A Phase 1/2 Study of Betalutin for Treatment of Relapsed Non-Hodgkin Lymphoma

Follicular Lymphoma Clinical Trial

— LYMRIT-37-01  

Official title:

A Phase 1/2 Study of Lutetium (177Lu)-Lilotomab Satetraxetan (Betalutin®) Antibody-radionuclide-conjugate for Treatment of Relapsed Non-Hodgkin Lymphoma.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01796171
• Other study ID #: EudraCT: 2011-000033-36
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: December 2012
• Est. completion date: October 27, 2022

Study information

• Verified date: December 2023
• Source: Nordic Nanovector
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 191
• Est. completion date: October 27, 2022
• Est. primary completion date: October 25, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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).

Related Conditions & MeSH terms

• Follicular Lymphoma
• Lymphoma
• Lymphoma, Non-Hodgkin
• Non-Hodgkin Lymphoma

Intervention

Drug:
• 10 MBq/kg Betalutin

• 15 MBq/kg Betalutin

• 20 MBq/kg Betalutin

• 40 mg lilotomab

• 100 mg/m2 lilotomab

• 60 mg/m2 lilotomab

• Rituximab

• 12.5 mBq/kg Betalutin

Locations

Country	Name	City	State
Australia	Royal Hobart Hospital	Hobart
Austria	Medizinische Universitaet Innsbruck	Innsbruck
Austria	Medizinische Universität Wien - AKH Wien, Universitaetsklinik fuer Innere Medizin I	Wien
Belgium	Universitair Ziekenhuis Gent (UZ Gent)	Gent
Belgium	CH Jolimont	La Louvière
Belgium	UZ Leuven	Leuven
Canada	London Health Sciences Centre	London
Canada	Sault Area Hospital	Sault Ste Marie
Canada	Princes Margaret Cancer Centre	Toronto
Croatia	Clinical Hospital Centre Zagreb	Zagreb
Czechia	University Hospital Olomouc	Olomouc
Czechia	FNsP Ostrava	Ostrava-Poruba
Denmark	Aarhus Universitetshospital	Aarhus
Denmark	Odense Univerisity Hospital	Odense
Finland	Helsinki University Hospital Comprehensive Cancer Center	Helsinki
Finland	Central Hospital Of Central Finland	Jyväskylä
France	Institut Bergonie	Bordeaux
France	Chu Grenoble - Hopital Michallon	Grenoble
France	AP-HP La Pitié salpétrière	Paris
France	Hôpital Saint Louis	Paris
France	Centre Hospitalier Lyon Sud	Pierre-Bénite
France	Centre Hospitalier Regional Universitaire de Tours (CHRU de Tours) - Hopital Bretonneau	Tours
Hungary	Orszagos Onkologiai Intezet, A-Belgyogyaszati Onkologiai Osztaly	Budapest
Hungary	Semmelweis Egyetem, I Belgyogyaszati Klinika, Hematologiai Osztaly	Budapest
Ireland	Mater Misericordiae University Hospital	Dublin
Ireland	St James's Hospital	Dublin
Ireland	University Hospital Galway	Galway
Israel	Haemek Medical Center	Afula
Israel	Asaf Harofeh Medical Center	Be'er Ya'aqov
Israel	Bnai Zion Medical Center (BZMC)	Haifa
Israel	Rambam Health Care Campus (RHCC)	Haifa
Israel	?Hadassah Ein Karem Medical Center	Jerusalem
Israel	Sourasky Medical Center	Tel Aviv
Italy	SS Antonio & Biagio and C. Arrigo Hospital	Alessandria
Italy	"Istituto di Ematologia ed Oncologia Medica "" L. & A. Seragnoli""-Policlinico S. Orsola Malpighi"	Bologna
Italy	Universita Degli Studi Di Firenze-Azienda Ospedaliero-Universitaria Careggi (AOUC)	Firenze
Italy	Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS	Meldola
Italy	Istituto Europeo di Oncologia (IEO)	Milano
Italy	"Istituto Nazionale Tumori Fondazione G. Pascale"	Napoli
Italy	Azienda Ospedaliera Arcispedale Santa Maria Nuova - IRCCS	Reggio Emilia
Italy	AO Ordine Mauriziano di Torino	Torino
Korea, Republic of	Chonbuk National University Hospital	Jeonju
Korea, Republic of	Samsung Medical Center	Seoul
Korea, Republic of	Ulsan University Hospital	Ulsan
Netherlands	University Medical Center Groningen	Groningen
Norway	Haukeland Universitetssjukehus	Bergen
Norway	The Norwegian Radium Hospital	Oslo
Norway	St Olav Hospital	Trondheim
Poland	Szpital Morski Im.Pck W Gdynia	Gdynia
Poland	Pratia MCM Kraków	Krakow
Poland	Centrum Onkologii	Warszawa
Singapore	National University Hospital	Singapore
Spain	Corporacio Sanitaria Parc Taulí	Barcelona
Spain	Hospital Universitario Puerta del Mar	Cadiz
Spain	Hospital Universitario Puerta de Hierro de Majadahonda	Majadahonda
Spain	Complexo Hospitalario Universitario de Ourense	Ourense
Spain	Clinica Universidad De Navarra	Pamplona
Spain	Hospital Clinico Universitario de Salamanca	Salamanca
Spain	Hospital Universitario Virgen Macarena	Seville
Spain	Health Research Institute La Fe - Hospital La Fe	Valencia
Spain	Hospital Universitario Doctor Peset	Valencia
Sweden	Cancercentrum -Center of Oncology	Umeå
Switzerland	Kantonsspital Graubünden	Chur
Turkey	Cukurova Universitesi Tip Fakültesi, Ic Hastaliklari Anabilim Dali	Adana
Turkey	Ankara Onkoloji Egitim ve Arastirma Hastanesi	Ankara
Turkey	Ankara Universitesi Tip Fakultesi Cebeci Hastanesi Ic	Ankara
Turkey	Hacettepe University Oncology Hospital	Ankara
Turkey	Eskisehir Osmangazi Universitesi Tip Fakultesi Ic Hastaliklar	Eskisehir
Turkey	Istanbul Universitesi Istanbul Tip Fakultesi	Fatih
Turkey	Ege Universitesi Tip Fakültesi	Izmir
Turkey	Celal Bayar Universitesi Tip Fakultesi	Manisa
Turkey	Ondokuz Mayis Universitesi	Samsun
Turkey	Gaziantep Universitesi Sahinbey Arastirma ve Uygulama	Sehitkamil
United Kingdom	Bristol Haematology and Oncology Centre	Bristol
United Kingdom	Western General Hospital	Edinburgh
United Kingdom	Beatson West of Scotland Cancer Centre	Glasgow
United Kingdom	Imperial College Healthcare NHS Trust, Hammersmith Hospital	London
United Kingdom	University College London Hospitals Nhs Foundation Trust	London
United Kingdom	The Christie NHS Foundation Trust	Manchester
United Kingdom	Derriford Hospital	Plymouth
United Kingdom	Dorset Cancer Centre Poole Hospital	Poole	Dorset
United Kingdom	The Royal Marsden NHS Foundation Trust	Sutton
United States	Boca Raton Regional Hospital	Boca Raton	Florida
United States	Baylor College of Medicine	Dallas	Texas
United States	Duke University Medical Center	Durham	North Carolina
United States	University Of Arkansas For Medical Sciences	Little Rock	Arkansas
United States	Pacific Shores Medical Group	Long Beach	California
United States	Norton Cancer Institute	Louisville	Kentucky
United States	Loyola University Medical Center	Maywood	Illinois
United States	Ochsner Clinic Foundation	New Orleans	Louisiana
United States	University of Pennsylvania	Philadelphia	Pennsylvania
United States	University of Pittsburgh Medical Center	Pittsburgh	Pennsylvania
United States	West Penn Hospital	Pittsburgh	Pennsylvania
United States	Oregon Health & Science University	Portland	Oregon
United States	University of California, San Francisco (UCSF)	San Francisco	California
United States	Stony Brook University Medical Center	Stony Brook	New York

Sponsors (2)

Lead Sponsor	Collaborator
Nordic Nanovector	ICON Clinical Research

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Belgium,  Canada,  Croatia,  Czechia,  Denmark,  Finland,  France,  Hungary,  Ireland,  Israel,  Italy,  Korea, Republic of,  Netherlands,  Norway,  Poland,  Singapore,  Spain,  Sweden,  Switzerland,  Turkey,  United Kingdom, 

References & Publications (4)

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. — View 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. — View 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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Part A, Phase I	Number of participants with dose limiting toxicities (DLTs) in Part A	12 weeks
Primary	Part A, Phase IIa	Tumour response rates in patients in Part A receiving Betalutin based on evaluation of CT scan images including PET/CT imaging (and bone marrow biopsy if applicable).	5 years
Primary	Part B, Phase IIb	Overall response rate in Part B defined as the number of participants with a best response of complete remission or partial remission at any time	up to 5 years