CDK4/6 Inhibition in Locally Advanced/Metastatic Chordoma

  • STATUS
    Recruiting
  • End date
    Sep 30, 2023
  • participants needed
    43
  • sponsor
    University Hospital Heidelberg
Updated on 7 January 2022
vasectomy
hysterectomy
imatinib
lapatinib
cancer chemotherapy
sorafenib
palbociclib
metastatic chordoma

Summary

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.

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).

Details
Condition Chordoma
Treatment Palbociclib
Clinical Study IdentifierNCT03110744
SponsorUniversity Hospital Heidelberg
Last Modified on7 January 2022

Eligibility

Yes No Not Sure

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)) not amenable to curative treatment with surgery or radiotherapy
At least one measurable tumor lesion according to RECIST 1.1 criteria
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
Prior treatment with other CDK4/6 inhibitors
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
Co-therapy with corticosteroids above 7.5 mg prednisolone/prednisone equivalent
Anticancer treatment less than 2 weeks prior to study treatment
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
Clinical signs of active infection (° grade 2-CTCAE Vers.5.0)
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
Clear my responses

How to participate?

Step 1 Connect with a study center
What happens next?
  • You can expect the study team to contact you via email or phone in the next few days.
  • Sign up as volunteer to help accelerate the development of new treatments and to get notified about similar trials.

You are contacting

Investigator Avatar

Primary Contact

site

0/250

Additional screening procedures may be conducted by the study team before you can be confirmed eligible to participate.

Learn more

If you are confirmed eligible after full screening, you will be required to understand and sign the informed consent if you decide to enroll in the study. Once enrolled you may be asked to make scheduled visits over a period of time.

Learn more

Complete your scheduled study participation activities and then you are done. You may receive summary of study results if provided by the sponsor.

Learn more

Similar trials to consider

Loading...

Browse trials for

Not finding what you're looking for?

Every year hundreds of thousands of volunteers step forward to participate in research. Sign up as a volunteer and receive email notifications when clinical trials are posted in the medical category of interest to you.

Sign up as volunteer

user name

Added by • 

 • 

Private

Reply by • Private
Loading...

Lorem ipsum dolor sit amet consectetur, adipisicing elit. Ipsa vel nobis alias. Quae eveniet velit voluptate quo doloribus maxime et dicta in sequi, corporis quod. Ea, dolor eius? Dolore, vel!

  The passcode will expire in None.
Loading...

No annotations made yet

Add a private note
  • abc Select a piece of text from the left.
  • Add notes visible only to you.
  • Send it to people through a passcode protected link.
Add a private note