Investigational New Drugs Journal Impact Factor & Information

Publisher: Springer Verlag

Journal description

The development of new anticancer agents is one of the most rapidly changing aspects of cancer research. Investigational New Drugs provides a forum for the rapid dissemination of information on new anticancer agents. The papers published are of interest to the medical chemist toxicologist pharmacist pharmacologist biostatistician and clinical oncologist. Investigational New Drugs provides the fastest possible publication of new discoveries and results for the whole community of scientists developing anticancer agents. Each issue contains original articles dealing with anticancer drug development. Other sections are devoted to invited review articles and letters to the editor. The journal also affords the opportunity to publish the proceedings of special workshops and symposia devoted to the development of new anticancer agents. Provided they add to the understanding of the investigational agents the journal is not adverse to publishing clinical trials with negative results. Investigational New Drugs cuts across all the usual lines or subdisciplines providing a locus for the presentation of relevant investigations and the discussion of critical questions appropriate to the entire field of new anticancer drug development.

Current impact factor: 2.92

Impact Factor Rankings

2015 Impact Factor Available summer 2016
2014 Impact Factor 2.919
2013 Impact Factor 2.927
2012 Impact Factor 3.498
2011 Impact Factor 3.357
2010 Impact Factor 3.007
2009 Impact Factor 3.072
2008 Impact Factor 3.396
2007 Impact Factor 2.806
2006 Impact Factor 2.538
2005 Impact Factor 2.417
2004 Impact Factor 1.854
2003 Impact Factor 2.272
2002 Impact Factor 2.842
2001 Impact Factor 3.822
2000 Impact Factor 1.322
1999 Impact Factor 1.89
1998 Impact Factor 1.837
1997 Impact Factor 0.543
1996 Impact Factor 0.703
1995 Impact Factor 0.495
1994 Impact Factor 0.809
1993 Impact Factor 0.713
1992 Impact Factor 0.554

Impact factor over time

Impact factor

Additional details

5-year impact 2.74
Cited half-life 3.70
Immediacy index 0.69
Eigenfactor 0.01
Article influence 0.71
Website Investigational New Drugs website
Other titles Investigational new drugs (Online)
ISSN 0167-6997
OCLC 41569296
Material type Document, Periodical, Internet resource
Document type Internet Resource, Computer File, Journal / Magazine / Newspaper

Publisher details

Springer Verlag

  • Pre-print
    • Author can archive a pre-print version
  • Post-print
    • Author can archive a post-print version
  • Conditions
    • Author's pre-print on pre-print servers such as
    • Author's post-print on author's personal website immediately
    • Author's post-print on any open access repository after 12 months after publication
    • Publisher's version/PDF cannot be used
    • Published source must be acknowledged
    • Must link to publisher version
    • Set phrase to accompany link to published version (see policy)
    • Articles in some journals can be made Open Access on payment of additional charge
  • Classification
    ​ green

Publications in this journal

  • [Show abstract] [Hide abstract]
    ABSTRACT: Purpose LY2090314 (LY) is a glycogen synthase kinase 3 inhibitor with preclinical efficacy in xenograft models when combined with platinum regimens. A first-in-human phase 1 dose-escalation study evaluated the combination of LY with pemetrexed/carboplatin. Patients and Methods Forty-one patients with advanced solid tumors received single-dose LY monotherapy lead-in and 37 patients received LY (10-120 mg) plus pemetrexed/carboplatin (500 mg/m(2) and 5-6 AUC, respectively) across 8 dose levels every 21 days. Primary objective was maximum tolerated dose (MTD) determination; secondary endpoints included safety, antitumor activity, pharmacokinetics, and beta-catenin pharmacodynamics. Results MTD of LY with pemetrexed/carboplatin was 40 mg. Eleven dose-limiting toxicities (DLTs) occurred in ten patients. DLTs during LY monotherapy occurred at ≥40 mg: grade 2 visual disturbance (n = 1) and grade 3/4 peri-infusional thoracic pain during or shortly post infusion (n = 4; chest, upper abdominal, and back pain). Ranitidine was added after de-escalation to 80 mg LY to minimize peri-infusional thoracic pain. Following LY with pemetrexed/carboplatin therapy, DLTs included grade 3/4 thrombocytopenia (n = 4) and grade 4 neutropenia (n = 1). Best overall response by RECIST included 5 confirmed partial responses (non-small cell lung cancer [n = 3], mesothelioma, and breast cancer) and 19 patients having stable disease. Systemic LY exposure was approximately linear over dose range studied. Transient upregulation of beta-catenin measured in peripheral blood mononuclear cells (PBMCs) occurred at 40 mg LY. Conclusions The initial safety profile of LY2090314 was established. MTD LY dose with pemetrexed/carboplatin is 40 mg IV every 3 weeks plus ranitidine. Efficacy of LY plus pemetrexed/carboplatin requires confirmation in randomized trials.
    Investigational New Drugs 09/2015; DOI:10.1007/s10637-015-0278-7
  • [Show abstract] [Hide abstract]
    ABSTRACT: Objective VS-6063 (also known as defactinib or PF-04554878) is a second-generation inhibitor of focal adhesion kinase (FAK) and proline-rich tyrosine kinase-2 (Pyk2). This phase I dose-escalation study was conducted in patients with advanced solid malignancies. Methods Using a traditional 3 + 3 design, VS-6063 was administered orally twice daily (b.i.d.) in 21-day cycles to cohorts of three to six patients. In cycle 1, a lead-in dose was administered to assess single-dose pharmacokinetics; steady-state pharmacokinetics was assessed after 15 days of continuous dosing. Dose escalation was performed in the fasted state, and repeated in two additional cohorts in the fed state. Results Forty-six patients were treated across nine dose levels (12.5-750 mg b.i.d.). Dose-limiting toxicities, comprising headache (n = 1), fatigue (n = 1) and unconjugated hyperbilirubinemia (n = 3), occurred at the 300- or 425-mg b.i.d. dose level and were reversible. Frequent adverse events included nausea (37 %), fatigue (33 %), vomiting (28 %), diarrhea (22 %) and headache (22 %). A maximum-tolerated dose was not defined. Dose escalation was stopped at the 750-mg b.i.d. dose due to decreased serum exposure in the 500- and 750-mg versus 300- and 425-mg groups. Food delayed the time to peak serum concentration without affecting serum drug exposure. No radiographic responses were reported. Disease stabilization at ~12 weeks occurred in six of 37 (16 %) patients receiving doses ≥100 mg b.i.d. Conclusions VS-6063 has an acceptable safety profile. Treatment-related adverse events were mild to moderate, and reversible. The recommended phase II fasting dose of VS-6063 is 425 mg b.i.d.
    Investigational New Drugs 09/2015; 33(5). DOI:10.1007/s10637-015-0282-y
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: Docetaxel-prednisone (DP) is an approved therapy for metastatic castration-resistant prostate cancer (mCRPC). Orteronel (TAK-700) is an investigational, selective, non-steroidal inhibitor of 17,20-lyase, a key enzyme in androgenic hormone production. This phase 1/2 study evaluated orteronel plus DP in mCRPC patients. Methods: Adult men with chemotherapy-naïve mCRPC, serum prostate-specific antigen (PSA) ≥5 ng/mL, and serum testosterone <50 ng/dL received oral orteronel 200 or 400 mg twice-daily (BID) in phase 1 to determine the recommended dose for phase 2, plus intravenous docetaxel 75 mg/m(2) every 3 weeks, and oral prednisone 5 mg BID. Phase 2 objectives included safety, pharmacokinetics, and efficacy. Results: In phase 1 (n = 6, orteronel 200 mg; n = 8, orteronel 400 mg), there was one dose-limiting toxicity of grade 3 febrile neutropenia at 400 mg BID. This dose was evaluated further in phase 2 (n = 23). After 4 cycles, 68, 59, and 23% of patients achieved ≥30, ≥50, and ≥90% PSA reductions, respectively; median best PSA response was -77%. Seven of 10 (70%) RECIST-evaluable patients achieved objective partial responses. Median time to PSA progression and radiographic disease progression was 6.7 and 12.9 months, respectively. Dehydroepiandrosterone-sulfate (DHEA-S) and testosterone levels were rapidly and durably reduced. Common adverse events were fatigue (78%), alopecia (61%), diarrhea (48%), nausea (43%), dysgeusia (39%), and neutropenia (39%). Orteronel and docetaxel pharmacokinetics were similar alone and in combination. Conclusions: Orteronel plus DP was tolerable, with substantial reductions in PSA, DHEA-S, and testosterone levels, and evidence for measurable disease responses.
    Investigational New Drugs 01/2015; 33(2). DOI:10.1007/s10637-014-0199-x
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background We hypothesized that targeting two mechanisms of epigenetic silencing would be additive or synergistic with regard to expression of specific target genes. The primary objective of the study was to establish the maximum tolerated dose (MTD) of belinostat in combination with a fixed dose of azacitidine (AZA). Methods In Part A of the study, patients received a fixed dose of AZA, with escalating doses of belinostat given on the same days 1–5, in a 28 day cycle. Part B was designed to evaluate the relative contribution of belinostat to the combination based on analysis of pharmacodynamic markers, and incorporated a design in which patients were randomized during cycle 1 to AZA alone, or the combination, at the maximally tolerated dose of belinostat. Results 56 patients with myeloid neoplasia were enrolled. Dose escalation was feasible in part A, up to 1000 mg/m2 dose level of belinostat. In Part B, 18 patients were assessable for quantitative analysis of specific target genes. At day 5 of therapy, MDR1 was significantly up-regulated in the belinostat/AZA arm compared with AZA alone arm (p = 0.0023). There were 18 responses among the 56 patients. Conclusions The combination of belinostat and AZA is feasible and associated with clinical activity. The recommended phase II dose is 1000 mg/m2 of belinostat plus 75 mg/m2 of AZA on days 1–5, every 28 days. Upregulation in MDR1 was observed in the combination arm at day 5 compared with the AZA alone arm, suggesting a relative biologic contribution of belinostat to the combination.
    Investigational New Drugs 12/2014; 33(2). DOI:10.1007/s10637-014-0194-2
  • [Show abstract] [Hide abstract]
    ABSTRACT: Posterior reversible encephalopathy syndrome (PRES) is a clinical/radiological syndrome characterized by symptoms that can include seizure, headache, impaired vision and hypertension, and can be confirmed by magnetic resonance imaging. Numerous reports have emerged that describe PRES in cancer patients. The list of medications linked to PRES can include traditional cytotoxic chemotherapeutics (e.g., cisplatin, cyclophosphamide, and high-dose corticosteroids), newer agents that target the vascular endothelial growth factor pathway (e.g., bevacizumab, sunitinib, and pazopanib), and supportive care mediations (e.g., granulocyte colony stimulating factors and erythropoietin). We report, for the first time, a case of PRES that is secondary to treatment with enzalutamide, a potent androgen receptor antagonist used in the treatment of metastatic castration-resistant prostate cancer. Enzalutamide is approved for the treatment of both docetaxel-pretreated and chemotherapy-naïve metastatic castration-resistant prostate cancer. Enzalutamide has been previously linked to the increased risk of seizures. Clinicians should be aware that, in rare cases, patients treated with enzalutamide could potentially be at risk for PRES. If symptoms suggestive of PRES arise in patients receiving enzalutamide, the drug should be discontinued immediately and the diagnostic process should be initiated.
    Investigational New Drugs 12/2014; 33(3). DOI:10.1007/s10637-014-0193-3
  • [Show abstract] [Hide abstract]
    ABSTRACT: Ibrutinib (formerly PCI-32765) is a specific, irreversible, and potent inhibitor of Burton's tyrosine kinase (BTK) developed for the treatment of several forms of blood cancer. It is now an FDA-approved drug marketed under the name Imbruvica(TM) (Pharmacyclics, Inc.) and successfully used as an orally administered second-line drug in the treatment of mantle cell lymphoma. Since BTK is predominantly expressed in hematopoietic cells, the sensitivity of solid tumor cells to Ibrutinib has not been analyzed. In this study, we determined the effect of Ibrutinib on breast cancer cells. We demonstrate that Ibrutinib efficiently reduces the phosphorylation of the receptor tyrosine kinases ErbB1, ErbB2 and ErbB3, thereby suppressing AKT and MAPK signaling in ErbB2-positive (ErbB2+) breast cancer cell lines. Treatment with Ibrutinib significantly reduced the viability of ErbB2+ cell lines with IC50 values at nanomolar concentrations, suggesting therapeutic potential of Ibrutinib in breast cancer. Combined treatment with Ibrutinib and the dual PI3K/mTOR inhibitor BEZ235 synergistically reduces cell viability of ErbB2+ breast cancer cells. Combination indices below 0.25 at 50 % inhibition of cell viability were determined by the Chou-Talalay method. Therefore, the combination of Ibrutinib and canonical PI3K pathway inhibitors could be a new and effective approach in the treatment of breast cancer with activated ErbB receptors. Ibrutinib could thus become a valuable component of targeted therapy in aggressive ErbB2+ breast cancer.
    Investigational New Drugs 08/2014; 32(6). DOI:10.1007/s10637-014-0141-2
  • [Show abstract] [Hide abstract]
    ABSTRACT: Resistance of cancer cells towards chemotherapy is the major cause of therapy failure. Hence, the evaluation of cellular defense mechanisms is essential in the establishment of new chemotherapeutics. Archazolid B, a novel vacuolar H(+)-ATPase inhibitor, displayed cytotoxicity in the low nanomolar range on a panel of different tumor cell lines. First, we investigated tumor-specific cytotoxicity of archazolid B by comparing cancer to non-cancer cells. Breast, liver and colon cancer cells displayed higher drug sensitivity than corresponding non-tumorous cells, whereas leukemia cell lines were as sensitive as peripheral mononuclear blood cells. Investigating classical drug resistance mechanisms, archazolid B was identified as a possible substrate of the ABC transporters ABCB1 (P-glycoprotein) and ABCG2 (BCRP), whereas collateral sensitivity was observed in ABCB5-expressing cells. Our results pointed to a possible binding competition of archazolid B with verapamil on P-glycoprotein. However, archazolid B did not reverse resistance towards doxorubicin indicating that it might be a substrate but not an inhibitor of P-glycoprotein mediated transport. Furthermore, the cytotoxicity of archazolid B was independent of the p53 status of the cell. Mechanisms of aquired resistance were investigated establishing an archazolid B-resistant MCF-7 cell line. Interestingly, drug resistance was not conferred by aberrant expression or DNA mutations of the gene encoding vacuolar H(+)-ATPase subunit c, the direct target of archazolids. Instead, long-term treatment with archazolid B led to a slight overexpression of ABCB1 and a significant overexpression of the epidermal growth factor receptor and reduced cell growth, all of which can be assumed to contribute to archazolid B resistance.
    Investigational New Drugs 07/2014; 32(5). DOI:10.1007/s10637-014-0134-1
  • [Show abstract] [Hide abstract]
    ABSTRACT: Introduction: Afatinib, an irreversible ErbB family blocker, demonstrated synergistic inhibition of epidermal growth factor receptor-mutant cell growth with pemetrexed. This phase I study investigated the maximum tolerated dose (MTD), safety, pharmacokinetics, and antitumor activity of afatinib plus pemetrexed in patients with advanced solid tumors. Methods: In a 3 + 3 dose-escalation design, patients were given intravenous pemetrexed (500 mg/m(2)) on day 1 of a 21-day cycle (maximum 6 cycles), combined with continuous daily oral afatinib (schedule A [SA]; starting dose 30 mg, escalation to 50 mg) or pulsed-dose daily oral afatinib (schedule B [SB]; starting dose 50 mg, escalation to 70 mg) on days 1-6 of each 21-day cycle. Primary endpoint was determination of MTD based on dose-limiting toxicities (DLTs) in cycle 1. Results: Fifty-three patients were treated (SA: n = 23; SB: n = 30). Eight patients had DLTs in SA, 11 patients in SB; diarrhea and fatigue were the most common. MTD of afatinib was 30 mg in SA and 50 mg in SB. Six patients in SA and eight in SB completed 6 treatment cycles. One patient in each schedule had confirmed objective response; 18/53 patients had disease control (SA: n = 7; SB: n = 11). Most frequent drug-related adverse events were diarrhea, rash, fatigue, and stomatitis. No relevant pharmacokinetic interactions were observed. Conclusions: Continuous- or pulsed-dose afatinib combined with pemetrexed exhibited a manageable safety profile. Pulsed dosing conferred no apparent safety or dose advantage. Continuous-dose afatinib 30 mg/day with pemetrexed is recommended for phase II studies.
    Investigational New Drugs 07/2014; 32(6). DOI:10.1007/s10637-014-0139-9
  • Investigational New Drugs 07/2014; 32(5). DOI:10.1007/s10637-014-0133-2
  • [Show abstract] [Hide abstract]
    ABSTRACT: Introduction Continuous efforts from scientists of diverse fields are necessary not only to better understand the mechanism by which multidrug resistant (MDR) cancer cells occur, but also to boost the discovery of new cytotoxic compounds. This work was designed to assess the cytotoxicity and the mechanism of action of flavonoids abyssinone IV (1), atalantoflavone (3) and neocyclomorusin (6) and isoflavonoids sigmoidin I (2), sophorapterocarpan A (4), bidwillon A (5) and 6α-hydroxyphaseollidin (7) isolated from Erythrina sigmoidea against nine drug sensitive and multidrug resistant (MDR) cancer cell lines. Methods The resazurin reduction assay was used to evaluate the cytotoxicity of the studied compounds whilst caspase-Glo assay was used to detect the activation of caspases enzymes by 1, 2, 4 and 7. Cell cycle, mitochondrial membrane potential and levels of reactive oxygen species were all analyzed via flow cytometry. Results The pterocarpan isoflavonoid 7 displayed the best antiproliferative activity with the IC50 values below 10 μM obtained on the nine tested cancer cell lines. The IC50 values below 50 μM were also recorded with compounds 1, 2 and 4 against the nine cancer cell lines whilst 3, 5 and 6 showed selective activities. The IC50 values varied from 14.43 μM (against MDA-MB-231-pcDNA cells) to 20.65 μM [towards HCT116 (p53 +/+) cells] for compound 1, from 4.24 μM (towards CCRF-CEM cells) to 30.98 μM (towards MDA-MB-231-BCRP cells) for 2, from 3.73 μM (towards CCRF-CEM cells) to 14.81 μM (against U87MG.ΔEGFR cells) for 4, from 3.36 μM (towards CCRF-CEM cells) to 6.44 μM (against HepG2 cells) for 7, and from 0.20 μM (against CCRF-CEM cells) and 195.12 μM (against CEM/ADR5000 cells) for the positive control drug, doxorubicin. Compared to their corresponding sensitive cell lines, collateral sensitivity was observed with HCT116 (p53 −/−) to 1, 2, 4, 5, and 7 and with U87MG.ΔEGFR to 1 to 6. Compound 7 induced apoptosis in CCRF-CEM cells mediated by the activation of caspases 3/7, 8 and 9 and breakdown of MMP and increase in ROS production, whereas the apoptotic process induced by 1, 2 and 4 was mediated by the loss of MMP as well as increase in ROS production. Conclusions Compounds from Erythrina sigmoidea and mostly 6α-hydroxyphaseollidin are potential antiproliferative natural products that deserve more investigations to develop novel anticancer drugs against sensitive and otherwise drug-resistant phenotypes.
    Investigational New Drugs 07/2014; 32(6). DOI:10.1007/s10637-014-0137-y
  • [Show abstract] [Hide abstract]
    ABSTRACT: Growth hormone-releasing hormone (GHRH) and its receptors have been implicated in a variety of cellular phenotypes related with tumorigenesis process. Human epidermal growth factor receptor family members (HER) such as EGFR and HER2 are involved in mitogenic signaling pathways implicated in the progression of prostate cancer. We analyzed the cross-talk between GHRH and EGF receptors in prostate cancer. The effects of GHRH in HER signaling were evaluated on human androgen-independent PC3 prostate cancer cells in vitro and GHRH antagonist in vitro and in nude mice xenografts of PC3 prostate cancer. Time-course studies indicated that GHRH had a stimulatory activity on both the expression of EGFR and HER2. GHRH analogues, JMR-132 and JV-1-38, endowed with antagonistic activity for GHRH receptors, abrogated the response to GHRH in PC3 cells. GHRH stimulated a rapid ligand-independent activation of EGFR and HER2 involving at least cAMP/PKA and Src family signaling pathways. GHRH also stimulated a slow ligand-dependent activation of EGFR and HER2 involving an extracellular pathway with an important role for ADAM. Preliminary results also revealed an increase of mRNA for GHRH and GHRH receptor induced by EGF. The inhibition of tumor growth, in vivo, was associated with a substantial reduction in the expression of mRNA and protein levels of EGFR and HER2 in the tumors. GHRH antagonist JV-1-38, significantly decreased the phosphorylated Src levels. The cross-talk between HER and GHRH-R may be impeded by combining drugs acting upon GHRH receptors and HER family members in human advanced prostate cancer.
    Investigational New Drugs 07/2014; 32(5). DOI:10.1007/s10637-014-0131-4
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: Aldo-keto reductase 1C3 [AKR1C3;17β-hydroxysteroid dehydrogenase type 5 (17βHSD5)], plays a crucial role in persistent production of androgens despite castration, by catalysing conversion of the adrenal androgens dehydroepiandrosterone and androstenedione (AD) into androstenediol and testosterone (T). Hence, AKR1C3 is a promising therapeutic target in castration-resistant prostate cancer, as combination of an AKR1C3 inhibitor and a gonadotropin-releasing hormone analogue may lead to complete androgen blockade. This study describes the preclinical characterisation of the novel AKR1C3 inhibitor ASP9521. Methods: The inhibitory effect of ASP9521 on AKR1C3-mediated conversion from AD into T was evaluated both in vitro and in vivo, using CWR22R xenografted mice. The effect of ASP9521 on PSA production and cell proliferation was tested using LNCaP cells stably expressing human AKR1C3 (LNCaP-AKR1C3). Pharmacokinetics of ASP9521 were studied in rats, dogs and cynomolgus monkeys. Results: ASP9521 inhibited conversion of AD into T by recombinant human or cynomolgus monkey AKR1C3 in a concentration-dependent manner (IC50,human: 11 nmol/L; IC50,monkey: 49 nmol/L). ASP9521 showed >100-fold selectivity for AKR1C3 over the isoform AKR1C2. In LNCaP-AKR1C3 cells, ASP9521 suppressed AD-dependent PSA production and cell proliferation. In CWR22R xenografts, single oral administration of ASP9521 (3 mg/kg) inhibited AD-induced intratumoural T production and this inhibitory effect was maintained for 24 h. After oral administration, ASP9521 was rapidly eliminated from plasma, while its intratumoural concentration remained high. The bioavailability of ASP9521 after oral administration (1 mg/kg) was 35 %, 78 % and 58 % in rats, dogs and monkeys, respectively. Conclusions: ASP9521 is a potent, selective, orally bioavailable AKR1C3 inhibitor.
    Investigational New Drugs 07/2014; 32(5). DOI:10.1007/s10637-014-0130-5