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Marine Natural Products and Related Compounds as Anticancer Agents: an Overview of their Clinical Status
Abstract and Figures
Marine ecosystems constitute a huge reservoir of biologically active secondary metabolites. Consequently during the last past few decades, several marine-derived molecules have been approved for anticancer treatment or are under clinical trials. This review reports the present state of the art of the sixteen molecules approved or currently on the clinical pipeline for anticancer chemotherapy. The molecules are classified according to their current status in the phase (approved / phase IV / phase III / phase II / phase I) and data are updated to April 2012.
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... Recent advances in therapeutic research have successfully developed new potent anticancer agents capable of targeting tumors with minimal side effects [4,5]. Natural compounds have been and are the main source for the development of several anticancer agents [6][7][8][9][10]. Terpenes and their functionalized derivatives, especially heterocyclic analogues, are often used as a source for the preparation of new semi-synthetic compounds displaying various biological properties including anticancer activity [11,12]. ...
Aseries of novel 1,4-disubstituted 1,2,3-triazoles were synthesized from an (R)-carvone terminal alkyne derivative via a Cu (I)-catalyzed azide–alkyne cycloaddition reaction using CuSO4,5H2O as the copper (II) source and sodium ascorbate as a reducing agent which reduces Cu (II) into Cu(I). All the newly synthesized 1,2,3-triazoles 9a–h were fully identified on the basis of their HRMS and NMR spectral data and then evaluated for their cell growth inhibition potential by MTS assay against HT-1080 fibrosarcoma, A-549 lung carcinoma, and two breast adenocarcinoma (MCF-7 and MDA-MB-231) cell lines. Compound 9d showed notable cytotoxic effects against the HT-1080 and MCF-7 cells with IC50 values of 25.77 and 27.89 µM, respectively, while compound 9c displayed significant activity against MCF-7 cells with an IC50 value of 25.03 µM. Density functional calculations at the B3LYP/6-31G* level of theory were used to confirm the high reactivity of the terminal alkyne as a dipolarophile. Quantum calculations were also used to investigate the mechanism of both the uncatalyzed and copper (I)-catalyzed azide–alkyne cycloaddition reaction (CuAAC). The catalyzed reaction gives complete regioselectivity via a stepwise mechanism streamlining experimental observations. The calculated free-energy barriers 4.33 kcal/mol and 29.35 kcal/mol for the 1,4- and 1,5-regioisomers, respectively, explain the marked regioselectivity of the CuAAC reaction.
... Currently, there are more than 20 marine-derived anti-cancer candidates in one of the three phases of drug development. Many of these candidates showed high selectivity index (SI) and few side-effects compared with the existing chemotherapeutic agents [1,2]. ...
Manoalide was studied as a potential anti-inflammatory agent for the last forty years and more than 200 publications and 180 patents were reported on this compound. However, the configurations at positions 24 and 25 and configuration-dependent bioactivity were not yet studied. In the current report, ten manoalide-like sesterterpenoids were isolated from Luffariella sp. (1-10). These stereoisomers were identified and separated for the first time since 1980 and their configurations at positions 24 and 25 were determined by analyzing their spectroscopic spectra. The configuration-dependent anti-proliferative activity of manoalide derivatives was examined by evaluating their effect on four leukemic cancer cell lines (Molt 4, K562, Sup-T1, and U937). The 24R,25S-isomers exhibited the most potent activity (IC50 0.50-7.67 μM). The anti-proliferative mechanism of action of 24R,25S-manoalide (7) was further studied on Molt 4 cells. Compound 7 exhibited apoptotic activity on Molt 4 cells through the disruption of mitochondrial membrane potential (MMP) and the generation of intracellular reactive oxygen species (ROS). It also inhibited the activity of human topoisomerase I and II. The apoptotic-inducing effect of 7 was further supported by the in vivo experiment by suppressing the volume of xenograft tumor growth (66.11%) compared with the control.
... For a comprehensive list of NRPs and their precursors, one can refer to Norine [12], a database dedicated to NRPs. Currently, several NRPs have been commercialized: for example, biosurfactants produced by Bacillus species [13] and Pseudomonas species [14] as oil spill cleanup agents; ecteinascidin produced by Ecteinascidia turbinata as an anticancer drug [15]; and cephalosporin produced by Cephalosporium acremonium as an antibiotic [16]. In case of biosurfactants, their market was evaluated to generate revenues of approximately 6.5 billion US dollars in 2012 [8]. ...
Non-ribosomal peptides (NRPs) are a family of secondary metabolites with the highest number among entire secondary metabolite types. They are biosynthesized by a multi-modular enzyme complex called non-ribosomal peptide synthetase (NRPS), which is encoded by a biosynthetic gene cluster (BGC) in plants and a special group of microorganisms. NRPs are structurally and functionally diverse with numerous industrial applications. However, native producers of these valuable NRPs have several biotechnological limitations for efficient production, including their slow growth, inefficient genetic manipulations, and silent BGCs. Heterologous expression of NRPS can address these challenges, especially using an array of model organisms with well-studied metabolic networks and readily available genetic engineering tools. Here, we review the applications of representative bacterial heterologous hosts, namely representative model Streptomyces species, Escherichia coli, Pseudomonas putida, and Bacillus subtilis, which have been engineered for the enhanced production of NRPs.
... Numerous proteins, peptides, and chemical agents in the venom of venomous marine animals are potentially useful biologically active molecules with pharmacological properties. During the past decade, many studies have been focused on tracing of novel drugs from marine animals (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15). ...
Chemotherapy is still one of the main therapeutic regimens in cancer patients but its toxicity is a hard challenge for every patient yet. One of the available solutions is tracing for non-toxic anticancer agents from natural resources. Numerous proteins and peptides in the venom of sea anemones are potentially useful agents with pharmacological properties. Concerning to significance of this issue, the current study was aimed to finding a non-toxic anticancer fraction from the venom of the Persian Gulf sea anemone, Stichodactyla haddoni. Anticancer and hemolytic activity of crude venom was evaluated and followed by fractionation using RP-HPLC. Breast, Brain, and Colon cancer cell lines 1 were selected to assessment of anticancer activity and toxicity. IC50 of crude venom on the abovementioned cancer cell lines was as 4.13, 6.58, and 31.54 µg, respectively. According to the results obtained by paired sample t-test and comparison of toxicity of the fractions in normal cell line, F10, designated as hadonin, was determined as the candidate anti-cancer fraction. The non-toxic dose of F10 was 20 ng in which showed respectively 66, 29, and 7 anticancer activities on breast, brain, and colon cancer cell lines. According to results, anticancer activity of hadonin is of high pharmaceutical value to follow its therapeutic potency in animal model. In conclusion, the venom of the Persian Gulf sea anemone contains a potential anticancer agent with reasonable activity at nanogram level against three kinds of cancer cells with no toxicity on normal cells.
Background: Cancer is a global health burden, and the discovery of novel therapeutic agents remains a critical pursuit. Marine organisms, including sponges, have emerged as a promising source of structurally diverse natural products with potential anticancer properties. Objectives: In the present study, the cytotoxic activity of the fraction containing Ergosta-14,22-dien-3-ol (3β, 5α, and 22E), a steroid compound derived from Dysidea avara, was evaluated against Jurkat/E6-1 and Hek293 cells. Methods: Multiple analytical techniques, including column chromatography, TLC, and GC-MS, were used to isolate and identify the compound from marine sponges from the Persian Gulf. The XTT assay determined the cytotoxic activity and western blot for P53 expression in the Jurkat/ E6-1 cell line. The compound was also docked within the poly (ADP-ribose) polymerase-1 (PARP1) and E3 ubiquitin-protein ligase (MDM2) to investigate its potential mechanism of action. Furthermore, the pharmacological properties of the compound were predicted using PerADME, SwissADME, and Molinspiration tools. Results: The results showed that Ergosta-14,22-dien-3-ol (3β, 5α, and 22E) exhibited significant cytotoxic activity against Jurkat/E6-1 cells with an IC50 of 26.59 μg/mL. Western blotting analysis demonstrated a noticeable increase in the expression of P53 protein in cells treated with 50 and 100 µg/mL of the compound. In silico analysis revealed adequate binding energy against PARP1 and E3 MDM2 receptors. The compound also demonstrated favorable pharmacokinetic characteristics, specifically in absorption, distribution, metabolism, and excretion (ADME). Conclusions: Ergosta-14,22-dien-3-ol (3β, 5α, and 22E) has the potential to be developed as a promising anti-cancer agent.
Macroalgae are found as a great source of biologically active compounds important in pharmaceutical industry. In this study, 8 algal samples namely Ulvafasciata (Green algae), Padinagymnosphora, Sargassamwightii, and Turbinariaornate (brown algae), Gracilariacorticata, Halimedamacrolopa, Halymeniadilatata, and Gracilariacrassa (red algae) were collected and identified its fatty acid compositions. U. fasciatawhich showed high fatty acid constituents was further analysed for its anticancer activity against Hela cells by MTT assay and AO/EtBr staining. The results confirmed that U. fasciata could inhibit the Hela cells by cytotoxic activity and by inducing apoptosis and thus could be used as apontential source in treating cancers.
Article History:
A novel series of 4,5-dihydroisoxazole-5-carboxamide derivatives were designed, synthesized and evaluated for their anti-cancer activity against two different human cancer cell lines. Most of the synthesized compounds showed anti-cancer activity with IC50 values ranging from 4.03 to 104.45 μM. Further, compounds 17h, 17i, 17e, and 18e were showed potent inhibitory activity against two cancer cell lines, with IC50 values close to that of standard drug. It is important to note that compound 17h was more potent than the standard drug cisplatin with IC50 values of 4.11 and 4.03 μM against Hela cell line and MCF-7 cell line respectively.
8500
Background: A defining feature of HL and sALCL is CD30 expression on malignant cells. The ADC SGN-35 comprises an anti-CD30 antibody conjugated to the antitubulin agent monomethyl auristatin E (MMAE). SGN-35 causes cell cycle arrest and apoptosis by binding to CD30 on the tumor cell surface, internalizing, and releasing MMAE into the cell. In a previous phase 1 study with q3 wk dosing, 54% of pts achieved an objective response (CR/PR) at SGN-35 doses ≥1.2 mg/kg [ASH 2008 abstract 1006]. Methods: To assess if more frequent dosing might maximize anti-tumor activity with acceptable tolerability, a multicenter, phase 1, weekly dosing, dose-escalation study (3+3 design) was conducted in pts with refractory or recurrent HL or sALCL. SGN-35 was administered weekly at doses of 0.4–1 mg/kg (2-hr IV infusions). Pts with stable disease or better (Cheson 2007) after two 28-day cycles (6 doses) were eligible to continue SGN-35 treatment. Results: In 17 pts, median age was 38 yrs (range 25–67). Pts received a median of 4 prior therapies; 65% received an autologous SCT. MTD has not been defined. One related G3 event (diarrhea) and no related G4 events occurred. The most common related adverse events were G1/G2 rash, nausea, and peripheral neuropathy. Exposure to SGN-35 (AUC) increased relative to dose level. Multiple CRs were observed at higher doses ( table ); observed time to response in the 1 mg/kg dose group was approximately 8 wks. The 7 pts with CRs all remain on treatment. Enrollment to SGN-35 monotherapy continues at 1.2 mg/kg; combination therapy will be subsequently explored. Conclusions: SGN-35 was generally well tolerated and induced CRs in 7 of 8 evaluable pts at the two highest doses in heavily pretreated patients. Pivotal trials of this antibody-drug conjugate will initiate in early 2009.
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3516
Background: NPI-0052 is a second-generation proteasome inhibitor that has a novel structure with preclinical studies suggesting unique proteasome inhibition (PI), signal transduction, efficacy and toxicology profiles, and activities in a broad range of models including bortezomib (BZ) resistant models. Methods: Patients were treated with NPI-0052 IV weekly x 3 in 4-week cycles in a 3+3 design dose escalation to a Recommended Phase 2 Dose (RP2D). PI was assayed in whole blood (PWB) and in PBMCs. Up to 10 patients each (lymphoma and solid tumors) are treated at the RP2D. Results: 39 patients have been treated between 0.0125 mg/m ² to 0.8 mg/m ² for up to 12 cycles. The RP2D was 0.8 mg/m ² and has been well tolerated in this study, with the most notable drug-related adverse events being N/V, fatigue, diarrhea, dizziness, headache, decreases in hemoglobin, and insomnia. Thrombocytopenia or neuropathy did not appear to be induced by NPI-0052. Escalation was halted at 0.8 mg/m ² , as DLT of transient “hallucinations” (visual imprints when eyes closed) and dizziness/unsteady gait were reported in another study at 0.9 mg/m ² . PK data indicate T1/2 ∼4–10 minutes, with clearance at 3–15 L/min and Vz of 35–85L. PI (chymotrypsin-like activity) in PWB and PBMC were dose dependent (mean D1 and D15 PI in PWB at 0.8 mg/m ² was 75 and 100%) (efficacious doses of BZ have been reported to result in a range of ∼40–70% PI). PI in PBMC returned to ∼baseline within one week of each dose, while inhibition remained in PWB. Stable disease was observed in patients with cervical carcinoma (11 months; maximum response was 24%; PI increased with dose escalation), colorectal, hepatocellular, adenoid cystic, melanoma, granulosis cell and ovarian. Conclusions: NPI-0052 produces dose-dependent pharmacologic effects, with equal to greater PI seen than reported with therapeutic doses of BZ. At the RP2D toxicity is mild-to-moderate, without the toxicity profile associated with BZ. Together with preclinical data this suggests NPI-0052 may have utility in treating patients who are not candidates for BZ as well as in indications and combinations that have not supported BZ use. Additional trials have been initiated including combinations with other targeted agents.
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e13509
Background: E7389 (E) is a synthetic analogue of halichondrin B, an investigational tubulin-based antimitotic drug. Gemcitabine (G) is a nucleoside analogue clinically active in several human tumours. These two drugs exhibit synergistic cytotoxic effects against the H522 non-small cell lung cancer (NSCLC) xenografts. Methods: A phase I study of these two drugs in combination was initiated in patients with advanced solid tumours. Two prior chemotherapy regimens for metastatic disease were allowed. Results: Patient characteristics: male 11/female 10; median age 59 (range 28–84); performance status 0 /1/2: n=1/13/7; prior chemotherapy 21, prior radiotherapy 7, prior immunotherapy 1; tumour types: ovarian cancer 3, endometrial cancer 3, NSCLC 3, gastric/esophageal adenocarcinoma 3, miscellaneous 9. Total number of cycles given 52, median cycles/patient (range) 2 (1, 8). Cohort (CT) 1: E/G given days 1,8,15 q28 days. Due to DLT, regimen changed in CT 2 with E/G given days 1, 8 q21 days. Cycles (C) given: median 2 range 1–8, total 52. Response: partial response 1 (ovarian cancer), stable 8 [minor response 4 (NSCLC 2, endometrial cancer 1, head and neck cancer 1)], progression 8, inevaluable 4. Conclusions: Further phase II investigation of this regimen should be considered at a dose of E 1.0 g/m ² /G 1000 mg/m ² q 3 weeks.
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No significant financial relationships to disclose.
9059
Background: AUM remains incurable in most patients (pts). DTIC alone had a 8–15% response rate (RR), while plitidepsin (Aplidin [APL]) showed a 6% RR and a 14% stable disease (SD) in a Phase (Ph) II study in 35 relapsed/refractory pts after DTIC failure. Furthermore, APL + DTIC has additive activity in preclinical models. Methods: This multicenter Ph Ib study aim to determine the safe recommended dose (RD) of APL on days 1, 8 & 15 + DTIC only day 1 q4wk. RD was defined as the highest dose with >5 days G4 neutropenia or G4 thrombocytopenia (TC) and/or febrile neutropenia (FN); any drug-related ≥ G3 toxicity (except nausea/vomiting or hypersensitivity reaction) in cycle 1. Results: Of 28pts with AUM, 23 were evaluable for DLT; 57% were males, median (med) age was 48 y (20–77), med ECOG 0 (0–2) and med LDH was 226 IU/l (126–983). Most pts (96%) had metastasis with a median of 2 sites involved (1–5). Dose levels of APL + DICT (mg/m ² ), were: DL1 (1.8 + 800), 7 pts; DL2 (2.4 + 800), 8 pts; DL 2b (2.4 + 1000), 5 pts; DL3 (3.0 + 800), 8 pts. Pts received 4 (2–6), 2 (2–5), 2 (1–2), 2 (1–8) median cycles respectively. The number of DLTs were 1/6, 1/7, 2/4, 2/6, respectively. DLTs were G3 ALT in 4 pts and FN + TC in 1 pt. The MTD was at DL 2B and the RD was at DL 2. There were 3 partial responses (PR, 14%) and 4 SD > 3 months (19%); all PR at DL2/3. Five pts were not evaluable, 2 pts had G3 hypersensitivity reactions related to Cremophor oil (APL formulation) and 1 pt had a idiosyncratic reaction to DTIC with prolonged pancytopenia. One pt had a wrong diagnosis and 1 pt had early progressive disease (PD). Conclusions: APL + DTIC can be safely combined at ≥ 70% of their respective single- agent RD in AUM. Main DLTs were asymptomatic, transient and reversible ALT elevations. Ph Ib showed 14 % PR and 19% clinically meaningful SD. A randomised Ph II study of DTIC + APL vs APL alone is ongoing.
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5526
Background: In an open-label, multicenter, randomized phase III study comparing the combination of trabectedin and PLD to PLD alone in patients with relapsed ovarian cancer, the combination demonstrated significantly improved progression free survival and response rates, manageable non-cumulative toxicity, and fewer PLD-associated adverse events. We studied the impact of the combination of trabectedin with PLD on the quality of life (QoL)/patient-reported outcomes (PRO) evaluated as part of the trial. Methods: QoL/PRO questionnaires, EORTC-QLQ C30, OV28, and EQ-5D were completed by patients at screening and on Day 1 of every other treatment cycle starting with Cycle 1, and at the end-of-treatment visit. Global health status/QoL, fatigue, rain subscales from QLQ C30, and abdominal pain/GI symptoms scale from OV28 were chosen a priori for primary analyses. Other scales of the three questionnaires were analyzed on a supportive basis. Results: A total of 672 patients were randomized. 663 (98%) completed at least the baseline questionnaires. Median cycles of treatment was 6 (131 days) for the combination arm and 5 (143 days) for the monotherapy arm. Mixed effects models (using a covariance structure of AR[1]) predicting the score at baseline and follow-up scores as a function of treatment, days after baseline, and interaction between treatment and days after baseline showed no significant differences between the treatment arms for any of the prespecified scales. Similar analyses of other scales, including EQ-5D Health Index scores and Health State on the Visual Analog Scale, support the findings. Conclusions: The addition of trabectedin to PLD results in superior efficacy in patients with relapsed ovarian cancer, with no added decrement to overall health status as assessed by PRO.
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3571
Background: NPI-2358 is a vascular disrupting agent (VDA) that destabilizes tumor vascular endothelial cell architecture resulting in selective collapse of established tumor vasculature. In murine tumor models NPI-2358 produces tumor regression alone and synergistically with agents such as paclitaxel, docetaxel (TXT) and irinotecan, often with decreased toxicity. Methods: The objective was to determine the Recommended Phase 2 Dose (RP2D) of NPI-2358 in combination with TXT. Patients with previously treated advanced NSCLC or other malignancies where TXT use was appropriate were enrolled. Patients received 75 mg/m ² TXT every 21 days. NPI-2358 was administered IV 2 hours after TXT on Day 1, and alone on Day 8. The dose of NPI-2358 was escalated from the single agent biologic effect dose (BED) of 13.5 mg/m ² to the single agent RP2D of 30 mg/m ² using a 3+3 design. PK was assessed on Days 1 and 8. Results: 13 patients were enrolled of whom 10 had NSCLC. At all dose levels adverse events were consistent with those of both agents given alone. Adverse events commonly associated with NPI-2358 were seen, including nausea, vomiting, fatigue, fever, tumor pain and transient blood pressure elevations. One DLT of nausea, vomiting, dehydration and neutropenia occurred at 30mg/m ² . PK analysis did not indicate a drug-drug interaction. Of the patients with NSCLC, 8 had measureable disease of which 2 demonstrated a partial response (PR), with 4 others having lesser regressions. The RP2D was thus 30 mg/m ² of NPI-2358 with 75 mg/m ² TXT. Conclusions: The combination of full dose NPI-2358 and TXT is tolerable. Although a limited data set, activity appears favorable relative to the 5–10% response rate reported with TXT alone in this population. Based on these results, efficacy is now being assessed in Phase 2 (the ADVANCE study), a randomized comparison of TXT ± 30 mg/m ² of NPI-2358 in 2 nd - line NSCLC. Of note, entry criteria allow patients with squamous cell carcinoma, as VDAs do not appear to result in unfavorable outcomes associated with some other agents in this sub-population.
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10509
Background: This prospective, international randomized study evaluated two trabectedin dosing regimens [1.5 mg/m ² 24-hour i.v. infusion once every 3 weeks (q3wk 24-h) vs. 0.58 mg/m ² 3-hour i.v. infusion every week for 3 weeks of a 4-week cycle (qwk 3-h)] in adult patients (pts) with unresectable and/or metastatic liposarcoma or leiomyosarcoma following failure of at least prior anthracycline and ifosfamide chemotherapy. Methods: Pts were treated and continuously followed in this trial, and we now present final OS data with long-term follow-up (median = 41 mo). With 234 deaths, the study would have >80% power to detect a minimum 45% improvement in median overall survival (OS) (2-sided 5% significance level). Results: The primary efficacy endpoint (time to progression, TTP) was superior for the q3wk 24-h arm, as previously reported [Morgan, et al. J Clin Oncol: 25(18S June 20 Suppl.) 10060 (2007)]. At cutoff, 235 deaths had occurred (13% censored). This final OS analysis confirms the previously reported trend towards improved survival with trabectedin q3wk 24-h despite crossover of 32% of pts from qwk 3-h to the q3wk 24-h dosing regimen. Pts treated with q3wk 24-h had a 16% reduction in the relative risk of death (HR=0.843; p=0.1931). Median (95%CI) OS were 13.9 mo (12.5–18.6; q3wk 24-h) and 11.8 mo (9.9–14.9; qwk 3-h) (log-rank p=0.1920). OS rates at 12 mo were 60% (q3wk 24-h) and 50% (qwk 3-h). Sensitivity analyses censoring at crossover further highlighted this favorable trend in survival with trabectedin q3wk 24-h. With longer follow-up, updated median TTP (investigator assessment, 223 progression events) was 4.2 vs. 2.5 mo [HR: 0.658; p=0.0032], favoring the q3wk 24-h arm. With 59 additional cycles (for a total of 1,532 cycles) and longer exposure, trabectedin safety profile was consistent with that previously reported. Conclusions: Final survival data reinforce the internal consistency of all efficacy-related endpoints showing improved outcomes associated with the trabectedin q3wk 24-h regimen with an acceptable safety profile in this population of patients with advanced, previously-treated leiomyosarcomas and liposarcomas.
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Background: NPI-0052 is a novel proteasome inhibitor that produces prolonged inhibition of all three catalytic activities (C-L, T-L, CT-L) of the 20S proteasome. Preclinical data suggest NPI-0052 may demonstrate an improved therapeutic ratio, with significant activity in hematologic and solid tumor malignancies including multiple myeloma (MM) resistant to bortezomib and other agents (Chauhan et al, Blood 2006). Studies have therefore been initiated in patients with multiple myeloma, lymphoma, leukemia and solid tumors.
Materials and Methods: This Phase 1 dose escalation study evaluated NPI-0052 monotherapy in patients with relapsed and relapsed/refractory MM, including those that have received bortezomib and/or lenalidomide. Patients were assessed for safety, pharmacodynamics (including ex vivo proteasome inhibition), plasma pharmacokinetics (PK), and clinical activity (with response assessed by modified EBMT criteria). Patients were treated with NPI-0052 administered as a weekly IV injection on Days 1, 8 and 15 every 4 weeks with concomitant hydration. The dose of NPI-0052 was escalated in cohorts of 3 patients dependent on observed adverse events utilizing a 3+3 design. Proteasome inhibition and PK were assayed after the 1st and 3rd dose and upon any intra-patient dose escalation. Proteasome inhibition was also assessed in CD138 positive cells isolated from bone marrow aspirates obtained at baseline and after the 3rd dose in a subset of patients.
Preliminary Results: To date, 10 patients have been treated at doses ranging from 0.025 mg/m2 to 0.075 mg/m2 without reaching an MTD. One patient experienced reversible elevation in serum creatinine that responded to drug cessation and steroids; this event may have been related to progression of his underlying light chain nephropathy (as interval worsening of renal function was noted prior to enrollment). Drug-related adverse events have been otherwise unremarkable at all dose levels tested. PK data demonstrate a rapid elimination half life (estimated to be 3–4 minutes) with clearance between 8–21 mL/min and Vz of 44–99L; no change in PK has been observed comparing the 1st and 3rd injection. Proteasome inhibition in whole blood suggests drug-dependent CT-L inhibition, with inhibition up to 28% observed (inhibition up to 100% at doses of up to 0.7 mg/m2 has been observed in other clinical trials with NPI-0052 without producing the profile of toxicity reported with standard doses of bortezomib). Whilst no responses have been confirmed, two patients with relapse/refractory MM remained on study for over 6 months and one year, respectively, with stable disease and no significant toxicity. Importantly, no peripheral neuropathy or myelosuppression has been seen in 41 treatment cycles in patients to date.
Conclusions: In patients with relapsed and relapsed, refractory MM, NPI-0052 affects parameters relevant to pharmacodynamics, PK and demonstrated potential clinical benefit at doses well below the MTD anticipated from Phase 1 clinical trials with NPI-0052 in lymphoma and solid tumors. Drug administration to date has been well tolerated. Dose escalation continues to define DLT and MTD, and to recommend a phase 2 dose for further study in patients with advanced MM.
7106
Background: E7389, a synthetic analog of halichondrin B that was isolated from a marine sponge, has broad anti-proliferative activity at nanomolar levels and a unique profile of tubulin interactions. Methods: This is an open-label, single-arm, stratified phase II study of E7389 in patients with measurable, recurrent and/or metastatic NSCLC who progressed during or after platinum-based doublet chemotherapy. E7389 (1.4 mg/m ² ) was administered as a bolus IV on days 1, 8, and 15 of a 28-day cycle to 72 patients (cohort 1) in stratum I (55 taxane pretreated patients) and stratum II (17 taxane-naive patients) and on Days 1 and 8 of a 21-day cycle (cohort 2), providing an additional 22 patients in stratum I. The primary efficacy endpoint was objective response rate to E7389 monotherapy. Results: As of 9 December 2005, 94 evaluable patients received E7389. Nineteen tumors were classified as squamous cell carcinomas, 39 as adenocarcinomas, and 36 were large cell carcinomas or unclassified. The median number of cycles completed was 3. Fifteen patients completed 6 or more cycles and 75 patients underwent tumor assessments after cycle 2. Major toxicities related to study drug included myelosuppression, nausea, fatigue, dehydration, arthralgias, dyspnea, and peripheral neuropathy. Based on RECIST criteria, 6 partial responses (PR) were observed among 94 evaluable patients (PR rate = 6.4%, 95% CI: 2.8%, 12.8%). For 33 patients the best response was stable disease (SD rate = 35.1%, 95% CI: 25.5%, 45.1%). Disease control rate (PR + SD) was 41.5% (95% CI: 31.4%, 51.7%). For cohort 1, the 12-week progression free survival rate was 57.2%. As of 9 December 2005, median PFS time was 108 days (95% CI = 55, min-max = 1–239+). Cohort 2 is being followed to estimate their 12-week PFS. The correlation of beta tubulin isotype, stathmin, microtubule-associated protein 4 (MAP4) and tau protein mRNA expression with tumor responses is on-going. Conclusions: Based on this data, E7389 has been shown to be safe and effective in the treatment of NSCLC patients. Updated information and results of molecular correlations of responses will be presented.
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1034
Background: Eribulin is a structurally simplified analog of halichondrin B, which inhibits microtubule dynamics via a novel mechanism characterized by suppression of microtubule growth, lack of effect on microtubule depolymerization, and sequestration of tubulin into nonfunctional aggregates. This study was designed to assess the activity and tolerance of eribulin in chemotherapy refractory patients with advanced breast cancer. Methods: Eribulin was evaluated in a single-arm Phase II trial in female patients with refractory breast cancer, ECOG performance status of 0–1, measurable disease, and neuropathy ≤ Grade 2. Patients received ≥ 1 prior chemotherapy regimen, including an anthracycline and a taxane. Eribulin was administered as a 2–5 min IV bolus of 1.4 mg/m ² on Days 1, 8, and 15 of a 28-Day cycle (Group 1). The schedule was modified to Days 1 and 8 of a 21-Day cycle (Group 2), because of dose delays. The primary efficacy endpoint was ORR according to RECIST criteria based upon independent review (IR) of tumor assessment. Results: Of 104 patients enrolled, 103 received eribulin treatment: 70 in Group 1, 33 in Group 2. Median age was 55 yrs (range 32–84). Patients had received a median of 4 prior chemotherapy regimens (range 1–11). Sixty-one percent of tumors were ER+, 14% Her2/neu 3+, and 29% were triple (ER, PR, Her-2) negative. The incidence of dose interruption, delay, or omission during Cycle 1 was 63% (Group 1) and 18% (Group 2). The most common drug related toxicities were neutropenia (75%, Grades 3: 31%, Grade 4: 30%, febrile neutropenia: 3.9%), fatigue (52%, Grade 3: 2.9%, no Grade 4), alopecia (Grade 1/2: 41%), nausea (37%, Grade 3: 1%, no Grade 4), and anemia (36%, Grade 3: 1%, no Grade 4). Peripheral neuropathy occurred in 34% of patients (Grade 3: 3.9%, no Grade 4). Best overall response rate (all PR) by IR was 14.5% and 15.2% in Groups 1 and 2, respectively; the combined ORR was 14.7% (95 % CI: 9–23%). Median PFS was 85 days, and the 6 mo PFS rate was 31%. Conclusions: Eribulin given as a 2–5 min IV infusion on Days 1, 8 of a 21-Day cycle or Days 1, 8, 15 of a 28-Day cycle exhibited a 15% PR rate by IR and a low incidence of Grade 3 neuropathy in this heavily chemotherapy pretreated population. The most common toxicity was neutropenia. The 21-Day schedule had an acceptable toxicity profile.
No significant financial relationships to disclose.