A Phase II Single-arm Intervention Trial of Nelfinavir in Patients With Grade 2/3 or 3 Cervical Intraepithelial Neoplasia

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Brief Title

A Phase II Single-arm Intervention Trial of Nelfinavir in Patients With Grade 2/3 or 3 Cervical Intraepithelial Neoplasia

Official Title


Brief Summary

      Preliminary data showed that Nelfinavir has selective apoptotic effects on HPV+ cervical
      tumor cell lines. Furthermore, in a Phase I clinical trial, the combination of NFV and
      chemoradiotherapy showed acceptable toxicity and promising activity in patients with
      pancreatic cancer. Therefore, for the proposed research, the principal investigator will use
      a single-arm Phase II intervention trial study design with focus on the efficacy of NFV to
      induce complete or partial remission of CIN 2/3 or CIN 3 as well as biomarker evaluation.

Detailed Description

      2.0 BACKGROUND AND RATIONALE 2.1 Cervical Cancer Etiology and Targets for Intervention
      Cervical cancer is one of the most common causes of cancer-related deaths in women worldwide.
      Implementation of widespread screening has created drastic improvements in the incidence of
      cervical cancer as well as significant decreases in mortality over the last 30 years. It is
      estimated that in 2011, there will be 12,710 women in the US diagnosed with cervical cancer
      and ultimately 4,290 women will die from the disease. Cervical cancer is unique in that there
      exists a well-defined pre-malignant phase, referred to as cervical dysplasia, which can be
      suspected on cytological examination (pap smear) of exfoliated cervical cells and confirmed
      on histological examination of cervical biopsy material. The pre-cancerous changes represent
      a spectrum of histological abnormalities or cervical intraepithelial neoplasia (CIN) ranging
      from CIN 1 (mild dysplasia) to CIN2 (moderate dysplasia) to CIN3 (severe dysplasia/ carcinoma
      in situ). The timeline of progression for CIN 3 to invasive cancer in untreated women
      averages between 8.1 and 12.6 years.The surgical treatment of cervical pre-cancerous is
      therapeutically efficacious. However, it is an invasive procedure which has been associated
      with fertility and obstetrical complications in reproductive aged women. An attractive
      alternative to an excisional or ablative procedure would be to utilize an agent which could
      be applied topically or taken by mouth to foster regression of cervical dysplasia. The use of
      natural, synthetic, or biologic chemical agents to reverse, suppress, or prevent carcinogenic
      progression is called chemoprevention.

      A prerequisite for cervical cancer is persistent infection by a high-risk human
      papillomavirus allowing viral gene products sufficient time with which to induce
      carcinogenesis through a generally well understood natural history. Cancer-associated HPV
      types encode three oncogenes, E5, E6 and E7, and the E6 and E7 proteins have a significant
      role in malignant transformation. E6 and E7 stimulate cell proliferation by interfering with
      the function of regulatory proteins in cells, including the tumor suppressors p53 and pRB.
      Co-expression of both E6 and E7 leads to indefinite proliferation and immortalization of
      keratinocytes and induces premalignant neoplasms. HPV-E5, a transmembrane protein, can
      activate PI3K-Akt signalling. The up-regulation of PI3K-Akt survival signaling protects
      HPV-16 E5-expressing cells from apoptosis induced by ultraviolet irradiation. The major
      transforming capability of HPV is dependent on E6 and E7. However, E5 is necessary for full
      activation of E7, and the induction of PI3K-Akt-dependent apoptotic inhibition by E5
      contributes to E7-mediated oncogenesis.

      The work done to evaluate PI3K activity as a potential marker of CIN progression further
      supports the idea that this pathway is also up-regulated in pre-cancerous lesions. The
      catalytic subunit alpha of PI3K is expressed in non-invasive cervical lesions and has shown
      potential as a carcinogenesis-related marker for early intraepithelial lesion of the uterine
      cervix in cytology samples. Among other potential markers, PIK3CA showed a superior
      specificity to distinguish CIN3 from other groups. Yao et al 2008 showed that positive rates
      of PI3K and Akt were significantly lower in normal cervical epithelium and cervical
      intraepithelial neoplasia than in cervical carcinoma (0.0% and 42.9% vs. 69.7%, P<0.01; 10.0%
      and 52.4% vs. 75.0%,P<0.01). Specifically, PI3K/Akt activation increased with grade of
      dysplasia with invasive carcinoma having the highest activity. They also showed that
      expression of PI3K protein positively correlated to the expression of Akt protein(r=0.425,

      2.2 Nelfinavir (NFV) Background Nelfinavir (NFV) induces cell cycle arrest, endoplasmic
      reticulum stress, autophagy, and apoptosis is cancer cells. As a protease inhibitor used in
      patients with HIV, NFV predominately targets proteases 1 and 2, but it is also known that
      part of the efficacy is due to selective inhibition of the proteosome. The pathogenecity of
      high risk HPV is dependent on expression of viral E6 proteins which inappropriately activate
      the 26S proteosome to degrade p53 and other cellular proteins that are detrimental to viral
      replication; specific HIV protease inhibitors can block the ability of HPV16 E6 to degrade
      p53 and selectively kill E6-dependent cervical carcinoma cells. Furthermore, HIV protease
      inhibitors have been shown to inhibit the PI3K/Akt signaling pathway with NFV being the most
      potent. NFV's mechanism of action involves decreasing Akt phosphorylation. In addition, at
      concentrations (micromolar) achievable in the serum of patients taking usual dosing of the
      drug (1250mg PO BID), Akt phosphorylation is inhibited. At our institution, we have shown
      that HPV-infected cervical cancer cells lines treated with NFV underwent apoptosis and
      decreased cell proliferation in a dose dependent manner. Furthermore, we have shown through a
      recent retrospective study that HIV-infected women with cervical dysplasia who were treated
      with protease inhibitors (PI), including NFV were more likely to regress than those not on a
      PI-containing regimen.

      Because PI3K/Akt is up-regulated in CIN2/3 and NFV has been shown to inhibit this pathway in
      HPV-infected cervical cancer cell lines, we aim to further evaluate the effectiveness of NFV
      as an intervention for CIN2/3 and correlate these findings with phospho-Akt levels in
      cervical tissue. Several intervention trials have been conducted in women with CIN using
      retinoids, ß-carotene, difluoromethylornithine, and indole-3- carbinol and over 300 women
      with CIN 3 were followed in these trials for one to 15 months while none of them developed
      invasive cervical cancer. Therefore, this proposed intervention trial of 24 weeks (6 months)
      duration should allow a safe evaluation of NFV as a potential agent for a future randomized
      Phase III trial.

      Development of a new drug for cancer treatment is expensive and time consuming. Repositioning
      of a drug which is already FDA approved for another indication allows for more rapid
      evaluation and potential implementation of a novel cancer therapy. NFV has been identified to
      have anti-cancer effects in vitro, and compared to other protease inhibitors it is more
      potent in causing cell death. NFV has over 10 years of safety and pharmacokinetic data in
      HIV-infected individuals. Standard dosing for the treatment of HIV is 1,250 mg PO BID, and
      this dose has demonstrated plasma concentrations in vivo which correlate with necessary
      concentrations of successful in vitro studies. Furthermore, evaluation of the standard dose
      offers the availability of commercially produced tablets, the known and acceptable side
      effect profile, and the ease of twice daily dosing. For these reasons NFV is an excellent
      candidate for repositioning as an intervention for cervical dysplasia, which can be quickly
      evaluated in this phase II clinical trial.

Study Phase

Phase 2

Study Type


Primary Outcome

1.1 Efficacy of Nelfinavir (NFV) to induce complete remission (or partial regression to CIN 1) of CIN 2/3 or CIN 3 as evaluated in the post-treatment excisional biopsy.

Secondary Outcome

 targeted mechanism of NFV in histological response


Cervical Dysplasia



Study Arms / Comparison Groups

Description:  This is a single arm intervention trial of nelfinavir in women with grade 2/3 or grade 3 cervical intraepithelial neoplasia


* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information

Recruitment Status


Estimated Enrollment


Start Date

November 7, 2018

Completion Date

December 2022

Primary Completion Date

December 2022

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have a Cytology report with a High Grade Squamous Intra Epithelial
             Lesion "HSIL" or have histologically proven CIN 2/3 or CIN 3 diagnosed by cervical
             biopsy between 2 and 8 weeks prior to enrollment. For a patient to be eligible, the
             Cytology report must state High Grade Squamous Intra Epithelial Lesion "HSIL" or the
             pathology report must clearly state "CIN 2/3" or "CIN 3" or must state
             "moderate-severe dysplasia", "moderate severe dyskaryosis," "severe dysplasia," or
             "severe dyskaryosis." Patients with a diagnosis of CIN 2 alone or moderate dysplasia
             or dyskaryosis alone are not eligible for this study.

          -  Patients must be at least 18 years of age.

          -  Patients must have a satisfactory (readable, good quality) colposcopic evaluation at
             least 14 days after diagnostic biopsy.

          -  Patients must have colposcopically visible cervical lesion at entry consistent with

          -  Patients must have a negative urine pregnancy test within 14 days of starting the NFV.
             Women of childbearing potential must practice an acceptable form of contraception
             (e.g. intrauterine device, contraceptive pills, diaphragm, condoms).

          -  Patients must have a GOG Performance Status of 0, 1, or 2.

          -  Patients must be good candidates for delayed treatment of their CIN, i.e. they must be
             reliable to return for follow-up and provide a combination of at least three phone
             numbers or addresses for contact.

          -  Patients must have adequate*:

          -  CBC/Platelets: Hemoglobin (HgB) greater than 10.0g/dl; white blood cell (WBC) count
             greater than 3000/mcl; Platelet count greater than 125,000/mcl.

          -  Renal function: Creatinine less than or equal to 1.5 x Upper Limit Normal (ULN).

          -  Hepatic function: Total bilirubin less than or equal to 1.5 x ULN excluding Gilbert's
             disease; aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 2.0 x

          -  Glycemic control: fasting glucose < 126; random glucose <200; hemoglobin A1C ≤ 7.0%

             *These lab results must be evaluated prior to patient enrollment.

          -  Patients must have signed an approved informed consent and authorization permitting
             release of personal health information.

          -  Patients must have a negative HIV test within 14 days of starting the NFV.

          -  Patients with allergies or known sensitivity to Nelfinavir will be excluded or
             withdrawn after treatment, if deemed a safety concern by the principal Investigator.

        Exclusion Criteria:

        Ineligible Patients

          -  Patients who are pregnant or breast-feeding.

          -  Patients with cytologic or biopsy evidence of endocervical dysplasia or invasive

          -  Patients with undiagnosed abnormal vaginal bleeding.

          -  Patients with a known immunocompromised condition or a positive HIV test. Patients
             with a prior history of cervical cancer.

          -  Patients with a chronic or acute renal, or hepatic disorder, a significant bleeding
             disorder, or any other condition which in the Investigator's opinion might preclude
             study participation for the duration of the trial.

          -  Patients taking concurrent medication that is metabolized by the CYP3A4 isoenzyme.

          -  Patients taking the following concurrent medications: astemizole, cisapride,
             salmeterol, alfuzosin, terfinadine, amiodarone, midazolam, quinadine, ergot
             derivatives, pimozide, rifampin, triazolam, warfarin, azithromycin, carbamezpine,
             cyclosporine, didanosine, fluticasone propionate, phenobarbital, phenytoin, trazadone,
             sirolimus, tacrolimus , and St. John's wart.

          -  Patients who are unwilling, or unable, to practice an acceptable form of contraception
             (e.g. intrauterine device, contraceptive pills, diaphragm, condoms). For those women
             who choose to use oral contraceptive pills, they will be encouraged to use a second
             form of contraception, such as condoms, because of the potential for altered serum
             levels of oral contraceptives.

          -  Patients with uncontrolled diabetes; as defined by hemoglobin A1C ≥ 7.1%




18 Years - N/A

Accepts Healthy Volunteers



Joseph A Lucci, MD, , 

Location Countries

United States

Location Countries

United States

Administrative Informations



Organization ID


Responsible Party

Principal Investigator

Study Sponsor

The University of Texas Health Science Center, Houston

Study Sponsor

Joseph A Lucci, MD, Principal Investigator, The University of Texas Health Science Center, Houston

Verification Date

November 2020