Metastatic renal cell carcinoma with clear cell component MedDRA version: 20.1 Level: LLT Classification code 10080007 Term: Clear cell renal cell carcinoma metastatic System Organ Class: 100000004864
Conditions
Interventions
Trade Name: Cyclophosphamide
Product Name: Cyclophosphamide
Pharmaceutical Form: Coated tablet
INN or Proposed INN: Cyclophosphamide monohydrate
CAS Number: 6055-19-2
Concentration unit: mg milligram(
Sponsors
The Christie NHS Foundation Trust
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Histological confirmation of renal cell carcinoma (RCC) of predominantly (>50%) clear cell type. 2. Presence of metastatic / locally advanced inoperable disease. 3. Current evidence of disease progression on IO therapy as determined by CT / MRI imaging performed within 28 days prior to the first dose of study drug. Last dose of IO therapy must have been administered within 42 days prior to the first dose of study drug. IO therapy may consist of either: a. First-line Ipilimumab / Nivolumab combination OR b. Second / Third-line single agent Nivolumab OR c. Other PD-1 / PD-L1 / anti-CTLA-4 therapy within a clinical trial 4. Measurable disease according to RECIST version 1.1 criteria. 5. Site(s) of disease which are easily accessible and suitable for repeated biopsies (bone metastases are not suitable as a biopsy site). 6. Provision of archival tumour tissue sample (formalin-fixed, paraffin embedded (FFPE) tissue blocks) and a newly obtained core or excisional biopsy of a tumour lesion not previously irradiated. 7. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Evaluation of ECOG is to be performed within 7 days prior to the first dose of study drug. 8. Age > 18 years. 9. Have adequate organ function as defined in Table 2 in the protocol (page 35). Specimens must be collected within 10 days prior to the start of study treatment. 10. Able to take oral medications. 11. Life expectancy of > 6 months in the opinion of the investigator. 12. Male participants must agree to use a form of contraception as detailed in Appendix 3 of this protocol during the treatment period and for at least 180 days after the last dose of study treatment and refrain from donating sperm during this period. 13. Female participants are eligible to participate if they are not pregnant (see Appendix 3), not breastfeeding, and at least one of the following conditions applies: a. Not a woman of childbearing potential (WOCBP) as defined in Appendix 3 OR b. A WOCBP who agrees to follow the contraceptive guidance in Appendix 3 during the treatment period and for at least 180 days after the last dose of study treatment. 14. The participant provides written informed consent for the trial. 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 7 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 14
Exclusion criteria
Exclusion criteria: 1. Treatment with more than one prior line of IO therapy (including previous standard of care and trial treatments). 2. High burden / symptomatic disease which in the opinion of the treating investigator requires TKI / alternative therapeutic approach. 3. Prior treatment with either pembrolizumab or cyclophosphamide. 4. Known severe hypersensitivity (=Grade 3) to pembrolizumab, cyclophosphamide and/or any of their excipients. 5. Prior intolerance to IO therapy (any > Grade 2 toxicity which required permanent IO treatment discontinuation). 6. Ongoing AEs due to previous therapies or surgery which have not resolved to = Grade 1 or baseline. Participants with = Grade 2 neuropathy may be eligible. 7. Active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. 8. Diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug. 9. Known additional malignancy that is progressing or has required active treatment within the past 3 years. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial transitional cell carcinoma of the bladder / urothelial tract, or carcinoma in situ (e.g. breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded. 10. Prior radiotherapy within 2 weeks of start of study treatment. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (=2 weeks of radiotherapy) to non-CNS disease. 11. Live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g. FluMist®) are live attenuated vaccines and are not allowed. 12. Currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment. Note: Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent. 13. Known previous or current CNS metastases and/or carcinomatous meningitis. 14. History of (non-infectious) pneumonitis that required steroids or has current pneumonitis. 15. Active infection requiring systemic therapy or has had requirement for antibiotics within 14 days prior to first dose of study treatment. 16. Known history of Human Immunodeficiency Virus (HIV). Note: no testing for HIV is required. 17. Known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (defined as HCV RNA positive) infection. Note: no t
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To evaluate whether the combination of oral metronomic (low doses of drug taken more often) cyclophosphamide and pembrolizumab will lead to objective tumour responses (a measurable shrinking of the tumour) in metastatic clear cell renal carcinoma (cancer of kidney cells that have spread to other parts of the body) patients who have previously progressed on immuno-oncology therapy (therapy that stimulates the immune system to fight cancer).;Secondary Objective: 1.To evaluate the median (middle value average) progression free survival (how long patients survive without their cancer growing or spreading) and overall survival (how long patients live) in patients receiving cyclophosphamide and pembrolizumab in combination 2.To evaluate the safety profile of the combination of oral cyclophosphamide and pembrolizumab ;Primary end point(s): The primary endpoint of the trial is ORR according to RECIST version 1.1 from baseline until end of study or death, and will be calculated using the best response achieved during study treatment for each participant. Objective response is defined as occurrence of complete (CR) or partial responders (PR) as defined by the RECIST version 1.1 at any point in follow-up to death or end of study. Deaths before assessment, non-assessable or missing values will be counted as non-response. Best Objective Response is the highest value achieved.;Timepoint(s) of evaluation of this end point: RECIST (tumour measurement) will be performed at baseline (screening and registration) and then Week 4, Week 7 and then every 9 weeks until confirmed disease progression. The measurements analysed will be the baseline and final confirmed disease progression measurement. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1. Progression Free Survival, measured from the time of first treatment to the time of first documented progression or the censor date in months 2. Overall Survival, defined as the time from first treatment to death by any cause in months 3. Safety and tolerability of the combination of cyclophosphamide and pembrolizumab, reported following the CTCAE version 5 guidelines. Progression-free survival Event of interest = progression or death from any cause Event date = min (date of death, progression date) Progression-free Survival (months) = (Exit date – date of first treatment)/30.4 Overall survival Event of interest = death from any cause Event date = date of death Overall Survival (months) = (Exit date – date of first treatment)/30.4 Safety and tolerability The number and percentage of patients reporting a Serious Adverse Event (SAE) and Grade 3 or higher toxicity will be summarised overall and by preferred term (if severity is missing, the worst case will be assumed).;Timepoint(s) of evaluation of this end point: 1. Baseline to progression/death 2. Baseline to death 3. Baseline to end of study | — |
Countries
United Kingdom
Contacts
Public ContactRawcliffe
Liverpool Cancer Trials Unit
Outcome results
None listed