Pleural Mesotheliomas
Conditions
Keywords
pleural mesothelioma, ivonescimab, bispecific antibody, anti-VEGF, anti-PD-1
Brief summary
Multicentre, open-label, single arm phase II study for patients with PM previously treated by immunotherapy and standard chemotherapy. 38 patients will be given second or third-line treatment with ivonescimab 20mg/kg every 3 weeks. An estimated 38 patients will be enrolled in approximately 20 centres. Patients will be treated for a maximum of 2 years, until disease progression, unacceptable toxicity, withdrawal of consent or another discontinuation criterion is met. The null hypothesis is disease control rate (DCR) at 12 weeks ≤ 30%. The alternative hypothesis is DCR ≥ 55% at 12 weeks.
Interventions
DRUGIvonescimab
Ivonescimab is administered IV Q3W on Day 1 of each cycle. Ivonescimab is given at a dose of 20 mg/kg (a fixed dose of 3200 mg for ivonescimab should be used for patients ≥160 kg). The total duration of ivonescimab treatment is up to 24 months.
Sponsors
Intergroupe Francophone de Cancerologie Thoracique
Summit Therapeutics
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Signed Informed consent. Subjects must have signed and dated an IEC approved written informed consent form in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol-related procedures that are not part of normal subject care. Subjects must be willing and able to comply with scheduled visits, treatment schedule, and laboratory testing. 2. Histologically-proven Pleural Mesothelioma (no cytology allowed, biopsies by thoracoscopy recommended). Note: pathology certification by national expert network NETMESO/MESOPATH should be checked as already done in routine in France by NETMESO regional expert MTB for PM (or similar national certification if the patient had his/her PM diagnosis obtained outside France, e.g. Belgium). 3. Documented progression by CT with iodine injection according to modified RECIST 1.1 for mesothelioma (mRECIST 1.1; pleural thickness perpendicular to the chest wall or mediastinum of 7mm or more, on 2 positions, at 3 separate levels on transverse cuts of CT-scan, at least 1cm apart, the sum of 6 measurements defining a pleural unidimensional measure), or according to RECIST 1.1 for mediastinal nodes or metastatic lesion, after maximum 2 lines including immunotherapy by nivolumab ± ipilimumab, and standard P/P chemotherapy \[with (maximum 40% total of patients) or without bevacizumab\], sequentially (regardless of treatment order), or first-line combining standard chemotherapy + IO (pembrolizumab or other IO investigational drug but no anti-angiogenic drug). Note: treatment continued beyond disease progression because the patient derived clinical benefit, will not count as another line (limited to one oligoprogression with local ablative treatment ((stereotactic) radiotherapy / cryotherapy etc.). However, restarting a systemic therapy with an identical protocol after an interruption of \>3 months will be considered as a new line of treatment. 4. Measurable disease according to mRECIST 1.1. 5. ECOG PS 0 or 1. 6. Weight loss \<10% within 3 months of study entry. 7. Age ≥18 years. 8. Life expectancy \>3 months. 9. Available pathological samples (at least 10 slides from the thoracoscopy biopsies) for centralized PD-L1, MTAP, immunohistochemistry, and NGS / transcriptome analyses, all slides being centrally reviewed by the French panel MESOPATH for mesothelioma histological certification. If archival tissue is either insufficient or unavailable, the patient may still be eligible upon discussion with IFCT. 10. Adequate biological functions: Creatinine Clearance ≥45 mL/min (Cockroft or MDRD or CKD-epi); neutrophils ≥1500/mm3; platelets ≥100 000/mm3; haemoglobin ≥9 g/dL; AST and ALT \<3 x ULN, total bilirubin \<2 x ULN (patients with hepatic metastases or Gilbert's syndrome must have AST and ALT ≤5 x ULN and a baseline total bilirubin ≤2 x ULN), urine protein \<2+ or 24 hours urine protein quantification \<1.0 g, prothrombin time (PT) or international normalized ratio (INR) ≤1.5 x ULN, and partial prothrombin time (PTT) or activated partial thromboplastin time (aPTT) ≤1.5 × ULN (unless abnormalities are unrelated to coagulopathy or are secondary to prophylactic coagulation). 11. Women of childbearing potential and sexually active should use a highly effective contraception method within the 28 days preceding the first dose and during the 6 months following the last dose of treatment. Women must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of study drug. 12. For male subjects who are sexually active with women of childbearing potential, an efficacious contraception method should be used during the treatment and during the 6 months following the last dose. 13. Patient covered by a national health insurance. 14. Washout period: 21 days from last dose of treatment
Exclusion criteria
1. ECOG PS\>1. 2. Previous treatment for PM by more than 2 lines of systemic treatment, or by bevacizumab (or another anti-angiogenic / anti-VEGF pathway drug) except if combined with P/P chemotherapy \[scheme validated by ASCO, NCCN, and ESMO guidelines\] in maximum 40% of the total of recruited patients (n=15). 3. Suspicion of hyperprogressive disease or rapid tumour progression when treated by previous IO (i.e. progressive disease within 9 weeks of treatment by previous nivolumab ± ipilimumab or alternative immunotherapy, starting from C1D1 or from randomization if previous experimental immunotherapy). 4. Pleural effusion as the only radiological abnormality without measurable pleural thickness or mediastinal node enlargement. 5. Peritoneal, pericardial or tunica vaginalis testis mesothelioma, without any pleural involvement at the time of diagnosis. 6. Previous diagnosis of adenocarcinoma from any anatomic site within the previous 3 years, with the exception of prostate adenocarcinoma history in case of localized prostate cancer with good prognostic factors according to d'Amico classification (\<T2a, Gleason score ≤6 and PSA ≤10 ng/ml), provided they were treated in a curative modality (surgery or radiotherapy, without any chemotherapy). 7. Previous or active cancer within the previous 3 years (except for already treated in situ carcinoma of the cervix, or basal cell skin cancer, treated or not). 8. Uncontrolled pleural effusion despite previous (talc or other) pleurodesis, requiring thoracocentesis (by pleural aspiration) more often than every 21 days. However, patients with efficient indwelling pleural catheter (IPC) are eligible. 9. Symptomatic untreated brain metastasis (without previous whole brain radiotherapy or stereotactic ablative brain radiotherapy or without surgical resection). At least 2 weeks delay between the end of radiotherapy and the beginning of the treatment should be respected. Asymptomatic brain metastasis, not needing corticosteroids (\>10 mg prednisone equivalent daily) or mannitol infusions, are allowed. 10. Radiotherapy needed at initiation of treatment, except bone palliative radiotherapy on a painful or compressive tumour site (in this case, target lesions should not be selected in the irradiated zone). 11. History of previous primary immunodeficiency, organ transplantation needing an immunosuppressive treatment, any immunosuppressive drug within 28 days before registration date, or history of severe toxicity (grade 3/4) by immune mechanism linked to another immunotherapy treatment for any kind of disease . (patients must have recovered from all toxicities associated with prior treatment, to acceptable baseline status, or NCI CTCAE v5.0 Grade 0 or 1, except for toxicities not considered a safety risk, such as alopecia or vitiligo. According to national (FITC) and international recommendations, certain severe immuno-induced toxicities are absolute
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| To assess the therapeutic value of the bispecific antibody anti-VEGF / anti-PD-1 ivonescimab as 2nd/3rd line treatment in relapsing PM patients | 12 weeks after start of treatment. | The analysis of the primary efficacy endpoint will be conducted in all eligible patients, based on the disease control rate (DCR) at 12 weeks according to mRECIST 1.1 for mesothelioma, which was defined as the proportion of patients with compete response (CR), partial response (PR) or stable disease (SD) at 12 weeks as assessed by the independent review committtee. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Tolerance, safety of treatment | From time of informed consent through treatment period and up to 90 days post last dose of study treatment (maximum of 2 years and 3 months). | Incidence, nature and severity of AEs, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0 (NCI CTCAE v5.0). |
| Progression free survival (PFS) | At progression, up to 2 years after start of treatment. | PFS is defined as the time from date of inclusion to the earliest date of disease progression, as determined by Investigator review and review of radiographic disease assessments by IRC as per mRECIST v1.1 for mesothelioma, or death due to any cause. If a patient has not had a PFS event at the time of the analysis cut-off or at the start of any new anticancer therapy, PFS is censored at the date of last adequate tumour assessment. |
| Overall survival | Around 45 months. | Overall survival is defined as the time from date of inclusion to the date of death due to any cause. If a death has not been observed by the date of the analysis cut-off, OS will be censored at the date of last contact. |
| Best response rate | At progression, up to 2 years after start of treatment. | Best response rate is defined as the percentage of patients who have achieved a best response of a complete response (CR) or partial response (PR) as determined by Investigator review and review of radiographic disease assessments by IRC as per mRECIST v1.1 for mesothelioma. |
| Duration of response | At progression, up to 2 years after start of treatment. | DOR is defined as the time from the date of the first response (CR or PR) to the earliest date of disease progression, as determined by Investigator review and review of radiographic disease assessments by IRC as per mRECIST v1.1 for mesothelioma, or death due to any cause. If a patient with a CR or PR has neither progressed nor died at the time of the analysis cut-off or at the start of any new anticancer therapy, the patient will be censored at the date of last adequate tumour assessment. DOR will be calculated for patients who have achieved a confirmed overall response (i.e. CR or PR). |
Countries
France
Contacts
CONTACTIFCT
Outcome results
None listed