Primary: Phase I part 1) Assessment of the recommended dosing and schedule for metronomic cyclophosphamide when administered in combination with fixed dose (10 mg) oral everolimus in patients with mRCC with respect to the selective induction of CD4+…
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Source
Brief title
Condition
- Renal and urinary tract neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary objectives Phase I
1) Assessment of the recommended dosing and schedule for metronomic
cyclophosphamide when administered in combination with fixed dose (10 mg) oral
everolimus in patients with mRCC with respect to the selective induction of
CD4+CD25+ regulatory T cell depletion.
2) Assessment of safety and tolerability for the combination of metronomic
cyclophosphamide and fixed dose oral everolimus in patients with mRCC.
Primary objectives Phase II
1) To investigate the proportion of patients with mRCC receiving everolimus and
metronomic cyclophosphamide that is alive and progression-free at 4 months.
2) Assessment of safety and tolerability for the combination of metronomic
cyclophosphamide and fixed dose oral everolimus in patients with mRCC.
Secondary outcome
Secondary Objectives Phase I and II study
1) To assess the response rate, time to progression, and overall survival of
the combination of metronomic cyclophosphamide and fixed dose oral everolimus
in patients with mRCC.
2) Assessment of the immunological effects of combining metronomic
cyclophosphamide with everolimus.
3) Assessment of the effect of the combination of metronomic cyclophosphamide
and everolimus on selected angiogenesis parameters.
4) To assess whether intrapatient changes in thrombocyte numbers correlate with
response rate and/or time to progression in patients using the combination of
metronomic cyclophosphamide and fixed dose oral everolimus.
5) To asess the effects of the combination of metronomic cyclophosphamide and
everolimus on tumor-infiltrating leukocytes, including CD4+CD25+FOXP3+
regulatory T cells.
6) To assess the effects of cyclophosphamide administration on the drug levels
of everolimus.
Background summary
In the present phase 1-2 study we aim to determine whether depletion of Tregs
using metronomic cyclophosphamide can enhance the antitumor efficacy of
everolimus in patients with mRCC not amenable to or progressive after a
VEGF-receptor tyrosine kinase inhibitor containing treatment regimen. In the
phase 1 part of the study we will determine the optimal CD4+CD25+ regulatory T
cell-depleting dose and schedule of metronomic oral cyclophosphamide when given
in combination with a fixed dose (10 mg daily) of everolimus. In the phase 2
part of the study we will subsequently evaluate whether the number of patients
who are cancer progression free at 4 months can be increased from 50% to 70% by
adding metronomic cyclophosphamide (in the dose and schedule determined in the
phase 1 part) to everolimus. In addition to efficacy, we will evaluate
treatment toxicity to determine whether this combination strategy is feasible
and safe.
Study objective
Primary:
Phase I part
1) Assessment of the recommended dosing and schedule for metronomic
cyclophosphamide when administered in combination with fixed dose (10 mg) oral
everolimus in patients with mRCC with respect to the selective induction of
CD4+CD25+ regulatory T cell depletion.
2) Assessment of safety and tolerability for the combination of metronomic
cyclophosphamide and fixed dose oral everolimus in patients with mRCC.
Phase II part
1) To investigate the proportion of patients with mRCC receiving everolimus and
metronomic cyclophosphamide that is progression-free at 4 months.
2) Assessment of safety and tolerability for the combination of metronomic
cyclophosphamide and fixed dose oral everolimus in patients with mRCC.
Secondary:
1) To assess the response rate, time to progression, and overall survival of
the combination of metronomic cyclophosphamide and fixed dose oral everolimus
in patients with mRCC.
2) Assessment of the immunological effects of combining metronomic
cyclophosphamide with everolimus.
3) Assessment of the effect of the combination of metronomic cyclophosphamide
and everolimus on selected angiogenesis parameters.
4) To assess whether intrapatient changes in thrombocyte numbers correlate with
response rate and/or time to progression in patients using the combination of
metronomic cyclophosphamide and fixed dose oral everolimus.
5) To asess the effects of the combination of metronomic cyclophosphamide and
everolimus on tumor-infiltrating leukocytes, including CD4+CD25+FOXP3+
regulatory T cells.
6) To assess the effects of cyclophosphamide administration on the drug levels
of everolimus.
Study design
This is a phase I/II, national multi-center study of different doses and
schedules of low-dose oral cyclophosphamide in combination with fixed dose
everolimus in patients with mRCC not amenable to or progressive after a
VEGF-receptor tyrosine kinase inhibitor containing treatment regimen.
Phase I part:
Patients will be enrolled in cohorts of 5 per dose level. The first 5 patients
enrolled will be assigned to dose level 0 in order to assess immune and
angiogenic effects caused by everolimus monotherapy. The second 5 patients
enrolled will be assigned to dose level 1. If there are <=1 dose-limiting
toxicities (DLTs) experienced by the first 5 patients in a cohort during the
first 28 days after the first study treatment, further patients will be entered
in the next dose level. Entry of patients into the expansion cohort will not
occur until at least 28 days after the last patient in the escalation phase
received his/her first study treatment. At the final dose level recommended for
the phase II study a minimum of 10 patients will be treated.
Phase II part:
In the phase 2 part of the study up to 56 patients will be treated at the dose
level that has been selected based on its capacity to most selectively deplete
circulating Treg levels in the phase 1 part of the study. Based on data of
patients with mRCC treated with everolimus monotherapy after previous treatment
with sunitinib ± sorafenib, we aim to increase the number of patients who are
alive and cancer progression free at 4 months from 50% to 70% by adding
metronomic cyclophosphamide. In addition, we consider this increase meaningful
as long as the combination treatment does not cause combination treatment
related toxicity >= grade 3 in >= 30% of patients.
Intervention
Phase I part:
Cohorts of 5-10 patients will be treated with escalating doses of oral
cyclophosphamide to determine the recommended safe dosing for the combination
of everolimus plus cyclophosphamide in patients with metastatic renal cell
cancer.
Phase II part:
In the phase II part of the study up to 56 patients will be treated at the dose
level that has been selected based on its capacity to most selectively deplete
circulating Treg levels in the phase I part of the study.
Study burden and risks
Common undesirable side effects of everolimus are: rash, hypercholesterolemia,
and/or hypertriglyceridemia, stomatitis/oral mucositis, fatigue, headache,
anorexia, non-infectious pneumonitis, nausea, vomiting, diarrhea, lung
diseases, neutropenia, thrombocytopenia, and infections.
Common undesirable side effects of cyclophosphamide are: nausea/vomiting,
anorexia, diarrhea, constipation, stomatitis, mucositis, hematological
toxicity, pneumonitis, interstitial pneumonia, alopecia, pigment changes
skin/nails, hyponatremia, allergy, dizziness, neutropenia and thrombocytopenia
De Boelelaan 1117
Amsterdam 1081 HV
NL
De Boelelaan 1117
Amsterdam 1081 HV
NL
Listed location countries
Age
Inclusion criteria
1. Patients with histologically or cytologically confirmed clear-cell mRCC with progressive disease and not amenable to or progressive on or within 6 months of stopping treatment with a VEGF receptor tyrosine kinase inhibitor (sunitinib (or pazopanib) ± sorafenib).
2. Prior therapy with cytokines (i.e. IL-2, interferon) and/or VEGF-ligand inhibitors (i.e. bevacizumab) is permitted.
3. Patients with brain metastases are eligible if they have been stable for at least two months post-radiation therapy or surgery.
4. Aged 18 years or older.
5. No other current malignant disease, except for basal cell carcinoma of the skin.
6. WHO performance status 0-2.
7. Life expectancy of at least 12 weeks.
8. Adequate hematologic function: ANC >= 1.5 x 109/L, platelets >= 100 x 109/L, Hb >= 6.0 mmol/L.
9. Adequate hepatic function: serum bilirubin <= 1.5 x ULN, ALT and AST <= 2.5 x ULN (or <= 5 times ULN if liver metastases are present).
10. Adequate renal function: calculated creatinine clearance >= 50 ml/min.
11. Measurable or evaluable disease as defined by RECIST 1.1.
12. Patients with reproductive potential must use effective contraception. Female patients of child baring potential must have a negative pregnancy test.
13. Signed informed consent.
14. Able to receive oral medication.
Exclusion criteria
1. Patients currently receiving chemotherapy, immunotherapy, or radiotherapy or who have received these <= 4 weeks prior to visit 1. Radiotherapy on a non-target lesion is allowed >= 2 weeks prior to visit 1.The wash-out period for sunitinib or sorafenib is at least 2 weeks from the first dose of the study medication.
2. Known human immunodeficiency virus (HIV) or other major immunodeficiency.
3. Immunosuppressive agents within 3 weeks of study entry, except for low dose corticosteroids with a maximum daily dose of 10mg prednisone or equivalent. Topical or inhaled corticosteroids are permitted.
4. Patients with an active bleeding diathesis or on oral anti-vitamin K medication.
5. Patients with untreated CNS metastases with clinical symptoms or who have received treatment for CNS metastases within 2 months of study entry. Patients with treated CNS metastases, who are neurologically stable and off of corticosteroids for more than 2 months prior to study entry are eligible to enter the study.
6. Active infection or serious intercurrent illness, except asymptomatic bacteriuria.
7. Presence of unstable angina, recent myocardial infarction (within the previous 6 months), or use of ongoing maintenance therapy for life-threatening ventricular arrhythmia.
8. Macroscopic hematuria
9. Prior therapy with mTOR inhibitors.
10. Known hypersensitivity to everolimus or other rapamycins (sirolimus/temsirolimus) or to its excipients.
11. Pregnant or nursing women, or women who were of childbearing potential and who were not utilizing an effective contraceptive method. A woman of childbearing potential is defined as a female who is biologically capable of becoming pregnant. Men with partners of childbearing potential not using an effective method of contraception. (Use of effective contraceptives must continue for 3 months after the last dose of everolimus).
12. Presence of any significant central nervous system or psychiatric disorder(s) that would hamper the patient*s compliance.
13. Uncontrolled diabetes as defined by fasting serum glucose > 2 ULN, severely impaired lung function.
14. Cirrhosis/chronic active hepatitis/chronic persistent hepatitis, history of HCV infection (for hepatitis screening indications see section 3.3).
15. Drug or alcohol abuse.
16. Any other major illness that, in the investigator*s judgment, substantially increased the risk associated with the subject*s participation in the study.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2010-024515-13-NL |
| CCMO | NL35150.029.11 |