ChordomaPhase 2NCT-PMO-1601NCT03110744
CDK4/6 Inhibition in Locally Advanced/Metastatic Chordoma
A Phase 2 study testing Palbociclib in people with Chordoma, run by University Hospital Heidelberg at 3 sites in Germany.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Chordoma
- What is being tested?
- Palbociclib
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 43 participants
- Where
- 3 sitesGermany
- Study dates
- 15 Dec 2017to 22 Dec 2022
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
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- 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
Who cannot join
- Prior treatment with palbociclib or known intolerance/allergy to the compound or any ingredient (acquired or hereditary).
- Prior treatment with other CDK4/6 inhibitors
- 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.
- Co-therapy with corticosteroids above 7.5 mg prednisolone/prednisone equivalent
- Anticancer treatment less than 2 weeks prior to study treatment
- 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
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- Clinical signs of active infection (° grade 2-CTCAE Vers.5.0)
- 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
Trial locations and contacts
3 sites in 1 country.
Germany3 sites
Universitätsklinikum Essen
Essen, 45147
National Center for Tumor Diseases
Heidelberg, 69120
Universitätsklinikum Ulm
Ulm, 89081
About this study
Official title: CDK4/6 Inhibition in Locally Advanced/Metastatic Chordoma (NCT-PMO-1601)
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.
Read the 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).
- Conditions
- Chordoma
- Being tested
- Palbociclib
- Medical subject headings
- Chordoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PalbociclibDrug
Also called Ibrance
application on 21 consecutive days of a 28 days cycle
| Study group | Role | What they receive |
|---|---|---|
| Palbociclib | Experimental | application on 21 consecutive days of a 28 days cycle Receives: Drug: Palbociclib |
What is being measured
The primary outcome is the main question the study is designed to answer.
Disease control rate (DCR)
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.
Measured: 6 months
Secondary outcomes (5)
Tumor response rate (TRR)
- defined as the sum of complete remission (CR) and partial remission (PR) according to RECIST version 1.1 after six cycles of study medication.
Measured: 6 months
Progression-free survival (PFS)
- 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.
Measured: 6 months
Overall survival (OS)
- 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.
Measured: 6 months
Safety (toxicity, tolerability): Toxic effects will be graded according to CTCAE v4.03.
- Toxic effects will be graded according to CTCAE v4.03.
Measured: 6 months
Quality of life (QoL)
- 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
Measured: 6 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted12 Apr 2017
- Study start15 Dec 2017
- Primary completion22 Dec 2022
- Study completion22 Dec 2022
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for ChordomaStudies of the same condition, open and under way.
- More trials run by University Hospital HeidelbergThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 43 participants (actual)
Sponsor and investigators
- Lead sponsor
- University Hospital Heidelberg
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Prof. Dr. Richard F Schlenk, University Hospital Heidelberg
- Investigators
- Stefan Fröhling, Prof. Dr., Principal investigator, University Hospital Heidelberg
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03110744
- Sponsor's protocol ID
- NCT-2016-415 / Chordoma
- Acronym
- NCT-PMO-1601
- Status last verified
- Mar 2023
- First submitted
- 31 Mar 2017
- Last updated
- 27 Mar 2023
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 27 Mar 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- CDK4/6 Inhibition in Locally Advanced/Metastatic Chordoma (NCT-PMO-1601)
- ClinicalTrials.gov ID
- NCT03110744
- Acronym / sponsor ID
- NCT-PMO-1601 / NCT-2016-415 / Chordoma
- Conditions
- Chordoma
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 43 participants (actual)
- Lead sponsor
- University Hospital HeidelbergUniversity, hospital or other
- Study start
- 15 Dec 2017 (actual)
- Primary completion
- 22 Dec 2022 (actual)
- Study completion
- 22 Dec 2022 (actual)
- First posted
- 12 Apr 2017 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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).
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Palbociclib | Experimental | Drug: Palbociclibapplication on 21 consecutive days of a 28 days cycle |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (12 listed)
- 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)
Key exclusion criteria (16 listed)
- Prior treatment with palbociclib or known intolerance/allergy to the compound or any ingredient (acquired or hereditary).
- Prior treatment with other CDK4/6 inhibitors
- 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.
- Co-therapy with corticosteroids above 7.5 mg prednisolone/prednisone equivalent
- Anticancer treatment less than 2 weeks prior to study treatment
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| PalbociclibAlso: Ibranceapplication on 21 consecutive days of a 28 days cycle | Drug | Palbociclib |
Primary outcome
Disease control rate (DCR)
Time frame: 6 months
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.
5 secondary outcomes
Tumor response rate (TRR)
Time frame: 6 months
Progression-free survival (PFS)
Time frame: 6 months
Overall survival (OS)
Time frame: 6 months
Safety (toxicity, tolerability): Toxic effects will be graded according to CTCAE v4.03.
Time frame: 6 months
Quality of life (QoL)
Time frame: 6 months
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 27 Mar 2023.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Stefan Fröhling, Prof. Dr. principal investigator
University Hospital Heidelberg
3 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Palbociclib in people with Chordoma, run by University Hospital Heidelberg at 3 sites in Germany.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 12 inclusion and 16 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 27 Mar 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 3 sites in Germany. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Disease control rate (DCR) (time frame: 6 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 27 Mar 2023.