Clinical Trial: CDK4/6 Inhibition in Locally Advanced/Metastatic Chordoma

Study Status: Not yet recruiting
Recruit Status: Not yet recruiting
Study Type: Interventional

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

Brief 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.

Detailed Summary: 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 (C
Sponsor: National Center for Tumor Diseases, Heidelberg

Current 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.


Original Primary Outcome: Same as current

Current Secondary Outcome:

  • Tumor response rate (TRR) [ Time Frame: 6 months ]
    • defined as the sum of complete remission (CR) and partial remission (PR) according to RECIST version 1.1 after six cycles of study medication.
  • Progression-free survival (PFS) [ Time Frame: 6 months ]
    • 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.
  • Overall survival (OS) [ Time Frame: 6 months ]
    • 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.
  • Safety (toxicity, tolerability): Toxic effects will be graded according to CTCAE v4.03. [ Time Frame: 6 months ]
    • Toxic effects will be graded according to CTCAE v4.03.
  • Quality of life (QoL) [ Time Frame: 6 months ]
    • 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


Original Secondary Outcome: Same as current

Information By: National Center for Tumor Diseases, Heidelberg

Dates:
Date Received: March 31, 2017
Date Started: August 1, 2017
Date Completion: July 31, 2021
Last Updated: April 11, 2017
Last Verified: April 2017