WO2018157069A1

WO2018157069A1 - Treatment of chronic hpv infection with the pan cdk inhibitor dinaciclib

Info

Publication number: WO2018157069A1
Application number: PCT/US2018/019745
Authority: WO
Inventors: Anthony LEONARDI
Original assignee: Leonardi Anthony
Priority date: 2017-02-25
Filing date: 2018-02-26
Publication date: 2018-08-30

Abstract

The invention provides a method of treating HPV related proliferative lesions including Cervical Intraepithelial Neoplasia comprising: a) treating a patient with the a CDK inhibitor, including dinaciclib, or chemical combination of the inhibitor. The invention also provides a method of preventing cancer with treatment by a CDK inhibitor, including dinaciclib.

Description

TREATMENT OF CHRONIC HPV INFECTION WITH THE PAN CDK INHIBITOR DINACICLIB

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims benefit of US provisional application 62/463,655 filed February 25, 2017, the entire content of which is incorporated herein by reference.

FIELD OF THE INVENTION

[0002] The present invention relates generally to the methods for treating patients with HPV-producing lesions with the cyclin-dependent kinase (CDK) inhibitor dinaciclib, as well as treating HPV positive cervical intraepithelial neoplasia (CIN) using dinaciclib.

BACKGROUND OF THE INVENTION

[0003] Cervical Intraepithelial Neoplasia (CIN) is one of the most common types of dysplasia in the world. HPV positive cervical dysplasia is diagnosed in about 250,000 to 1 million women each year in the United States. HPV positive cervical dysplasia follows an extremely variable clinical course with 30 to 50 percent of untreated cases leading to cervical cancer. Additionally, HPV can cause malignancies in the head and neck, and on or around any mucous membranes including the oral or anal passages.

[0004] Cyclin-dependent kinases (CDKs) are serine/threonine protein kinases, which are the driving force behind the cell cycle and cell proliferation. Most of the known CDK's, including CDK1 through CDK9, are involved either directly or indirectly in cell cycle progression. Those directly involved with cell cycle progression, such as CDKI-4 and 6, can be classified as Gl, S, or G2M phase enzymes. Uncontrolled proliferation is a hallmark of cancer cells and the alteration of CDK function occurs with high frequency in many solid tumors.

[0005] In cases of chronic viral infection, some viruses such as HPV16, HPV18, and HPV45 commandeer the cell cycle machinery in order to replicate the viral genome and maintain the host cell in a chronic state of replication. This state of chronic infection and replication precedes the event of an HPV-infected cell's transformation into cancer. Certain isoforms of CDK are targeted by HPV virus in order to enable virus-specific production by the cell.

[0006] CDK2 and CDK4 are of particular interest because their activity is frequently affected in a wide variety of human cancers, i.e. dysregulated states of the cell. CDK2 activity is required for progression through Gl to the S phase of the cell cycle and, as such, is one of the key components of the Gl checkpoint. Checkpoints serve to maintain the proper sequence of cell cycle events and allow the cell to respond to insults or to proliferative signals. The loss of proper checkpoint control in cancer cells contributes to tumorigenesis., and in cases of chronic HPV infection in cells that are precancerous, the loss of checkpoint control enables constant production of virus.

[0007] The CDK2 pathway influences tumorigenesis at the level of tumor suppressor function (e.g., p52, RB, and p27) and oncogene activation (cyclin E). Many reports have demonstrated that the CDK2 coactivator, cyclin E, and the CDK2 inhibitor, p27, are either over- or under-expressed, respectively, in breast, colon, non-small cell lung, gastric, prostate, bladder, non-Hodgkin's lymphoma, ovarian, and other cancers. Their altered expression has been shown to correlate with increased CDK2 activity and poor overall survival. This observation makes CDK2 and its regulatory pathways compelling targets for the development of therapeutic agents for anti-proliferative disorders, such as cancer. See Bannerji et al., WO 2013/188355 (describing the uses of CDK inhibitors for treating refractory chronic lymphocytic leukemia) incorporated herein by reference.

[0008] The CDK pathway has also been implicated in chronic viral infection of HPV16 and HPV18. Certain CDK inhibitors like flavopiridol have shown efficacy in vitro in suppressing the cell's viral manufacturing (see Groves et al, Oncogene. 2016, 35(36):4773-86.) This viral suppression by targeting CDK9 with the inhibitors flavopiridol (CDK9), Roscovitine (CDK2, CDK5, CDK7, and CDK9), and DRB (CDK7 and CDK9) was possible after measured viral genome integration into the host genome and epigenetic remodeling.

[0009] Dinaciclib is an inhibitor of CDK1, CDK2, CDK5, and CDK9, and has single-agent efficacy in the treatment of Myeloma. It is generally better tolerated than Flavopiridol, and targets a different repertoire of CDKs.

[0010] Adenosine 5'-triphosphate (ATP) competitive small molecule compounds, as well as peptides, have been reported in the literature as CDK inhibitors for the potential treatment of cancers. See, for example, US Patent 6,413,974, incorporated herein by references, which describes various CDK inhibitors and their relationship to various types of cancer.

[0011] Other CDK inhibitors are known. For example, flavopiridol is a non-selective CDK inhibitor investigated in human clinical trials in patients with refractory neoplasms (see, e.g., Senderowicz et al. J. Clin. Oncol. 1998, 16(9):2986-2999). Other known CDK inhibitors include, for example, olomoucine (Vesely et a I, Eur. J. Biochem. 1994, 224:771-786) and roscovitine (Meijer et al, Eur. J. Biochem. 1997, 243:527-536). U.S. Patent 6,107,305 describes certain pyrazolo[3,4-b] pyridine compounds as CDK inhibitors (e.g., Kim et al, J. Med. Chem. 2002, 45:3905-3927) and international patent publication WO 02/10162 discloses certain aminothiazole compounds as CDK inhibitors.

[0012] There remains a critical need for additional therapeutic options for treating chronic HPV infection, particularly as to patients with treatment refractory HPV positive cervical dysplasia, cytogenetically high-risk HPV positive cervical dysplasia, and HPV-infected lesions on or around the mouth, vagina, anus or penis.

BRIEF SUMMARY OF THE INVENTION

[0013] In one aspect the invention provides a method for reducing HPV production and shedding by HPV producing growths (lesions). In one approach the invention provides a method for treating an HPV positive cervical dysplasia or an HPV positive lesion anywhere in the body in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of dinaciclib. In one approach the invention provides a method for reducing HPV production or shedding from a tissue in a patient not diagnosed with dysplasia.

[0014] In one aspect, the patient has HPV positive cervical dysplasia, e.g., cervical intraepithelial neoplasia (CIN). In one aspect, the patient is refractory to cryosurgery and/or electrocauterization and/or laser surgery treatment, or any combination of those treatments. In one aspect, the refractory patient is HPV positive. In one aspect, the patient has an HPV positive lesion in the throat or other mucous membrane. In one aspect, the HPV positive lesion is on the skin.

[0015] In one approach the invention provides a method for treating a patient with CIN, refractory or nonrefractry, by determining if said patient has detectable HPV virus and administering to said patient a therapeutically effective amount of dinaciclib, if said patient has detectable HPV virus.

[0016] In one aspect of the invention the patient is refractory to cryosurgery treatment or laser surgery or electrocauterization.

[0017] In one approach the invention provides a method for selecting a refractory patient with CIN for treatment with dinaciclib comprising determining if said patient has detectable HPV, wherein said patient is selected if said patient has detectable HPV. In some aspects the patient is refractory to cryosurgery treatment or laser surgery or electrocauterization. In related aspects therapeutically effective amount of dinaciclib is administered to the patient if the patient is selected.

[0018] In some aspects of the aforementioned methods, the dinaciclib is ((S)-(-)~(-)2-(l- 13-ethyl-7-[(l-oxy-pyridin-3-ylmethyl)] amino] pyrazolo [l,5-a]pyrimidin-5-yl} piperidin-2- yl)ethanol)).

[0019] Also provided are pharmaceutical preparations comprising a therapeutically effective amount of dinaciclib, together with a pharmaceutically acceptable carrier or diluent, for treating a patient with CIN. The patient may be refractory to cryosurgery treatment or laser surgery or electrocauterization; may have detectable HPV; or may not have detectable HPV.

BRIEF DESCRIPTION OF THE DRAWING

[0020] Figure 1 shows the ratio of HPV 16 E6/E7 RNA to vehicle control (DMSO) following a 24 hour incubation with 2 μΜ, 10 μΜ, or 100 μΜ of dinaciclib or flavopiridol as described in Example 1.

DETAILED DESCRIPTION OF THE INVENTION

[0021] I. Definitions

[0022] The use of the word "a" or "an" when used in conjunction with the term

[0023] "Comprising" in the claims and/or the specification may mean "one," but it is also consistent with the meaning of "one or more," "at least one," and "one or more than one." The use of the term "or" in the claims is used to mean "and/or" unless explicitly indicated to refer to alternatives only or the alternatives are mutually exclusive, although the disclosure supports a definition that refers to only alternatives and "and/or."

[0024] "CDK inhibitor" means any compound or agent that affects the activity of one or more CDK proteins or CDK/cyclin kinase complexes. The compound or agent may inhibit CDK activity by direct or indirect interaction with a CDK protein or it may act to prevent expression of one or more CDK genes. Examples of small molecule CDK inhibitors are described above. In addition, the mechanism of the CDK inhibitors, flavopiridol and SNS-032, are described in Chen et a I, Blood. 2005, 106(7):2513-2519 and Chen et al, Blood. 2009, 113 (19):4637-4645, respectively. The CDK Inhibitor dinaciclib is described in Parry et al, Mol. Cancer Ther. 2010, 9(8):2344-235, Fu et al, Mol. Cancer Ther. 2011, 10(6):1018-1027, and U.S. Patent 7,119,200, which are incorporated herein by reference as if set forth at length.

[0025] As used herein, reference to dinaciclib, (S)-(-)-(-)2-(l-13-ethyl-7-[(l-oxy-pyridin-3- ylmethyl)]amino] pyrazolo [l,5-a]pyrimidin-5-yl) piperidin-2-yl)ethanol), includes pharmaceutically acceptable salts or hydrates thereof.

[0026] As used herein, the term "refractory HPV positive cervical dysplasia patient" or "refractory HPV positive cervical dysplasia patient" means a patient who is refractory to either curettage or cryosurgery. Refractory means a patient defined as failing to respond to or relapsed within 6 months of completing either technique of curettage or cryosurgery.

[0027] As used herein, the term "progression-free survival (PFS)" means the time from the date of randomization until the first date of documented disease progression or date of death due to any reason, whichever occurs earlier.

[0028] As used herein, the term "overall response rate (ORR)" means the sum of the number of patients determined to have a complete response (CR) and a partial response (PR) (ORR = CR + PR), as assessed using the 2008 International Workshop on HPV positive cervical dysplasia criteria (Hallek, et al, Blood. 2008, 11-5446-5456).

[0029] As used herein, the term "overall survival" or "OS" is calculated from the date of randomization until the date of death.

[0030] "Patient" as that term is used herein, refers to the recipient in need of medical intervention or treatment. In one embodiment, the patient is a mammal, such as a human. In a particular embodiment, the patient is a human.

[0031] The term "treating" in its various grammatical forms in relation to the present invention refers to preventing (i.e. chemoprevention), curing, reversing, attenuating, alleviating, minimizing, suppressing or halting the deleterious effects of a disease state, disease progression, disease causative agent (e.g., bacteria or viruses) or other abnormal condition. For example, treatment may involve alleviating a symptom (i.e., not necessary all symptoms) of a disease or attenuating the progression of a disease.

[0032] As used herein, the term "therapeutically effective amount" is intended to qualify the amount of the treatment in a therapeutic regimen necessary to reduce HPV production (shedding) from HPV positive lesions and/or reduction of a HPV positive neoplasia and/or reduction of a HPV positive cervical intraepithelial neoplasia, for example in a human. A "therapeutically effective amount" may be the amount of dinaciclib that achieves the desired effect when used in combination therapy involving the use of multiple therapeutic agents, such as a combined amount of a first and second treatment where the combined amount will achieve the desired biological response. It will be appreciated that a therapeutically effective amount of dinaciclib may be administered to a patient over a course of treatment over days, weeks or even months.

[0033] As used herein, the terms "combination treatment", "combination therapy", "combined treatment" or "combinatorial treatment", used interchangeably, refer to a treatment of an individual with at least two different therapeutic agents. According to the invention, the individual is treated with a first therapeutic agent, preferably and/or a CDK inhibitor (dinaciclib) as described herein. The second therapeutic agent may be a DNA damaging agent or another CDK inhibitor A combinatorial treatment may include a third or even further therapeutic agent.

[0034] II. Treatment Methods

[0035] In one aspect, the invention herein is directed to the use of the CDK inhibitor dinaciclib to reduce their HPV viral production. In one aspect, the invention herein is directed to the use of the CDK inhibitor dinaciclib to arrest proliferation of dysplastic cells and reduce their HPV viral production. Such an effect is beneficial to patients in prevention of viral spread and transformation of the dysplasia to cancer. The ability to arrest viral production of the dysplastic cells would be beneficial to the patient in prevention of viral spread and possibly the transformation of the dysplasia to cancer. In one aspect, the invention herein is directed to methods for treating HPV positive cervical dysplasia and HPV related growths and, in particular, refractory HPV positive cervical dysplasia, with the CDK inhibitor dinaciclib.

[0036] CDK inhibitors offer the possibility of simultaneously blocking cell cycle progression and transcription, and facilitating the induction of apoptosis (Johnstone et al, Cell 2002, 108:153-164; Wesierska-Gadek et al, J. Cell Biochem. 2008, 105(5):1161-1171). Therefore, the potential diversified action of a CDK inhibitor, e.g., can be a significant advantage in HPV positive cervical dysplasia, in that it can increase the chance of efficiently reducing the proliferation of dysplastic cells with varying mitotic potential, before the cells transform and become cancerous. Without intending to be bound by a particular mechanism, dinaciclib is an inhibitor of a particular combination of CDKs, making it a potent inhibitor of HPV production. The antiviral effect of dinaciclib will prevent the spread and maintenance of infection. This may offer the immune system an opportunity to clear the infected cells, and reduce the spread of infection. Thus, dinaciclib is a more selective inhibitor of CDKs compared to flavopiridol, with more potent inhibition of DNA synthesis. See, e.g., Bannerji et al., supra; Parry et al, Mol. Cancer Ther. 2010, 9(8):2344-2353. As shown in the experimental data below (see Example) dinaciclib is a significantly more potent inhibitor of HPV production than is flavopiridol.

[0037] III. Dose and Administration

[0038] Dinaciclib is typically administered intravenously, although other routes of administration may be used. While CDK inhibitors can be administered by various means, dinaciclib is typically administered intravenously by a person skilled in the medical practice of oncology. Examples of routes of administration include but are not limited to oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, transbuccal, intranasal, liposomal, via inhalation, vaginal, intraocular, via local delivery by catheter or stent, subcutaneous, intraadiposal, intraarticular, intrathecal, or in a slow release dosage form.

[0039] Dinaciclib (including pharmaceutically acceptable salts or hydrates thereof), can be administered intravenously in accordance with any dose and dosing schedule that, achieves a dose effective for treating HPV infection (e.g., arrest proliferation of the dysplastic cells and reduce their HPV viral production).

[0040] Dinaciclib can be administered in a total daily dose that may vary from patient to patient, and may be administered at varying dosage schedules. Suitable dosages are total daily dosage of between about 25-4000 mg/m² administered orally once-daily, twice-daily or three times-daily, continuous (every day) or intermittently (e.g. 3-5 days a week). In one approach dinaciclib can be administered in a total daily dose of 0.1 mg up to 1000 mg, once, twice or three times daily, continuously (every day) or intermittently (e.g., 3-5 days a week).

[0041] Furthermore, the compositions may be administered in cycles, with rest periods in between the cycles (e.g. treatment for two to eight weeks with a rest period of up to a week between treatments). [0042] The optimal dinaciclib dose for treatment of HPV-related conditions can be determined in clinical trials. In one approach the dinaciclib doses described in WO 2013/188355 for treatment of refractory chronic lymphocytic leukemia (CLL) are used, e.g., 14 mg/m² once per week on Days 1, 8, and 15, every 28 days. In one approach, 7 mg/m² of dinaciclib is administered on Day 1, 10 mg/m² on Day 8, and 14 mg/m² on Day 15 in Cycle 1, intravenously (IV) over 2 hours, via an IV infusion pump. Antiemetic prophylaxis with a serotonin-receptor antagonist (e.g. ondansetron), with dexamethasone (or equivalent) may be administered prior to treatment with dinaciclib. In Cycle 2 and thereafter, dinaciclib is dosed at 14 mg/m² on Days 1, 8, and 15 of each 28 day cycle for a total of 12 cycles.

[0043] In the Phase 1 trial (P04629), the recommended Phase 2 dose (RPTD) for CLL, based on a maximal tolerated dose (MTD) algorithm, for dinaciclib was determined to be 14 mg/m2 on Days 1, 8, and 15, every 28 days. Additional patients were enrolled to evaluate the dose-titration to minimize the incidence of tumor lysis syndrome (TLS) by starting individual patients at a lower dose and increasing the dose up to 14 mg/m2.

[0044] In a Phase 2 Trial of treatment of refractory myeloma with dinaciclib (NCT01096342), dinaciclib was administered on day 1 of a 21-day cycle at doses of 30 to 50 mg/m2, and a dose level of 50 mg/m2 was determined to be the maximally tolerated dose.

[0045] Other treatment combinations and dosing regiments are set forth in WO2007/126122, WO2007/126128 and WO 2008/133866, each of which is incorporated by reference.

[0046] IV. Therapeutic Outcomes

[0047] Administration of dinaciclib as described herein to patients with HPV-producing lesions, such as cervical epithelium infected with HPV, suppress HPV viral shedding and reduce autoinfection in patients with chronic HPV infection.

[0048] In one approach, the invention approach, HPV levels are measured in a patient, a therapeutically effective amount of dinaciclib is administered to the patient, and HPV levels are measured again in the patient at a second point in time, and a reduction in HPV levels is observed. For example, the HPV levels may be reduced by 10% or more, by 25% or more, or by 50% or more. In some cases HPV levels are reduced to less than 5% of the first measured value. In some cases HPV levels are reduced to undetectable levels. Reduction of HPV production in a patient tissue can be assessed using a variety of art-known methods. See, for example, Rebel M., et al., "Human Papillomavirus Assays and Cytology in Primary Cervical Screening of Women Aged 30 Years and Above" PLoS One. 2016; 11(1): e0147326; Arbyn et al., "Human papillomavirus testing versus repeat cytology for triage of minor cytological cervical lesions" Cochrane Database Syst Rev. 2013 Mar 28;(3):CD008054; Heideman et al., "Clinical validation of the Cobas^® 4800 HPV Test for cervical screening purposes." J Clin Microbiol. 2011;49(ll):3983-3985.

[0049] Dinaciclib treatment also reduces progression of cervical intraepithelial neoplasia

(CIN) lesions to HPV positive cervical dysplasia and full blown cancer.

[0050] Dinaciclib treatment also provides benefit to patients with HPV-related cancers and may increase progression-free survival (PFS), overall response rate (ORR), overall survival.

[0051] V. Example 1

[0052] This example demonstrates that dinaciclib achieves near complete suppression of HPV virus in CaSki cells and does so at a lower dose than flavopiridol. These data indicate that dinaciclib can be used to suppress HPV viral shedding and reduce autoinfection in patients with chronic HPV infection. Advantageously, dinaciclib suppresses HPV at lower doses that flavopiridol. One expected benefit of dinaciclib treatment is reduced side-effects compared to flavopiridol.

[0053] Cell Culture Method

[0054] CaSki cells (ATCC^® CRM-CRL-1550; 10⁴ cells/well) were seeded and cultured in a 24-well plate in DMEM supplemented with 10% FBS, 2 mM L-glutamine, 100 U/mL penicillin, and 100 μg/mL streptomycin. These cells contain an integrated human papillomavirus type 16 genome (HPV-16, about 600 copies per cell). Following a 24 hour incubation period, media was removed and new media containing either dinaciclib or flavopiridol was supplied to the cells at 2 μΜ, 10 μΜ, or 100 μΜ, each in triplicate, with three wells of vehicle control (DMSO). Following 24 hours incubation at 37 °C and 5% CO2, cells were harvested via trypsinization for RNA analysis (Sybr Green).

[0055] RT-PCR

[0056] Total RNA was harvested using the RNeasy Plus Mini Kit (Qiagen, Cat# 74134) following 24 hour incubation with the drug. Reverse transcription was done using QuantiSureTM First Strand cDNA Synthesis Kit (Gene Scientific, Cat# 11025-50). In the first step of this procedure, human total RNA was treated by gDNA Removing Buffer (4x) to avoid interference of residue genomic DNA. Quantitative RT-PCR (qRT-PCR) was performed by using AccuAmpTM SYBR Green master mix. After RT reaction was done, the resulting first strand cDNA was used for real-time PCR analysis in Agilent X3000P instrument in technical triplicates.

[0057] HPV16 E6/E7 transcripts were detected using primers 1 and 2 (which annealed to the E7 ORF present in both transcripts). GAPDH RNA was detected using primers 3 and 4 [0058] Primer 1: 5'-ACAAGCAGAACCGGACAGAG-3' (forward primer; SEQ ID NO:l).

[0059] Primer 2: 5'-G CCCATTA ACAG GTCTTCCA-3' (reverse primer; SEQ ID NO:2).

[0060] Primer 3: 5'-CAGCCTCAAGATCATCAGCA-3' (forward primer; SEQ ID NO:3).

[0061] Primer 4: 5'-TGTGGTCATGAGTCCTTCCA-3' (reverse primer; SEQ ID NO:4).

[0062] Table 1 below outlines the PCR conditions used.

Table 1

[0063] Results and Analysis

[0064] The mean annealing time was calculated with each RT-PCR technical replicate. Mean cooling times for each biological replicate were plotted in PRISM graphpad. Statistical analyses were performed between drugs at each concentration using Welch's unequal variances t-test. FIG. 1 shows the ratio of HPV 16 E6/E7 RNA to vehicle control (DMSO) following the 24 hour incubation with 2 μΜ, 10 μΜ, or 100 μΜ of dinaciclib or flavopiridol. GAPDH was used for normalization. Statistical analysis was performed at each drug concentration using Welch's unequal variances t-test. "**" is P=0.002.

SEQUENCE LISTING

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Claims

CLAIMS:

1. A method for treating an HPV positive cervical dysplasia or an HPV positive lesion in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of dinaciclib.

2. The method of claim 1, wherein the HPV positive cervical dysplasia is cervical intraepithelial neoplasia (CIN).

3. The method according to claim 2, wherein said patient is refractory to cryosurgery and/or electrocauterization and/or laser surgery treatment, or any combination of those treatments.

4. A method for treating a patient in need thereof, comprising administering to said patient a therapeutically effective amount of dinaciclib, wherein the patient has a lesion or tissue that sheds HPV.

5. The method of claim 4 wherein the patient but does not have and/or has not been diagnosed with, dysplasia.

6. A method for treating a cervical dysplasia or an HPV positive lesion in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of dinaciclib.

7. A method for treating a patient with CIN, refractory or nonrefractry, by determining if said patient has detectable HPV virus and administering to said patient a therapeutically effective amount of dinaciclib, if said patient has detectable HPV virus.

8. The method according to claim 7, wherein said patient is refractory to cryosurgery treatment or laser surgery or electrocauterization.

9. A method comprising (a) measuring HPV levels are measured in a tissue from a patient, (b) administering a therapeutically effective amount of dinaciclib to the patient, and (c) measuring HPV levels a second time from the tissue from the patient, wherein HPV levels in (c) are lower than in (a).

10. The method of claim 9 wherein the HPV levels may be reduced by 25% or more.

11. A method for selecting a refractory patient with CIN for treatment with dinaciclib comprising determining if said patient has detectable HPV, wherein said patient is selected if said patient has detectable HPV.

12. The method according to claim 11, wherein said patient is refractory to cryosurgery treatment or laser surgery or electrocauterization.

13. The method according to claim 11, wherein said patient is administered a therapeutically effective amount of dinaciclib if said patient is selected.

14. The method according to claim 1 in which the patient has an HPV related lesion in the throat or other mucous membrane.

15. The method according to claim 1 in which the HPV related lesion is on the skin.

16. The method according to any preceding claim, wherein dinaciclib is ((S)-(-)~(-)2-(l-13- ethyl-7-[(l-oxy-pyridin-3-ylmethyl)] amino] pyrazolo [l,5-a]pyrimidin-5-yl} piperidin-2- yl)ethanol)).

17. A pharmaceutical preparation comprising a therapeutically effective amount of dinaciclib, together with a pharmaceutically acceptable carrier or diluent, for treating a patient with CIN.

18. The pharmaceutical preparation of claim 17, wherein said patient is refractory to cryosurgery treatment or laser surgery or electrocauterization.

19. The pharmaceutical preparation of claim 17, wherein said patient has detectable HPV.

20. The pharmaceutical preparation of claim 17, wherein said patient does not have detectable HPV.

21. The pharmaceutical preparation of any of claims 17-21, wherein dinaciclib is ((S)-(- )~(-)2-(l-13-ethyl-7-[(l-oxy-pyridin-3-ylmethyl)]amino] pyrazolo [l,5-a]pyrimidin-5-yl} piperidin-2-yl)ethanol)).

22. The use of a pharmaceutical preparation of any of claims 17-21 for treatment of a patient infected with HPV.