Advanced or unresectable melanoma.
Conditions
Interventions
Product Name: Pembrolizumab
Product Code: MK-3475
Pharmaceutical Form: Powder for solution for infusion
INN or Proposed INN: Pembrolizumab
Sponsors
Royal Marsden
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Be willing and able to provide written informed consent for the trial. 2. Diagnosis of Stage III (unresectable) or stage IV cutaneous melanoma or melanoma of unknown primary, as per AJCC staging system. 3. Confirmed metastatic disease by diagnostic biopsy. 4. Be more than or equal to 18 years of age on day of signing informed consent. 5. Have at least one lesion and a maximum of 3 which are appropriate targets for high dose radiotherapy. This lesion must be 1cm-5cm in size and measurable by RECIST v1.1. The lesions should also be asymptomatic or, in the opinion of the investigator, threaten to become symptomatic. 6. Have in addition at least one other lesion which will not be irradiated but must be measurable by RECIST v1.1 to assess the abscopal effect of the treatment. 7. Have a performance status of 0 or 1 on the ECOG Performance Scale. 8. Demonstrate adequate organ function as defined in Table 1 of the protocol. All screening labs should be performed within 7 days of randomisation. 9. Female patient of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to randomisation. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. 10. Female patients of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication. Patients of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year. 11. Male patients should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy. Are the trial subjects under 18? no Number of subjects for this age range: 0 F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 188 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 46
Exclusion criteria
Exclusion criteria: 1. Has lesions that if irradiated would result in unacceptable radiation induced toxicity to normal tissue, in particular to the CNS and bowel 2. Requires palliative radiotherapy for symptom control 3. Is currently participating in or has participated in a study of an investigational agent or device within 4 weeks of the first dose of trial treatment. 4. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. 5. Has had a monoclonal antibody within 4 weeks prior to the first dose of trial treatment or who has not recovered (i.e. = Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier. 6. Has had chemotherapy, targeted small molecule therapy, or radiation therapy within 4 weeks prior to the first dose of trial treatment or who has not recovered (i.e., = Grade 1 or at baseline) from adverse events due to a previously administered agent. - Note: Patients with an AE = Grade 2 neuropathy are an exception to this criterion and may qualify for the study. - Note: If patient received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy. 7. Has history of severe colitis related to previous immunotherapy treatment. 8. Has a past or current history of SjÖgrens Syndrome. 9. Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy. 10. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. 11. Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. Participants with vitiligo or resolved childhood asthma/atopy would be an exception to this rule. Participants that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study. Participants with hypothyroidism stable on hormone replacement will not be excluded from the study. 12. Has evidence of interstitial lung disease or active, non-infectious pneumonitis. 13. Has an active infection requiring systemic therapy. 14. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the participant’s participation for the full duration of the trial, or is not in the best interest of the participant to participate, in the opinion of the treating investigator. 15. Has kn
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: -To evaluate the effectiveness of pembrolizumab alone and in combination with high dose radiotherapy in patients with metastatic melanoma over 12 weeks of treatment.; Secondary Objective: -To evaluate the response to pembrolizumab alone and with radiotherapy 6 months post treatment. -To evaluate the response of individual lesions that have and have not been treated by radiotherapy to see if any effect from the radiotherapy can be seen in distant tumours. -To assess patient safety when combining pembrolizumab with radiotherapy. -To assess progression free survival at 1, 2 and 3 years after the treatment has finished. -To assess overall survival of patients in both study treatment groups. ;Primary end point(s): The difference in response rate(RR)between the treatment arms will be calculated at 12 weeks post treatment start in the intention to treat (ITT) population. This will be presented using the percentage of patients, including 95% confidence intervals, who achieve CR or PR according to the RECIST v1.1 criteria in each treatment group. Analysis of the primary endpoint will be carried out when all patients have completed treatment and 12 week follow-up assessments.;Timepoint(s) of evaluation of this end point: Patients will be assessed 12 weeks after the start of pembrolizumab. The analysis of this endpoint will be performed when the last patient completes their 12 weeks of treatment or comes off study for any other reason. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): - To determine response rates by RECIST v1.1 at 6 months post treatment - Individual lesion response assessment to assess abscopal effect. - To assess the toxicity of the combination of pembrolizumab and high dose radiotherapy. - To assess Progression-free survival at 1, 2 and 3 years post treatment. - To assess Overall survival in the arms of the study. ; Timepoint(s) of evaluation of this end point: • RR will be determined at 6 months post treatment start. • Individual lesion response assessment every 12 weeks taking account of within patient data. • Toxicity will be assessed after 12 weeks of treatment. • PFS will be calculated at 1, 2 and 3 years from treatment start until PD or death from any cause. • OS will be calculated from treatment start until date of death from any cause. | — |
Countries
United Kingdom
Contacts
Public ContactJames Larkin
Royal Marsden NHS Foundation Trust
Outcome results
None listed