Chordoma, Chordomas
Conditions
Keywords
Pembrolizumab, Pemetrexed, High-Dose Pemetrexed
Brief summary
Primary Objective: 1\. To determine objective response rate (ORR) according to RECIST v1.1 of pembrolizumab and high-dose pemetrexed in the treatment of patients with chordoma until disease progression. The OOR will be investigator assessed. Secondary Objectives: 1. To describe the adverse events associated with administering pembrolizumab and high-dose pemetrexed combination treatment. 2. To determine disease control rate based on imaging and overall survival. 3. To determine median PFS and PFS rates at 6, 9, 12, and 18 months. 4. To evaluate changes in volumetric tumor measurements based on imaging. 5. To determine the effects of combination treatment on quality of life, assessed by the EORTC-QLQ-C30 questionnaire. 6. To assess tumor evolution over time in patients with chordoma based on imaging, and molecular profiling. 7. To assess the pharmacodynamic effects of treatment in blood. Exploratory Objective: 1\. To explore the relationship between molecular phenotype and patient response.
Detailed description
This purpose of this study is to test the effectiveness and safety of the research study drug combination of pembrolizumab and high-dose pemetrexed. Both drugs are approved by the U.S. Food and Drug Administration (FDA) for many different types of cancer but is considered investigational because it is not approved by the FDA for use in patients with a rare type of cancer called chordoma. Pembrolizumab (Keytruda) is approved for use in more than ten types of cancer. Pemetrexed (Alimta) is approved for use in patients with certain types of lung cancer called non-squamous non-small cell lung cancer (NSCLC) and malignant pleural mesothelioma. Pemetrexed is also approved for use with pembrolizumab and cisplatin or carboplatin for certain non-squamous NSCLC. The approved dose of pemetrexed is 500 mg/m2, but this study is evaluating a higher dose (900 mg/m2) in effort to deliver more drug to chordoma. Outcome measures will be monitored until disease progression, through study completion (estimated average of 2 years), or withdrawal from study. Chordoma tumors can occur anywhere along the spine, from the head to the tailbone, and surgery and radiation therapy are currently used as treatment for chordoma. There are no drugs at this time that are approved for treating this cancer type. This study is being done to determine how the combination treatment regimen of pembrolizumab and high-dose pemetrexed might affect the growth of chordoma and to learn more about this regimen's safety in patients with chordoma.
Interventions
DRUGPembrolizumab
pembrolizumab 200 mg by intravenous (IV) infusion on Day 1 of each 21-day treatment cycle
pemetrexed 900 mg/m2 IV on Day 1 of each 21-day treatment cycle and supportive medications (folic acid, vitamin B12, and dexamethasone).
Sponsors
Chordoma Foundation
Saint John's Cancer Institute
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Participants who qualify for the study based upon baseline assessments will have pembrolizumab and pemetrexed administered by intravenous infusion (IV) on Day 1 of each 21-day cycle (every three weeks).
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
In order to be eligible to participate in this study, an individual must meet the criteria listed below. 1. Participant has the ability to understand and the willingness to provide a signed and dated informed consent form. 2. Participant has the willingness to comply with all study procedures and availability for the duration of the study. 3. Participant has a pathologic diagnosis of chordoma. 4. Evidence of progressive disease within the past six months before study entry, according to RECIST v1.1. 5. Participant has measurable disease, according to RECIST v1.1. 6. Participant is male or female, ≥ 18 years of age. 7. Participant has an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 1 at study entry: ECOG Performance Status Grade Description 0 Normal activity. Fully active, able to carry on all pre-disease performance without restriction. 1. Symptoms, but ambulatory. Restricted in physically strenuous activity, but ambulatory and able to carry out work of a light or sedentary nature (e.g., light housework, office work). 2. In bed \<50% of the time. Ambulatory and capable of all self-care, but unable to carry out any work activities. Up and about more than 50% of waking hours. 3. In bed \>50% of the time. Capable of only limited self-care, confined to bed or chair more than 50% of waking hours.- 4. 100% bedridden. Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 5. Dead. Note: Special allowance may be made for inclusion of participants with an ECOG PS of 2 if status is due to disease-related impingement of the spinal cord rather than other underlying comorbidities. 8\. Participant has adequate organ function: 1. ANC ≥ 1.5 x 109/L 2. Platelets ≥ 100 x 109/L 3. Hemoglobin ≥ 9 g/dL or ≥ 5.6 mmol/L Note: Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within last 2 weeks. 4. Total bilirubin ≤ 1.5 x ULN Note: Patients with Gilbert's syndrome with a total bilirubin ≤ 2.0 ULN and direct bilirubin within normal limits are permitted. 5. ALT and AST ≤ 2.5 x ULN (≤ 5 x ULN in presence of known hepatic metastasis) 6. Serum creatinine ≤ 1.5 x ULN 9. Participant has the ability to interrupt non-steroidal anti-inflammatory drugs (NSAIDS) 2 days before (5 days for long-acting NSAIDs), the day of, and for 2 days following administration of Pemetrexed. 10\. Participant has the ability to take folic acid, Vitamin B12, and dexamethasone according to the protocol schedule. 11\. Participant has recovered from any previous therapy-related toxicity to CTCAE Grade 1 or to their clinical baseline at study entry. 12\. Criteria for known Hepatitis B and C positive participant: Hepatitis B screening tests are required. 12.1 Hepatitis B positive participants • Participants who are HBsAg positive are eligible if they have received HBV antiviral therapy for at least 4 weeks and have undetectable HBV viral load prior to study intervention. * Participants should remain on anti-viral therapy throughout study intervention and follow local guidelines for HBV anti-viral therapy post completion of study intervention. 12.2 Participants with history of HCV infection are eligible if HCV viral load is undetectable at screening. * Participants must have completed curative anti-viral therapy at least 4 weeks prior to study intervention 13. Male participant: agrees to use highly effective contraception as detailed in Section 4.3.2 of this protocol during the treatment period and for at least 120 days after the last dose of study intervention and refrain from donating sperm during this period. 14\. Female participant: meets at least one of the following conditions: a. Not a woman of childbearing potential (WOCBP) as defined in Section 4.3.2. OR b. Is a WOCBP who agrees to use highly effective contraception as detailed in Section 4.3.2 of this protocol during the study treatment period and for at least 120 days after the last dose of study intervention.
Exclusion criteria
4.2 PARTICIPANT
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) | Day 1 of study treatment until disease progression up to 2 years | 1\. To determine objective response rate (ORR) according to RECIST v1.1 of pembrolizumab and high-dose pemetrexed in the treatment of patients with chordoma. The OOR will be investigator assessed. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Adverse Events of Combination Therapy | From time of 1st Treatment to End of Treatment or Diease Progression for approximately 1 year | To describe the adverse events associated with administering pembrolizumab and high-dose pemetrexed combination treatment. |
| Median progression-free survival | From time of 1st Treatment to End of Treatment or Disease Progression up to 2 years | To determine the median progression-free survival (PFS). |
Other
| Measure | Time frame | Description |
|---|---|---|
| PFS at 12 months | From time of 1st Treatment to 12 months | To assess the rate of progression free survival at 12 months from start of treatment. |
| PFS at 18 months | From time of 1st Treatment to 18 months | To assess the rate of progression free survival at 18 months from start of treatment. |
| Tumor Volume | From time of 1st Treatment to End of Treatment or Disease Progression up to 5 years | To evaluate the percent reduction or increase of tumor volume (length x width x height) compared to volume measured prior to study treatment initiation based on appropriate imaging (CT scan or MRI scan). |
| Disease Control | From time of 1st Treatment to End of Treatment or Disease Progression up to 2 years | To determine Disease Contral Rate according to RECIST v1.1, as determined by appropriate imaging modality (CT scan or MRI scan) |
| Tumor genome sequence analysis of available tumor samples | From time of 1st Treatment to End of Treatment or Disease Progression up to 5 years | To assess genetic mutations and copy number alterations in tumor before and after study treatment from patients who undergo tumor or surgery or biopsies for clinical management. |
| Tumor transcriptome sequence analysis of available tumor samples | From time of 1st Treatment to End of Treatment or Disease Progression up to 5 years | To assess gene expression in tumor before and after study treatment from patients who undergo tumor or surgery or biopsies for clinical management |
| Circulating tumor DNA in blood | From time of 1st Treatment to End of Treatment or Disease Progression up to 5 years | To assess circulating chordoma tumor DNA in blood before and after study treatment. |
| Treatment Effect on Quality of Life | From time of 1st Treatment to End of Treatment or Disease Progression up to 2 years | To determine the effects of combination treatment on quality of life, assessed by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire core 30 (EORTC- QCL-30). High scores on the functioning scales indicate better functioning, whereas high symptom scores represent higher levels of symptom burden. |
| PFS at 6 months | From time of 1st Treatment to six months | To assess the rate of progression free events at six months from start of treatment. |
| PFS at 9 months | From time of 1st Treatment to nine months | To assess the rate of progression free survival at 9 months from start of treatment. |
Countries
United States
Contacts
Primary ContactNaveed Wagle, MD
Backup ContactAkanksha Sharma, MD
Outcome results
None listed