC50: >100 and 97 ± 2 μM respectively for TIIA and CRY). Taken together the results reported here demonstrated the long-lasting pain-relieving effects of Danshen and its related bioactive constituents in animal models of neuropathic pain and their selective in vitro neuroprotective properties on certain central malignancy cells lines. Thus, suggest that S. miltiorrhiza roots could be considered as a new potential source of active diterpenoidic compounds useful for pharmaceutical or nutraceutical industries and beneficial as food complements.

Vincristine-Loaded and sgc8-Modified Liposome as a Potential Targeted Drug Delivery System for Treating Acute Lymphoblastic Leukemia.

Cytotoxic compounds vincristine sulphate (VCR) is widely used to against hemato-oncology, and especially the acute lymphoblastic leukemia (ALL). However, VCR's full therapeutic potential has been limited by its dose-limiting neurotoxicity, classically resulting in autonomic and peripheral sensory-motor neuropathy. Therefore, we developed a targeted liposomal drug delivery system (sgc8/VCR-Lipo) for improving the therapeutic effects of VCR against leukemia and reducing its systematic adverse effects. sgc8/VCR-Lipo could specifically bind to CCRF-CEM cells and significantly inhibit proliferation of cancer cells in vitro and tumor growth in vivo. The sgc8/VCR-Lipo nanoparticles may improve the anti-tumor efficacy of VCR and reduce side effects induced by non-specific drug release. These results suggest that our findings provide scientific evidence for developing novel aptamer-based targeted drug delivery systems for leukemia treatment.

Critical Considerations in Anticancer Drug Development and Dosing Strategies: The Past, Present, and Future.

Critical Considerations in Anticancer Drug Development and Dosing Strategies: The Past, Present, and Future.

Effects of natural and synthetic isothiocyanate-based H2S-releasers against chemotherapy-induced neuropathic pain: Role of Kv7 potassium channels

Hydrogen sulfide (H2S) is a crucial signaling molecule involved in several physiological and pathological processes. Nonetheless, the role of this gasotransmitter in the pathogenesis and treatment of neuropathic pain is controversial.The aim of the present study was to investigate the pain relieving profile of a series of slow releasing H2S donors (the natural allyl-isothiocyanate and the synthetics phenyl- and carboxyphenyl-isothiocyanate) in animal models of neuropathic pain induced by paclitaxel or oxaliplatin, anticancer drugs characterized by a dose-limiting neurotoxicity. The potential contribution of Kv7 potassium channels modulation was also studied.Mice were treated with paclitaxel (2.0 mg kg−1) i.p. on days 1, 3, 5 and 7; oxaliplatin (2.4 mg kg−1) was administered i.p. on days 1–2, 5–9, 12–14. Behavioral tests were performed on day 15. In both models, single subcutaneous administrations of H2S donors (1.33, 4.43, 13.31 μmol kg−1) reduced the hypersensitivity to cold non-noxious stimuli (allodynia-related measurement). The prototypical H2S donor NaHS was also effective. Activity was maintained after i.c.v. administrations. On the contrary, the S-lacking molecule allyl-isocyanate did not increase pain threshold; the H2S-binding molecule hemoglobin abolished the pain-relieving effects of isothiocyanates and NaHS. The anti-neuropathic properties of H2S donors were reverted by the Kv7 potassium channel blocker XE991. Currents carried by Kv7.2 homomers and Kv7.2/Kv7.3 heteromers expressed in CHO cells were potentiated by H2S donors.Sistemically- or centrally-administered isothiocyanates reduced chemotherapy-induced neuropathic pain by releasing H2S. Activation of Kv7 channels largely mediate the anti-neuropathic effect.

Nelarabine in the treatment of pediatric and adult patients with T-cell acute lymphoblastic leukemia and lymphoma

ABSTRACTIntroduction: T-cell acute lymphoblastic leukemia (ALL) and lymphoma (LBL) are aggressive hematologic neoplasms that are treated with combination chemotherapy in the frontline, but have limited options in the relapsed or refractory setting. Based on observations in patients with purine nucleoside phosphorylase (PNP) deficiency, a guanosine nucleoside analogue, arabinosylguanine (ara-G) was developed that provided T-cell specificity. Nelarabine was developed as the water-soluble, clinically useful-prodrug of ara-G and based on its activity was approved for the treatment of relapsed or refractory T-ALL/LBL.Areas covered: In this narrative review, we will summarize the preclinical studies, early dose-finding studies, and efficacy studies that led to approval of nelarabine. The review will succinctly cover response rates and safety signals reported during clinical development. We will also cover more recent work with nelarabine, including combination studies, modified dosing schedules, and frontline treatment approaches.Expert commentary: Based on evidence from the literature review and our own experience with nelarabine, we conclude that it is an effective agent in the treatment of T-cell malignancies. Understanding the factors that modulate the risk of dose-limiting neurotoxicity, how to mitigate this toxicity, and how to safely combine it with other active agents will continue to broaden its use.

Hitting the brakes: targeting microtubule motors in cancer.

Despite the growing number of therapies that target cancer-specific pathways, cytotoxic treatments remain important clinical tools. The rationale for targeting cell proliferation by chemotherapeutic agents stems from the assumption that tumours harbour a greater fraction of actively dividing cells than normal tissues. One such group of cytotoxic drugs impair microtubule polymers, which are cytoskeletal components of cells essential for many processes including mitosis. However, in addition to their antimitotic action, these agents cause debilitating and dose-limiting neurotoxicity because of the essential functions of microtubules in neurons. To overcome this limitation, drugs against mitosis-specific targets have been developed over the past decade, albeit with variable clinical success. Here we review the key lessons learnt from antimitotic therapies with a focus on inhibitors of microtubule motor proteins. Furthermore, based on the cancer genome data, we describe a number of motor proteins with tumour type-specific alterations, which warrant further investigation in the quest for cytotoxic targets with increased cancer specificity.

Is more better in myeloma? Treatment intensity and outcome in newly diagnosed myeloma patients

During the course of disease multiple myeloma subclones acquire more and more additional genetic changes causing an aggressive proliferative growth with less responsiveness to therapeutic agents. On the other hand new therapeutic options are getting available, leading to the question, if a more intensive treatment in newly diagnosed myeloma patients may result in a better outcome concerning progression-free survival, quality of life and overall survival. In newly diagnosed myeloma patients, physicians have to distinguish between patients eligible for autologous stem cell transplantion (ASCT) and patients ineligible for ASCT. Transplant eligibility is mainly based on biological age, performance status and co-morbidities. New data suggest that prolonged treatment—synonymously called maintenance therapy—may lead to additional survival benefit even in the elderly/frail patient group. Yet there is no clear data on overall survival for prolonged treatment. At time the first-line armoury in myeloma consists of chemotherapy, steroids, proteasome inhibitors and immunmodulatory/antiangiogenetic drugs. The role of new antibodies in myeloma treatment is evolving but there is only limited (but promising) data available yet. New agents might reduce the therapeutic side-effects of an intensive treatment despite increasing efficacy as shown, e.g., for the new proteasome inhibitor carfilzomib. In the first-line setting, other new oral proteasome inhibitors with low dose-limiting neurotoxicity rates will be available shortly. In this short review, therapeutic strategies will be discussed focusing on treatment intensity.

Long-term administration and efficacy of oxaliplatin with no neurotoxicity in a patient with rectal cancer: Association between neurotoxicity and the GSTP1 polymorphism.

Neurotoxicity is one of the most frequent side-effects of oxaliplatin. Oxaliplatin-induced cumulative and dose-limiting neurotoxicity either results in dose reduction or decreases the patients’ quality of life. However, the symptoms of neurotoxicity often vary among patients. The current study presents the case of a male with rectal cancer, who was administered a cumulative oxaliplatin dose of >5,000 mg/m2 without developing neurotoxicity or allergic reactions. Consequently, this patient continued therapy with modified 5-fluorouracil, leucovorin and oxaliplatin treatment for four years, with stabilization of the disease. This case indicates that if oxaliplatin-containing chemotherapy shows efficacy with no toxicity, the long-term administration of oxaliplatin would be effective and tolerable. Previously, the analysis of genomic polymorphisms in drug target genes has been important for explaining interindividual variations in the efficacy and toxicity of anti-cancer drugs. In the present patient, the glutathione S-transferase P1 (GSTP1) gene polymorphism, which is involved in the detoxification of platinum drugs, was analyzed. The genotype of the present case has been revealed as wild type (Ile/Ile) genotype. In addition, the associations between oxaliplatin-induced neurotoxicity and the GSTP1 polymorphism were also assessed. Certain studies have demonstrated that oxaliplatin-induced neurotoxicity occurs more frequently in patients with the Ile/Ile genotype, while others have demonstrated that those patients with the Val/Val or Ile/Val genotypes are more likely to develop neurotoxicity. Therefore, correlation between the GSTP1 polymorphism and oxaliplatin-induced neurotoxicity remains controversial. Overall, further development of individualized chemotherapy with an analysis of genomic polymorphisms in the drug target genes is required for the prophylaxis oxaliplatin-induced neurotoxicity.

A phase I and pharmacokinetic study of oxaliplatin and bortezomib: activity, but dose-limiting neurotoxicity

The potential synergy of modulating platinum-induced DNA damage by combining the proteasome inhibitor bortezomib with oxaliplatin was studied in patients with solid tumors, with special attention to avoidance of cumulative neurotoxicity (NT). In a 3 + 3 dose escalation design, patients received bortezomib at 1.0-1.5 mg/m² on days 1 and 4 and oxaliplatin at 60-85 mg/m² on day 1 of a 14-day cycle. NT assessments were performed at the start of every two cycles. Oxaliplatin pharmacokinetics (PK) were determined pre- and post-bortezomib. Thirty patients were enrolled with 25 (11 men, 14 women) fully evaluable for NT assessments at cycle 2. The median age was 56 years (range 35-74 years); median number of cycles received 2 (range 1-10). At dose levels 2-5 (B 1.3 mg/m²), patients manifested NT grades 3 and 4 at a median 3.4 cycles (range 2-9 cycles): 3 had ataxia (one also with sensory neuropathy or neurogenic hypotension, respectively) and 3 had just sensory neuropathy. A 6th dose-level reducing bortezomib to 1.0 mg/m² with oxaliplatin 85 mg/m²) was explored and no NT or dose limiting toxicities were noted among 7 evaluable patients (5 receiving two or more cycles). Four patients experienced a partial response--one with platinum-resistant ovarian cancer, another with gastroesophageal cancer, another with ampulla of Vater carcinoma, and a patient with cholangiocarcinoma. PK studies at dose levels 1 and 2 showed greater mean ultrafiltrable platinum when oxaliplatin was dosed after bortezomib. Bortezomib 1.0 mg/m² × 2 every 14 days combines safely with oxaliplatin. At higher doses, cumulative NT (i.e., cerebellar signs and sensory neuropathy) occurs at an accelerated pace perhaps from a PK interaction.

Comparison of acute toxicity and mortality after two different dosing regimens of high-dose interleukin-2 for patients with metastatic melanoma

We compared acute toxicity, drug exposure, in-hospital mortality, and inpatient length of stay between two currently recommended dosing protocols (from the National Comprehensive Cancer Network Guidelines) of high-dose interleukin-2 (IL-2) treatment for patients with metastatic melanoma. Patients with metastatic melanoma who received high-dose IL-2 treatment between 2003 and 2010 were identified. Chemotherapy orders, electronic medical records, paper medical charts, and patient discharge summaries were reviewed retrospectively. We identified 13 patients who had received 600,000 units/kilogram (kg)/dose and 15 patients who had received 720,000 units/kg/dose. Patients in the 720,000 units/kg/dose group had a higher rate of grade 3 and 4 bilirubin elevations (34 vs. 12%), weight gain (any grade, 96 vs. 89%), and thrombocytopenia (any grade, 75 vs. 65%). Patients receiving the higher dose also experienced more dose-limiting neurotoxicity (45 vs. 23%), large-volume diarrhea (15 vs. 0%), and hepatotoxicity (7 vs. 0%). There was no in-hospital mortality during treatment in either group. The average length of stay was similar between both groups (5days, SD = 1 for both groups), and the median cumulative IL-2 exposure was similar between both groups for the first course (10.1 vs.10.5 million units/kg) and for all courses (approximately 11-12 million units/kg). Both high-dose IL-2 protocols had comparable in-hospital mortality and cumulative IL-2 exposure. The 720,000 units/kg/dose dosing scheme did not shorten the length of stay but did lead to greater acute toxicity. Therefore, as a result, we recommend 600,000 units/kg/dose when deciding between the two regimens.

A Phase I Study of the Metal Ionophore Clioquinol in Patients With Advanced Hematologic Malignancies

Clioquinol is a small-molecule metal ionophore that inhibits the proteasome through a metal-dependent mechanism. Here, we report a phase I study of clioquinol in patients with refractory hematologic malignancies. Neuropathy and abdominal pain were dose-limiting toxicities. Minimal pharmacodynamic effects were observed, and there were no clinical responses. Clioquinol is a small-molecule metal ionophore that inhibits the enzymatic activity of the proteasome and displays preclinical efficacy in hematologic malignancies in vitro and in vivo. Therefore, we conducted a phase I clinical trial of clioquinol in patients with refractory hematologic malignancies to assess its safety and determine its biological activity in this patient population. Patients with refractory hematologic malignancies were treated with increasing doses of oral clioquinol twice daily for 15 doses. Plasma and intracellular levels of clioquinol were measured. Enzymatic activity of the proteasome was measured before and after drug administration. Sixteen cycles of clioquinol were administered to 11 patients with 5 patients reenrolled at the next dose level as per the permitted intrapatient dose escalation. Dose-limiting neurotoxicity and abdominal pain were observed at a dose of 1600 mg twice daily. Intracellular drug levels were low. Minimal inhibition of the proteasome was observed. No clinical responses were observed. In patients with refractory hematologic malignancies, the maximal tolerated dose of clioquinol was determined. Minimal inhibition of the proteasome was observed at tolerable doses, likely due to low intracellular levels of the drug.

Abstract 4766: The use of deuterium isotope effects to shift the partitioning of cyclophosphamide and ifosfamide among competing, P450-dependent, oxidative pathways

Abstract Prodrugs cyclophosphamide and ifosfamide are each ‘activated’ through a P450 oxidation at the C-4 position of the oxazaphosphorine ring. This reaction triggers a series of spontaneous (non-enzymatic) steps resulting in the formation of the ultimate DNA crosslinking agents, phosphoramide mustard and isophosphoramide mustard. Competing with reaction at C-4 are P450-catalyzed oxidations at the alpha positions of the chloroethyl side-chains; reactions at the side chains result in the production of the neurotoxic chloroacetaldehyde. Predominance of one pathway over another is isozyme-dependent and of greatest impact in ifosfamide therapy where about 50% of this drug is lost to side-chain oxidation (relative to an average of 10% for cyclophosphamide) and dose-limiting neurotoxicity. In this project, deuterium isotope effects are being explored as a means to effect ‘metabolic switching’ in the oxidations of cyclophosphamide and ifosfamide; that is, favoring oxidation at the C-4 position by disfavoring oxidations at the side chains. Cyclophosphamide and ifosfamide were synthesized with deuterium at the alpha and alpha’ positions of the chloroethyl chains. After optimizing reaction times, drug and enzyme concentrations, cyclophosphamide and ifosfamide (unlabeled and labeled) were incubated (20 min) with three, relevant, cDNA-expressed supersomes (human CYP2B6, CYP3A4, CYP3A5). The concentration of each metabolite produced by C-4 and the two possible side-chain oxidations was measured quantitatively using LC-MS-MS techniques developed for this project. For unlabeled cyclophosphamide, the fraction of products derived from C-4 oxidation was 73% (3A4), 90% (3A5) and 100% (2B6). Use of deuterium labeled cyclophosphamide gave 89% (3A4), 94% (3A5) and 100% (2B6); the amount of product produced by 2B6 and labeled drug was more than twice that given by unlabeled drug (56 micromoles versus 23 micromoles, respectively). For unlabeled ifosfamide, the fraction of products given by C-4 oxidation was 63% (3A4), 55% (3A5) and 36% (2B6). Use of deuterium labeled ifosfamide gave 82% (3A4), 75% (3A5) and 88% (2B6). Aside from the initial oxidation, the metabolic steps most likely to be impacted by deuterium isotope effects are those of the alkylation sequence by the metabolites phosphoramide mustard and isophosphoramide mustard. To determine the effect, if any, phosphoramide mustard and isophosphoramide mustard are being synthesized with deuterium at the alpha and alpha’ positions of the chloroethyl chains and their alkylation kinetics, relative to unlabeled compounds are being determined using 31P NMR spectroscopy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4766. doi:1538-7445.AM2012-4766