Pembrolizumab and Pemetrexed for Progressive Chordoma

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 signedand dated informed consent form.

2. Participant has the willingness to comply with all study procedures and availabilityfor 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, butambulatory and able to carry out work of a light or sedentary nature (e.g., lighthousework, office work).

2. In bed <50% of the time. Ambulatory and capable of all self-care, but unable tocarry 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 chairmore than 50% of waking hours.-

4. 100% bedridden. Completely disabled. Cannot carry on any self-care. Totally confinedto 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:

9. ANC ≥ 1.5 x 109/L

10. Platelets ≥ 100 x 109/L

11. Hemoglobin ≥ 9 g/dL or ≥ 5.6 mmol/L Note: Criteria must be met withouterythropoietin dependency and without packed red blood cell (pRBC) transfusionwithin last 2 weeks.

12. Total bilirubin ≤ 1.5 x ULN Note: Patients with Gilbert's syndrome with a totalbilirubin ≤ 2.0 ULN and direct bilirubin within normal limits are permitted.

13. ALT and AST ≤ 2.5 x ULN (≤ 5 x ULN in presence of known hepatic metastasis)

14. Serum creatinine ≤ 1.5 x ULN 9. Participant has the ability to interruptnon-steroidal anti-inflammatory drugs (NSAIDS) 2 days before (5 days for long-actingNSAIDs), the day of, and for 2 days following administration of Pemetrexed.

15. Participant has the ability to take folic acid, Vitamin B12, and dexamethasoneaccording to the protocol schedule.

16. Participant has recovered from any previous therapy-related toxicity to CTCAEGrade 1 or to their clinical baseline at study entry.

17. Criteria for known Hepatitis B and C positive participant: Hepatitis Bscreening 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 andfollow local guidelines for HBV anti-viral therapy post completion of studyintervention.

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 priorto study intervention 13. Male participant: agrees to use highly effectivecontraception as detailed in Section 4.3.2 of this protocol during the treatmentperiod and for at least 120 days after the last dose of study intervention andrefrain 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 daysafter the last dose of study intervention.

Exclusion Criteria:

4.2 PARTICIPANT EXCLUSION CRITERIA

An individual who meets any of the following appropriate criteria below will be excluded from participation in this study.

1. Participant has insufficient time from prior therapy to the first dose of studytreatment:

2. Less than 4 weeks for an investigational agent or investigational device

3. Less than 3 weeks for major surgery

4. Less than 2 weeks for radiation therapy

5. Less than 3 weeks for a cytotoxic agent

6. Less than 2 weeks or 5 half-lives, whichever is shorter, for a targeted therapy (e.g. tyrosine kinase inhibitor)

7. Less than 3 weeks or 5 half-lives, whichever is shorter, for an antibody-basedtherapy

8. Participant has received a live vaccine or live-attenuated vaccine within 30 daysbefore the first dose of study intervention. Note: Please refer to Section 6.4 for information on COVID-19 vaccines.

9. Participant has a diagnosis of immunodeficiency or is receiving chronic systemicsteroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or anyother form of immunosuppressive therapy within 7 days prior to the first dose ofstudy intervention.

10. Participant has active autoimmune disease that has required systemic treatment inthe past 2 years (i.e., with use of disease modifying agents, corticosteroids, orimmunosuppressive drugs). Note: Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroidreplacement therapy for adrenal or pituitary insufficiency, etc.) is not considereda form of systemic treatment and is allowed.

11. Participant has an active bacterial infection requiring intravenous [IV] antibioticsat time of initiating study treatment, fungal infection, or detectable viralinfection.

12. Participant has a known history of non-infectious pneumonitis or currently haspneumonitis.

13. Participant has a known history of human immunodeficiency virus (HIV) infection.

14. Participant has concurrent active Hepatitis B (defined as HBsAg positive and/ordetectable HBV DNA) or Hepatitis C virus (defined as anti-HCV Ab positive anddetectable HCV RNA) infection. Note: Hepatitis C screening is not required unless the participant has a knownhistory of HCV infection.

15. Participant has had an allogenic tissue/solid organ transplant.

16. Participant has third space fluid which cannot be controlled by drainage. Note: Forpatients who develop or have baseline clinically significant pleural or peritonealeffusions (on the basis of symptoms or clinical examination) before or duringinitiation of pemetrexed therapy, consideration should be given to draining theeffusion prior to dosing. However, if, in the investigator's opinion, the effusionrepresents progression of disease, the patient should be discontinued from studytherapy.

17. Participant has a severe or uncontrolled medical disorder that would, in theinvestigator's opinion, impair ability to receive study intervention, including, butnot limited to:

18. Uncontrolled diabetes;

19. Renal disease that requires dialysis;

20. Pulmonary disorder requiring supplemental oxygen to keep saturation >95% andthe situation is not expected to resolve within 2 weeks;

21. Severe dyspnea at rest or requiring oxygen therapy;

22. Interstitial lung disease;

23. History of major surgical resection involving the stomach or small bowel;

24. Preexisting Crohn's disease;

25. Ulcerative colitis;

26. Uncontrolled vasculitis and/or disease with known vasculitis;

27. Preexisting chronic condition resulting in baseline Grade 2 or higher diarrhea;

28. Psychiatric illness, substance abuse, or other social situation that wouldinterfere with cooperation with the requirements of the trial.

29. Participant has a personal history or presence of any of the followingcardiovascular conditions:

30. Syncope of cardiovascular etiology;

31. Ventricular arrhythmia of pathological origin (including, but not limited to,ventricular tachycardia and ventricular fibrillation);

32. Myocardial infraction within 6 months of investigational productadministration;

33. Unstable angina;

34. Sudden cardiac arrest;

35. Congestive heart failure (NYHA classification ≥ 3): New York Heart Association Functional Classification Class Patient Symptoms I Nolimitation of physical activity. Ordinary physical activity does not cause unduefatigue, palpitation, dyspnea (shortness of breath). II Slight limitation of physical activity. Comfortable at rest. Ordinary physicalactivity results in fatigue, palpitation, dyspnea (shortness of breath). III Marked limitation of physical activity. Comfortable at rest. Less than ordinaryactivity causes fatigue, palpitation, or dyspnea. IV Unable to carry on any physical activity without discomfort. Symptoms of heartfailure at rest. If any physical activity is undertaken, discomfort increases.

36. Participant has a known additional malignancy that is progressing or has requiredactive treatment with the past 3 years. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma ofthe skin, organ confined prostate cancer, or carcinoma in situ, excluding carcinomain situ of the bladder, that have undergone potentially curative therapy are notexcluded.

37. Participant is a woman of childbearing potential (WOCBP) who is pregnant or nursing. Note: WOCBP should only be included after a negative highly sensitive urine or serumpregnancy test.

38. Participant has a history of severe hypersensitivity (≥ Grade 3) to pembrolizumaband/or any of its excipients (L-histidine, polysorbate 80, or sucrose).