| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic renal cell carcinoma with clear cell component |
|
| E.1.1.1 | Medical condition in easily understood language |
| Cancer of the kidneys that has spread to other parts of the body |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10080007 |
| E.1.2 | Term | Clear cell renal cell carcinoma metastatic |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| 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). |
|
| E.2.2 | Secondary objectives of the trial |
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
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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. |
|
| E.4 | Principal 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 testing for Hepatitis B and Hepatitis C is required.
18. Known history of active TB (Bacillus Tuberculosis). Note: no testing for TB is required.
19. History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject’s participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
20. Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
21. Pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of trial treatment. Note: WOCBP must have a negative urine pregnancy test within 72 hours prior to trial entry (see Appendix 3). If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. In the event that 72 hours have elapsed between the screening pregnancy test and the first dose of study treatment, another pregnancy test (urine or serum) must be performed and must be negative in order for subject to start receiving study medication. |
|
| E.5 End points |
| E.5.1 | 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. |
|
| E.5.1.1 | 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. |
|
| E.5.2 | 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). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Baseline to progression/death
2. Baseline to death
3. Baseline to end of study |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| Unless early termination is required, the end of trial is defined as once all patients have died / come off study for other reasons or reached 24 months treatment/follow-up whichever is sooner together with sufficient time to collect outstanding data and resolve queries. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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