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Dive into the research topics where Johan Harmenberg is active.

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Featured researches published by Johan Harmenberg.


Lancet Oncology | 2007

Bone-targeted radium-223 in symptomatic, hormone-refractory prostate cancer: a randomised, multicentre, placebo-controlled phase II study

Sten Nilsson; Lars Franzén; Chris Parker; Christopher Tyrrell; René Blom; Jan Tennvall; Bo Lennernäs; Ulf Petersson; Dag Clement Johannessen; Michael Sokal; Katharine Pigott; Jeff rey Yachnin; Michael Garkavij; Peter Strang; Johan Harmenberg; Bjørg Bolstad; Øyvind S. Bruland

BACKGROUNDnThe alpha-emitter radium-223 ((223)Ra) is a bone-seeking radionuclide studied as a new treatment for patients with bone metastases from hormone-refractory prostate cancer. We aimed to study mature outcomes from a randomised, multicentre, phase II study of (223)Ra.nnnMETHODSnPatients with hormone-refractory prostate cancer and bone pain needing external-beam radiotherapy were assigned to four intravenous injections of (223)Ra (50 kBq/kg, 33 patients) or placebo (31 patients), given every 4 weeks. Primary endpoints were change in bone-alkaline phosphatase (ALP) concentration and time to skeletal-related events (SREs). Secondary endpoints included toxic effects, time to prostate-specific-antigen (PSA) progression, and overall survival. All tests were done at a 5% significance level, based on intention to treat.nnnFINDINGSnMedian relative change in bone-ALP during treatment was -65.6% (95% CI -69.5 to -57.7) and 9.3% (3.8-60.9) in the (223)Ra group and placebo groups, respectively (p<0.0001, Wilcoxon ranked-sums test). Hazard ratio for time to first SRE, adjusted for baseline covariates, was 1.75 (0.96-3.19, p=0.065, Cox regression). Haematological toxic effects did not differ significantly between two groups. No patient discontinued (223)Ra because of treatment toxicity. Median time to PSA progression was 26 weeks (16-39) versus 8 weeks (4-12; p=0.048) for (223)Ra versus placebo, respectively. Median overall survival was 65.3 weeks (48.7-infinity) for (223)Ra and 46.4 weeks (32.1-77.4) for placebo (p=0.066, log rank). The hazard ratio for overall survival, adjusted for baseline covariates was 2.12 (1.13-3.98, p=0.020, Cox regression).nnnINTERPRETATIONn(223)Ra was well tolerated with minimum myelotoxicity, and had a significant effect on bone-ALP concentrations. Larger clinical trials are warranted to study (223)Ra on the prevention of SREs and on overall survival in patients with hormone-refractory prostate cancer. Bone-targeting properties of (223)Ra could also potentially be used for treating skeletal metastasis from other primary cancers.


Acta Oncologica | 2011

Clinical Phase I study with an Insulin-like Growth Factor-1 receptor inhibitor: experiences in patients with squamous non-small cell lung carcinoma.

Simon Ekman; Jan-Erik Frödin; Johan Harmenberg; Antonina Bergman; Åsa Hedlund; Pia Dahg; Carina Alvfors; Birgitta Ståhl; Stefan Bergström; Michael Bergqvist

Abstract Background. Inhibition of the Insulin-like Growth Factor-1 receptor (IGF-1R) has resulted in extensive anti-tumor effects. Picropdophyllin (PPP, AXL1717) is a small-molecule inhibitor of the IGF-1R without inhibition of closely related receptors including the insulin receptor and has shown extensive effects against a wide range of tumors in animals. PPP is currently tested as an orally administrated single agent treatment in an open-label combined Phase I/II clinical study in advanced cancer patients with solid tumors which progress in spite of several lines of treatment. Patients and methods. The first part (Phase IA) consisted of single day BID dosing every three weeks with consecutive dose escalations. The second part (Phase IB) consists of seven days or longer BID dosing every three weeks, dosing range being 520–700 mg BID. Non-progressing patients could continue treatment within a compassionate use setting. Results and discussion. The present report describes our experience with the four patients with progressive squamous non-small cell lung cancer (NSCLC) that have received treatment with PPP. Despite more than seven months of PPP treatment as third or fourth line treatment, the reported patients did not develop any additional metastases. Furthermore, CT scans as well as 18FDG-Positron Emission Tomography (PET) scans of the patients demonstrated large central necrotic areas, which may suggest tumor response. At the same time, the study drug is so far well tolerated. The phenomenon of necrosis in the tumors suggestive of tumor response has not been reported before in anti-IGF-1R treatment and will be subject to further studies in the present clinical trial.


Antiviral Chemistry & Chemotherapy | 1998

Combinations of Antiviral and Anti-Inflammatory Preparations for the Topical Treatment of Herpes Simplex Virus Assessed using a Murine Zosteriform Infection Model

Aftab R. Awan; Johan Harmenberg; O Flink; Hugh J. Field

Recently we have reported a zosteriform murine infection model which employs the adoptive transfer of immune cells (ATI) to recipient infected mice to produce a disease that mimics human recurrent herpes simplex virus (HSV) disease. Mice were infected with HSV-1 by scarification at the lateroventral line of the neck; 2 days later, the mice received immune cells from HSV-1-infected syngeneic mice. Although virus was cleared more quickly from the target tissues of virus replication in recipient mice, ATI resulted in a heightened inflammatory response and delayed healing. This model was used to test the effects of topical formulations containing foscarnet and/or the anti-inflammatory agent, hydrocortisone. Virus clearance and clinical signs, including ear thickness and zosteriform spread of lesions, were studied. Treatment with 3% foscarnet accelerated virus clearance but had little effect on clinical parameters. By contrast, 0.5% hydrocortisone increased the titre and extended the presence of infectious virus for at least 6 days, although the reduction in clinical signs was greater than that obtained with topical foscarnet. Foscarnet in combination with hydrocortisone produced a marked reduction in clinical signs while virus replication was reduced. These results are discussed in relation to the inflammation and discomfort experienced by patients and a possible role for anti-inflammatory formulations in the treatment of HSV reactivation episodes in man.


Antiviral Chemistry & Chemotherapy | 2003

ME-609: a treatment for recurrent herpes simplex virus infections

Johan Harmenberg; Aftab R. Awan; Stefan Alenius; Lars Ståhle; Anna Erlandsson; Gunilla Lekare; Ola Flink; Elisabeth Augustsson; Torbjörn Larsson; Ann-Charlotte Wikström; Pontus Stierna; Hugh J. Field; Alf G Larsson; Bo Öberg

Studies in conventional murine models of HSV infection use immunologically naive animals. These models thus mimic primary infections rather than recurrent infections in humans. We have, therefore, used a newly developed mouse model that more closely mimics recurrent HSV infection in humans. In this model, the mice are infected, and zosteriform HSV-1 infection develops in the presence of a primed immune response using adoptive transfer of immunity (ATI) as we have described previously. Using the ATI mouse model, it has been shown that a more beneficial therapy for recurrent mucocutaneous HSV infection could be achieved by controlling both the viral replication and the inflammatory response to the virus. Topical treatment was initiated in this model at the time of first occurrence of symptoms and was given three times daily for 4 days. Topical treatment with ME-609 (which contains 5% acyclovir and 1% hydrocortisone) in the ATI mouse model was substantially more efficacious than 5% Zovirax® cream, 1% hydrocortisone or no treatment, respectively. The beneficial properties of ME-609 were also found to be superior to those of Zovirax cream when tested in the standard guinea pig model, representing a primary HSV infection. ME-609 represents a novel treatment principle of recurrent HSV infections and the present paper summarizes the preclinical and early clinical experience of ME-609.


Journal of The American Academy of Dermatology | 2011

Early treatment of cold sores with topical ME-609 decreases the frequency of ulcerative lesions: A randomized, double-blind, placebo-controlled, patient-initiated clinical trial

Christopher M. Hull; Johan Harmenberg; Eva Arlander; Fred Y. Aoki; Johan Bring; Borje Darpo; Myron J. Levin; Stephen K. Tyring; Spotswood L. Spruance

BACKGROUNDnPrior pilot studies support the use of antiviral medications with topical corticosteroids for herpes simplex labialis (HSL). ME-609 (Xerese, Xerclear) is a combination of 5% acyclovir and 1% hydrocortisone developed for the topical treatment of HSL.nnnOBJECTIVESnThe primary study end point was the prevention of ulcerative HSL lesions.nnnMETHODSnIn all, 2437 patients with a history of HSL were randomized to self-initiate treatment with ME-609, 5% acyclovir in ME-609 vehicle, or ME-609 vehicle (placebo) at the earliest sign of a cold sore recurrence. Cream was applied 5 times/d for 5 days. A total of 1443 patients experienced a recurrence and initiated treatment with ME-609 (n = 601), acyclovir (n = 610), or placebo (n = 232).nnnRESULTSnOf patients receiving ME-609, 42% did not develop an ulcerative lesion compared with 35% of patients receiving acyclovir in ME-609 vehicle (P = .014) and 26% of patients receiving placebo (P < .0001). In patients with ulcerative lesions, healing times were reduced in the ME-609 and acyclovir groups compared with placebo (P < .01 for both). The cumulative lesion area for all lesions was reduced 50% in patients receiving ME-609 compared with the placebo group (P < .0001). There were no differences among groups in the number of patients with positive herpes simplex virus cultures. The side-effect profile was similar among treatments.nnnLIMITATIONSnThe study did not contain a group treated with a topical corticosteroid alone.nnnCONCLUSIONSnME-609 prevented progression of cold sores to ulcerative lesions and significantly reduced the cumulative lesion area compared with acyclovir and placebo. ME-609 treatment offers additional therapeutic benefit compared with therapy with topical acyclovir alone.


Antiviral Chemistry & Chemotherapy | 1990

Comparison of the intracellular metabolism of 3'-azido-3'-deoxythymidine and 3'-fluoro-3'-deoxythymidine in lymphocytes in the presence of 5-fluoro-2'-deoxyuridine

S. Cox; Johan Harmenberg

The mechanism of action of 2′, 3′-dideoxythymidine analogues such as azidothymidine (AZT) and fluorothymidine (FLT) is thought to be chain termination and inhibition of reverse transcriptase by the triphosphate. However, little triphosphate is formed intracellularly relative to monophosphate and diphosphate. Azidothymidine and fluorothymidine are phosphorylated intracellularly by the thymidine salvage pathway and therefore must compete with thymine nucleotides for phosphorylation, which may limit the rate of phosphorylation. We have investigated the degree to which competition with thymidine limits the phosphorylation of azidothymidine and fluorothymidine. In this paper we show that inhibition of thymidylate synthase by 5-fluoro-2′-deoxyuridine monophosphate increases the phosphorylation of azidothymidine and fluorothymidine by reducing the pools of thymine nucleotides and therefore removing the competition. 5-fluoro-2′-deoxyuridine abolished the pools of TTP and dGTP and caused the appearance of dUTP in treated lymphocytes. Three times more triphosphate was formed in cells treated with 5-fluoro-2′-deoxyuridine. Ten times more fluorothymidine triphosphate than azidothymidine triphosphate was formed. The results suggest that while competition with intracellular thymine nucleotides does hinder the phosphorylation of AZT and FLT, the major limiting factor is their ability to act as substrates for the phosphorylating enzymes.


Acta Oncologica | 2016

A novel oral insulin-like growth factor-1 receptor pathway modulator and its implications for patients with non-small cell lung carcinoma: A phase I clinical trial

Simon Ekman; Johan Harmenberg; Jan-Erik Frödin; Stefan Bergström; Cecilia Wassberg; Staffan Eksborg; Olle Larsson; Magnus Axelson; Markus Jerling; Lars Abrahmsen; Åsa Hedlund; Carina Alvfors; Birgitta Ståhl; Michael Bergqvist

Background. A phase Ia/b dose-escalation study was performed to characterize the safety, efficacy and pharmacokinetic properties of the oral small molecule insulin-like growth factor-1-receptor pathway modulator AXL1717 in patients with advanced solid tumors. Material and methods. This was a prospective, single-armed, open label, dose-finding phase Ia/b study with the aim of single day dosing (phase Ia) to define the starting dose for multi-day dosing (phase Ib), and phase Ib to define and confirm recommended phase II dose (RP2D) and if possible maximum tolerated dose (MTD) for repeated dosing. Results and Conclusion. Phase Ia enrolled 16 patients and dose escalations up to 2900 mg BID were successfully performed without any dose limiting toxicity (DLT). A total of 39 patients were treated in phase Ib. AXL1717 was well tolerated with neutropenia as the only dose-related, reversible, DLT. RP2D dose was found to be 390 mg BID for four weeks. Some patients, mainly with NSCLC, demonstrated signs of clinical benefit, including four partial tumor responses (one according to RECIST and three according to PET). The 15 patients with NSCLC with treatment duration longer than two weeks with single agent AXL1717 in third or fourth line of therapy showed a median progression-free survival of 31 weeks and overall survival of 60 weeks. Down-regulation of IGF-1R on granulocytes and increases of free serum levels of IGF-1 were seen in patients treated with AXL1717. AXL1717 had an acceptable safety profile and demonstrated promising efficacy in this heavily pretreated patient cohort, especially in patients with NSCLC. RP2D was concluded to be 390 mg BID for four weeks. Trial number is NCT01062620.


Journal of Chromatography B | 2011

Determination of picropodophyllin and its isomer podophyllotoxin in human serum samples with electrospray ionization of hexylamine adducts by liquid chromatography-tandem mass spectrometry.

Yuko Rönquist-Nii; Staffan Eksborg; Magnus Axelson; Johan Harmenberg; Olof Beck

A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for determination of the new anticancer agent picropodophyllin (AXL1717) and its isomer podophyllotoxin levels in human serum has been developed. Monitoring of hexylamine adducts rather than proton adducts was used to optimize sensitivity. The chromatography system was an Acquity BEH C18, 2.1 mm × 50 mm 1.7 μm column with gradient elution (mobile phase A: 2.5 mM hexylamine and 5 mM formic acid in Milli-Q water and mobile phase B: methanol). The retention times were 1.4 min for picropodophyllin, 1.5 min for podophyllotoxin and 1.9 min for internal standard deoxypodophyllotoxin. The isomers were base-line separated. The analytes were detected after electrospray ionization in positive mode with selected reaction monitoring (SRM) with ion transitions m/z 516→102 for picropodophyllin and podophyllotoxin and m/z 500→102 for internal standard. The sample preparation was protein precipitation with acetonitrile (1:3) containing internal standard followed by dilution of the supernatant with mobile phase A (1:1). The limit of quantification (LOQ) was 0.01 μmol/L for picropodophyllin and podophyllotoxin. The limit of detection (LOD) at 3 times the signal to noise (S/N) was estimated below 0.001 μmol/L for picropodophyllin and podophyllotoxin. The quantification range of the method was between 0.01 μmol/L and 5 μmol/L for both isomers. The accuracy was within ±15% of the theoretical value for both picropodophyllin and podophyllotoxin and inter-assay precision did not exceed ±15%, except for the 0.016 μmol/L level of podophyllotoxin, which was 18%. The selectivity of the method was verified by analysis of two different product ions for each analyte and by analysis for interference of seven different batches of blank human serum. The combined recovery and matrix effects were about 83% for picropodophyllin and podophyllotoxin. The new LC-MS/MS method showed sufficient sensitivity and selectivity for determination of picropodophyllin and its isomer podophyllotoxin levels in human serum from subjects receiving therapeutic doses of AXL1717.


Acta Oncologica | 2017

Phase II randomized study of the IGF-1R pathway modulator AXL1717 compared to docetaxel in patients with previously treated, locally advanced or metastatic non-small cell lung cancer.

Michael Bergqvist; Georg Holgersson; Igor Bondarenko; Elena Grechanaya; Alexey Maximovich; György Andor; Maria Klockare; Marcus Thureson; Markus Jerling; Johan Harmenberg

Abstract Background: The primary objective of this study was to compare the progression-free survival (PFS) at 12 weeks between patients treated with IGF-1R pathway modulator AXL1717 (AXL) and patients treated with docetaxel (DCT). Material and methods: The study was conducted at 19 study centers in five countries. A total of 99 patients with previously treated, locally advanced or metastatic non-small cell lung cancer (NSCLC) of the squamous cell carcinoma (SCC) or adenocarcinoma (AC) subtypes in need of additional treatment were randomized and treated with either 300 or 400u2009mg of AXL as daily BID treatment (58 patients) or DCT given as 75u2009mg/m2 in three-week cycles (41 patients) as monotherapy in a 3:2 ratio for each NSCLC subtype. Patients were treated in the primary study treatment period for a maximum of four treatment cycles. Results: The 12-week PFS rate, median PFS and overall survival (OS), as well Kaplan-Meier hazard ratio for PFS and OS, did not show any statistically significant differences between the treatment groups. For the primary endpoint, the AXL group had a lower percentage of patients (25.9%) who were progression-free at Week 12 as compared to the DCT group (39.0%), although the difference was not statistically significant. The most notable difference in the incidence of treatment emergent adverse effects (TEAEs) was the lower incidence of treatment-related grade 3/4 neutropenia in patients treated with AXL. Conclusion: These results suggest neither of the treatments to be superior of the other when treating locally advanced or metastatic NSCLC. Considering the lower incidence of grade 3/4 neutropenia in the AXL group this treatment warrants further research.


Medical Oncology | 2015

A phase I pilot study of the insulin-like growth factor 1 receptor pathway modulator AXL1717 in combination with gemcitabine HCl and carboplatin in previously untreated, locally advanced, or metastatic non-small cell lung cancer

Georg Holgersson; Stefan Bergström; Johan Harmenberg; Magnus Ringbom; Maria Klockare; Markus Jerling; Simon Ekman; Kristina Lamberg Lundström; Hirsh Koyi; Eva Brandén; Olle Larsson; Michael Bergqvist

AbstractnAXL1717 is an orally bioavailable IGF-1R pathway modulator that has been shown to have anti-tumoral effects. The objectives of the present study were to define maximum tolerated dose and the recommended phase II dose (RPTD) of AXL1717 in combination with gemcitabine HCl and carboplatin in non-small cell lung cancer (NSCLC). Patients with previously untreated, locally advanced, or metastatic NSCLC (squamous cell cancer or adenocarcinoma) in good performance status and with preserved major organ functions were enrolled in the study. The study was an open-label phase I study with planned cohorts of three patients per dose level of AXL1717 (215, 290, and 390xa0mg BID). In total, 12 patients were enrolled in the study, and of these, two were prematurely excluded. AXL1717 was administered at one dose level, 215xa0mg BID. A total number of 81 unique adverse events were reported. Bone marrow toxicity was reported in 10 out of 12 patients, and this organ class showed the largest number of related events. AXL1717 in combination with gemcitabine HCl and carboplatin is a possible treatment approach in previously untreated, locally advanced, or metastatic non-small cell lung cancer. However, due to the bone marrow toxicity profile shown in the present study, further dose increases of AXL1717 above 215xa0mg BID will probably not be feasible. Therefore, 215xa0mg BID constitutes maximum tolerated dose and RPTD.

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Simon Ekman

Karolinska University Hospital

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Magnus Axelson

Karolinska University Hospital

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Jan-Erik Frödin

Karolinska University Hospital

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Carina Alvfors

Uppsala University Hospital

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