Clinical Trials /

CDK4/6 Inhibition in Locally Advanced/Metastatic Chordoma

NCT03110744

Description:

In chordoma cell lines and patient biopsies, the p16 (CDKN2A) tumor suppressor is consistently deleted. Thus, chordomas are an example of a tumor with universal activation of the cyclin-dependent kinases 4 and 6 (CDK4/6) pathway, and experiments with patient-derived chordoma cell lines demonstrate aberrant CDK4/6 activity downstream of p16 loss can be efficiently inhibited by the CDK4/6 inhibitor palbociclib, resulting in reduced proliferation and growth of neoplastic cells. The investigators aim to conduct a phase II clinical trial to evaluate the efficacy of the small-molecule CDK4/6 inhibitor palbociclib in patients with locally advanced/metastatic chordoma who are not candidates for standard therapy. The primary objective is disease control in patients with chordoma treated with palbociclib as single agent. The study design of this phase II study is based on a Simon two-stage design.

Related Conditions:
  • Chordoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: CDK4/6 Inhibition in Locally Advanced/Metastatic Chordoma
  • Official Title: CDK4/6 Inhibition in Locally Advanced/Metastatic Chordoma (NCT-PMO-1601)

Clinical Trial IDs

  • ORG STUDY ID: NCT-2016-415 / Chordoma
  • NCT ID: NCT03110744

Conditions

  • Chordoma

Interventions

DrugSynonymsArms
PalbociclibIbrancePalbociclib

Purpose

In chordoma cell lines and patient biopsies, the p16 (CDKN2A) tumor suppressor is consistently deleted. Thus, chordomas are an example of a tumor with universal activation of the cyclin-dependent kinases 4 and 6 (CDK4/6) pathway, and experiments with patient-derived chordoma cell lines demonstrate aberrant CDK4/6 activity downstream of p16 loss can be efficiently inhibited by the CDK4/6 inhibitor palbociclib, resulting in reduced proliferation and growth of neoplastic cells. The investigators aim to conduct a phase II clinical trial to evaluate the efficacy of the small-molecule CDK4/6 inhibitor palbociclib in patients with locally advanced/metastatic chordoma who are not candidates for standard therapy. The primary objective is disease control in patients with chordoma treated with palbociclib as single agent. The study design of this phase II study is based on a Simon two-stage design.

Detailed Description

      Chordoma is a rare bone tumor with slow growth. The standard treatment is en bloc excision,
      but the site of origin of the disease often prevents complete surgery. For these patients,
      debulking surgery followed by radiation therapy (RT) or high-dose RT alone can be an
      alternative. However, local relapses or more rarely metastatic disease frequently occur, and
      there is no efficient standard systemic therapy available. Only very limited responses are
      seen with chemotherapy or targeted agents, such as imatinib and lapatinib. In chordoma cell
      lines and patient biopsies, the p16 (CDKN2A) tumor suppressor is consistently deleted. Thus,
      chordomas are an example of a tumor with universal activation of the CDK4/6 pathway, and
      experiments with patient-derived chordoma cell lines demonstrate aberrant CDK4/6 activity
      downstream of p16 loss can be efficiently inhibited by the CDK4/6 inhibitor palbociclib,
      resulting in reduced proliferation and growth of neoplastic cells. The investigators aim to
      conduct a phase II clinical trial to evaluate the efficacy of the small-molecule CDK4/6
      inhibitor palbociclib in patients with locally advanced/metastatic chordoma who are not
      candidates for standard therapy. The primary objective is disease control in patients with
      chordoma treated with palbociclib as single agent. The study design of this phase II study is
      based on a Simon two-stage design. This trial will establish whether the overreliance of
      chordomas on the activation of the CDK4/6-Retinoblastoma 1 (RB1) pathway can be exploited for
      therapeutic benefit. Based on previous experience with 125 mg palbociclib once daily for 21
      days followed by 7 days of rest in patients with breast cancer, liposarcoma, non-small cell
      lung cancer, hepatocellular carcinoma, ovarian cancer, mantle-cell lymphoma, and
      glioblastoma, this regimen is chosen. Based on a Simons optimal two-stage design the disease
      control rate (DCR) will be the primary end-point, whereby response is defined as complete
      response (CR), partial response (PR), or stable disease (SD) according to RECIST v1.1
      criteria after six cycles. For sample size calculation the investigators estimate a poor
      response with 10% and a good response with 25% (power, 80%; alpha, 5%) leading to a first
      stage of 18 patients and, if three or more patients responded to a second stage with
      additional 25 patients (total n=43).
    

Trial Arms

NameTypeDescriptionInterventions
PalbociclibExperimentalapplication on 21 consecutive days of a 28 days cycle
  • Palbociclib

Eligibility Criteria

        Inclusion Criteria:

          -  Patients with locally advanced or metastatic chordoma with confirmed diagnosis in a
             reference pathology (with immunohistology for epithelial membrane antigen, S100,
             Brachyury, Integrase interactor 1 (INI-1)) who have no response or have lost response
             to treatment with a tyrosine kinase inhibitor e.g. imatinib, lapatinib, erlotinib,
             sunitinib, sorafenib, etc.

          -  At least one measurable tumor lesion

          -  Loss of p16 determined immunohistochemically or CDKN2A/B genomically, presence of
             CDK4/6 and RB1 determined immunohistochemically or by RNA-Sequencing.

          -  Age ≥ 18 years, no upper age limit

          -  Availability of tissue blocks preferably not older than 12 months for immunohistologic
             assessment (if no adequate material is available, re-biopsy should be considered
             before entering the study)

          -  No chemotherapy two weeks before study

          -  Non-pregnant and non-nursing. Women of child-bearing potential must have a negative
             serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL within 72 hours
             prior to registration (WOCBP is defined as a sexually active mature woman who has not
             undergone a hysterectomy or who has had menses at any time in the preceding 24
             months).

          -  Women of child-bearing potential must either commit to continued abstinence from
             heterosexual intercourse or begin one acceptable method of birth control (double
             barrier contraceptive method (IUD, condome), tubal ligation, or partner's vasectomy)
             while on therapy and for 14 weeks after the last dose of therapy. Hormonal
             contraception alone is an inadequate method of birth control. Female patients must
             agree not to donate lactation during treatment and until 14 weeks after end of
             treatment.

          -  Men must agree not to father a child and must use a latex condom during any sexual
             contact with WOCBP while receiving therapy and for 14 weeks after therapy is stopped,
             even if they have undergone successful vasectomy. Sperm donation is not permitted for
             the same time interval.

          -  Signed written informed consent

          -  Performance status ≤ 2 according to Eastern Cooperative Oncology Group (ECOG) /World
             Health Organization (WHO) criteria

          -  Ability of patient to understand the character and individual consequences of clinical
             trial

        Exclusion Criteria:

          -  Prior treatment with palbociclib or known intolerance/allergy to the compound or any
             ingredient (acquired or hereditary).

          -  Co-therapy with strong/potent CYP3A inducers and/or inhibitors, (e.g., Clarithromycin,
             Indinavir, Itraconazol, Ketoconazol, Lopinavir/Ritonavir, Nefazodon, Nelfinavir,
             Posaconazol, Saquinavir, Telaprevir, Telithromycin, Voriconazol, and St. John's Wort
             [Hypericum perforatum])) while on treatment with study drug.

          -  Organ insufficiency: creatinine clearance <30ml/min; total bilirubin > 1.5x upper
             normal serum level; AST > upper normal serum level ; abnormal blood counts; heart
             failure (New York Heart Association (NYHA) III/IV); uncontrolled hypertension;
             unstable angina; serious cardiac arrhythmia; severe obstructive or restrictive
             ventilation disorder

          -  Uncontrolled infection

          -  Patients with a "currently active" second malignancy other than non-melanoma skin
             cancer. Patients are not considered to have a "currently active" malignancy if the
             patients have completed therapy and are considered by the patients physician to be at
             less than 30% risk of relapse within one year.

          -  Severe neurologic or psychiatric disorder interfering with ability of giving informed
             consent

          -  Known or suspected active alcohol or drug abuse

          -  Known positivity for HIV, active hepatitis A virus (HAV), hepatitis B virus (HBV), or
             hepatitis C virus (HCV) infection

          -  Uncontrolled central nervous system (CNS) involvement (treatment for CNS-involvement
             prior to inclusion is allowed)

          -  Cytopenia: platelets <100 G/l, neutrophils <1.0 G/l, hemoglobin <10.0 g/dl

          -  corrected QT interval (QTc) >470 msec (based on the mean value of triplicate ECGs),
             family or personal history of long or short QT syndrome, Brugada syndrome, or known
             history of QTc prolongation or Torsade de Pointes

          -  Uncontrolled electrolyte disorders that can aggravate the effects of a QTc-prolonging
             drug (e.g., hypocalcemia, hypokalemia, hypomagnesemia)

          -  Participation in other ongoing interventional clinical trials
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Disease control rate (DCR)
Time Frame:6 months
Safety Issue:
Description:The primary endpoint is the DCR after six cycles of palbociclib, which is defined as the presence of at least one confirmed complete response (CR) or confirmed partial response (PR) or stable disease (SD) according to RECIST version 1.1.

Secondary Outcome Measures

Measure:Tumor response rate (TRR)
Time Frame:6 months
Safety Issue:
Description:• defined as the sum of complete remission (CR) and partial remission (PR) according to RECIST version 1.1 after six cycles of study medication.
Measure:Progression-free survival (PFS)
Time Frame:6 months
Safety Issue:
Description:• defined as the time from first administration of the Investigational Medicinal Product (IMP) to radiologically confirmed progression of disease or death from any cause, whichever occurs first. Patients without the event are censored on the last date of follow-up.
Measure:Overall survival (OS)
Time Frame:6 months
Safety Issue:
Description:• defined as the time from first administration of the IMP to time of death from any cause. Patients without the event are censored on the last date of follow-up.
Measure:Safety (toxicity, tolerability): Toxic effects will be graded according to CTCAE v4.03.
Time Frame:6 months
Safety Issue:
Description:• Toxic effects will be graded according to CTCAE v4.03.
Measure:Quality of life (QoL)
Time Frame:6 months
Safety Issue:
Description:• QoL will be assessed by the EORTC Quality of Life Core Questionnaire (QLQ-C30), supplemented by information on self-assessed concomitant diseases and demographics initially, after the first, and after the sixth 28-day treatment cycle

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University Hospital Heidelberg

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