thrombocytopenia caused by chemotherapy drug lomustine MedDRA version: 20.0 Level: PT Classification code 10043554 Term: Thrombocytopenia System Organ Class: 10005329 - Blood and lymphatic system disorders
Conditions
Interventions
Trade Name: Nplate
Product Name: romiplostim
Pharmaceutical Form: Powder for solution for injection
INN or Proposed INN: Romiplostim
CAS Number: 267639-76-9
Concentration unit: µg microgram(s)
Concent
Sponsors
European Organisation for Research and Treatment of Cancer EORTC
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: • Age 18 years or more on day of signing informed consent • Karnofsky Performance Score (KPS) of 60-100 • Life expectancy > 8 weeks • Stable or decreasing dose of steroids for at least 1 week prior to enrolment • Glioblastoma, isocitrate dehydrogenase (IDH1) R132H wild-type, per cIMPACT NOW recommendations (Brat et al., 2018; Brat et al., 2020) • MGMT promoter methylation determined by methylation-specific PCR or pyrosequencing or methylation profiling per local assessment • Treatment with lomustine alone for first progression after any treatment comprising intent to treat with standard TMZ /RT ?TMZ for newly diagnosed disease, with at least one dose of maintenance TMZ received. Hypofractionated regimens of RT are allowed. Patients should have received at least 75% of the RT dose. Patients enrolled in a clinical study for newly diagnosed disease and treated with standard of care and an experimental agent can participate. Patients who had RT alone or TMZ alone for newly diagnosed disease are not eligible. Patients must have received at least one dose of lomustine. • Clinically relevant thrombocytopenia defined as thrombocytopenia requiring dose delay of lomustine for at least one week (more than 7 days) (for any grade of toxicity) or requiring a dose reduction of lomustine because of grade 3 or 4 thrombocytopenia. • Diagnosis of first recurrence according to RANO criteria (Wen et al., 2010) more than 3 months after the end of radiotherapy for first-line treatment • Patients may have been operated for recurrence. If operated, patients should have fully recovered from surgery as assessed by the investigator. Criteria for full recovery include absence of post-operative infection, recovery from medical complications (CTCAE grade 0 and 1 acceptable). Residual and measurable disease after surgery is not required, but surgery must have confirmed the recurrence. The post-surgery MRI (performed within 72 h) can be used for enrolment if dated within 6 weeks of enrolment. • For non-operated patients: recurrent disease must correspond to at least one bi-dimensionally measurable contrast-enhancing lesion with clearly defined margins by MRI scan, with minimal diameters of 10 mm (10x10 mm), visible on 2 or more axial slices 5 mm apart (measurable disease according to RANO criteria)[20]. The MRI can be used for enrolment if dated within 6 weeks prior to enrolment. • In case of clinical deterioration or increase of steroids since the last MRI, a new MRI should be done prior to enrolment and should be dated within 6 weeks prior to enrolment. • Capacity for adequate fluid and oral intake • Adequate bone marrow (except for platelet count, which can be 30 mL/min (using the Cockcroft-Gault formula) • Women of childbearing potential (WOCBP) must have a negative urine or serum pregnancy test within 7 days prior to enrolment. • Patients of childbearing / reproductive potential must agree to use adequate birth control measures, as defined by the investigator, during the study treatment period and for at least 6 months after the last study treatment, due to mutagenic effect of lomustine. A highly
Exclusion criteria
Exclusion criteria: • Radiotherapy or stereotactic radiosurgery for the treatment of first recurrence prior to enrolment in this study • Known further progression after initiation of lomustine at the time of enrolment. Any suspicion of progression should be explored by a new MRI prior to enrolment • Prior exposure to romiplostim or other TPO mimetics • Contraindications for MRI, including intolerance of gadolinium as a contrast agent • Known coagulation disease or known haematological disease even if resolved. • Known hypercoagulative state (e.g., factor V Leiden, protein C deficiency, III deficiency, protein S deficiency, antiphospholipid antibody syndrome) • Other haematological toxicity (anaemia, neutropenia) requiring erythropoietin or GCSF. • New or uncontrolled venous thromboembolism or thrombotic events within 3 months prior to enrolment. Patients diagnosed with a venous thromboembolism or thrombotic events within the last 3 months can be enrolled if they have been on a stable regimen of anticoagulation for at least 14 days • Clinically significant cardiac comorbidities, including: history of arterial thrombotic events (eg, myocardial ischemia, transient ischemic attack, or stroke) within 6 months prior to enrolment, any history of active congestive heart failure (NYHA class II to IV), symptomatic ischaemia including known myocardial infarction, uncontrolled cardiac arrythmias, clinically significant ECG abnormalities, including screening ECG with QTc interval > 470 msec in women, >450 msec in men, known pericardial disorder . • Evidence of active infection within 2 weeks prior to enrolment • Known hypersensitivity to any E-coli derived product • Known hypersensitivity to the active substances or to any of the excipients of the study drugs, • History or present acute lymphoblastic leukaemia, acute myeloid leukaemia, any myeloid malignancy, myelodysplastic syndrome, myeloproliferative disease, multiple myeloma • Live attenuated vaccine within 3 months of lomustine initiation. • Known coeliac disease or wheat allergy • Concurrent severe or uncontrolled medical disease (e.g., active systemic infection, diabetes, hypertension, coronary artery disease) that, in the opinion of the Investigator, would compromise the safety of the patient or compromise the ability of the patient to complete the study • Known human immunodeficiency virus infection or acquired immune deficiency syndrome • Known chronic active HBV or HCV • Previous other malignancies, except for any previous malignancy which was treated with curative intent more than 2 years prior to enrolment, and except for adequately controlled limited basal cell carcinoma of the skin, adequately treated and without evidence of disease non-melanoma of the skin, squamous carcinoma of the skin and carcinoma in situ of the cervix, adequately treated breast ductal carcinoma in situ without evidence of disease, prostatic intraepithelial neoplasia without evidence of prostate cancer, low risk prostate cancer (cT1-2a N0 and Gleason score = 6 and PSA < 10 ng/mL), either totally resected or irradiated with curative intent (with PSA of less than or equal to 0.1 ng/mL) or under active surveillance as per ESMO guidelines • Pregnant women • Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: comparison of progression-free survival (PFS) between: • patients treated by lomustine at first progression and receiving best standard of care for thrombocytopenia, in the control group • patients treated by lomustine at first progression and receiving secondary prophylaxis of lomustine-induced thrombocytopenia by romiplostim, in addition to best standard of care for thrombocytopenia, in the experimental group;Secondary Objective: • To assess overall survival • To compare PFS by central review according to RANO criteria • To assess response by local investigator and by central review in patients with measurable disease • To determine the exposure to lomustine for both arms, romiplostim in arm B, platelet values, platelet transfusions • To assess health-related quality of life • To investigate treatment safety • To perform health care resource use analysis (including platelet transfusions and days of hospitalization);Primary end point(s): Progression-free survival (PFS) as assessed by local investigator according to RANO criteria (measured from the date of enrolment.);Timepoint(s) of evaluation of this end point: until disease progression | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): • Overall survival (measured from the date of enrolment) • PFS by central review according to RANO criteria (measured from the date of enrolment). • Response by local investigator and by central review according to RANO criteria (objective response (PR+CR) rate, complete response rate and duration of objective and complete response (for non-surgical patients or patients with surgery for recurrence but measurable disease thereafter). • Parameters of drug delivery for lomustine in both arms and romiplostim in arm B, platelet values, platelet transfusions: • Total number of lomustine cycles prior and after enrolment, reason for discontinuation (haematological toxicities, in particular thrombocytopenia, non-haematological toxicities, progression, toxicity, patient or investigator decision, other reasons,....). • Number of lomustine cycles with dose delays for more than one week, number of cycles with dose reductions, and number of patients who discontinue lomustine for toxicity in both arms (due to thrombocytopenia, other haematological toxicity, non-haematological toxicities, and other causes); • Reason for lomustine dose delays, dose reductions and discontinuations in both groups (progression, toxicity including thrombocytopenia, other haematological toxicity, non-haematological toxicities, and other causes of discontinuation); • HRQoL measured by EORTC QLQ-C30 and QLQ-BN20 including one additional item from EORTC Symptom Based Questionnaire (Q940: have you bruised easily?) • Frequency of worst Adverse Events (AEs) or Laboratory Event grades according to CTCAE v5.0, notably platelet values and thrombocytopenia-related adverse events in both arms • Health care resource use measured by the number of platelet transfusions, number of days of hospitalization and causes of hospitalization (any cause and specifically for thrombocytopenia), stays at hospital (including admission at the emergency room).;Timepoint(s) of evaluation of this end point: O | — |
Countries
Austria, Belgium, France, Germany, Italy, Netherlands, Spain, Switzerland, United Kingdom
Contacts
Public ContactRegulatory Affairs Department
EORTC
Outcome results
None listed