30 juli 2013: Aanvullend op artikel hieronder heb ik een nieuwe studie publicatie geplaatst onderaan dit artikel. Bij patiënten met vergevorderde liposarcomen bleek de aanpak met PD 0332991 toch succesvol:

Treatment with the CDK4 inhibitor PD0332991 was associated with a favorable progression-free rate in patients with CDK4-amplified and RB-expressing WDLS/DDLS who had progressive disease despite systemic therapy

Voor het volledige studierapport: Phase II Trial of the CDK4 Inhibitor PD0332991 in Patients With Advanced CDK4-Amplified Well-Differentiated or Dedifferentiated Liposarcoma moet u betalen. Het abstract ervan heb ik onderaan geplaatst

19 juli 2011: vorig jaar kwam het nieuws naar buiten dat een bepaald middel de groei van hersentumoren zou stoppen. Inmiddels is in New York een fase I studie gedaan met dit middel bij patienten met nierkanker en lymfklierkanker. In het academisch ziekenhuis Groningen zijn inmiddels laboratoriumproeven met dit middel gedaan. Hier het abstract van de studie met patienten uit New York:

Br J Cancer. 2011 Jun 7;104(12):1862-8. doi: 10.1038/bjc.2011.177. Epub 2011 May 24.

Phase I study of PD 0332991, a cyclin-dependent kinase inhibitor, administered in 3-week cycles (Schedule 2/1).

Schwartz GK, Lorusso PM, Dickson MA, Randolph SS, Shaik MN, Wilner KD, Courtney R, O'Dwyer PJ.

Source

Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA.

Abstract

Background:This phase I, open-label, first-in-human study determined dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of PD 0332991, an oral cyclin-dependent kinase 4/6 inhibitor with potent anti-proliferative activity in vitro/vivo.

Methods:A total of 33 patients with retinoblastoma protein-positive advanced solid tumours or non-Hodgkin's lymphoma refractory to standard therapy or for which no therapy was available received PD 0332991 once daily (QD) for 14 days followed by 7 days off treatment (21-day cycles; Schedule 2/1).

Results:Six patients had DLTs (18%; four receiving 200 mg QD; two receiving 225 mg QD); the MTD was 200 mg QD. Treatment-related, non-haematological adverse events occurred in 29 patients (88%) during cycle 1 and 27 patients (82%) thereafter. Adverse events were generally mild-moderate. Of 31 evaluable patients, one with testicular cancer achieved a partial response; nine had stable disease (10 cycles in three cases). PD 0332991 was slowly absorbed (mean T(max) 4.2 h) and eliminated (mean half-life 26.7 h). Volume of distribution was large (mean 3241 l) with dose-proportional exposure. Using a maximum effective concentration model, neutropenia was proportional to exposure.

Conclusion:PD 0332991 was generally well tolerated, with DLTs related mainly to myelosuppression. The MTD, 200 mg QD, is recommended for phase II study.

PMID:: 21610706; [PubMed - in process]

18 april 2010: Bron: Cancer Res. 2010 Apr 15;70(8):3228-38. Epub 2010 Mar 30.

Wetenschappers aan de universiteit van San Fransisco melden dat zij in preklinische studies in het laboratorium alswel bij dieren een medicijn PD-0332991 hebben getest dat de groei van tumoren in de hersenen (glioblastomen) zou stoppen. Uit verschillende studies bleek dat muizen zo lang zij dit medicijn innamen doorleefden met een hersentumor en de tumor zelf niet groeide. Zodra de wetenschappers stopten met dit medicijn gingen de tumoren weer groeien en stierven de muizen. De muizen in de controlegroep waren daarvoor al lang dood gegaan aan de tumoren.

Het medicijn slaat alleen aan bij die tumoren die een bepaald gen P16 missen in combinatie met bepaalde moleculen, de cycline-afhankelijke kinasen 4 en 6 (CDK4 / 6),of waarbij dit gen weinig aanwezig is. De status van dit gen in combinatie met CDK4 / 6, is gemakkelijk vooraf aan de behandeling vast te stellen aldus de onderzoekers. De wetenschappers zeggen ook dat zij dit medicijn nu onderzoeken en uitproberen bij dieren ingespoten met tumoren van Kahler - multiple myeloma en borstkanker.

Hier een bericht over dit medicijn van clinical trials:

Cancer Res. 2010 Apr 15;70(8):3228-38. Epub 2010 Mar 30.

Pharmacologic inhibition of cyclin-dependent kinases 4 and 6 arrests the growth of glioblastoma multiforme intracranial xenografts.

Michaud K, Solomon DA, Oermann E, Kim JS, Zhong WZ, Prados MD, Ozawa T, James CD, Waldman T.

Department of Neurological Surgery, Helen Diller Comprehensive Cancer Center, University of California San Francisco, California 94143-0520, USA.

Abstract

Activation of cyclin-dependent kinases 4 and 6 (cdk4/6) occurs in the majority of glioblastoma multiforme (GBM) tumors, and represents a promising molecular target for the development of small molecule inhibitors. In the current study, we investigated the molecular determinants and in vivo response of diverse GBM cell lines and xenografts to PD-0332991, a cdk4/6-specific inhibitor. In vitro testing of PD-0332991 against a panel of GBM cell lines revealed a potent G(1) cell cycle arrest and induction of senescence in each of 16 retinoblastoma protein (Rb)-proficient cell lines regardless of other genetic lesions, whereas 5 cell lines with homozygous inactivation of Rb were completely resistant to treatment. Short hairpin RNA depletion of Rb expression conferred resistance of GBM cells to PD-0332991, further demonstrating a requirement of Rb for sensitivity to cdk4/6 inhibition. PD-0332991 was found to efficiently cross the blood-brain barrier and proved highly effective in suppressing the growth of intracranial GBM xenograft tumors, including those that had recurred after initial therapy with temozolomide. Remarkably, no mice receiving PD-0332991 died as a result of disease progression while on therapy. Additionally, the combination of PD-0332991 and radiation therapy resulted in significantly increased survival benefit compared with either therapy alone. In total, our results support clinical trial evaluation of PD-0332991 against newly diagnosed as well as recurrent GBM, and indicate that Rb status is the primary determinant of potential benefit from this therapy. (c) 2010 AACR.

PMID: 20354191 [PubMed - in process]

Treatment with the CDK4 inhibitor PD0332991 was associated with a favorable progression-free rate in patients with CDK4-amplified and RB-expressing WDLS/DDLS who had progressive disease despite systemic therapy

Published online before print April 8, 2013, doi: 10.1200/JCO.2012.46.5476 JCO June 1, 2013 vol. 31 no. 16 2024-2028

Phase II Trial of the CDK4 Inhibitor PD0332991 in Patients With Advanced CDK4-Amplified Well-Differentiated or Dedifferentiated Liposarcoma

+ Author Affiliations

All authors: Memorial Sloan-Kettering Cancer Center, New York, NY.

Corresponding author: Mark A. Dickson, MD, 300 E 66th St, New York, NY 10065; e-mail: dicksonm@mskcc.org.

Presented in part at the 48th Annual Meeting of the American Society for Clinical Oncology, Chicago, IL, June 1-5, 2012.

Abstract

Purpose CDK4 is amplified in > 90% of well-differentiated (WDLS) and dedifferentiated liposarcomas (DDLS). The selective cyclin-dependent kinase 4 (CDK4)/CDK6 inhibitor PD0332991 inhibits growth and induces senescence in cell lines and xenografts. In a phase I trial of PD0332991, several patients with WDLS or DDLS experienced prolonged stable disease. We performed an open-label phase II study to determine the safety and efficacy of PD0332991 in patients with advanced WDLS/DDLS.

Patients and Methods Patients age ≥ 18 years experiencing disease progression while receiving systemic therapy before enrollment received PD0332991 200 mg orally once per day for 14 consecutive days in 21-day cycles. All were required to have CDK4 amplification by fluorescence in situ hybridization and retinoblastoma protein (RB) expression by immunohistochemistry (≥ 1+). The primary end point was progression-free survival (PFS) at 12 weeks, with 12-week PFS of ≥ 40% considered promising and ≤ 20% not promising. If ≥ nine of 28 patients were progression free at 12 weeks, PD0332991 would be considered active.

Results We screened 48 patients (44 of 48 had CDK4 amplification; 41 of 44 were RB positive). Of those, 30 were enrolled, and 29 were evaluable for the primary end point. Grade 3 to 4 events included anemia (17%), thrombocytopenia (30%), neutropenia (50%), and febrile neutropenia (3%). At 12 weeks, PFS was 66% (90% CI, 51% to 100%), significantly exceeding the primary end point. The median PFS was 18 weeks. There was one partial response.

Conclusion Treatment with the CDK4 inhibitor PD0332991 was associated with a favorable progression-free rate in patients with CDK4-amplified and RB-expressing WDLS/DDLS who had progressive disease despite systemic therapy.

Footnotes

Supported by Pfizer and in part by National Cancer Institute, National Institutes of Health, Soft Tissue Sarcoma Program Project Grant No. P01 CA047179 (C.R.A., S.S, G.K.S.).
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
Clinical trial information: NCT01209598.

lymfklierkanker, nierkanker, PD-0332991, liposarcomen