Clinical trial NCT02658968: Study of Betalutin for Treatment of Relapsed or Refractory Non-Hodgkin Lymphoma (LYMRIT-37-05)
Official title: A Phase 1 Dose Finding Study of Lutetium (177Lu)-Lilotomab Satetraxetan (Betalutin®) in Patients With Relapsed/Refractory, Diffuse Large B-cell Lymphoma, Not Eligible for Autologous Stem Cell Transplant
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Relapsed, Diffuse Large B-cell Lymphoma
Refractory Diffuse Large B-Cell Lymphoma
Keywords: Radioimmunotherapy
Lu-177
Phase I study
Betalutin
ARC
Antibody Radionuclide Conjugate
HH1
Rituximab
177Lu-DOTA-HH1
Lilotomab
Lutetium (177Lu)-lilotomab satetraxetan
Additional relevant MeSH terms:
Lymphoma
Lymphoma, Non-Hodgkin
Immune System Diseases
Immunoproliferative Disorders
Diffuse Large B-Cell Lymphoma
Lymphatic Diseases
Lymphoproliferative Disorders
Neoplasms
Neoplasms by Histologic Type
DLBCL
Refractory DLBCL
Relapsed DLBCL
Lead sponsor: Nordic Nanovector
Sponsor class: INDUSTRY
First posted: 2016-01-20
Enrollment: 18
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: This study is a phase 1, dose finding, open-label study in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). This is a dose escalating study to define the maximum tolerated dose (MTD) of lutetium (177Lu)-lilotomab satetraxetan (Betalutin®) in DLBCL patients who are not eligible for autologous stem cell transplant. The study will also assess safety and tolerability, pharmacokinetics, biodistribution and efficacy.


Eligibility criteria: Inclusion Criteria:

1. Male or female aged ≥18 years.
2. Histologically confirmed DLBCL (WHO classification).
3. Received at least one prior line of therapy including immuno-chemotherapy.
4. In first or subsequent relapse, or refractory to the last treatment (defined as less than a complete metabolic response to the last treatment, or disease progression within 6 months from the last treatment).
5. Not suitable for, or declined/unwilling to undergo intensive therapy, including high dose chemotherapy and autologous stem cell transplantation (ASCT).
6. Presence of radiographically measurable lymphadenopathy or extranodal lymphoid malignancy (at least one objectively bi-dimensionally measurable (nodal) lesion (\>1.5 cm in its largest dimension by CT scan).
7. Negative human anti-mouse antibody (HAMA) test.
8. Life expectancy of at least 3 months.
9. Bone marrow tumour infiltration \<25% tumour cells.
10. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2.
11. Normal organ and bone marrow function defined as:

    1. Absolute neutrophil count ≥1.5 x 109/L
    2. Platelet count ≥150 x 109/L;
    3. Haemoglobin ≥9 g/dL
    4. Total bilirubin ≤1.5 x upper limit of normal (ULN) (except patients with documented Gilbert's syndrome)
    5. Liver enzymes: Aspartate transaminase (AST); Alanine transaminase (ALT) or Alkaline phosphatase (ALP) ≤2.5 x ULN (or ≤5.0 x ULN if liver involvement by primary disease)
    6. Adequate renal function as demonstrated by a serum creatinine ≤1.5 mg/dL or a creatinine clearance \>60 mL/min
    7. Normal coagulation parameters (elevated international normalized ratio (INR), prothrombin time or activated partial thromboplastin time (APTT) ≤1.3 ULN range acceptable)
12. Women of childbearing potential must:

    1. Understand that the study medication may have teratogenic risk
    2. Have a negative serum pregnancy test at screening and before Betalutin injection
    3. Commit to continued abstinence from heterosexual intercourse (excluding periodic abstinence or the withdrawal method) or begin two acceptable methods of birth control with a Pearl-Index ≤ 1%. without interruption from 4 weeks before starting study drug, throughout study drug therapy and for 12 months after end of study drug therapy, even if she has amenorrhoea. Apart from abstinence, acceptable methods of birth control are:

       * Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal)
       * Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable)
       * Intrauterine device (IUD)
       * Intrauterine hormone-releasing system (IUS)
       * Bilateral tubal occlusion
       * Vasectomised partner
13. Male patients must agree to use condoms during intercourse throughout study drug therapy and the following 12 months.
14. Ability to give written, informed consent prior to any study-specific screening procedures, with the understanding that the consent may be withdrawn by the patient at any time without prejudice.
15. Capable of understanding the protocol requirements, is willing and able to comply with the study protocol procedures, and has signed the informed consent document.
16. A negative Hepatitis B test (HBsAg and anti-HBc) and negative HIV test during screening

Exclusion Criteria:

1. Prior hematopoietic allogenic stem cell transplantation.
2. Prior autologous stem cell transplantation.
3. Previous total body irradiation.
4. Prior anti-lymphoma therapy (chemotherapy, immunotherapy or other investigational agent), excluding corticosteroids within 4 weeks prior to start of study treatment (i.e. rituximab) (G-CSF or GM-CSF are permitted up to 2 weeks prior to start of study treatment.)
5. Patients who are receiving any other investigational agents.
6. Patients with known or suspected central nervous system involvement of lymphoma.
7. History of a previous treated cancer except for the following:

   1. Adequately treated local basal cell or squamous cell carcinoma of the skin
   2. Cervical carcinoma in situ
   3. Superficial bladder cancer
   4. Localized prostate cancer undergoing surveillance or surgery
   5. Localised breast cancer treated with surgery and radiotherapy but not including systemic chemotherapy
   6. Other adequately treated Stage 1 or 2 cancer currently in complete remission
8. Pregnant or breastfeeding women.
9. Exposure to another CD37 targeting drug.
10. Allergy to X ray contrast agents.
11. A known hypersensitivity to rituximab, HH1, 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 enrolling in the study.
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, including:

       * history of acute coronary syndromes (including unstable angina)
       * class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system;
       * known uncontrolled arrhythmias (except sinus arrhythmia) in the past 24 weeks.

Primary outcomes:
measure: Number of Participants With DLTs to Determine the MTD
timeFrame: 12 weeks
Secondary outcomes:
measure: The Best Overall Tumour Response
timeFrame: 3 months - 2 years
measure: Dosimetry
timeFrame: 3 weeks
Other outcomes:
Locations:
city: San Diego
country: United States
facility: University of California, San Diego (UCSD) - Moores Cancer Center
state: California
city: San Francisco
country: United States
facility: University of California, San Francisco (UCSF) - Innovation, Technology & Alliances
state: California
city: Miami
country: United States
facility: Sylvester Comprehensive Cancer Centre
state: Florida
city: Munich
country: Germany
facility: Klinikum rechts der Isar der TU München
city: Bologna
country: Italy
facility: Azienda Ospedaliero-Universitaria di Bologna Policlinico S. Orsola-Malpighi
city: Torino
country: Italy
facility: Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino
city: Verona
country: Italy
facility: Azienda Ospedaliera Universitaria Integrata Verona - Ospedale Borgo Trento
city: Valencia
country: Spain
facility: Hospital Universitari i Politècnic La Fe
city: Bristol
country: United Kingdom
facility: University Hospitals Bristol NHS Foundation Trust - Bristol Haematology and Oncology Centre
city: Manchester
country: United Kingdom
facility: Christie NHS Foundation Trust
Study officials:
affiliation: University of Manchester, The Christie NHS Foundation Trust
name: Timothy Illidge, PhD MB BS
role: PRINCIPAL_INVESTIGATOR
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.