A Phase I/II Study of Betalutin for Treatment of Relapsed Non-Hodgkin Lymphoma (LYMRIT-37-01)

• Sponsor: Nordic Nanovector
• Collaborator: ICON Clinical Research
• Information provided by (Responsible Party): Nordic Nanovector

Study Description

Brief Summary:

This study is a phase I/II, open-label study in patients with relapsed indolent non-Hodgkin lymphoma. Part A of the study included a phase I dose escalation to define the maximum tolerated / recommended dose for expansion of (177Lu)-lilotomab (Betalutin), and a phase IIa part to evaluate safety and preliminary efficacy. Part B of the study will assess the efficacy and safety of two different Betalutin/lilotomab dosing regimens in adult patients with relapsed rituximab / anti-CD20-refractory follicular lymphoma who have received 2 or more prior therapies.

Condition or disease	Intervention/treatment	Phase
Non-Hodgkin Lymphoma; Follicular Lymphoma	Drug: Betalutin	Phase 1; Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 204 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I/II Study of Lutetium (177Lu)-Lilotomab Satetraxetan (Betalutin®) Antibody-radionuclide-conjugate for Treatment of Relapsed Non-Hodgkin Lymphoma.
• Actual Study Start Date: December 2012
• Estimated Primary Completion Date: June 2020
• Estimated Study Completion Date: March 2025

Arms and Interventions

Arm	Intervention/treatment
Experimental: Part A, Arm 1: with lilotomab pre-dosing; Betalutin, 10 MBq/kg b.w. in escalated doses with lilotomab pre-dosing.	Drug: Betalutin; Betalutin, 10 MBq/kg b.w. in escalated doses with 40 mg lilotomab pre-dosing
Experimental: Part A, Arm 2: without pre-dosing; Betalutin, 15 MBq/kg b.w. in escalated doses without pre-dosing.	Drug: Betalutin; Betalutin, 15 MBq/kg b.w. in escalated doses without pre-dosing
Experimental: Part A, Arm 3: with rituximab pre-dosing; Betalutin, 15 MBq/kg b.w. in escalated doses with rituximab pre-dosing.	Drug: Betalutin; Betalutin, 15 MBq/kg b.w. in escalated doses with rituximab pre-dosing
Experimental: Part A, Arm 4: with higher dose lilotomab pre-dosing; Betalutin, 15 MBq/kg b.w. in escalated doses with a higher dose lilotomab pre-dosing regimen.	Drug: Betalutin; Betalutin, 15 MBq/kg b.w. in escalated doses with 100 mg/m2 lilotomab pre-dosing
Experimental: Part A, Arm 5: with intermediate dose lilotomab pre-dosing; Betalutin, 20 MBq/kg b.w. with an intermediate dose lilotomab pre-dosing regimen.	Drug: Betalutin; Betalutin, 20 MBq/kg b.w. in escalated doses with 60 mg/m2 lilotomab pre-dosing
Experimental: Part B; Betalutin, 15 MBq/kg b.w. with 40mg lilotomab compared to Betalutin, 20 MBq/kg b.w. with 100mg/m2 lilotomab	Drug: Betalutin; Betalutin, 15 MBq/kg b.w. with 40mg lilotomab compared to Betalutin, 20 MBq/kg b.w. with 100 mg/m2 lilotomab

Outcome Measures

Primary Outcome Measures :

1. Part A, Phase I [ Time Frame: 12 weeks ]
   To define Maximum tolerated dose (MTD) of Betalutin Adverse events and abnormal laboratory values will be graded for toxicity according to CTCAE version 4.
2. Part A, Phase IIa [ Time Frame: 3 months - 5 years ]
   To explore tumour response rates in patients receiving Betalutin
3. Part B, Phase IIb [ Time Frame: 3 months - 5 years ]
   Overall response rate

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Part A:

Inclusion Criteria:

• Histologically confirmed (by WHO classification) relapsed incurable non-Hodgkin B-cell lymphoma of following subtypes; follicular grade I-IIIA, marginal zone, small lymphocytic, lymphoplasmacytic, mantle cell.
• Age ≥ 18 years
• A pre-study WHO performance status of 0-1
• Life expectancy should be ≥ 3 months
• <25% tumour cells in bone marrow biopsy
• Measurable disease by radiological methods

Exclusion Criteria:

• Absolute Neutrophil Counts (ANC) ≤ 1.5 x 109 /l
• Platelet count ≤ 150 x 109 /l
• Total bilirubin ≥ 30 mmol/l
• ALP and ALAT ≥ 4x normal level
• Creatinine ≥ 115 µmol/l (men), 97 µmol/l (women))
• Known CNS involvement of lymphoma
• Previous total body irradiation
• Known history of HAMA
• Chemotherapy or immunotherapy received within the last 4 weeks prior to start of study treatment. Pretreatment with rituximab is allowed
• Previous hematopoietic stem cell transplantation (autologous and allogenic)
• Previous treatment with radioimmunotherapy
• Receipt of live, attenuated vaccine within 30 days prior to enrolment
• Test positive for hepatitis B (HBsAg and anti-HBc)
• A known hypersensitivity to rituximab, HH1, Betalutin or murine proteins or any excipient used in rituximab, HH1 or Betalutin

Part B:

Inclusion Criteria:

• Histologically confirmed (by WHO classification) relapsed non-Hodgkin B-cell FL (follicular grade I-IIIA).
• Male or female aged ≥ 18 years.
• Received at least 2 prior chemotherapy- or immunotherapy-based regimens. Prior therapy must include a rituximab/anti-CD20 agent and alkylating agent. Prior exposure to other systemic anti-neoplastic agents (including idelalisib or other PI3K inhibitors) is also allowed.
• Patients must be refractory to any previous regimen containing rituximab/anti-CD20 agent, defined as no response (no CR or PR) during therapy or a response (CR/PR) lasting less than 6 months after the completion of a regimen of 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).
• WHO performance status of 0-2.
• Life expectancy of ≥ 3 months.
• Bone marrow tumour infiltration < 25% (in biopsy taken from a site not previously irradiated).
• Measurable disease by CT or MRI: longest diameter (LDi) > 1.5 cm for nodal lesion, LDi > cm for extra nodal lesion within 28 days prior to start of treatment.
• ANC ≥ 1.5 x 109/L.
• Platelet count ≥ 150 x 109/L.
• Haemoglobin ≥ 9.0 g/dL.
• Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (except patients with documented Gilbert's syndrome [< 3.0 mg/dL]).
• 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).
• Adequate renal function as demonstrated by a serum creatinine < 1.5 x ULN.
• Negative HAMA test at screening.
• Negative test at screening for Hepatitis B (negative HBsAG and anti-HBC), Hepatitis C and HIV.

Exclusion Criteria:

• Prior hematopoietic allogenic stem cell transplantation.
• Prior autologous stem cell transplantation.
• Evidence of histological transformation from FL to DLBCL at time of screening.
• Previous total body irradiation.
• 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, G-CSF or 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.
• Patients with known or suspected CNS involvement of lymphoma.
• History of a previous treated cancer except for the following: adequately treated local basal cell or squamous cell carcinoma of the skin, cervical carcinoma in situ, superficial bladder cancer, localised prostate cancer undergoing surveillance or surgery, localised breast cancer treated with surgery and radiotherapy but not including systemic chemotherapy, other adequately treated Stage 1 or 2 cancer currently in CR.
• Exposure to another CD37 targeting drug.
• A known hypersensitivity to rituximab, lilotomab, Betalutin or murine proteins or any excipient used in rituximab, lilotomab, or Betalutin.
• Has received a live-attenuated vaccine within 30 days prior to enrolment.

Contacts and Locations

Contacts

Contact: Clinical Trials; clinicaltrials@nordicnanovector.com

  Show 75 Study Locations

Sponsors and Collaborators

Nordic Nanovector

ICON Clinical Research

Investigators

• Principal Investigator: Arne Kolstad, MD, PhD; Oslo University Hospital

More Information

Publications:

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.

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.

• Responsible Party: Nordic Nanovector
• ClinicalTrials.gov Identifier: NCT01796171 History of Changes
• Other Study ID Numbers: EudraCT: 2011-000033-36
• First Posted: February 21, 2013
• Last Update Posted: May 29, 2019
• Last Verified: May 2019

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Nordic Nanovector:

Radioimmunotherapy; Lu-177; Phase I study; Phase II study; Betalutin

Additional relevant MeSH terms:

Lymphoma; Lymphoma, Follicular; Lymphoma, Non-Hodgkin; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Rituximab; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immunologic Factors; Physiological Effects of Drugs; Antirheumatic Agents