Clinical trial NCT01796171: A Phase 1/2 Study of Betalutin for Treatment of Relapsed Non-Hodgkin Lymphoma
Official title: A Phase 1/2 Study of Lutetium (177Lu)-Lilotomab Satetraxetan (Betalutin®) Antibody-radionuclide-conjugate for Treatment of Relapsed Non-Hodgkin Lymphoma.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Non-Hodgkin Lymphoma
Follicular Lymphoma
Keywords: Radioimmunotherapy
Lu-177
Phase I study
Phase II study
Betalutin
Lead sponsor: Nordic Nanovector
Sponsor class: INDUSTRY
Collaborators: name: ICON Clinical Research
First posted: 2013-02-21
Enrollment: 191
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: This study is a Phase 1/2 open-label three part study in patients with relapsed indolent Non-Hodgkin's lymohoma (NHL) (Parts A and C) or relapsed/refractory follicular lymphoma (FL) (Part B).

Detailed description: Part A of the study was a Phase 1/2a study to assess the safety and preliminary efficacy of different treatment regimens of Betalutin with expansion at the candidate recommended Phase 2 doses. Part B was a dedicated Phase 2b randomized substudy to further assess the efficacy and safety of the candidate recommended Phase II doses. Part C was a Phase 2a fixed dose expansion cohort planned to obtain supplementary pharmacokinetic data.

Eligibility criteria: Part A and Part C:

Inclusion Criteria:

1. Histologically confirmed (by World Health Organization \[WHO\] classification) relapsed incurable non-Hodgkin B-cell lymphoma of following subtypes; follicular grade I-IIIA (for Part C, this excludes patients meeting Part B criteria, who should enter Part B), marginal zone, small lymphocytic, lymphoplasmacytic, mantle cell.
2. Age ≥ 18 years.
3. Part A: A pre-study WHO performance status of 0-1; Part C: WHO performance status of 0-2.
4. Life expectancy should be ≥3 months.
5. \<25% tumour cells in bone marrow biopsy (biopsy taken from a site not previously irradiated).
6. Measurable disease by radiological methods.
7. Women of childbearing potential must:

   1. understand that the study medication is expected to have teratogenic risk.
   2. have a negative pregnancy test.
   3. agree to use, and be able to comply with, effective contraception without interruption, 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.
8. Male patients must agree to use condoms during intercourse throughout study medication therapy and the following 12 months.
9. Patients previously treated with native rituximab are eligible.
10. The patient is willing and able to comply with the protocol, and agrees to return to the hospital for follow up visits and examination.
11. The patient has been fully informed about the study and has signed the informed consent form.

Exclusion Criteria:

Medical contraindications, including uncontrolled infection, severe cardiac, pulmonary, neurologic, psychiatric or metabolic disease, uncontrolled asthma/allergy requiring systemic steroids, known to be human immunodeficiency virus (HIV) positive.

2. Laboratory values within 15 days pre-registration:

1. Absolute neutrophil counts (ANC) ≤1.5×109/L.
2. Part A: Platelet count ≤150×109/L; Part C: Platelet count \<150×109/L. For Part C, criteria 2a and 2b must be satisfied within 72 hours of the administration of rituximab
3. Total bilirubin ≥30 mmol/L (Part A only). Total bilirubin \> 1.5×ULN (except patients with documented Gilbert's syndrome \[≥3.0 mg/dL\]) (Part C only).
4. Alkaline phosphatase (ALP) and alanine transaminase (ALT) ≥4×normal level (Part A only).

   Aspartate transaminase (AST), ALT or ALP \>2.5×ULN (or \>5.0×ULN with liver involvement by primary disease). (Part C only).
5. Creatinine ≥115 µmol/L (men), 97 µmol/L (women) (Part A only). Serum creatinine ≥1.5×ULN (Part C only).
6. Haemoglobin \<9.0 g/dL (Part C only). 3. Known central nervous system (CNS) involvement of lymphoma. 4. Previous total body irradiation. 5. Positive test for human anti-murine antibody (HAMA) at screening. 6. Chemotherapy or immunotherapy received within the last 4 weeks prior to start of study treatment. Pre treatment with rituximab is allowed.

   7. Pregnant or lactating women. 8. Previous hematopoietic stem cell transplantation (autologous and allogenic). 9. Part A: Previous treatment with radioimmunotherapy. Part C: Not applicable. 10. Actively participating in another study or received an IMP within 4 weeks prior to enrolment.

   11. Receipt of live-attenuated vaccine within 30 days prior to enrolment. 12. Part A and Part C: Test positive for hepatitis B (HBsAg and anti-HBc). Part C only: Test positive for hepatitis C and human immunodeficiency virus (HIV).

   13. A known hypersensitivity to rituximab, lilotomab, Betalutin or murine proteins or any excipient used in rituximab, lilotomab, or Betalutin.

   Part B:

   Inclusion Criteria:

   Histologically confirmed (by WHO classification) relapsed non-Hodgkin B-cell FL (grade I IIIA).

   2. Male or female aged ≥18 years. 3. Received at least 2 prior systemic anti-neoplastic or immunotherapy-based regimens (maintenance therapy following a CR/PR is not considered to be a separate line of therapy). Systemic regimens including agents such as idelalisib or other PI3K inhibitors qualify as a prior line of therapy.

   4. Prior therapy must have included a rituximab/anti-CD20 agent and an alkylating agent - which may be been administered in separate regimens.

   5. Patients must be refractory to any at least one previous regimen that contained rituximab or an anti CD20 agent, with refractoriness defined as:

i. no response (no CR or PR) during therapy, or ii. 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).

6. 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).

9. Measurable disease by CT or MRI: longest diameter (LDi) \>1.5 cm for nodal lesion, LDi \>1.0 cm for extra nodal lesion on an assessment performed during the screening period.

Criteria 10 and 11 must be satisfied within 72 hours of the administration of rituximab:

10. ANC ≥1.5×109/L. 11. Platelet count ≥100×109/L.

Criteria 12 to 15 must be verified at time of eligibility review within 2 weeks prior to rituximab administration:

12. Haemoglobin ≥9.0 g/dL. 13. Total bilirubin ≤1.5×upper limit of normal (ULN) (except patients with documented Gilbert's syndrome \[\<3.0 mg/dL\]).

14. Liver enzymes: AST; ALT or ALP ≤2.5×ULN (or ≤5.0×ULN with liver involvement by primary disease).

15. Adequate renal function as demonstrated by a serum creatinine \<1.5×ULN. 16. Women of childbearing potential must:

1. understand that the study medication is expected to have teratogenic risk.
2. have a negative serum beta human-chorionic gonadotropin (ß-HCG) pregnancy test at screening.
3. 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 treatment administration and for 12 months following administration of Betalutin.

18. The patient is willing and able to comply with the protocol, and agrees to return to the hospital for follow up visits and examination.

19. The patient has been fully informed about the study and has signed the informed consent form.

20. Negative HAMA test at screening. 21. Negative test at screening for Hepatitis B (negative HBsAg and anti-HBc), Hepatitis C and HIV.

Exclusion Criteria

1. Prior hematopoietic allogenic stem cell transplantation.
2. Patients with a prior autologous SCT are excluded unless at least two years have elapsed since transplantation.
3. Evidence of histological transformation from FL to diffuse large B-cell lymphoma (DLBCL) at time of screening (transformation to grade IIIB that was successfully treated with recurrence of grade I-IIIA initial clone is accepted).
4. Previous total body irradiation.
5. Prior anti-lymphoma therapy (chemotherapy, immunotherapy or other systemic agent including any 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 rituximab)..
6. Patients who are receiving any other investigational medicinal products.
7. Patients with known or suspected CNS involvement of lymphoma.
8. History of malignancy other than FL within 5 years prior to screening( i.e. patients with cancer diagnosed within 5 years prior to screening or who were diagnosed prior to 5 years and were not in CR or were on treatment within 5 years prior to screening), with the exception of malignancies with a negligible risk of metastasis or death (e.g. 5-year OS rate \>90%), such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localised prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer.

.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.

12. Has received a live-attenuated vaccine within 30 days prior to enrolment. 13. Evidence of severe or uncontrolled systemic diseases:

1. 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.
2. Pulmonary conditions e.g. unstable or uncompensated respiratory disease.
3. Hepatic, renal, neurological, or metabolic conditions - which in the opinion of the investigator would compromise the protocol objectives.
4. 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.
5. History of erythema multiforme, toxic epidermal necrolysis, or Stevens-Johnson syndrome.
6. 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).

Primary outcomes:
measure: Part A, Phase I
timeFrame: 12 weeks
measure: Part A, Phase IIa
timeFrame: 5 years
measure: Part B, Phase IIb
timeFrame: up to 5 years
Secondary outcomes:
Other outcomes:
Locations:
city: Little Rock
country: United States
facility: University Of Arkansas For Medical Sciences
state: Arkansas
city: Long Beach
country: United States
facility: Pacific Shores Medical Group
state: California
city: San Francisco
country: United States
facility: University of California, San Francisco (UCSF)
state: California
city: Boca Raton
country: United States
facility: Boca Raton Regional Hospital
state: Florida
city: Maywood
country: United States
facility: Loyola University Medical Center
state: Illinois
city: Louisville
country: United States
facility: Norton Cancer Institute
state: Kentucky
city: New Orleans
country: United States
facility: Ochsner Clinic Foundation
state: Louisiana
city: Stony Brook
country: United States
facility: Stony Brook University Medical Center
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Portland
country: United States
facility: Oregon Health & Science University
state: Oregon
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Pittsburgh
country: United States
facility: West Penn Hospital
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center
state: Pennsylvania
city: Dallas
country: United States
facility: Baylor College of Medicine
state: Texas
city: Hobart
country: Australia
facility: Royal Hobart Hospital
city: Innsbruck
country: Austria
facility: Medizinische Universitaet Innsbruck
city: Wien
country: Austria
facility: Medizinische Universität Wien - AKH Wien, Universitaetsklinik fuer Innere Medizin I
city: Gent
country: Belgium
facility: Universitair Ziekenhuis Gent (UZ Gent)
city: La Louvière
country: Belgium
facility: CH Jolimont
city: Leuven
country: Belgium
facility: UZ Leuven
city: London
country: Canada
facility: London Health Sciences Centre
city: Sault Ste Marie
country: Canada
facility: Sault Area Hospital
city: Toronto
country: Canada
facility: Princes Margaret Cancer Centre
city: Zagreb
country: Croatia
facility: Clinical Hospital Centre Zagreb
city: Olomouc
country: Czechia
facility: University Hospital Olomouc
city: Ostrava-Poruba
country: Czechia
facility: FNsP Ostrava
city: Aarhus
country: Denmark
facility: Aarhus Universitetshospital
city: Odense
country: Denmark
facility: Odense Univerisity Hospital
city: Helsinki
country: Finland
facility: Helsinki University Hospital Comprehensive Cancer Center
city: Jyväskylä
country: Finland
facility: Central Hospital Of Central Finland
city: Bordeaux
country: France
facility: Institut Bergonie
city: Grenoble
country: France
facility: Chu Grenoble - Hopital Michallon
city: Paris
country: France
facility: Hôpital Saint Louis
city: Paris
country: France
facility: AP-HP La Pitié salpétrière
city: Pierre-Bénite
country: France
facility: Centre Hospitalier Lyon Sud
city: Tours
country: France
facility: Centre Hospitalier Regional Universitaire de Tours (CHRU de Tours) - Hopital Bretonneau
city: Budapest
country: Hungary
facility: Orszagos Onkologiai Intezet, A-Belgyogyaszati Onkologiai Osztaly
city: Budapest
country: Hungary
facility: Semmelweis Egyetem, I Belgyogyaszati Klinika, Hematologiai Osztaly
city: Dublin
country: Ireland
facility: Mater Misericordiae University Hospital
city: Dublin
country: Ireland
facility: St James's Hospital
city: Galway
country: Ireland
facility: University Hospital Galway
city: Afula
country: Israel
facility: Haemek Medical Center
city: Be'er Ya'aqov
country: Israel
facility: Asaf Harofeh Medical Center
city: Haifa
country: Israel
facility: Bnai Zion Medical Center (BZMC)
city: Haifa
country: Israel
facility: Rambam Health Care Campus (RHCC)
city: Jerusalem
country: Israel
facility: יHadassah Ein Karem Medical Center
city: Tel Aviv
country: Israel
facility: Sourasky Medical Center
city: Alessandria
country: Italy
facility: SS Antonio & Biagio and C. Arrigo Hospital
city: Bologna
country: Italy
facility: Istituto di Ematologia ed Oncologia Medica " L. & A. Seragnoli"-Policlinico S. Orsola Malpighi
city: Firenze
country: Italy
facility: Universita Degli Studi Di Firenze-Azienda Ospedaliero-Universitaria Careggi (AOUC)
city: Meldola
country: Italy
facility: Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS
city: Milano
country: Italy
facility: Istituto Europeo di Oncologia (IEO)
city: Napoli
country: Italy
facility: "Istituto Nazionale Tumori Fondazione G. Pascale"
city: Reggio Emilia
country: Italy
facility: Azienda Ospedaliera Arcispedale Santa Maria Nuova - IRCCS
city: Torino
country: Italy
facility: AO Ordine Mauriziano di Torino
city: Jeonju
country: Korea, Republic of
facility: Chonbuk National University Hospital
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Ulsan
country: Korea, Republic of
facility: Ulsan University Hospital
city: Groningen
country: Netherlands
facility: University Medical Center Groningen
city: Bergen
country: Norway
facility: Haukeland Universitetssjukehus
city: Oslo
country: Norway
facility: The Norwegian Radium Hospital
city: Trondheim
country: Norway
facility: St Olav Hospital
city: Gdynia
country: Poland
facility: Szpital Morski Im.Pck W Gdynia
city: Krakow
country: Poland
facility: Pratia MCM Kraków
city: Warszawa
country: Poland
facility: Centrum Onkologii
city: Singapore
country: Singapore
facility: National University Hospital
city: Barcelona
country: Spain
facility: Corporacio Sanitaria Parc Taulí
city: Cadiz
country: Spain
facility: Hospital Universitario Puerta del Mar
city: Majadahonda
country: Spain
facility: Hospital Universitario Puerta de Hierro de Majadahonda
city: Ourense
country: Spain
facility: Complexo Hospitalario Universitario de Ourense
city: Pamplona
country: Spain
facility: Clinica Universidad De Navarra
city: Salamanca
country: Spain
facility: Hospital Clinico Universitario de Salamanca
city: Seville
country: Spain
facility: Hospital Universitario Virgen Macarena
city: Valencia
country: Spain
facility: Health Research Institute La Fe - Hospital La Fe
city: Valencia
country: Spain
facility: Hospital Universitario Doctor Peset
city: Umeå
country: Sweden
facility: Cancercentrum -Center of Oncology
city: Chur
country: Switzerland
facility: Kantonsspital Graubünden
city: Adana
country: Turkey
facility: Cukurova Universitesi Tip Fakültesi, Ic Hastaliklari Anabilim Dali
city: Ankara
country: Turkey
facility: Ankara Onkoloji Egitim ve Arastirma Hastanesi
city: Ankara
country: Turkey
facility: Ankara Universitesi Tip Fakultesi Cebeci Hastanesi Ic
city: Ankara
country: Turkey
facility: Hacettepe University Oncology Hospital
city: Eskişehir
country: Turkey
facility: Eskisehir Osmangazi Universitesi Tip Fakultesi Ic Hastaliklar
city: Fatih
country: Turkey
facility: Istanbul Universitesi Istanbul Tip Fakultesi
city: İzmir
country: Turkey
facility: Ege Universitesi Tip Fakültesi
city: Manisa
country: Turkey
facility: Celal Bayar Universitesi Tip Fakultesi
city: Samsun
country: Turkey
facility: Ondokuz Mayis Universitesi
city: Şehitkamil
country: Turkey
facility: Gaziantep Universitesi Sahinbey Arastirma ve Uygulama
city: Poole
country: United Kingdom
facility: Dorset Cancer Centre Poole Hospital
state: Dorset
city: Bristol
country: United Kingdom
facility: Bristol Haematology and Oncology Centre
city: Edinburgh
country: United Kingdom
facility: Western General Hospital
city: Glasgow
country: United Kingdom
facility: Beatson West of Scotland Cancer Centre
city: London
country: United Kingdom
facility: Imperial College Healthcare NHS Trust, Hammersmith Hospital
city: London
country: United Kingdom
facility: University College London Hospitals Nhs Foundation Trust
city: Manchester
country: United Kingdom
facility: The Christie NHS Foundation Trust
city: Plymouth
country: United Kingdom
facility: Derriford Hospital
city: Sutton
country: United Kingdom
facility: The Royal Marsden NHS Foundation Trust
Study officials:
affiliation: Nordic Nanovector
name: Chris Freitag
role: STUDY_DIRECTOR
References:
citation: Dahle J, Repetto-Llamazares AH, Mollatt CS, Melhus KB, Bruland OS, Kolstad A, Larsen RH. Evaluating antigen targeting and anti-tumor activity of a new anti-CD37 radioimmunoconjugate against non-Hodgkin's lymphoma. Anticancer Res. 2013 Jan;33(1):85-95.
citation: Repetto-Llamazares AH, Larsen RH, Mollatt C, Lassmann M, Dahle J. Biodistribution and dosimetry of (177)Lu-tetulomab, a new radioimmunoconjugate for treatment of non-Hodgkin lymphoma. Curr Radiopharm. 2013 Mar;6(1):20-7. doi: 10.2174/1874471011306010004.
citation: Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, Coiffier B, Fisher RI, Hagenbeek A, Zucca E, Rosen ST, Stroobants S, Lister TA, Hoppe RT, Dreyling M, Tobinai K, Vose JM, Connors JM, Federico M, Diehl V; International Harmonization Project on Lymphoma. Revised response criteria for malignant lymphoma. J Clin Oncol. 2007 Feb 10;25(5):579-86. doi: 10.1200/JCO.2006.09.2403. Epub 2007 Jan 22.
citation: Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, Lister TA; Alliance, Australasian Leukaemia and Lymphoma Group; Eastern Cooperative Oncology Group; European Mantle Cell Lymphoma Consortium; Italian Lymphoma Foundation; European Organisation for Research; Treatment of Cancer/Dutch Hemato-Oncology Group; Grupo Espanol de Medula Osea; German High-Grade Lymphoma Study Group; German Hodgkin's Study Group; Japanese Lymphorra Study Group; Lymphoma Study Association; NCIC Clinical Trials Group; Nordic Lymphoma Study Group; Southwest Oncology Group; United Kingdom National Cancer Research Institute. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014 Sep 20;32(27):3059-68. doi: 10.1200/JCO.2013.54.8800.
citation: Londalen A, Blakkisrud J, Revheim ME, Madsbu UE, Dahle J, Kolstad A, Stokke C. FDG PET/CT parameters and correlations with tumor-absorbed doses in a phase 1 trial of 177Lu-lilotomab satetraxetan for treatment of relapsed non-Hodgkin lymphoma. Eur J Nucl Med Mol Imaging. 2021 Jun;48(6):1902-1914. doi: 10.1007/s00259-020-05098-x. Epub 2020 Nov 16.
citation: Kolstad A, Illidge T, Bolstad N, Spetalen S, Madsbu U, Stokke C, Blakkisrud J, Londalen A, O'Rourke N, Beasley M, Jurczak W, Fagerli UM, Kascak M, Bayne M, Obr A, Dahle J, Rojkjaer L, Pascal V, Holte H. Phase 1/2a study of 177Lu-lilotomab satetraxetan in relapsed/refractory indolent non-Hodgkin lymphoma. Blood Adv. 2020 Sep 8;4(17):4091-4101. doi: 10.1182/bloodadvances.2020002583.