Romiplostim for thrombocytopenia induced by lomustine at first progression of MGMT promoter-methylated glioblastoma: a randomized phase II open label multicenter study

Phase 1

Conditions: thrombocytopenia caused by chemotherapy drug lomustine
Therapeutic area: Diseases [C] - Blood and lymphatic diseases [C15]

Registration Number: EUCTR2020-005429-10-IT

Lead Sponsor: EORTC AISBL/IVZW

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 100

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.
• 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.
• 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 <100 000 x 109/L at enrolment), renal and hepatic function within 7 days before enrolment:
• Haemoglobin = 8 g/dl
• Leukocytes count NOT requiring CGSF per local SOC
• Total bilirubin = 1.5 ULN
• alanine aminotransferase (SGPT), aspartate aminotransferase (SGOT), alkaline phosphatase (ALP) = 2.5 × ULN
• Serum creatinine < 1.5 x ULN or creatinine clearance (CrCl) > 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 effective method of birth control is defined as those which result in low failure rate (i.e. less than 1% per year) when used consistently and correctly. (see Appendix F).
• Patients must also agree not to donate sperm during the study and for 6 months after receiving the last dose of study treatment due to mutagenic effect of lomustine.
• Women who are breast feeding must agree to discontinue nursing prior to the first dose of study treatment and until 6 months after the last study treatment.
• Ability to understand the requirements of the study, provide written informed consent and authorization of use and disclosure of protected health information, and agree to abide by the study restrictions and return for the required assessments
• Before patient enrolment, written informed consent mu

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

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method

Secondary Outcome Measures

Name	Time	Method

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