Chronos -2
Criteria
Inclusion Criteria:
- Histologically confirmed diagnosis of indolent B-cell NHL, with histological subtype limited to the following:
- Follicular lymphoma (FL) grade 1-2-3a.
- Small lymphocytic lymphoma (SLL) with absolute lymphocyte count < 5 x 10*9/L at the time of diagnosis and at study entry.
- Lymphoplasmacytoid lymphoma/Waldenström macroglobulinemia (LPL/WM).
- Marginal zone lymphoma (MZL) (splenic, nodal, or extra-nodal).
- Patients must have received two or more prior lines of treatment. A previous regimen is defined as one of the following: at least two months of single-agent therapy, at least two consecutive cycles of polychemotherapy, autologous transplant, radioimmunotherapy.
- Prior therapy must include rituximab and alkylating agents.Prior exposure to idelalisib or other PI3K inhibitors is acceptable (except to copanlisib) provided that there is no resistance.
- Patients must be refractory to the last rituximab-based treatment, defined as no response or response lasting < 6 months after completion of treatment. Time interval to assess refractoriness will be calculated between the end date (last day) of the last rituximab-containing regimen and the day of diagnosis confirmation of the subsequent relapse.
- Patients must have at least one bi-dimensionally measurable lesion (which has not been previously irradiated) according to the Recommendations for Initial Evaluation, Staging, and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification.
- Patients affected by WM, who do not have at least one bi-dimensionally measurable lesion in the baseline radiologic assessment, must have measurable disease, defined as presence of immunoglobulin M (IgM) paraprotein with a minimum IgM level ≥ 2 x upper limit of normal (ULN)and positive immunofixation test.
- ECOG performance status ≤ 1
- Adequate bone marrow, liver and renal function
Exclusion Criteria:
- Histologically confirmed diagnosis of FL grade 3b.
- Chronic lymphocytic leukemia (CLL).
- Transformed disease (assessed by investigator):
- histological confirmation of transformation, or
- clinical and laboratory signs: rapid disease progression, high standardized uptake value (SUV) (> 12) by positron emission tomography (PET) at baseline if PET scans are performed (optional).
- Bulky disease - Lymph nodes or tumor mass (except spleen) >= 7cm LD (longest diameter)
- Known lymphomatous involvement of the central nervous system.
- Uncontrolled arterial hypertension despite optimal medical management (per investigator’s assessment).
- Type I or II diabetes mellitus with HbA1c > 8.5% at Screening.
- Known history of human immunodeficiency virus (HIV) infection.
- Active clinically serious infections > CTCAE Grade 2
- Active Hepatitis B or hepatitis C
- History or concurrent condition of interstitial lung disease of any severity and/or severely impaired lung function (as judged by the investigator)
- History of having received an allogeneic bone marrow or organ transplant
- Positive cytomegalovirus (CMV) PCR test at baseline
- Pregnant or breast-feeding patients
Betalutin:
Part B:
Inclusion Criteria:
Histologically confirmed (by WHO classification) relapsed non-Hodgkin B-cell FL (follicular grade I-IIIA).
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Male or female aged ≥ 18 years. 3. Received at least 2 prior anti-neoplastic or immunotherapy-based regimens (maintenance therapy following a CR/PR is not considered to be a separate line of therapy).
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Prior therapy must include rituximab/anti-CD20 agent and an alkylating agent. Prior exposure to other systemic anti-neoplastic agents (including idelalisib or other phosphatidylinositol 3-kinase (PI3K) inhibitors etc.) is also allowed.
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Patients must be refractory to any previous regimen containing rituximab or an anti-CD20 agent, defined as: no response (no CR/PR) during therapy, or a response (CR/PR) lasting less than 6 months after the completion of a regimen including rituximab/anti-CD20 therapy (including occurrence of progressive disease (PD) during rituximab/anti-CD20 maintenance therapy, or within 6 months of completion of maintenance therapy).
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WHO performance status of 0-2. 7. Life expectancy of ≥ 3 months. 8. Bone marrow tumour infiltration < 25% (in biopsy taken from a site not previously irradiated).
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Measurable disease by CT or MRI: longest diameter (LDi) > 1.5 cm for nodal lesion, LDi > 1.0 cm for extra nodal lesion within 28 days prior to start of treatment.
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ANC ≥ 1.5 x 109/L. 11. Platelet count ≥ 100 x 109/L . 12. Haemoglobin ≥ 9.0 g/dL. 13. Total bilirubin ≤1.5 x upper limit of normal (ULN) (except patients with documented Gilbert’s syndrome [< 3.0 mg/dL]).
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Liver enzymes: Aspartate transaminase (AST); Alanine transaminase (ALT) or ALP ≤ 2.5 x ULN (or ≤ 5.0 x ULN with liver involvement by primary disease).
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Adequate renal function as demonstrated by a serum creatinine < 1.5 x ULN. 16. Women of childbearing potential must:
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understand that the study medication is expected to have teratogenic risk.
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have a negative serum beta human-chorionic gonadotropin (ß-HCG) pregnancy test at screening.
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commit to continued abstinence from heterosexual intercourse (excluding periodic abstinence or the withdrawal method) or begin a highly effective method of birth control with a Pearl-Index < 1%, without interruption, from 4 weeks before starting study medication, throughout study medication therapy and for 12 months after end of study medication therapy, even if she has amenorrhoea. Apart from abstinence, highly effective methods of birth control are: i. Combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal).
ii. Progestogen-only hormonal contraception associated with inhibition of ovulation ((oral, injectable, implantable) iii. Intrauterine device (IUD). iv. Intrauterine hormone-releasing system (IUS). v. Bilateral tubal occlusion. vi. Vasectomised partner. 17. Male patients must agree to use condoms during intercourse throughout study medication therapy and the following 12 months.
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The patient is willing and able to comply with the protocol, and agrees to return to the hospital for follow-up visits and examination.
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The patient has been fully informed about the study and has signed the informed consent form.
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Negative HAMA test at screening. 21. Negative Hepatitis B (negative HBsAG and anti-HBC), Hepatitis C and HIV test at screening
Exclusion Criteria:
Prior hematopoietic allogenic stem cell transplantation. Patients with a prior autologous stem cell transplanted (SCT) are excluded unless at least two years have elapsed since transplantation and the patient has been without grade ≥1 Graft vs Host Disease (GvHD) in the 8 weeks before date of consent.
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Evidence of histological transformation from FL to diffuse large B-cell lymphoma (DLBCL) at time of screening. 4. Previous total body irradiation. 5. Prior anti-lymphoma therapy (chemotherapy, immunotherapy or other investigational agent) within 4 weeks prior to start of study treatment (corticosteroid treatment at doses of ≤ 20 mg/day, topical or inhaled corticosteroids, granulocyte colony-stimulating factor [G-CSF] or granulocyte-macrophage colony-stimulating factor [GM-CSF] are permitted up to 2 weeks prior to start of study treatment). Note: excludes pre-treatment with rituximab as part of this study.
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Patients who are receiving any other investigational medicinal products. 7. Patients with known or suspected CNS involvement of lymphoma. 8. History of a previous treated cancer except for the following:
a. adequately treated local basal cell or squamous cell carcinoma of the skin. b. cervical carcinoma in situ. c. superficial bladder cancer. d. localised prostate cancer undergoing surveillance or surgery. e. localised breast cancer treated with surgery and radiotherapy but not including systemic chemotherapy.
f. other adequately treated Stage 1 or 2 cancer currently in CR. 9. Pregnant or breastfeeding women. 10. Exposure to another CD37 targeting drug. 11. A known hypersensitivity to rituximab, lilotomab, Betalutin or murine proteins or any excipient used in rituximab, lilotomab, or Betalutin.
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Has received a live-attenuated vaccine within 30 days prior to enrolment. 13. Evidence of severe or uncontrolled systemic diseases:
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Uncontrolled infection including evidence of ongoing systemic bacterial, fungal, or viral infection (excluding viral upper respiratory tract infections) at the time of initiation of study treatment.
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Pulmonary conditions e.g. unstable or uncompensated respiratory disease.
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Hepatic, renal, neurological, or metabolic conditions - which in the opinion of the investigator would compromise the protocol objectives.
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Psychiatric conditions e.g. patients unlikely to comply with the protocol, e.g. mental condition rendering the patient unable to understand the nature, scope, and possible consequences of participating in the study.
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History of erythema multiforme, toxic epidermal necrolysis, or Stevens-Johnson syndrome.
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Cardiac conditions in the previous 24 weeks (before date of consent), including
i. history of acute coronary syndromes (including unstable angina). ii. class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system.
iii. known uncontrolled arrhythmias (except sinus arrhythmia).
Som du ser så er kriteriene for Betalutin av en litt mer “teknisk karakter”, samt mer detaljert (om du vil) i forhold til chronos-2, så jeg vil tro at pasienter som stod klar til å motta Copanlisib fortsatt må gjennom screening for betalutin. Alt annet blir vel for “løssluppent”. Selvsagt en kjempeantagelse fra min side.
EDIT:
Ser at The Lugano Classification inneholder en del av detaljene for Chronos sin del rundt måling etc.
